PMID- 42952261 OWN - NLM STAT- MEDLINE DCOM- 20261029 LR - 20261029 IS - 2165-6509 (Electronic) IS - 1092-8529 (Linking) VI - 31 IP - 1 DP - 2026 Oct 29 TI - Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer's disease: A narrative review. PG - e49 LID - 10.1017/S1092852926101291 [doi] AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia. Women are differentially affected by AD, and several sex-specific mechanisms have been explored, including hormonal differences (eg, estrogen). Glucagon-like peptide-1 (GLP-1R) are located in brain regions implicated in the pathogenesis of AD and shows preliminary evidence of modulating sex-specific pathways that may underlie differential disease risk and progression. Herein, we synthesize the extant literature on the mechanisms of GLP-1 in neurobiological systems relevant to AD pathology. Metabolic signalling (eg, GLP-1, insulin) intersects with known sex-specific pathways hypothesized to subserve AD progression in women. The preceding effects may be attributable to the disruption of estrogen signalling during the postmenopausal period, which impairs hippocampal insulin receptor function and exacerbates mitochondrial dysfunction. In addition, these mechanisms provide an explanation for AD comorbidities (eg, type 2 diabetes mellitus [T2DM]). The multidimensional effects demonstrated in GLP-1 paradigms provide a compelling rationale for further investigation of the role of metabolic signalling on sex-specific alterations in AD. Evidence across preclinical and early clinical studies suggests that GLP-1RAs may differentially influence neurobiological pathways implicated in AD pathogenesis, particularly those that interact with hormonal and metabolic systems. FAU - Lee, Serene AU - Lee S AD - Brain and Cognition Discovery Foundation, Canada. ROR: https://ror.org/02fmwa274 FAU - Purewal, Esha AU - Purewal E AD - Queen's University, Canada. FAU - Rasgon, Natalie AU - Rasgon N AD - Stanford University, USA. ROR: https://ror.org/00f54p054 FAU - Kwan, Angela AU - Kwan A AD - Brain and Cognition Discovery Foundation, University Health Network, Canada. ROR: https://ror.org/042xt5161 FAU - Dri, Christine E AU - Dri CE AD - Brain and Cognition Discovery Foundation, Canada. ROR: https://ror.org/02fmwa274 FAU - Ho, Roger AU - Ho R AD - National University of Singapore Yong Loo Lin School of Medicine, Singapore. ROR: https://ror.org/01tgyzw49 FAU - McIntyre, Roger S AU - McIntyre RS AUID- ORCID: 0000-0003-4733-2523 AD - Department of Psychiatry, University of Toronto, Canada. ROR: https://ror.org/03dbr7087 LA - eng PT - Journal Article PT - Review DEP - 20261029 PL - United States TA - CNS Spectr JT - CNS spectrums JID - 9702877 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - *Alzheimer Disease/metabolism MH - *Glucagon-Like Peptide 1/metabolism MH - *Sex Characteristics MH - Signal Transduction/physiology MH - Animals MH - Female MH - Male MH - *Brain/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 OT - T2DM OT - insulin OT - metabolism OT - sex EDAT- 2026/10/29 05:30 MHDA- 2026/10/29 05:31 CRDT- 2026/10/29 02:44 PHST- 2026/10/29 05:31 [medline] PHST- 2026/10/29 05:30 [pubmed] PHST- 2026/10/29 02:44 [entrez] AID - S1092852926101291 [pii] AID - 10.1017/S1092852926101291 [doi] PST - epublish SO - CNS Spectr. 2026 Oct 29;31(1):e49. doi: 10.1017/S1092852926101291. PMID- 42942883 OWN - NLM STAT- MEDLINE DCOM- 20261027 LR - 20261029 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 18 IP - 20 DP - 2026 Oct 9 TI - Impact of GLP-1 Receptor Agonists on Cognitive Performance in Adults at Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. LID - 10.3390/nu18203312 [doi] LID - 3312 AB - Background/Objectives: Type 2 diabetes, a widely recognized risk factor of Alzheimer's disease (AD), is mainly due to the role played by insulin resistance on neuronal degeneration. Mild Cognitive Impairment (MCI) also significantly increases the risk of developing AD by approximately 40%. Epidemiological studies have demonstrated correlations between glucagon-like peptide-1 agonists (GLP-1RAs) on reducing the risk of AD. We synthesize current data from randomized controlled trials (RCTs) to summarize the effects of GLP-1RA treatment in adults with Type 2 diabetes or with MCI on cognitive performance. Methods: We searched databases from inception to 1 January 2026 investigating effects of GLP-1RA(s) on cognition. PubMed, Web of Science and Scopus databases were explored following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We selected only RCTs in adults investigating GLP-1RA(s) on cognitive performance. Results: Overall mean age was 64.5 yrs with an average follow-up period of 28.4 months. A total of 13,711 participants from five RCTs were included. Following a source-data audit, four randomized controlled trials contributed analytically compatible data to at least one cognitive domain. Cognitive domains were analyzed separately using Hedges' g. Random-effects models used restricted maximum likelihood (REML) estimation with Knapp-Hartung inference when at least two compatible studies contributed. For global cognition, three studies yielded g = 0.014 (95% CI: -0.061 to 0.088; p = 0.515; I(2) = 0%). For attention, two studies yielded g = 0.072 (95% CI: -2.164 to 2.308; p = 0.753; I(2) = 31.1%). For delayed memory, executive function, and verbal function, only one compatible study was available per domain; these were therefore reported as single-study estimates rather than pooled effects. A sensitivity analysis excluding the dominant Cukierman trial yielded an imprecise and non-significant effect estimate for global cognition (g = -0.205, 95% CI: -2.678 to 2.269) indicating that the robustness of the pooled result could not be established. Conclusions: Current randomized evidence is insufficient to establish a consistent beneficial effect of GLP-1RA(s) on cognitive function in adults at risk of AD. The available findings should be considered exploratory and hypothesis-generating because few analytically compatible trials were available within each cognitive domain. FAU - Abbatecola, Angela M AU - Abbatecola AM AUID- ORCID: 0000-0001-5522-9257 AD - Department of Life Sciences, Health, and Health Professions, Link Campus University, Via del Casale Pio V, 00165 Rome, Italy. FAU - Migliara, Giuseppe AU - Migliara G AUID- ORCID: 0000-0002-4573-6025 AD - Department of Life Sciences, Health, and Health Professions, Link Campus University, Via del Casale Pio V, 00165 Rome, Italy. FAU - D'Agostino, Fausto AU - D'Agostino F AD - Department of Anaesthesia, Intensive Care and Pain Management, Campus Bio Medico University and Teaching Hospital, 00128 Rome, Italy. FAU - Veronese, Nicola AU - Veronese N AUID- ORCID: 0000-0002-9328-289X AD - Faculty of Medicine, Saint Camillus International University of Health Sciences, 00131 Rome, Italy. FAU - Giuliani, Angelica AU - Giuliani A AUID- ORCID: 0000-0002-8477-8519 AD - Clinic of Laboratory and Precision Medicine, IRCCS INRCA, 60121 Ancona, Italy. AD - Department of Clinical and Molecular Sciences, Universita Politecnica delle Marche, 60100 Ancona, Italy. FAU - Caponnetto, Salvatore AU - Caponnetto S AUID- ORCID: 0000-0003-2906-449X AD - Department of Life Sciences, Health, and Health Professions, Link Campus University, Via del Casale Pio V, 00165 Rome, Italy. FAU - Corbi, Graziamaria AU - Corbi G AUID- ORCID: 0000-0002-3441-889X AD - Department of Medical and Translational Medicine, University of Naples "Federico II", 80131 Naples, Italy. FAU - Signoriello, Elisabetta AU - Signoriello E AUID- ORCID: 0000-0001-5753-6752 AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy. FAU - Incalzi, Raffaele Antonelli AU - Incalzi RA AD - Research Unit of Geriatrics, Universita Campus Bio-Medico di Rome, 00128 Rome, Italy. AD - Operative Research Unit of Internal Medicine, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy. FAU - Paolisso, Giuseppe AU - Paolisso G AUID- ORCID: 0000-0002-2137-455X AD - Faculty of Medicine, Saint Camillus International University of Health Sciences, 00131 Rome, Italy. AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review PT - Systematic Review DEP - 20261009 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Alzheimer Disease/prevention & control/etiology MH - *Cognition/drug effects MH - *Cognitive Dysfunction/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Glucagon-Like Peptide-1 Receptor Agonists/pharmacology/therapeutic use MH - Randomized Controlled Trials as Topic MH - Risk Factors PMC - PMC13708722 OTO - NOTNLM OT - RCTs OT - T2DM OT - glucagon-like peptide-1 agonists OT - memory OT - mild cognitive impairment OT - nutrition COIS- The authors declare no conflicts of interest. EDAT- 2026/10/27 11:32 MHDA- 2026/10/27 22:05 PMCR- 2026/10/09 CRDT- 2026/10/27 10:43 PHST- 2026/08/17 00:00 [received] PHST- 2026/10/02 00:00 [revised] PHST- 2026/10/05 00:00 [accepted] PHST- 2026/10/27 22:05 [medline] PHST- 2026/10/27 11:32 [pubmed] PHST- 2026/10/27 10:43 [entrez] PHST- 2026/10/09 00:00 [pmc-release] AID - nu18203312 [pii] AID - nutrients-18-03312 [pii] AID - 10.3390/nu18203312 [doi] PST - epublish SO - Nutrients. 2026 Oct 9;18(20):3312. doi: 10.3390/nu18203312. PMID- 42928425 OWN - NLM STAT- Publisher LR - 20261026 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) DP - 2026 Oct 25 TI - Neuropsychiatric Outcomes Associated With GLP-1 Receptor Agonist Use in Medicare Beneficiaries With Type 2 Diabetes: Variation by Treatment Pattern and Obesity Status. LID - 10.1111/dom.71459 [doi] AB - AIMS: Glucagon-like peptide-1 (GLP-1) receptors are expressed in brain regions governing mood, reward and stress, yet the neuropsychiatric effects of GLP-1 receptor agonist (GLP-1 RA) therapy remain poorly characterized. We estimated associations between GLP-1 RA use and neuropsychiatric disorders and variation by obesity status and treatment pattern. MATERIAL AND METHODS: This population-based cohort study used claims data from Medicare enrolees with Type 2 diabetes mellitus. GLP-1 RAs were compared with other second-line glucose-lowering medications and evaluated across four treatment patterns: monotherapy, switch, escalation and augmentation. Eight neuropsychiatric outcomes were examined using 1:1 propensity score-matched, covariate-adjusted stratified Cox regression with time-varying covariates. RESULTS: GLP-1 RA use was associated with a small increase in aggregate psychiatric disorder risk (Hazard Ratio [HR] = 1.04; 95% Confidence Interval: 1.03-1.06; 1.7 excess events/1000 person-years), of uncertain clinical significance given the large cohort size. Risk was elevated for depression (HR = 1.11; 3.0 excess events/1000 person-years) but reduced for substance use disorders (HR = 0.84; 4.1 fewer events/1000 person-years), dementia (HR = 0.87; 2.8 fewer) and suicidal/self-harm (HR = 0.81; 0.4 fewer events/1000 person-years). Associations varied by treatment pattern: monotherapy showed elevated psychiatric (HR = 1.43) and elevated emotional symptom (HR = 1.32) risks; escalation also exhibited elevated psychiatric risk, whereas switch and augmentation demonstrated reduced or null risks. CONCLUSIONS: Rather than a uniform class effect, the neuropsychiatric profile of GLP-1 RA appears context-dependent, differing by treatment pattern, obesity status and outcome examined. Elevated risk with monotherapy or escalation may reflect baseline clinical differences rather than pharmacological effect. Reduced risks of substance use disorders, dementia and suicidal/self-harm are reassuring. CI - (c) 2026 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Baik, Seo Hyon AU - Baik SH AUID- ORCID: 0000-0002-2077-4316 AD - Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. FAU - Baye, Fitsum AU - Baye F AD - Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. FAU - Xian, Haotian AU - Xian H AD - Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. FAU - Fung, Kin Wah AU - Fung KW AD - Lister Hill National Center for Biomedical Communications, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. FAU - McDonald, Clement J AU - McDonald CJ AD - Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. LA - eng GR - U.S. National Library of Medicine, Intramural Research Program/ PT - Journal Article DEP - 20261025 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 SB - IM OTO - NOTNLM OT - GLP-1 analogue OT - antidiabetic drug OT - cohort study OT - diabetes complications OT - pharmaco-epidemiology OT - real-world evidence EDAT- 2026/10/26 05:30 MHDA- 2026/10/26 05:30 CRDT- 2026/10/26 00:33 PHST- 2026/10/07 00:00 [revised] PHST- 2026/07/15 00:00 [received] PHST- 2026/10/08 00:00 [accepted] PHST- 2026/10/26 05:30 [medline] PHST- 2026/10/26 05:30 [pubmed] PHST- 2026/10/26 00:33 [entrez] AID - 10.1111/dom.71459 [doi] PST - aheadofprint SO - Diabetes Obes Metab. 2026 Oct 25. doi: 10.1111/dom.71459. PMID- 42911774 OWN - NLM STAT- Publisher LR - 20261023 IS - 1751-2441 (Electronic) IS - 1751-2433 (Linking) DP - 2026 Oct 22 TI - Modern antidiabetic therapy in older adults with type 2 diabetes: evidence, best practice and a clinical pharmacist's framework. LID - 10.1080/17512433.2026.2754390 [doi] AB - INTRODUCTION: Older adults with type 2 diabetes require treatment that balances cardiovascular and kidney protection against hypoglycemia, treatment burden, undernutrition, and functional vulnerability. AREAS COVERED: This narrative review considers PubMed-indexed literature and ClinicalTrials.gov records covering January 2010-October 2026, with targeted updating on 12 October 2026. It examines sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, tirzepatide, and dipeptidyl peptidase-4 inhibitors. Age-stratified outcome evidence is distinguished from whole-trial results and the limited evidence in adults aged 80 years or older. Body-composition findings, neurodegenerative outcomes, kidney-protective treatment, and pharmacist-supported regimen modification are critically appraised. EXPERT OPINION: Organ protection and glycemic simplification should be considered separately. Frailty is not synonymous with kidney impairment, and reductions in lean mass do not establish treatment-induced sarcopenia. Weight-neutral therapy remains useful when weight loss is undesirable. A structured medication review should integrate patient priorities, nutrition, physical performance, renal function, and hypoglycemia risk, followed by explicit monitoring and communication across care transitions. Prospective validation of this integrated framework in the oldest and most vulnerable populations is needed. FAU - Martinc, Bostjan AU - Martinc B AD - Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. AD - University Rehabilitation Institute Republic of Slovenia (URI soca), Ljubljana, Slovenia. FAU - Sabovic, Miso AU - Sabovic M AD - Clinical Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. AD - Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. FAU - Janic, Miodrag AU - Janic M AD - Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. AD - Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. FAU - Lunder, Mojca AU - Lunder M AD - Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. AD - Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. LA - eng PT - Journal Article PT - Review DEP - 20261022 PL - England TA - Expert Rev Clin Pharmacol JT - Expert review of clinical pharmacology JID - 101278296 SB - IM OTO - NOTNLM OT - clinical pharmacist OT - deprescribing OT - dipeptidyl peptidase-4 inhibitors OT - frailty OT - glucagon-like peptide-1 receptor agonists OT - older adults OT - sarcopenia OT - sodium-glucose cotransporter-2 inhibitors OT - tirzepatide OT - type 2 diabetes mellitus EDAT- 2026/10/23 18:31 MHDA- 2026/10/23 18:31 CRDT- 2026/10/23 13:09 PHST- 2026/10/23 18:31 [medline] PHST- 2026/10/23 18:31 [pubmed] PHST- 2026/10/23 13:09 [entrez] AID - 10.1080/17512433.2026.2754390 [doi] PST - aheadofprint SO - Expert Rev Clin Pharmacol. 2026 Oct 22. doi: 10.1080/17512433.2026.2754390. PMID- 42871641 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20261014 LR - 20261015 IS - 2575-9108 (Electronic) IS - 2575-9108 (Linking) VI - 9 IP - 10 DP - 2026 Oct 9 TI - Diabetes-Associated Cognitive Dysfunction: Pathophysiology, Molecular Mechanisms, and Emerging Therapeutic Strategies. PG - 2688-2711 LID - 10.1021/acsptsci.6c00440 [doi] AB - Diabetes-associated cognitive dysfunction (DACD), which includes memory loss, executive dysfunction, attention, processing speed, and an increased risk of dementia, is a growing problem associated with diabetes mellitus (DM), especially type 2 diabetes mellitus. Due to a significant increase in the global burden of diabetes and population ageing, DACD is becoming an important public health issue. This review provides a comprehensive overview of the pathophysiology, molecular mechanisms, biomarkers, experimental models, and emerging therapeutic strategies associated with DACD. At present, it is believed that the multiple mechanisms associated with chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier disruption, and microvascular injury all contribute to the pathogenesis of DACD. These interrelated mechanisms are responsible for cognitive decline, synaptic dysfunction, and neuronal damage. Experimental research has shown that specific molecular pathways contribute to the pathogenesis of DACD, such as AGE-RAGE signaling, nuclear factor-kappaB activation, PI3K/Akt dysregulation, and inflammatory cascades. Emerging biomarkers including neurofilament light (NfL) chain, phosphorylated tau (p-tau), neuroimaging markers, exosomes, metabolomic profiles, and transcriptomic signatures may improve early diagnosis and risk stratification. Several therapeutic approaches, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, intranasal insulin, nanoparticle-based delivery systems, stem cell therapies, and bioactive compounds, have demonstrated promising neuroprotective effects in preclinical studies, although clinical translation remains limited. Finally, future studies should be directed toward the use of biomarker-driven diagnosis, clinically relevant disease models, and large-scale clinical studies in order to develop effective therapeutic interventions. Understanding more of the mechanisms that underlie DACD could help inform the creation of precision medicine strategies to prevent or delay diabetes-related cognitive decline. CI - (c) 2026 American Chemical Society. FAU - Sarkar, Ravin AU - Sarkar R AD - University Institute of Pharma Science, Chandigarh University, Gharuan 140413, Punjab, India. RINGGOLD: 418665 FAU - Kabra, Atul AU - Kabra A AUID- ORCID: 0000-0003-2890-1575 AD - University Institute of Pharma Science, Chandigarh University, Gharuan 140413, Punjab, India. RINGGOLD: 418665 FAU - S Saeedan, Abdulaziz AU - S Saeedan A AD - Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia. RINGGOLD: 204568 FAU - Ansari, Mohd Nazam AU - Ansari MN AUID- ORCID: 0000-0001-8580-3002 AD - Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia. RINGGOLD: 204568 LA - eng PT - Journal Article PT - Review DEP - 20260930 PL - United States TA - ACS Pharmacol Transl Sci JT - ACS pharmacology & translational science JID - 101721411 PMC - PMC13659845 OTO - NOTNLM OT - GLP-1 receptor agonists OT - diabetes-associated cognitive dysfunction (DACD) OT - insulin resistance OT - neuroinflammation OT - oxidative stress EDAT- 2026/10/14 18:14 MHDA- 2026/10/14 18:15 PMCR- 2026/09/30 CRDT- 2026/10/14 11:03 PHST- 2026/07/13 00:00 [received] PHST- 2026/09/19 00:00 [revised] PHST- 2026/09/23 00:00 [accepted] PHST- 2026/10/14 18:15 [medline] PHST- 2026/10/14 18:14 [pubmed] PHST- 2026/10/14 11:03 [entrez] PHST- 2026/09/30 00:00 [pmc-release] AID - 10.1021/acsptsci.6c00440 [doi] PST - epublish SO - ACS Pharmacol Transl Sci. 2026 Sep 30;9(10):2688-2711. doi: 10.1021/acsptsci.6c00440. eCollection 2026 Oct 9. PMID- 42860380 OWN - NLM STAT- MEDLINE DCOM- 20261011 LR - 20261014 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 22 IP - 10 DP - 2026 Oct TI - The effects of improved access to diabetes medications on risk of Alzheimer's disease and related dementias. PG - e71794 LID - 10.1002/alz.71794 [doi] LID - e71794 AB - INTRODUCTION: Diabetes is associated with elevated risk of Alzheimer's disease and related dementias (ADRD). Disease management with pharmaceutical therapies may mitigate this increased risk, but access and use of diabetes therapies are limited, especially for persons at highest risk of ADRD. METHODS: Using 10 years of data on Americans aged 51 and older with diabetes, we employed dynamic microsimulation to analyze the impact of increased utilization of glucagon-like peptide 1 receptor agonists (GLP1s) and sodium-glucose cotransporter-2 inhibitors (SGLT2s) on ADRD incidence. RESULTS: Over 10 years, utilization of GLP1s and SGLT2s by people with diabetes and HbA1c > 7 could avert 76,000-201,000 ADRD cases. The risk reduction is largest for Black and Hispanic individuals and individuals with HbA1c > 8. DISCUSSION: This study shows that improving diabetes management can lead to large reductions in ADRD risk. Improved adherence and access for those with higher HbA1c and higher risk of ADRD will have the largest benefit. CI - (c) 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Barthold, Douglas AU - Barthold D AD - The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, Washington, USA. FAU - Zissimopoulos, Julie AU - Zissimopoulos J AD - Price School of Public Policy, Leonard D. Schaeffer Institute for Public Policy and Government, University of Southern California, Los Angeles, California, USA. FAU - Basu, Anirban AU - Basu A AD - The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, Washington, USA. FAU - Tysinger, Bryan AU - Tysinger B AD - Price School of Public Policy, Leonard D. Schaeffer Institute for Public Policy and Government, University of Southern California, Los Angeles, California, USA. LA - eng GR - K01 AG071843/AG/NIA NIH HHS/United States GR - P30 AG043073/AG/NIA NIH HHS/United States GR - R33 AG081811/AG/NIA NIH HHS/United States PT - Journal Article PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Alzheimer Disease/epidemiology/prevention & control MH - *Hypoglycemic Agents/therapeutic use MH - *Dementia/epidemiology/prevention & control MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Female MH - Aged MH - Male MH - Middle Aged MH - Incidence MH - *Health Services Accessibility MH - *Diabetes Mellitus/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy PMC - PMC13655229 OTO - NOTNLM OT - ADRD OT - ADRD prevention OT - Alzheimer's disease OT - Alzheimer's disease and related dementias OT - GLP1 OT - SGLT2 OT - access to prescription drugs OT - chronic disease management OT - dementia OT - dementia prevention OT - diabetes OT - diabetes management OT - glucagon-like peptide 1 receptor agonists OT - sodium-glucose cotransporter-2 inhibitors COIS- The authors have no conflicts of interest to declare. Author disclosures are available in the Supporting Information. EDAT- 2026/10/12 05:32 MHDA- 2026/10/12 05:33 PMCR- 2026/10/11 CRDT- 2026/10/11 23:02 PHST- 2026/04/14 00:00 [revised] PHST- 2025/12/23 00:00 [received] PHST- 2026/08/03 00:00 [accepted] PHST- 2026/10/12 05:33 [medline] PHST- 2026/10/12 05:32 [pubmed] PHST- 2026/10/11 23:02 [entrez] PHST- 2026/10/11 00:00 [pmc-release] AID - ALZ71794 [pii] AID - 10.1002/alz.71794 [doi] PST - ppublish SO - Alzheimers Dement. 2026 Oct;22(10):e71794. doi: 10.1002/alz.71794. PMID- 42847987 OWN - NLM STAT- Publisher LR - 20261008 IS - 1473-0804 (Electronic) IS - 1369-7137 (Linking) DP - 2026 Oct 8 TI - GLP-1 receptor agonists in perimenopause and early postmenopause: clinical role, cardiometabolic benefits and knowledge gaps. PG - 1-11 LID - 10.1080/13697137.2026.2735765 [doi] AB - Perimenopause and early postmenopause represent a critical metabolic transition with adverse changes in body composition, insulin sensitivity, lipid metabolism and cardiometabolic health, contributing to increased rates of obesity, type 2 diabetes and cardiovascular disease. As the prevalence of obesity continues to rise among midlife women, effective therapeutic strategies are increasingly needed. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as highly effective treatments for obesity and type 2 diabetes through their effects on appetite regulation, weight reduction, glucose homeostasis and metabolic health. Beyond their established role, GLP-1 RAs have demonstrated favorable effects on visceral adiposity, glycemic control, lipid profiles, hepatic steatosis and cardiovascular outcomes. Preliminary experimental evidence also suggests possible complementary effects when combined with menopausal hormone therapy (MHT). However, menopause-specific evidence remains limited. This review summarizes the current evidence regarding the efficacy, safety and clinical application of GLP-1 RAs in perimenopausal and early postmenopausal women. Particular attention is given to their effects on cardiometabolic health, cardiovascular risk, bone and muscle health, cancer risk, cognition and potential interactions with MHT. Although GLP-1 RAs represent a promising therapeutic option for obesity and metabolic dysfunction during menopause, important knowledge gaps remain regarding their long-term safety, effects on menopause-related outcomes and optimal integration into comprehensive menopausal care. The efficacy, safety and potential interactions of GLP-1 RAs when used in combination with MHT remain to be determined. FAU - Ozcivit Erkan, Ipek Betul AU - Ozcivit Erkan IB AUID- ORCID: 0000-0002-5645-7064 AD - Department of Obstetrics and Gynecology, Acibadem Fulya Hospital, Istanbul, Turkey. AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. FAU - Senturk, Levent M AU - Senturk LM AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. AD - Department of Obstetrics and Gynecology, International School of Medicine, Istanbul Medipol University, Turkey. AD - Department of Obstetrics and Gynecology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey. FAU - Erel, C Tamer AU - Erel CT AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. AD - Department of Obstetrics and Gynecology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey. FAU - Seyisoglu, Hasan Hakan AU - Seyisoglu HH AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. AD - Department of Obstetrics and Gynecology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey. FAU - Sahmay, Sezai AU - Sahmay S AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. AD - Department of Obstetrics and Gynecology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey. FAU - Durmusoglu, Fatih AU - Durmusoglu F AD - Turkish Menopause and Osteoporosis Society, Istanbul, Turkey. AD - Department of Obstetrics and Gynecology, International School of Medicine, Istanbul Medipol University, Turkey. LA - eng PT - Journal Article PT - Review DEP - 20261008 PL - England TA - Climacteric JT - Climacteric : the journal of the International Menopause Society JID - 9810959 SB - IM OAB - Many women gain weight and develop changes in their metabolism during the menopausal transition. Falling estrogen levels can lead to increased abdominal fat, loss of muscle mass, insulin resistance and a higher risk of type 2 diabetes and cardiovascular disease. These changes can negatively affect long-term health and quality of life.Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are medications originally developed for type 2 diabetes that are now widely used to treat obesity. They work by reducing appetite, slowing stomach emptying and helping people feel full for longer. Clinical studies have shown that GLP-1 RAs can produce substantial weight loss and improve blood sugar control, blood pressure, cholesterol levels and other markers of metabolic health.This review summarizes current evidence on the use of GLP-1 RAs in perimenopausal and postmenopausal women. Available data suggest that these medications may help address several metabolic consequences of menopause, including weight gain, abdominal obesity, insulin resistance and increased cardiovascular risk. Preliminary studies also suggest that combining GLP-1 RAs with menopausal hormone therapy (MHT) may enhance weight loss, although stronger evidence is needed.GLP-1 RAs are generally well tolerated, but gastrointestinal side effects such as nausea, vomiting, diarrhea and constipation are common. Questions also remain about their long-term effects on bone health, muscle mass, cancer risk, cognition and quality of life in menopausal women. Further research is needed to determine how these medications can be most effectively integrated into menopause care and whether they provide additional benefits when used alongside MHT. OABL- eng OTO - NOTNLM OT - GLP-1 OT - Perimenopause: postmenopause OT - adipose tissue OT - glucagon-like peptide-1 receptor agonists OT - menopausal hormone therapy OT - obesity OT - weight gain EDAT- 2026/10/08 17:35 MHDA- 2026/10/08 17:35 CRDT- 2026/10/08 15:37 PHST- 2026/10/08 17:35 [medline] PHST- 2026/10/08 17:35 [pubmed] PHST- 2026/10/08 15:37 [entrez] AID - 10.1080/13697137.2026.2735765 [doi] PST - aheadofprint SO - Climacteric. 2026 Oct 8:1-11. doi: 10.1080/13697137.2026.2735765. PMID- 42831108 OWN - NLM STAT- MEDLINE DCOM- 20261005 LR - 20261006 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 20 DP - 2026 TI - GLP-1 Receptor Agonists Versus DPP-4 Inhibitors and Incident Dementia Risk in COVID-19 Survivors with Type 2 Diabetes: A Target Trial Emulation Study. PG - 638249 LID - 10.2147/DDDT.S638249 [doi] LID - 638249 AB - PURPOSE: Type 2 diabetes mellitus (T2DM) and COVID-19 are independently associated with an elevated risk of dementia, and COVID-19 survivors with T2DM may represent a clinically vulnerable population in whom metabolic, inflammatory, and vascular factors coexist. However, whether antidiabetic treatment choice is associated with incident dementia risk in this population remains unknown. METHODS: In this target trial emulation using the TriNetX US Collaborative Network, we compared COVID-19 survivors aged >/=50 years with T2DM initiating glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with those initiating dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy between January 1, 2020 and December 31, 2024. We applied an active-comparator, new-user design with a 90-day survivor landmark and 1:1 propensity score matching. The primary outcome was incident all-cause dementia (a composite of vascular dementia, Alzheimer's disease, and other dementias). Secondary outcomes included dementia subtypes, mild cognitive impairment, glycemic outcomes, and all-cause mortality. RESULTS: After matching, 25,263 patients per group were followed for up to 6 years (median, 919 days [GLP-1RA] vs 955 days [DPP-4i]). GLP-1RA initiation was associated with a lower hazard of incident dementia (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.58-0.72), vascular dementia (HR, 0.67; 95% CI, 0.52-0.85), and Alzheimer's disease (HR, 0.74; 95% CI, 0.59-0.93), as well as more favorable glycemic control and lower all-cause mortality (HR, 0.63; 95% CI, 0.59-0.68). The estimate for mild cognitive impairment was borderline (HR, 0.87; 95% CI, 0.75-1.00) and not consistently supported across sensitivity analyses. The association with incident dementia remained evident after the 6-month landmark analysis (HR, 0.66; 95% CI, 0.58-0.75) and was consistent across sensitivity and subgroup analyses. CONCLUSION: Among COVID-19 survivors with T2DM, GLP-1RA initiation was associated with a lower hazard of incident dementia than DPP-4i initiation. These hypothesis-generating results warrant confirmation before they can be used to inform clinical decision-making. CI - (c) 2026 Hung et al. FAU - Hung, Kuo-Chuan AU - Hung KC AUID- ORCID: 0000-0002-4507-8085 AD - Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan. AD - School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan. FAU - Yu, Ting-Sian AU - Yu TS AD - Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. FAU - Liu, Ping-Hsin AU - Liu PH AD - Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. FAU - Lai, Yi-Chen AU - Lai YC AD - Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan. AD - School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan. FAU - Chen, I-Wen AU - Chen IW AUID- ORCID: 0009-0004-7122-6901 AD - Department of Anesthesiology, Chi Mei Hospital, Liouying, Tainan, Taiwan. LA - eng PT - Comparative Study PT - Journal Article DEP - 20260930 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *COVID-19/complications/epidemiology MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - *Dementia/epidemiology MH - *Hypoglycemic Agents/therapeutic use MH - Male MH - Female MH - Aged MH - Middle Aged MH - Incidence MH - Survivors PMC - PMC13634317 OTO - NOTNLM OT - COVID-19 survivors OT - DPP-4 inhibitor OT - dementia OT - glucagon-like peptide-1 receptor agonist OT - target trial emulation OT - type 2 diabetes mellitus COIS- The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper. EDAT- 2026/10/05 05:31 MHDA- 2026/10/05 05:32 PMCR- 2026/09/30 CRDT- 2026/10/05 04:21 PHST- 2026/07/06 00:00 [received] PHST- 2026/09/25 00:00 [accepted] PHST- 2026/10/05 05:32 [medline] PHST- 2026/10/05 05:31 [pubmed] PHST- 2026/10/05 04:21 [entrez] PHST- 2026/09/30 00:00 [pmc-release] AID - 638249 [pii] AID - 10.2147/DDDT.S638249 [doi] PST - epublish SO - Drug Des Devel Ther. 2026 Sep 30;20:638249. doi: 10.2147/DDDT.S638249. eCollection 2026. PMID- 42812893 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260930 LR - 20261001 IS - 1662-5099 (Print) IS - 1662-5099 (Electronic) IS - 1662-5099 (Linking) VI - 19 DP - 2026 TI - Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies. PG - 1892506 LID - 10.3389/fnmol.2026.1892506 [doi] LID - 1892506 AB - Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal-mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer's disease, mitochondrial dysfunction and amyloid-beta/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions-including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists-have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whether these responses can be safely and effectively modulated in humans will be essential for establishing its therapeutic relevance in metabolic and neurodegenerative diseases. CI - Copyright (c) 2026 Otoda, Nakajima and Takayama. FAU - Otoda, Toshiki AU - Otoda T AD - Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan. FAU - Nakajima, Hideto AU - Nakajima H AD - Division of Neurology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan. FAU - Takayama, Tadateru AU - Takayama T AD - Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan. LA - eng PT - Journal Article PT - Review DEP - 20260915 PL - Switzerland TA - Front Mol Neurosci JT - Frontiers in molecular neuroscience JID - 101477914 PMC - PMC13621133 OTO - NOTNLM OT - dementia OT - metabolic disease OT - mitochondrial dysfunction OT - mitochondrial quality control OT - mitohormesis OT - neurodegeneration OT - oxidative stress OT - redox signaling COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/09/30 11:35 MHDA- 2026/09/30 11:36 PMCR- 2026/09/15 CRDT- 2026/09/30 06:21 PHST- 2026/05/27 00:00 [received] PHST- 2026/08/30 00:00 [revised] PHST- 2026/09/01 00:00 [accepted] PHST- 2026/09/30 11:36 [medline] PHST- 2026/09/30 11:35 [pubmed] PHST- 2026/09/30 06:21 [entrez] PHST- 2026/09/15 00:00 [pmc-release] AID - 10.3389/fnmol.2026.1892506 [doi] PST - epublish SO - Front Mol Neurosci. 2026 Sep 15;19:1892506. doi: 10.3389/fnmol.2026.1892506. eCollection 2026. PMID- 42812740 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260930 LR - 20261001 IS - 2376-7839 (Print) IS - 2376-7839 (Electronic) IS - 2376-7839 (Linking) VI - 12 IP - 5 DP - 2026 Oct TI - Genetic Insights Into Protective Effects of GLP-1 Receptor Agonists on Stroke and Alzheimer Disease Across Ancestries. PG - e200425 LID - 10.1212/NXG.0000000000200425 [doi] LID - e200425 AB - BACKGROUND AND OBJECTIVES: Stroke and dementia are leading causes of death and disability worldwide, requiring enhanced preventive strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA), widely used for type 2 diabetes (T2D) and obesity, have demonstrated pleiotropic effects, including cardiovascular benefits, with mounting evidence also suggesting potential beneficial effects on brain health. The objective of this study was to investigate the genetically proxied effect of GLP-1RA on stroke, Alzheimer disease (AD), and related endophenotypes, in a cross-ancestry setting. METHODS: We conducted a 2-sample Mendelian randomization (MR) study using both a locus-based and a protein quantitative trait loci (pQTL)-based approach. The study leveraged summary statistics from large-scale genome-wide association studies (GWAS). These GWAS comprised participants of European, East-Asian, and African ancestry with and without T2D, stroke, and AD, and with measurements of fasting glucose, glycated hemoglobin, stroke, and AD endophenotypes. Sample size ranged from 3,026 to 1,812,017 individuals. Genetically proxied GLP-1RA exposure was instrumented using independent T2D-associated variants (p < 5 x 10(-8)) within GLP1R (locus-based MR) and pQTLs for circulating GLP-1R protein levels (pQTL-based MR). Instruments were validated for effects on glycemic traits and GLP1R gene expression. Primary outcomes were stroke (any, ischemic, cardioembolic, small vessel, large artery, and intracerebral hemorrhage) and AD. Secondary analyses included etiologic factors and endophenotypes of stroke and AD: heart failure, atrial fibrillation, MRI markers (white matter hyperintensity volume, perivascular space burden, and hippocampal volume), and CSF biomarkers (beta-amyloid, tau). Outcomes were stratified by ancestry and meta-analyzed. RESULTS: In Europeans, locus-based MR indicated significant protective associations of GLP-1RA with any stroke and ischemic stroke (p (FDR) < 0.05) and nominally (p < 0.05) with AD. Cross-ancestry meta-analyses strengthened protective effects of GLP-1RA on any stroke (OR, 0.75; 95% CI 0.63-0.89), ischemic stroke (0.72; 0.56-0.91), cardioembolic stroke (0.55; 0.35-0.86), and AD (0.51; 0.31-0.83), all with p (FDR) < 0.05. pQTL-based MR analyses suggested protective effects of genetically proxied GLP-1RA on atrial fibrillation (p (FDR) < 0.05) and, nominally (p < 0.05), on hippocampal perivascular space burden and CSF beta-amyloid levels. DISCUSSION: GLP-1RAs may confer protective effects against stroke (especially ischemic and cardioembolic) and AD risk, across ancestries. These findings warrant further investigation in experimental models and clinical trials to confirm benefits on brain health and understand underlying mechanisms. CI - Copyright (c) 2026 The Author(s). Published by Wolters Kluwer Health, LLC. on behalf of the American Academy of Neurology. FAU - Caro-Chatelier, Ilana AU - Caro-Chatelier I AUID- ORCID: 0000-0003-3075-4682 AD - Bordeaux Population Health Research Center, Inserm, UMR U1219, Universite de Bordeaux, France. FAU - Sargurupremraj, Muralidharan AU - Sargurupremraj M AUID- ORCID: 0000-0003-1684-3750 AD - Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio. FAU - Yang, Chengran AU - Yang C AUID- ORCID: 0000-0003-4577-5590 AD - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO. AD - NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO. FAU - Akinleye, Callistus AU - Akinleye C AUID- ORCID: 0000-0003-3778-3638 AD - Osun State University, Osogbo, Nigeria. FAU - Tregouet, David-Alexandre AU - Tregouet DA AUID- ORCID: 0000-0001-9084-7800 AD - Bordeaux Population Health Research Center, Inserm, UMR U1219, Universite de Bordeaux, France. FAU - Akinyemi, Rufus Olusola AU - Akinyemi RO AUID- ORCID: 0000-0001-5286-428X AD - Center for Genomic and Precision Medicine, University of Ibadan, Nigeria. AD - Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Nigeria. FAU - Shigemizu, Daichi AU - Shigemizu D AUID- ORCID: 0000-0002-4412-0552 AD - Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan. AD - Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan. FAU - Coker, Motunrayo AU - Coker M AUID- ORCID: 0000-0003-4445-914X AD - Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Nigeria. AD - Cell Biology and Genetics Unit, Department of Zoology, University of Ibadan, Nigeria. FAU - Akinyemi, Joshua O AU - Akinyemi JO AUID- ORCID: 0000-0002-0675-2110 AD - Center for Genomic and Precision Medicine, University of Ibadan, Nigeria. AD - Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Nigeria. FAU - Tiwari, Hemant K AU - Tiwari HK AUID- ORCID: 0000-0003-4016-1856 AD - University of Alabama at Birmingham. FAU - Chasman, Daniel I AU - Chasman DI AUID- ORCID: 0000-0003-3357-0862 AD - Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA. AD - Harvard Medical School, Boston, MA. FAU - Ovbiagele, Bruce AU - Ovbiagele B AUID- ORCID: 0000-0002-9958-0644 AD - UCSF Weill Institute for Neurosciences, School of Medicine, University of California San Francisco. FAU - Chabriat, Hugues AU - Chabriat H AUID- ORCID: 0000-0001-8436-6074 AD - Centre Neurovasculaire Translationnel-CERVCO and Departement de Neurologie, Hopital Lariboisiere, APHP, Universite Paris-Cite and Brain Institute, Paris, France. FAU - Mooser, Vincent AU - Mooser V AUID- ORCID: 0000-0002-8632-0448 AD - Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill Genome Centre, McGill University Montreal, Quebec, Canada. FAU - Couffinhal, Thierry AU - Couffinhal T AUID- ORCID: 0000-0002-9217-2533 AD - Univ. Bordeaux, INSERM, Biologie des maladies Cardiovasculaires, U1034, Pessac, France. AD - Department of Cardiology, CHU de Bordeaux, France. FAU - Mishra, Aniket AU - Mishra A AUID- ORCID: 0000-0002-8141-1543 AD - Bordeaux Population Health Research Center, Inserm, UMR U1219, Universite de Bordeaux, France. FAU - Cruchaga, Carlos AU - Cruchaga C AUID- ORCID: 0000-0002-0276-2899 AD - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO. AD - NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO. FAU - Reitz, Christiane AU - Reitz C AD - Gertrude H. Sergievsky Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Epidemiology, Columbia University, New York, NY. FAU - Kunkle, Brian AU - Kunkle B AUID- ORCID: 0000-0002-9515-5157 AD - The John P. Hussman Institute for Human Genomics, University of Miami, FL. AD - Dr. John T. MacDonald Foundation, Department of Human Genetics, University of Miami, FL. FAU - Kamatani, Yoichiro AU - Kamatani Y AUID- ORCID: 0000-0001-8748-5597 AD - Graduate School of Frontier Sciences, The University of Tokyo, Japan. FAU - Owolabi, Mayowa Ojo AU - Owolabi MO AUID- ORCID: 0000-0003-1146-3070 AD - Center for Genomic and Precision Medicine, University of Ibadan, Nigeria. FAU - Mohammedi, Kamel AU - Mohammedi K AUID- ORCID: 0000-0001-6139-1197 AD - Univ. Bordeaux, INSERM, Biologie des maladies Cardiovasculaires, U1034, Pessac, France. AD - Department of Endocrinology, Diabetology and Nutrition, CHU de Bordeaux, France. FAU - Debette, Stephanie AU - Debette S AUID- ORCID: 0000-0001-8675-7968 AD - Bordeaux Population Health Research Center, Inserm, UMR U1219, Universite de Bordeaux, France. AD - Institut du Cerveau (ICM), INSERM U1127, UMR CNRS 7225 Paris, Sorbonne Universite, France; and. AD - Department of Neurology, Institute for Neurodegenerative Diseases, CMRR, CHU de Bordeaux, France. LA - eng PT - Journal Article DEP - 20260925 PL - United States TA - Neurol Genet JT - Neurology. Genetics JID - 101671068 CIN - Neurol Genet. 12:e200450. PMC - PMC13621555 COIS- C. Cruchaga is a member of the scientific advisory board of Circular Genomics; owns stocks and is on the scientific advisory board of ADmit and Alamar; consults for Sanofi, NovoNordisk, and Owkin; and has received research support from GSK, Danaher, and EISAI. K. Mohammedi reports consulting fees from Novo Nordisk, Boehringer-Ingelheim, and Sanofi; honoraria for lectures, presentations, or speaker bureaus from Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Sanofi, Abbott, and Bayer; and participation on advisory boards from Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Lifescan, and Amarin. The other authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures. EDAT- 2026/09/30 11:35 MHDA- 2026/09/30 11:36 PMCR- 2026/09/25 CRDT- 2026/09/30 06:03 PHST- 2025/09/16 00:00 [received] PHST- 2026/07/14 00:00 [accepted] PHST- 2026/09/30 11:36 [medline] PHST- 2026/09/30 11:35 [pubmed] PHST- 2026/09/30 06:03 [entrez] PHST- 2026/09/25 00:00 [pmc-release] AID - NXG-2025-200244 [pii] AID - 10.1212/NXG.0000000000200425 [doi] PST - epublish SO - Neurol Genet. 2026 Sep 25;12(5):e200425. doi: 10.1212/NXG.0000000000200425. eCollection 2026 Oct. PMID- 42808164 OWN - NLM STAT- MEDLINE DCOM- 20260929 LR - 20260929 IS - 1752-8984 (Electronic) IS - 1479-1641 (Linking) VI - 23 IP - 5 DP - 2026 Sep-Oct TI - Benefits of sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide-1 receptor agonists in older patients with type 2 diabetes. PG - 14791641261495569 LID - 10.1177/14791641261495569 [doi] AB - BackgroundType 2 diabetes mellitus (T2DM) increases the risk of cardiovascular and neurocognitive complications. GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors (SGLT2is) have pleiotropic effects beyond glycemic control, but comparative long-term data on dementia, cardiovascular events, and mortality in older adults are limited.MethodsThis retrospective cohort study used the TriNetX US Collaborative Network. Adults >/=60 years with T2DM on metformin plus either GLP-1 RAs or SGLT2is (n=56,211 per cohort after matching, 2014-2020) were propensity-score matched on demographic and clinical characteristics. Five-year outcomes included incident Alzheimer's disease, vascular dementia, other dementia, dementia-related medication use, NSTEMI, STEMI, and all-cause mortality.ResultsAfter propensity-score matching, GLP-1 RA use was associated with higher risks of Alzheimer's disease (RR 1.33, 95% CI 1.18-1.48), vascular dementia (RR 1.56, 95% CI 1.39-1.76), other dementia (RR 1.33, 95% CI 1.21-1.47), dementia-related medication initiation, and all-cause mortality (RR 1.11, 95% CI 1.08-1.15) compared with SGLT2is. NSTEMI and STEMI risks did not differ significantly between groups.ConclusionsIn older adults with T2DM, SGLT2is were associated with lower risks of dementia, dementia-related medication use, and all-cause mortality compared with GLP-1 RAs in propensity-score matched cohorts. These observational findings are hypothesis-generating and should be confirmed in prospective studies. FAU - Mortada, Ibrahim AU - Mortada I AUID- ORCID: 0009-0006-9215-880X AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Paul, Krishna AU - Paul K AD - Department of Emergency Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Rice, James AU - Rice J AUID- ORCID: 0009-0002-3473-0880 AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Joseph, Noah AU - Joseph N AD - John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Raum, Trevor L AU - Raum TL AUID- ORCID: 0009-0006-5547-1282 AD - John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Albayyaa, Mohanad AU - Albayyaa M AUID- ORCID: 0000-0003-4185-5294 AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Gaalema, Diann AU - Gaalema D AUID- ORCID: 0000-0002-6463-9925 AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Jehle, Dietrich AU - Jehle D AUID- ORCID: 0009-0002-6006-3903 AD - Department of Emergency Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Blackwell, Thomas A AU - Blackwell TA AUID- ORCID: 0009-0009-0659-2100 AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Jneid, Hani AU - Jneid H AUID- ORCID: 0000-0002-8754-358X AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. LA - eng PT - Comparative Study PT - Journal Article DEP - 20260929 PL - England TA - Diab Vasc Dis Res JT - Diabetes & vascular disease research JID - 101234011 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Incretins) RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/diagnosis/mortality MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Aged MH - Female MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - Retrospective Studies MH - Male MH - Treatment Outcome MH - Risk Factors MH - *Incretins/adverse effects/therapeutic use MH - Risk Assessment MH - Time Factors MH - Age Factors MH - Middle Aged MH - United States/epidemiology MH - Aged, 80 and over MH - Glucagon-Like Peptide-1 Receptor OTO - NOTNLM OT - Cardiology OT - Dementia OT - Diabetes mellitus type 2 OT - Glucagon-like peptide-1 receptor agonists OT - Sodium-glucose cotransporter 2 inhibitors COIS- Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2026/09/29 12:28 MHDA- 2026/09/29 12:29 CRDT- 2026/09/29 07:44 PHST- 2026/09/29 12:29 [medline] PHST- 2026/09/29 12:28 [pubmed] PHST- 2026/09/29 07:44 [entrez] AID - 10.1177/14791641261495569 [doi] PST - ppublish SO - Diab Vasc Dis Res. 2026 Sep-Oct;23(5):14791641261495569. doi: 10.1177/14791641261495569. Epub 2026 Sep 29. PMID- 42794768 OWN - NLM STAT- MEDLINE DCOM- 20260926 LR - 20260929 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 27 IP - 18 DP - 2026 Sep 19 TI - Trajectory-Oriented Brain Vulnerability Framework for Cognitive Decline in Type 2 Diabetes. LID - 10.3390/ijms27188342 [doi] LID - 8342 AB - Type 2 diabetes mellitus (T2DM) is associated with heterogeneous cognitive and functional trajectories rather than a single diabetes-specific encephalopathy. This structured narrative review proposes a conceptual, hypothesis-generating exposure-injury-structure-function framework linking metabolic, vascular, and frailty-related exposures with molecular and neurovascular injury, structural change, cognitive decline, and loss of independence. Its contribution is the temporal assignment of measurements, lagged testing between adjacent levels, and comparison with clinical-risk and unordered biomarker models. For example, a study-specific threshold of at least 10% improvement in held-out root-mean-square error for 24-36-month executive/processing-speed decline could indicate incremental value. Repeated failure of a specified temporal link challenges that link; failure to improve prediction rejects incremental predictive value, not biological plausibility. Molecular hypotheses focus on AGE-RAGE signalling, NLRP3-IL-1beta activation, mitochondrial quality control, endothelial dysfunction, and neuroglial injury, although human timing is uncertain. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are considered complementary therapeutic probes. Both offer systemic benefits, but neither has proven efficacy in preventing cognitive decline or direct target engagement in the human brain. Visceral adiposity, skeletal-muscle health, sarcopenia, sex/gender, kidney function, co-pathology, and reserve are treated as exposures or modifiers. This framework is intended for longitudinal research, not clinical staging or treatment selection. FAU - Komel, Jana AU - Komel J AUID- ORCID: 0009-0003-2644-3061 AD - Diabetes Outpatient Clinic, Community Health Centre Koper, 6000 Koper, Slovenia. AD - Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia. FAU - Klen, Jasna AU - Klen J AD - Department of Abdominal Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia. AD - Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia. LA - eng PT - Journal Article PT - Review DEP - 20260919 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Biomarkers) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/metabolism MH - *Cognitive Dysfunction/etiology/metabolism/pathology MH - *Brain/metabolism/pathology/physiopathology MH - Biomarkers/metabolism MH - Animals PMC - PMC13607053 OTO - NOTNLM OT - brain vulnerability OT - cognitive decline OT - molecular biomarkers OT - neuroimaging OT - type 2 diabetes mellitus COIS- The authors declare no conflicts of interest. EDAT- 2026/09/26 05:35 MHDA- 2026/09/26 05:36 PMCR- 2026/09/19 CRDT- 2026/09/26 01:08 PHST- 2026/07/31 00:00 [received] PHST- 2026/09/12 00:00 [revised] PHST- 2026/09/17 00:00 [accepted] PHST- 2026/09/26 05:36 [medline] PHST- 2026/09/26 05:35 [pubmed] PHST- 2026/09/26 01:08 [entrez] PHST- 2026/09/19 00:00 [pmc-release] AID - ijms27188342 [pii] AID - ijms-27-08342 [pii] AID - 10.3390/ijms27188342 [doi] PST - epublish SO - Int J Mol Sci. 2026 Sep 19;27(18):8342. doi: 10.3390/ijms27188342. PMID- 42789205 OWN - NLM STAT- MEDLINE DCOM- 20260925 LR - 20261008 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 63 IP - 1 DP - 2026 Sep 25 TI - The Interplay of Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Dysfunction in Balance Impairment: Insights from Type 2 Diabetes Mellitus and Alzheimer's Disease. LID - 922 [pii] LID - 10.1007/s12035-026-06237-5 [doi] AB - Balance impairment and postural instability represent critical challenges for the aging population, serving as primary precursors to falls and functional decline in individuals with Type 2 Diabetes Mellitus. While traditional clinical models have largely separated these conditions, attributing balance loss in T2DM to peripheral neuropathy and in AD to central cortical atrophy, mounting evidence suggests a convergence of multi-system impairments driven by a shared central pathophysiology. This narrative review proposes an integrative framework centered on a vicious, self-reinforcing cycle involving metabolic dysfunction, chronic neuroinflammation, and mitochondrial failure as the core mechanistic link driving balance impairment. We detail how systemic and cerebral insulin resistance, coupled with glucotoxicity, trigger the activation of the NLRP3 inflammasome and the subsequent release of pro-inflammatory cytokines. This inflammatory environment exacerbates mitochondrial bioenergetic failure and oxidative stress, selectively targeting high-energy motor circuits such as the striatum and basal ganglia while simultaneously contributing to musculoskeletal sarcopenia and peripheral nerve demyelination. By synthesizing the intricate interplay between these molecular pathways, this review moves beyond disease-specific silos to offer a novel perspective on the shared pathophysiology of postural instability. Furthermore, we explore the therapeutic potential of metabolic modulators, such as GLP-1 receptor agonists, and mitochondrial-targeted antioxidants, alongside multimodal rehabilitation strategies. Ultimately, this unified model provides a foundation for developing precision-based interventions to mitigate fall risk and preserve functional independence in vulnerable aging populations. CI - (c) 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Fakorede, Sodiq AU - Fakorede S AUID- ORCID: 0000-0001-7717-105X AD - Department of Prosthetics and Orthotics, Federal University of Technology, Owerri, Nigeria. Sodiq.fakorede@futo.edu.ng. FAU - Lateef, Olubodun Michael AU - Lateef OM AD - Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. FAU - Udefa, Augustine Lishilinimye AU - Udefa AL AD - Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA. AD - Department of Physiology, University of Calabar, Calabar, Cross River State, Nigeria. FAU - Ajagbe, Abayomi Oyeyemi AU - Ajagbe AO AD - Department of Anatomy, Nile University of Nigeria, Abuja, Nigeria. FAU - Roy, Sharmistha AU - Roy S AD - Department of Social and Behavioral Health, University of Nevada, Las Vegas, NV, USA. FAU - Akosile, Priscilla Onaopemipo AU - Akosile PO AD - Department of Population Health Sciences, University of Leicester, Leicester, UK. FAU - Awobona, Taiwo Ayomide AU - Awobona TA AD - Department of Nursing, University of Houston Downtown, Houston, TX, USA. FAU - Anyanwu, Godson Emeka AU - Anyanwu GE AD - Department of Anatomy, Kampala International University, Kampala, Uganda. LA - eng PT - Journal Article PT - Review DEP - 20260925 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 SB - IM MH - Humans MH - Animals MH - *Mitochondria/metabolism/pathology MH - *Diabetes Mellitus, Type 2/metabolism/physiopathology/complications MH - *Alzheimer Disease/metabolism/physiopathology/complications/pathology MH - *Neuroinflammatory Diseases/metabolism/physiopathology/pathology/complications MH - *Postural Balance/physiology MH - Inflammation OTO - NOTNLM OT - Alzheimer's Disease OT - Balance impairment OT - Mitochondrial Dysfunction OT - Neuroinflammation OT - Sarcopenia OT - Type 2 Diabetes Mellitus COIS- Declarations. Ethics Approval: Not applicable for this narrative review. Artificial Intelligence Use Disclosure: The authors used Claude AI (Anthropic) to assist with editing and grammar improvement during the preparation of this manuscript. All scientific content, interpretations, and conclusions are solely the work of the authors. Competing interests: The authors declare no competing interests. EDAT- 2026/09/25 17:33 MHDA- 2026/09/25 17:34 CRDT- 2026/09/25 11:34 PHST- 2026/04/12 00:00 [received] PHST- 2026/09/21 00:00 [accepted] PHST- 2026/09/25 17:34 [medline] PHST- 2026/09/25 17:33 [pubmed] PHST- 2026/09/25 11:34 [entrez] AID - 10.1007/s12035-026-06237-5 [pii] AID - 10.1007/s12035-026-06237-5 [doi] PST - epublish SO - Mol Neurobiol. 2026 Sep 25;63(1):922. doi: 10.1007/s12035-026-06237-5. PMID- 42785112 OWN - NLM STAT- Publisher LR - 20261007 IS - 2426-0266 (Electronic) IS - 2274-5807 (Print) IS - 2274-5807 (Linking) VI - 13 IP - 10 DP - 2026 Sep 24 TI - Evoke (+) trials of semaglutide for early alzheimer's disease: Innovations, lessons, and implications. PG - 100677 LID - S2274-5807(26)00200-1 [pii] LID - 10.1016/j.tjpad.2026.100677 [doi] LID - 100677 AB - The evoke and evoke+ trials for the treatment of early Alzheimer's disease (AD) with semaglutide were founded on the observation that semaglutide reduced the incidence of dementia in patients with type 2 diabetes. Non-clinical investigations support an effect of semaglutide on AD pathology. The evoke and evoke+ trials were large, well conducted, and innovative. These trials were negative, showing no clinical benefit of treatment with 14 milligrams of semaglutide for two years. Semaglutide produced a statistically significant and robust reduction in high sensitivity C-reactive protein consistent with suppression of peripheral inflammation. There was no effect on most plasma measures collected. CSF analyses showed nominally significant effects on biomarkers of the core biology of AD; YKL-40 and glial fibrillary acidic protein in CSF were decreased indicating a reduction in astroglial activation. The magnitude of these changes was small (7%-10%) and there was no correlative effect on AD progression. The discrepancy between observations in real world data and the trial outcomes indicates that treatment of symptomatic AD confirmed with biomarkers differs from treatment of patients with diabetes who were cognitively unimpaired and at risk for all cause cognitive decline. The evoke and evoke+ trials suggest that reduction in peripheral inflammation may be insufficient to produce beneficial clinical effects in AD. The results of the evoke(+) trials do not exclude the possibility that AD populations enriched for elevated levels of markers of peripheral inflammation or use of brain penetrant GLP-1 RAs could produce therapeutic benefit. CI - Copyright (c) 2026 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Cummings, Jeffrey L AU - Cummings JL AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Las Vegas, NV, USA. Electronic address: jcummings@cnsinnovations.com. FAU - Scheltens, Philip AU - Scheltens P AD - Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; EQT Life Sciences, Amsterdam, Netherlands. LA - eng GR - R01 NS139383/NS/NINDS NIH HHS/United States GR - R25 AG083721/AG/NIA NIH HHS/United States GR - R35 AG071476/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20260924 PL - United States TA - J Prev Alzheimers Dis JT - The journal of prevention of Alzheimer's disease JID - 101638820 SB - IM PMC - PMC13634738 COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey Cummings reports a relationship with AbbVie Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Acadia Pharmaceuticals Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Alkermes Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with ALZpath Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Annovis Bio Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Artery Therapeutics Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Axsome Therapeutics Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Biogen that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Bristol-Myers Squibb Company that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Eisai Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Shanghai Fosun Pharmaceutical Group Co Ltd that includes: consulting or advisory. Jeffrey Cummings reports a relationship with GAP Foundation that includes: consulting or advisory. Jeffrey Cummings reports a relationship with IGC that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Julius Clinical BV that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Kinoxis that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Lundbeck LLC that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Life Science Partner Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Merck Sharp & Dohme UK Ltd that includes: consulting or advisory. Jeffrey Cummings reports a relationship with MoCA Cognition that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Novo Nordisk Inc that includes: consulting or advisory. Jeffrey Cummings reports a relationship with NSC Therapeutics that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: consulting or advisory. Jeffrey Cummings reports a relationship with reMYND Nv that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Roche that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Scottish Brain Sciences that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Signant Health that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Simcere that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Sinaptica that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Jeffrey Cummings reports a relationship with Alzheimer's Drug Discovery Foundation that includes: funding grants. Jeffrey Cummings reports a relationship with Ted and Maria Quirk Endowment that includes: funding grants. Jeffrey Cummings reports a relationship with Joy-Chambers Grundy Endowment that includes: funding grants. Jeffrey Cummings reports a relationship with National Institute of General Medical Sciences that includes: funding grants. Jeffrey Cummings reports a relationship with National Institute on Aging that includes: funding grants. Jeffrey Cummings reports a relationship with National Institute of Neurological Disorders and Stroke that includes: funding grants. Philip Scheltens reports a relationship with EQT Life Sciences that includes: employment. Philip Scheltens reports a relationship with Novo Nordisk Inc that includes: consulting or advisory. Co-Chairs of the Steering Committee for the phase 3 trials evoke and evoke+ with Novo Nordisk - JC and PS. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/09/24 23:52 MHDA- 2026/09/24 23:52 PMCR- 2026/09/24 CRDT- 2026/09/24 18:50 PHST- 2026/06/09 00:00 [received] PHST- 2026/07/01 00:00 [revised] PHST- 2026/07/17 00:00 [accepted] PHST- 2026/09/24 23:52 [medline] PHST- 2026/09/24 23:52 [pubmed] PHST- 2026/09/24 18:50 [entrez] PHST- 2026/09/24 00:00 [pmc-release] AID - S2274-5807(26)00200-1 [pii] AID - 100677 [pii] AID - 10.1016/j.tjpad.2026.100677 [doi] PST - aheadofprint SO - J Prev Alzheimers Dis. 2026 Sep 24;13(10):100677. doi: 10.1016/j.tjpad.2026.100677. PMID- 42784708 OWN - NLM STAT- MEDLINE DCOM- 20260924 LR - 20260924 IS - 1028-768X (Print) IS - 1028-768X (Linking) VI - 35 IP - 3 DP - 2026 Jul 1 TI - The Intertwined Threat: How Diabetes Impacts Neurological Disorders - A Review Article. PG - 119-127 LID - 10.4103/ant.ANT-D-24-00046 [doi] AB - The chronic illness known as diabetes mellitus (DM) is typified by persistently high blood glucose levels or hyperglycemia. Both type 1 and type 2 diabetes, the latter of which is frequently referred to as "adult-onset diabetes" or "insulin-dependent diabetes," are progressing conditions with complex and poorly understood etiologies. Often, patients show positive pancreatic beta-cell antibodies, signifying an autoimmune factor. The long-term complications of uncontrolled diabetes are numerous, not just physically based and encompassing everything from kidney failure to foot ulcers and damage to the cardiovascular system, but also with serious neurological disorders, including stroke, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease (AD), and epilepsy. The interplay between neurological disorders and diabetes is complex, and the association of these pathological states in their general description proposes common events, namely oxidative stress, mitochondrial damage, amyloid protein aggregation, glucagon-like peptide-1 secretion skewing, and inflammation. Learning about these interconnections will help us to develop effective strategies for managing both diabetes and its neurological complications. CI - Copyright (c) 2026 Acta Neurologica Taiwanica. FAU - Rajput, Prajjwal AU - Rajput P AD - Department of Pharmacology, School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences and Technology, Baddi, Himachal Pradesh, India. FAU - Jakhar, Manju AU - Jakhar M AD - Department of Pharmacology, School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences and Technology, Baddi, Himachal Pradesh, India. FAU - Kashyap, Ashish AU - Kashyap A AD - Department of Pharmacology, Bhojia Institute of Dental Sciences, Nalagrah, Himachal Pradesh, India. FAU - Rani, Nidhi AU - Rani N AD - Chitkara College of Pharmacy, Chitkara University, Punjab, India. FAU - Singh, Thakur Gurjeet AU - Singh TG AD - Chitkara College of Pharmacy, Chitkara University, Punjab, India. LA - eng PT - Journal Article PT - Review DEP - 20260924 PL - India TA - Acta Neurol Taiwan JT - Acta neurologica Taiwanica JID - 9815355 SB - IM MH - Humans MH - *Nervous System Diseases/etiology MH - *Diabetes Complications MH - *Diabetes Mellitus MH - Oxidative Stress OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - diabetes mellitus OT - epilepsy OT - gestational diabetes OT - neurological disorders EDAT- 2026/09/24 23:52 MHDA- 2026/09/24 23:53 CRDT- 2026/09/24 18:36 PHST- 2024/10/23 00:00 [received] PHST- 2026/03/25 00:00 [accepted] PHST- 2026/09/24 23:53 [medline] PHST- 2026/09/24 23:52 [pubmed] PHST- 2026/09/24 18:36 [entrez] AID - 00127883-202607000-00001 [pii] AID - 10.4103/ant.ANT-D-24-00046 [doi] PST - ppublish SO - Acta Neurol Taiwan. 2026 Jul 1;35(3):119-127. doi: 10.4103/ant.ANT-D-24-00046. Epub 2026 Sep 24. PMID- 42769274 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260922 LR - 20260923 IS - 2352-8737 (Electronic) IS - 2352-8737 (Linking) VI - 12 IP - 3 DP - 2026 Jul-Sep TI - Dementia progression with GLP-1 receptor agonists in people with mild cognitive impairment and type 2 diabetes: target-trial emulation study. PG - e70315 LID - 10.1002/trc2.70315 [doi] LID - e70315 AB - INTRODUCTION: In people with type 2 diabetes (T2D) without dementia, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved cardiovascular, kidney, and mortality outcomes, with multiple real-world studies suggesting reduced risk of dementia onset. However, the EVOKE/EVOKE+ randomized-controlled trials (RCTs) found that oral semaglutide did not slow cognitive decline in individuals with early Alzheimer's disease (AD), most (86%) without T2D. It is unclear whether GLP-1 RA therapy influences progression to dementia in people with both T2D and mild cognitive impairment (MCI). METHODS: In a target-trial emulation hypothesis-generating study using TriNetX global collaborative network data, we compared incident dementia (including AD) in adults with MCI and T2D without dementia, who were new users of GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP4i). RESULTS: We included 1320 propensity-score-matched (1:1) individuals who initiated GLP-1 RAs or DPP4i in the period 2010 to 2021 (702 women; mean age 67.2 years). Over up to 5 years of follow-up, incident dementia occurred in 101 and 132 participants initiating GLP-1 RAs and DPP4i, respectively (Cox proportional hazard ratio 0.74 [95% confidence interval [CI]: 0.57 to 0.95]). At a mean follow-up of 3.9 years, the respective Kaplan-Meier-derived cumulative incidences were 15.5% and 20.4% (absolute difference -4.9% [95% CI -9.4 to -0.4], number needed to treat of 21 [11 to 234] individuals to prevent one event). Various sensitivity analyses supported the primary analysis: comparing GLP-1 RAs with basal insulin, using alternative outcome definitions, repeating the analyses across baseline subgroups, and using a negative control outcome. CONCLUSION: In this hypothesis-generating study, initiation of GLP-1 RAs versus DPP4i in people with T2D and MCI without dementia was associated with a lower risk of incident dementia. CI - (c) 2026 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Schechter, Meir AU - Schechter M AUID- ORCID: 0000-0002-5071-3143 AD - Diabetes Unit Department of Endocrinology and Metabolism Hadassah Medical Center Jerusalem Israel. AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. AD - Dina Recanati School of Medicine Reichman University Herzliya Israel. AD - The Gertner Institute for Epidemiology and Health Policy Research Sheba Medical Center Ramat Gan Israel. FAU - Sehtman-Shachar, Dvora R AU - Sehtman-Shachar DR AD - Diabetes Unit Department of Endocrinology and Metabolism Hadassah Medical Center Jerusalem Israel. AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. FAU - Fishkin, Alisa AU - Fishkin A AD - Diabetes Unit Department of Endocrinology and Metabolism Hadassah Medical Center Jerusalem Israel. AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. FAU - Mosenzon, Ofri AU - Mosenzon O AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. AD - Regeneron Pharmaceuticals Inc New York New York USA. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Division of Endocrinology Diabetes and Metabolism Sheba Medical Center Ramat Gan Israel. AD - Department of Epidemiology and Preventive Medicine School of Public Health Gray Faculty of Medical and Health Sciences Tel-Aviv University Tel Aviv Israel. FAU - Sharon, Ronit AU - Sharon R AD - Department of Biochemistry and Molecular Biology IMRIC The Hebrew University-Hadassah Medical School, Ein Kerem Jerusalem Israel. FAU - Leibowitz, Gil AU - Leibowitz G AD - Diabetes Unit Department of Endocrinology and Metabolism Hadassah Medical Center Jerusalem Israel. AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. FAU - Arkadir, David AU - Arkadir D AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. AD - Department of Neurology Hadassah Medical Center Jerusalem Israel. FAU - Aharon-Hananel, Genya AU - Aharon-Hananel G AD - Diabetes Unit Department of Endocrinology and Metabolism Hadassah Medical Center Jerusalem Israel. AD - Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel. LA - eng PT - Journal Article DEP - 20260920 PL - United States TA - Alzheimers Dement (N Y) JT - Alzheimer's & dementia (New York, N. Y.) JID - 101650118 PMC - PMC13590930 OTO - NOTNLM OT - TriNetX OT - dementia OT - glucagon-like peptide-1 receptor agonists OT - mild cognitive impairment OT - multinational cohort OT - real-world data OT - target-trial emulation OT - type 2 diabetes COIS- MS reports travel support from Novo Nordisk and AstraZeneca through Hadassah Medical Center and lecturing fees from AstraZeneca (2022). DRSS, AF, DA, and RS report no conflict of interest. OM reports advisory board membership for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and BOL Pharma, research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and speaker's bureau participation for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim (all before May 2023). Since May 1, 2023, OM has been an employee of Regeneron Pharmaceuticals Inc. Her contribution to this work was part of her ongoing academic role at the Hebrew University of Jerusalem, independent of that position. TCY reports receiving research support from Sanofi, MSD, Medtronic, Novo Nordisk, and Regeneron; honoraria for lectures from Sanofi, Lilly, Medtronic, Geffen Medical, AZ, BI, Novo Nordisk, Medison, Amgen; advisory board from Amgen, Abbott, Geffen Medical, and Novo Nordisk. GL reports participation in previous advisory boards: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Medtronic. He reports travel support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca through Hadassah Medical Center. Speaker's bureau: AstraZeneca, Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. GAH reported previous advisory board participation: Sanofi and Eli Lilly. She is a current PI in several RCTs conducted by Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, and Bayer, including the CONFIDENCE study, through Hadassah Medical Center. GAH reports travel support from Novo Nordisk and Medtronic through Hadassah Medical Center and AstraZeneca through Sheba Medical Center. Speaker's bureau: AstraZeneca, Novo Nordisk, Eli Lilly, and Sanofi.Author disclosures are available in the Supporting Information. EDAT- 2026/09/22 12:42 MHDA- 2026/09/22 12:43 PMCR- 2026/09/20 CRDT- 2026/09/22 05:29 PHST- 2026/02/15 00:00 [received] PHST- 2026/06/24 00:00 [revised] PHST- 2026/08/08 00:00 [accepted] PHST- 2026/09/22 12:43 [medline] PHST- 2026/09/22 12:42 [pubmed] PHST- 2026/09/22 05:29 [entrez] PHST- 2026/09/20 00:00 [pmc-release] AID - TRC270315 [pii] AID - 10.1002/trc2.70315 [doi] PST - epublish SO - Alzheimers Dement (N Y). 2026 Sep 20;12(3):e70315. doi: 10.1002/trc2.70315. eCollection 2026 Jul-Sep. PMID- 42768849 OWN - NLM STAT- Publisher LR - 20260922 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) DP - 2026 Sep 21 TI - Comparative Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Among Glucagon-Like Peptide-1 Receptor Agonists: An Integrated Safety and Mechanistic Analysis. LID - 10.1111/dom.71358 [doi] AB - AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for Type 2 diabetes (T2DM) and obesity, but emerging evidence links them to nonarteritic anterior ischemic optic neuropathy (NAION). Whether this risk differs across agents and the underlying mechanisms remains unclear. We aimed to compare the risks of NAION associated with different GLP-1RAs and to explore the potential molecular mechanisms underlying this adverse reaction. MATERIALS AND METHODS: A network meta-analysis was performed to quantitatively compare the differences in NAION risk. Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) were used for validation. Network toxicology was further applied to identify central hub targets and signalling pathways. Molecular docking was conducted to evaluate the binding capacity of GLP-1RAs to central hub targets. RESULTS: The network meta-analysis revealed significant differences in NAION risk across GLP-1RAs. Compared with non-GLP-1RA treatments, semaglutide showed the highest risk (HR = 1.538, 95% CI: 1.305-1.816), followed by liraglutide (HR = 1.251, 95% CI: 1.080-1.450). FAERS pharmacovigilance analysis suggested a strong disproportionate signal for semaglutide (ROR = 94.534, 95% CI: 83.093-107.552) and a statistically significant but weaker signal for liraglutide (ROR = 4.519, 95% CI: 2.617-7.802). Network toxicology identified CASP3 as the central hub target, and pathway enrichment analysis revealed that the underlying mechanisms were primarily related to Alzheimer's disease, neurodegeneration pathways, and lipid and atherosclerosis pathways. Molecular docking suggested that semaglutide and liraglutide had high binding affinity to CASP3. CONCLUSIONS: The combined strategy of network meta-analysis, pharmacovigilance, network toxicology and molecular docking provides insights into possible risk differences and potential mechanisms, and may guide future research on the safety profile of GLP-1RAs. CI - (c) 2026 John Wiley & Sons Ltd. FAU - Sun, Hong AU - Sun H AUID- ORCID: 0000-0001-9015-0480 AD - Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, China. FAU - Xin, Xiu AU - Xin X AD - Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, China. FAU - Yan, Jingchao AU - Yan J AD - Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, China. AD - Clinical Trial Institution, Eye & ENT Hospital, Fudan University, Shanghai, China. FAU - Huang, Taomin AU - Huang T AD - Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, China. LA - eng GR - Young Clinical Scientist Training Program at Shanghai Medical College of Fudan University/ PT - Journal Article DEP - 20260921 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 SB - IM OTO - NOTNLM OT - glucagon-like peptide-1 receptor agonist OT - network meta-analysis OT - network toxicology OT - nonarteritic anterior ischemic optic neuropathy OT - pharmacovigilance EDAT- 2026/09/22 05:37 MHDA- 2026/09/22 05:37 CRDT- 2026/09/22 02:45 PHST- 2026/08/27 00:00 [revised] PHST- 2026/07/05 00:00 [received] PHST- 2026/09/07 00:00 [accepted] PHST- 2026/09/22 05:37 [medline] PHST- 2026/09/22 05:37 [pubmed] PHST- 2026/09/22 02:45 [entrez] AID - 10.1111/dom.71358 [doi] PST - aheadofprint SO - Diabetes Obes Metab. 2026 Sep 21. doi: 10.1111/dom.71358. PMID- 42736531 OWN - NLM STAT- Publisher LR - 20260915 IS - 2520-8721 (Electronic) IS - 1109-3099 (Linking) DP - 2026 Sep 14 TI - Glucagon-like peptide-1 receptor agonists and cognitive function: beyond the metabolic effects. LID - 10.1007/s42000-026-00827-7 [doi] FAU - Polyzos, Stergios A AU - Polyzos SA AUID- ORCID: 0000-0001-9232-4042 AD - Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece. spolyzos@auth.gr. FAU - Doulberis, Michael AU - Doulberis M AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. AD - Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland. FAU - Zervogiannis, Nikolaos AU - Zervogiannis N AD - Sainsbury Wellcome Centre, University College of London (UCL), London, UK. FAU - Batakoias, Christos-Alexandros AU - Batakoias CA AD - Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece. FAU - Kountouras, Jannis AU - Kountouras J AD - Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Macedonia, Greece. LA - eng PT - Journal Article DEP - 20260914 PL - Switzerland TA - Hormones (Athens) JT - Hormones (Athens, Greece) JID - 101142469 SB - IM OTO - NOTNLM OT - Alzheimer's disease OT - Dementia OT - Glucagon-like peptide-1 receptor agonist OT - Metabolic dysfunction-associated steatotic liver disease OT - Obesity OT - Type 2 diabetes COIS- Declarations. Ethics approval: No institutional review board approval is required for commentaries. AI statement: No AI tool was used in this article. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. EDAT- 2026/09/15 05:36 MHDA- 2026/09/15 05:36 CRDT- 2026/09/15 02:51 PHST- 2026/07/22 00:00 [received] PHST- 2026/09/04 00:00 [accepted] PHST- 2026/09/15 05:36 [medline] PHST- 2026/09/15 05:36 [pubmed] PHST- 2026/09/15 02:51 [entrez] AID - 10.1007/s42000-026-00827-7 [pii] AID - 10.1007/s42000-026-00827-7 [doi] PST - aheadofprint SO - Hormones (Athens). 2026 Sep 14. doi: 10.1007/s42000-026-00827-7. PMID- 42695230 OWN - NLM STAT- Publisher LR - 20260904 IS - 1098-1128 (Electronic) IS - 0198-6325 (Linking) DP - 2026 Sep 4 TI - Glycolytic Reprogramming in Parkinson's Disease: From Bioenergetic Crosstalk to Therapeutic Modulation. LID - 10.1002/med.70103 [doi] AB - Parkinson's disease (PD) is increasingly recognized not merely as a localized proteinopathy, but as a systemic metabolic disorder driven by bioenergetic failure. While mitochondrial dysfunction is a well-established pathological hallmark, the compensatory reprogramming of glycolysis has emerged as a critical, yet double-edged, determinant of neuronal survival. This review critically examines the molecular and spatial architecture of glucose metabolism in the parkinsonian brain. We systematically dissect how upstream genetic regulators, including PTEN and PARK7/DJ-1, alongside downstream rate-limiting enzymes orchestrate the glycolytic shift in response to mitochondrial collapse and alpha-synuclein proteotoxicity. Moving beyond a neuron-centric view, we highlight cell-specific metabolic compartmentalization, emphasizing the disruption of the astrocyte-neuron lactate shuttle and the divergent glycolytic phenotypes of reactive microglia. Crucially, we evaluate the dual nature of glycolytic metabolites by demonstrating that a moderate flux sustains basal energy requirements and prevents apoptosis, whereas unchecked hyperglycolysis drives secondary pathological cascades through methylglyoxal-induced protein crosslinking and lactate-mediated neuroinflammation. By bridging these mechanistic insights with cross-disease metabolic links to type 2 diabetes and oncology, we evaluate the therapeutic potential of emerging metabolic modulators, including terazosin, cordycepin, and GLP-1 receptor agonists. Finally, we outline the pressing translational bottlenecks, particularly blood-brain barrier penetrance and cell-specific targeting, which must be overcome to successfully harness glycolytic modulation as a disease-modifying strategy for neurodegenerative disorders. CI - (c) 2026 Wiley Periodicals LLC. FAU - Yi, Ying AU - Yi Y AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Chen, Cen AU - Chen C AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - He, You AU - He Y AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Sun, Yu-Zhou AU - Sun YZ AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Cheng, Rui AU - Cheng R AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Liu, Ming-Xuan AU - Liu MX AUID- ORCID: 0000-0002-3797-8067 AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Liu, Zhao-Guo AU - Liu ZG AUID- ORCID: 0000-0001-6311-8338 AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. FAU - Zhang, Xiao-Ling AU - Zhang XL AUID- ORCID: 0000-0003-1157-0976 AD - College of Pharmacy, Nantong University, Nantong, People's Republic of China. LA - eng GR - 82104421/National Natural Science Foundation of China/ GR - JSTJ-2024-536/The Youth Science and Technology Talent Support Project of Jiangsu Province/ GR - 2022M721726/The China Postdoctoral Science Foundation/ GR - KFJN2668/The Large Instruments Open Foundation of Nantong University/ PT - Journal Article PT - Review DEP - 20260904 PL - United States TA - Med Res Rev JT - Medicinal research reviews JID - 8103150 SB - IM OTO - NOTNLM OT - Parkinson's disease OT - energy metabolism OT - glycolysis OT - glycolytic enzymes OT - neurodegenerative disease EDAT- 2026/09/04 17:40 MHDA- 2026/09/04 17:40 CRDT- 2026/09/04 11:20 PHST- 2026/08/05 00:00 [revised] PHST- 2026/06/01 00:00 [received] PHST- 2026/08/27 00:00 [accepted] PHST- 2026/09/04 17:40 [medline] PHST- 2026/09/04 17:40 [pubmed] PHST- 2026/09/04 11:20 [entrez] AID - 10.1002/med.70103 [doi] PST - aheadofprint SO - Med Res Rev. 2026 Sep 4. doi: 10.1002/med.70103. PMID- 42693696 OWN - NLM STAT- MEDLINE DCOM- 20260904 LR - 20260906 IS - 1742-7843 (Electronic) IS - 1742-7835 (Print) IS - 1742-7835 (Linking) VI - 139 IP - 4 DP - 2026 Oct TI - The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective. PG - e70294 LID - 10.1111/bcpt.70294 [doi] LID - e70294 AB - The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3beta (GSK-3beta) activity, promoting tau hyperphosphorylation and amyloid-beta (Abeta) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked beta-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways. CI - (c) 2026 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). FAU - Catakli, Deniz AU - Catakli D AUID- ORCID: 0000-0001-7327-5396 AD - Department of Medical Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey. FAU - Ozen-Basoglu, Ozlem AU - Ozen-Basoglu O AUID- ORCID: 0000-0003-1522-1271 AD - Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey. FAU - Tuncgovde, Ebru Busra AU - Tuncgovde EB AUID- ORCID: 0000-0002-0167-765X AD - Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir, Turkey. FAU - Ozsarlak-Sozer, Gonen AU - Ozsarlak-Sozer G AUID- ORCID: 0000-0001-7560-1976 AD - Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey. LA - eng PT - Journal Article PT - Review PL - England TA - Basic Clin Pharmacol Toxicol JT - Basic & clinical pharmacology & toxicology JID - 101208422 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications MH - Animals MH - Insulin Resistance MH - Signal Transduction/drug effects MH - Brain/metabolism/drug effects MH - Oxidative Stress MH - Amyloid beta-Peptides/metabolism MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Insulin/metabolism PMC - PMC13542629 OAB - Alzheimer's disease and type 2 diabetes are closely linked, leading scientists to call Alzheimer's 'type 3 diabetes.'. Both conditions share harmful mechanisms, including insulin resistance in the brain, chronic inflammation and cell energy failure. Normally, insulin helps the brain repair itself and maintain memory. However, when insulin signalling fails, toxic proteins build up, damaging nerve cells. Interestingly, common diabetes medications, such as GLP-1 agonists and SGLT-2 inhibitors, show promise in protecting the brain and improving memory by targeting these shared metabolic problems. OABL- eng OTO - NOTNLM OT - Alzheimer's disease OT - diabetes mellitus OT - insulin signalling OT - neuroinflammation OT - type 3 diabetes COIS- The authors declare no conflicts of interest. EDAT- 2026/09/04 05:35 MHDA- 2026/09/04 05:36 PMCR- 2026/09/04 CRDT- 2026/09/04 02:23 PHST- 2026/07/24 00:00 [revised] PHST- 2025/08/27 00:00 [received] PHST- 2026/08/14 00:00 [accepted] PHST- 2026/09/04 05:36 [medline] PHST- 2026/09/04 05:35 [pubmed] PHST- 2026/09/04 02:23 [entrez] PHST- 2026/09/04 00:00 [pmc-release] AID - BCPT70294 [pii] AID - 10.1111/bcpt.70294 [doi] PST - ppublish SO - Basic Clin Pharmacol Toxicol. 2026 Oct;139(4):e70294. doi: 10.1111/bcpt.70294. PMID- 42688951 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260919 LR - 20260919 IS - 2475-0360 (Electronic) IS - 2475-0360 (Linking) VI - 9 IP - 4 DP - 2026 Aug TI - Shared Metabolic-Proteinopathy Axis in Alzheimer's Disease and Parkinson's Disease: Evidence for a Convergent but Not Identical Disease Spectrum. PG - 426-437 LID - 10.1002/agm2.70099 [doi] AB - Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders globally and have long been classified as clinically and pathologically distinct syndromes. AD is defined by amyloid-beta (Abeta) plaques and tau-positive neurofibrillary tangles, whereas PD is characterized by alpha-synuclein aggregation and progressive degeneration of nigrostriatal dopaminergic neurons. However, mounting evidence has blurred the traditional boundaries between these disorders, revealing extensive overlaps in pathogenic cascades, clinical phenotypes, and epidemiological risk factors. In this review, we propose an integrated mechanistic framework in which AD and PD represent distinct yet partially overlapping disorders along a convergent neurodegenerative spectrum, unified by a core metabolic-proteinopathy axis. We highlight cerebral insulin resistance and impaired brain glucose metabolism as pivotal upstream triggers that initiate a cascade of pathological events, including mitochondrial dysfunction, energy depletion, oxidative stress, chronic neuroinflammation, and disrupted proteostasis. These disturbances collectively drive aberrant folding and aggregation of Abeta, tau, and alpha-synuclein, establishing a mechanistic link between systemic metabolic dysregulation and region-selective neuronal vulnerability. We synthesize evidence from molecular studies, preclinical models, clinicopathological analyses, neuroimaging, and longitudinal epidemiological surveys to delineate the extent and limitations of mechanistic convergence. We also emphasize consistent divergences between AD and PD, including distinct patterns of neuroanatomical involvement, dominant clinical presentations, pathological propagation trajectories, and genetic architectures. Epidemiological data confirm that Type 2 diabetes and insulin resistance are associated with elevated risk of both AD and PD. Moreover, antidiabetic agents such as GLP-1 receptor agonists exhibit convergent neuroprotective efficacy in preclinical and early clinical investigations, supporting metabolic modulation as a promising cross-disease therapeutic strategy. Despite shared downstream pathways and therapeutic targets, AD and PD retain unique pathological signatures and clinical progression patterns. This review provides a balanced, evidence-based interpretation of the AD-PD relationship, highlighting partial pathogenic convergence driven by metabolic dysfunction while affirming their identities as distinct disorders. The proposed metabolic-proteinopathy framework advances mechanistic understanding and informs the development of novel disease-modifying therapies targeting shared upstream pathways. CI - (c) 2026 The Author(s). Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd. FAU - Yao, Shun-Yu AU - Yao SY AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. FAU - Du, Miao-Qiao AU - Du MQ AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. FAU - Lin, Lan-Xin AU - Lin LX AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. FAU - Kang, Xu-Hui AU - Kang XH AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. FAU - Jiang, Dai-Yi AU - Jiang DY AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. FAU - Peng, Yong AU - Peng Y AUID- ORCID: 0000-0001-8390-7668 AD - Department of Neurology Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine Zhuzhou Hunan China. AD - Department of Neurology Affiliated First Hospital of Hunan Traditional Chinese Medical College (Hunan Provincial Directly Affiliated Hospital of Traditional Chinese Medicine) Zhuzhou Hunan China. LA - eng PT - Journal Article PT - Review DEP - 20260902 PL - Australia TA - Aging Med (Milton) JT - Aging medicine (Milton (N.S.W)) JID - 101741954 PMC - PMC13535938 OTO - NOTNLM OT - Alzheimer disease OT - Parkinson disease OT - glucose metabolism OT - insulin resistance OT - neuroinflammation COIS- The authors declare no conflicts of interest. EDAT- 2026/09/03 12:09 MHDA- 2026/09/03 12:10 PMCR- 2026/09/02 CRDT- 2026/09/03 10:22 PHST- 2025/12/14 00:00 [received] PHST- 2026/04/29 00:00 [revised] PHST- 2026/08/05 00:00 [accepted] PHST- 2026/09/03 12:10 [medline] PHST- 2026/09/03 12:09 [pubmed] PHST- 2026/09/03 10:22 [entrez] PHST- 2026/09/02 00:00 [pmc-release] AID - AGM270099 [pii] AID - 10.1002/agm2.70099 [doi] PST - epublish SO - Aging Med (Milton). 2026 Sep 2;9(4):426-437. doi: 10.1002/agm2.70099. eCollection 2026 Aug. PMID- 42661791 OWN - NLM STAT- MEDLINE DCOM- 20260828 LR - 20260902 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 17 DP - 2026 TI - Glucagon-like peptide-1 receptor agonists and the risk of Parkinson's disease in patients with type 2 diabetes: a systematic review and meta-analysis of large-scale real-world data. PG - 1849318 LID - 10.3389/fendo.2026.1849318 [doi] LID - 1849318 AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet effective disease-modifying therapies remain elusive. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes mellitus (T2DM), have shown neuroprotective potential in preclinical studies. However, real-world evidence on the association between GLP-1RAs use and PD risk remains inconsistent and has not been systematically synthesized. This systematic review and meta-analysis aimed to evaluate this association using large-scale real-world data. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science from database inception to March 18, 2026, for cohort and case-control studies exploring the association between GLP-1RA exposure and PD risk among patients with T2DM. Study selection, data extraction, and methodological quality assessment were independently conducted by two reviewers. All meta-analyses were performed using Stata 15.0 software. RESULTS: A total of six studies were included, involving 452,763 participants. The meta-analysis revealed that GLP-1RA exposure was significantly associated with a reduced risk of PD in patients with T2DM (HR = 0.68, 95%CI (0.54,0.85), P = 0.001). Subgroup analyses demonstrated that compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, and other hypoglycemic drugs, GLP-1RAs were linked to a lower risk of incident PD (DPP-4 inhibitors: HR = 0.60, 95%CI (0.43,0.83), P = 0.001; Metformin: HR = 0.83, 95%CI (0.73,0.95), P = 0.006; Other: HR = 0.73, 95%CI (0.60,0.87), P = 0.002). CONCLUSIONS: This meta-analysis based on large-scale real-world data indicates that GLP-1RA exposure is associated with a lower risk of PD in patients with T2DM, with robust and consistent results across diverse comparator groups. These findings support the hypothesis that GLP-1RAs may confer neuroprotective properties, a finding that merits further rigorous investigation. Nevertheless, given the inherent limitations inherent to observational study designs and the possibility of residual confounding in the included studies, the present results should be regarded as preliminary and hypothesis-generating rather than conclusive. Future large-scale prospective cohort studies with standardized methodologies, as well as well-designed randomized controlled trials, are warranted to validate these findings and clarify whether the observed inverse association reflects a causal neuroprotective effect of GLP-1RAs. CI - Copyright (c) 2026 Chen, Wang, Wang and Ma. FAU - Chen, Ying AU - Chen Y AD - Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China. FAU - Wang, Xueping AU - Wang X AD - Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China. FAU - Wang, Jingjuan AU - Wang J AD - Department of Neurology, Daping Hospital, Army Medical University, Chongqing, China. FAU - Ma, Gaiping AU - Ma G AD - Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, China. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20260813 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Parkinson Disease/epidemiology/etiology/prevention & control MH - *Hypoglycemic Agents/therapeutic use PMC - PMC13518207 OTO - NOTNLM OT - Parkinson's disease OT - glucagon-like peptide-1 receptor agonists OT - meta-analysis OT - real world study OT - systematic review COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/08/28 11:50 MHDA- 2026/08/28 11:51 PMCR- 2026/08/13 CRDT- 2026/08/28 05:16 PHST- 2026/04/07 00:00 [received] PHST- 2026/06/28 00:00 [revised] PHST- 2026/07/02 00:00 [accepted] PHST- 2026/08/28 11:51 [medline] PHST- 2026/08/28 11:50 [pubmed] PHST- 2026/08/28 05:16 [entrez] PHST- 2026/08/13 00:00 [pmc-release] AID - 10.3389/fendo.2026.1849318 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2026 Aug 13;17:1849318. doi: 10.3389/fendo.2026.1849318. eCollection 2026. PMID- 42653006 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260827 LR - 20260829 IS - 2075-1729 (Print) IS - 2075-1729 (Electronic) IS - 2075-1729 (Linking) VI - 16 IP - 8 DP - 2026 Aug 12 TI - Semaglutide Attenuates Type 2 Diabetes-Induced Neurotoxicity by Modulating Neuroinflammation, Oxidative Stress, and Neuroapoptosis. LID - 10.3390/life16081317 [doi] LID - 1317 AB - Type 2 diabetes mellitus (T2DM) is a widely distributed dysmetabolic condition increasingly linked to neurocognitive decline, neuroinflammation, oxidative stress, and neuronal apoptosis. Chronic hyperglycemia and insulin resistance disrupt homeostasis in the central nervous system, contributing to neurodegenerative processes. This study evaluated the effects of semaglutide (SMG), a glucagon-like peptide-1 receptor agonist, on T2DM-associated neurobehavioral and biochemical alterations using a rat model. T2DM was induced by nicotinamide-streptozotocin, followed by oral administration of SMG at a dose of 1.44 mg/kg for one month. Cognitive function was evaluated using the elevated plus maze (EPM) and novel object recognition (NOR) paradigms. Fasting blood glucose and body weight were monitored throughout the experiment. Neuroinflammatory markers (COX-2, TNF-alpha, and IL-6), oxidative stress biomarkers (MDA, GSH, and catalase), and apoptosis-associated proteins (Caspase-3, Bax, and Bcl-2) were measured in brain tissue homogenates using ELISA. Diabetic rats exhibited marked cognitive deficits, hyperglycemia, increased neuroinflammatory markers, and altered apoptosis-related biomarkers, with reduced Bcl-2 expression. Treatment with SMG significantly improved learning and memory performance, fasting blood glucose, and body weight. At the molecular level, SMG treatment was associated with lower levels of MDA, TNF-alpha, Bax, IL-6, COX-2, and Caspase-3, together with higher levels of Bcl-2, catalase, and GSH compared with untreated diabetic rats. Overall, oral SMG treatment was associated with improved cognitive performance and metabolic control, accompanied by attenuation of diabetes-associated neuroinflammatory, oxidative stress, and apoptosis-related alterations in brain tissue. However, the present study was not designed to distinguish direct neuroprotective effects from changes secondary to improved metabolic control. Further studies are required to clarify the underlying mechanisms and determine the translational relevance of these findings. FAU - Alharbi, Abdulellah Saad AU - Alharbi AS AD - Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia. FAU - Alshammari, Abdulaziz Arif A AU - Alshammari AAA AUID- ORCID: 0000-0002-4502-3797 AD - Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia. FAU - Alwesmi, Mai B AU - Alwesmi MB AD - Department of Medical-Surgical Nursing, College of Nursing, Princess Nourah bint Abdulrahman University, Riyadh 11564, Saudi Arabia. FAU - Mani, Vasudevan AU - Mani V AUID- ORCID: 0000-0002-8440-8366 AD - Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia. LA - eng GR - PNURSP2026R445/Princess Nourah bint Abdulrahman University/ PT - Journal Article DEP - 20260812 PL - Switzerland TA - Life (Basel) JT - Life (Basel, Switzerland) JID - 101580444 PMC - PMC13514282 OTO - NOTNLM OT - diabetes mellitus OT - neuroapoptosis OT - neuroinflammation OT - oxidative stress OT - semaglutide COIS- The authors declare no conflicts of interest. EDAT- 2026/08/27 05:35 MHDA- 2026/08/27 05:36 PMCR- 2026/08/12 CRDT- 2026/08/27 01:07 PHST- 2026/07/12 00:00 [received] PHST- 2026/08/09 00:00 [revised] PHST- 2026/08/09 00:00 [accepted] PHST- 2026/08/27 05:36 [medline] PHST- 2026/08/27 05:35 [pubmed] PHST- 2026/08/27 01:07 [entrez] PHST- 2026/08/12 00:00 [pmc-release] AID - life16081317 [pii] AID - life-16-01317 [pii] AID - 10.3390/life16081317 [doi] PST - epublish SO - Life (Basel). 2026 Aug 12;16(8):1317. doi: 10.3390/life16081317. PMID- 42648513 OWN - NLM STAT- MEDLINE DCOM- 20260911 LR - 20260911 IS - 1873-7528 (Electronic) IS - 0149-7634 (Linking) VI - 190 DP - 2026 Nov TI - Title: Gene expression, neuroinflammation, and neural plasticity in type 2 diabetes: Translational insights from exercise and cognitive modulation. PG - 106922 LID - S0149-7634(26)00379-9 [pii] LID - 10.1016/j.neubiorev.2026.106922 [doi] AB - Type 2 diabetes mellitus (T2DM) increases vulnerability to cognitive decline through interacting disturbances in insulin signaling, mitochondrial energetics, redox and lipid homeostasis, neuroimmune regulation, neurovascular coupling, and experience-dependent plasticity. This review integrates molecular, cellular, preclinical, and clinical evidence linking these processes to altered gene expression, glial dysfunction, synaptic instability, and impaired cognition. We distinguish well-supported mechanisms from unresolved questions concerning causality, cell-type specificity, human hippocampal remodeling, context-dependent pharmacological effects, and the translational limitations of experimental models. On this basis, we propose an integrative framework in which metabolic flexibility acts as a permissive gatekeeper for neural adaptation. AMPK-centered signaling supports mitochondrial quality control, autophagy, antioxidant defenses, and restraint of NF-kB/NLRP3-associated inflammation, but is considered necessary rather than sufficient for cognitive recovery. Durable plasticity additionally requires activity-dependent CREB-BDNF signaling and adequate neurovascular support to match energy delivery with circuit demand. Exercise, cognitive training, environmental enrichment, metformin, and incretin-based therapies engage complementary components of this network, although their efficacy is likely to vary with age, metabolic state, inflammatory burden, vascular reserve, treatment timing, and adherence. The framework predicts that metabolic activation without circuit engagement will provide limited cognitive benefit, whereas plasticity-promoting interventions will be constrained by persistent metabolic or vascular dysfunction. We therefore argue for multimodal, biomarker-informed strategies that integrate metabolic stabilization, vascular support, and structured physical and cognitive stimulation. Long-term randomized studies combining neuroimaging with molecular and metabolic profiling are required to test these predictions and define precision approaches for preserving cognitive resilience in T2DM. CI - Copyright (c) 2026 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Diniz, Cristovam Guerreiro AU - Diniz CG AD - Instituto Federal de Educacao Ciencia e Tecnologia do Para, Laboratorio de Biologia Molecular e Neuroecologia, Braganca, Para, Brazil. FAU - Bento-Torres, Natali Valim Oliver AU - Bento-Torres NVO AD - Universidade Federal do Para, Instituto de Ciencias da Saude, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil. FAU - da Costa, Emanuel Ramos AU - da Costa ER AD - Instituto Federal de Educacao Ciencia e Tecnologia do Para, Laboratorio de Biologia Molecular e Neuroecologia, Braganca, Para, Brazil. FAU - Morais Magalhaes, Nara Gyzely de AU - Morais Magalhaes NG AD - Instituto Federal de Educacao Ciencia e Tecnologia do Para, Laboratorio de Biologia Molecular e Neuroecologia, Braganca, Para, Brazil. FAU - Melo, Mauro Andre Damasceno de AU - Melo MAD AD - Instituto Federal de Educacao Ciencia e Tecnologia do Para, Laboratorio de Biologia Molecular e Neuroecologia, Braganca, Para, Brazil. FAU - Pereira, Patrick Douglas Correa AU - Pereira PDC AD - Instituto Federal de Educacao Ciencia e Tecnologia do Para, Laboratorio de Biologia Molecular e Neuroecologia, Braganca, Para, Brazil. FAU - Carvalho, Josilayne Patricia Ramos AU - Carvalho JPR AD - Universidade Federal do Para, Instituto de Ciencias Biologicas, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil. FAU - Magno, Gabriel Mileo AU - Magno GM AD - Hospital Jean Bitar, Preceptoria do Programa de Residencia Medica em Endocrinologia Belem, Para, Brazil. FAU - Bento-Torres, Joao AU - Bento-Torres J AD - Universidade Federal do Para, Instituto de Ciencias Biologicas, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil. FAU - Sosthenes, Marcia Consentino Kronka AU - Sosthenes MCK AD - Universidade Federal do Para, Instituto de Ciencias Biologicas, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil. FAU - Diniz, Daniel Guerreiro AU - Diniz DG AD - Universidade Federal do Para, Instituto de Ciencias Biologicas, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil; Instituto Evandro Chagas, Secao de Hepatologia, Laboratorio de Microscopia Eletronica, Belem, Para, Brazil; Universidade Federal do Para, Nucleo de Pesquisas em Oncologia, HUJBB, Belem, Para, Brazil; Instituto Tecnologico Vale - Desenvolvimento Sustentavel, Belem, Para, Brazil. FAU - Anthony, Daniel Clive AU - Anthony DC AD - University of Oxford, Department of Pharmacology, Laboratory of Experimental Neuropathology, Oxford, UK. FAU - Brites, Dora AU - Brites D AD - Universidade de Lisboa, Faculdade de Farmacia, Research Institute for Medicines (iMed. ULisboa), Lisboa, Portugal; Departamento de Ciencias Farmaceuticas e do Medicamento, Universidade de Lisboa, Lisbon, Portugal. FAU - Picanco Diniz, Cristovam Wanderley AU - Picanco Diniz CW AD - Universidade Federal do Para, Instituto de Ciencias Biologicas, Hospital Universitario Joao de Barros Barreto, Laboratorio de Investigacoes em Neurodegeneracao e Infeccao, Belem, Para, Brazil. Electronic address: cwpdiniz@ufpa.br. LA - eng PT - Journal Article PT - Review DEP - 20260826 PL - United States TA - Neurosci Biobehav Rev JT - Neuroscience and biobehavioral reviews JID - 7806090 SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/metabolism/complications/physiopathology/genetics/therapy MH - *Neuronal Plasticity/physiology MH - *Neuroinflammatory Diseases/metabolism/physiopathology/etiology/genetics MH - Animals MH - *Exercise/physiology MH - *Gene Expression/physiology MH - *Cognitive Dysfunction/etiology/metabolism/physiopathology/therapy MH - Cognitive Enhancement MH - Cognitive Training MH - Cognition/physiology OTO - NOTNLM OT - AMPK OT - BDNF OT - Cognitive training OT - Exercise OT - Neuroinflammation OT - Neurovascular coupling OT - Precision medicine OT - Type 2 diabetes COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/08/26 23:35 MHDA- 2026/09/11 23:36 CRDT- 2026/08/26 19:13 PHST- 2026/02/18 00:00 [received] PHST- 2026/08/05 00:00 [revised] PHST- 2026/08/21 00:00 [accepted] PHST- 2026/09/11 23:36 [medline] PHST- 2026/08/26 23:35 [pubmed] PHST- 2026/08/26 19:13 [entrez] AID - S0149-7634(26)00379-9 [pii] AID - 10.1016/j.neubiorev.2026.106922 [doi] PST - ppublish SO - Neurosci Biobehav Rev. 2026 Nov;190:106922. doi: 10.1016/j.neubiorev.2026.106922. Epub 2026 Aug 26. PMID- 42636218 OWN - NLM STAT- MEDLINE DCOM- 20260824 LR - 20260826 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 21 IP - 8 DP - 2026 TI - Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study. PG - e0356138 LID - 10.1371/journal.pone.0356138 [doi] LID - e0356138 AB - OBJECTIVE: To evaluate the associations between commonly used antidiabetic regimens and incidence of mild cognitive disorder, Alzheimer disease, and vascular dementia in adults with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used the TriNetX US Collaborative Network of electronic health records from 2010 to 2024. Adults aged 40-69 years with type 2 diabetes and at least 1 year of follow-up were included. Propensity score matching was applied to balance covariates. EXPOSURE: Patients were classified into 5 treatment groups: metformin only (reference), metformin plus DPP-4 inhibitors, metformin plus GLP-1 receptor agonists, metformin plus SGLT-2 inhibitors, and insulin monotherapy. Exposure was defined by first recorded prescription and continued use during follow-up. MAIN OUTCOMES AND MEASURES: Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia, identified using ICD-10 codes. Hazard ratios with 95% confidence intervals were estimated from Cox proportional hazards models, with landmark analyses for follow-up shorter and longer than 5 years. RESULTS: Among 1,528,885 adults with type 2 diabetes (mean age, 58 years; 49.2% women), GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (HR, 0.46; 95% CI, 0.37-0.57), mild cognitive disorder (HR, 0.79; 95% CI, 0.66-0.95), and Alzheimer disease (HR, 0.46; 95% CI, 0.31-0.70). SGLT-2 inhibitors plus metformin reduced vascular dementia risk (HR, 0.68; 95% CI, 0.54-0.87) but not other outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27; 95% CI, 3.03-3.52), mild cognitive disorder (HR, 1.71; 95% CI, 1.56-1.87), and Alzheimer disease (HR, 1.56; 95% CI, 1.32-1.84). CONCLUSIONS AND RELEVANCE: GLP-1 receptor agonists and SGLT-2 inhibitors combined with metformin were associated with reduced risk of cognitive decline. Insulin monotherapy was associated with higher incidence of all three outcomes; however, this association is likely influenced by confounding by indication, unmeasured markers of diabetes severity (including diabetes duration, cardiovascular and renal disease severity, and microvascular and macrovascular complications), and shorter follow-up among insulin users, and should not be interpreted as a direct drug effect. Because standard Cox models do not account for death as a competing event, reported hazard ratios reflect cause-specific hazards and may not directly correspond to cumulative incidence, particularly for the insulin group, in which mortality and censoring were substantially higher. Antidiabetic medication choice may influence long-term cognitive outcomes and should be considered in diabetes management. CI - Copyright: (c) 2026 Nasir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. FAU - Nasir, Ahmad Basil AU - Nasir AB AUID- ORCID: 0000-0003-1588-303X AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Kilani, Yassine AU - Kilani Y AD - Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Aldiabat, Mohammad AU - Aldiabat M AD - Department of Internal Medicine, Washington University, Saint Louis, Missouri, United States of America. FAU - Abdelghany, Omar AU - Abdelghany O AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Hafez, Youssef AU - Hafez Y AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Desai, Nitin AU - Desai N AD - Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Madi, Mahmoud Y AU - Madi MY AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Wade, Francis G AU - Wade FG AD - Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Qureshi, Kamran AU - Qureshi K AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Frey, Lewis J AU - Frey LJ AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. AD - Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. AD - VA St. Louis Healthcare System, St. Louis, Missouri, United States of America. FAU - Farmer, Adam D AU - Farmer AD AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. AD - Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. FAU - Syn, Wing-Kin AU - Syn WK AUID- ORCID: 0000-0001-7966-0500 AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. AD - Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. AD - Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Vizcaya, Spain. LA - eng PT - Journal Article DEP - 20260824 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Insulin) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Female MH - Retrospective Studies MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Metformin/therapeutic use/adverse effects MH - Middle Aged MH - Male MH - Aged MH - Insulin/therapeutic use/adverse effects MH - Adult MH - *Cognitive Dysfunction/epidemiology/chemically induced MH - Alzheimer Disease/epidemiology MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - Incidence MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - *Cognition Disorders/epidemiology MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Dementia, Vascular/epidemiology PMC - PMC13502699 COIS- The authors have declared that no competing interests exist. EDAT- 2026/08/24 18:42 MHDA- 2026/08/24 18:43 PMCR- 2026/08/24 CRDT- 2026/08/24 13:34 PHST- 2025/11/10 00:00 [received] PHST- 2026/07/30 00:00 [accepted] PHST- 2026/08/24 18:43 [medline] PHST- 2026/08/24 18:42 [pubmed] PHST- 2026/08/24 13:34 [entrez] PHST- 2026/08/24 00:00 [pmc-release] AID - PONE-D-25-60647 [pii] AID - 10.1371/journal.pone.0356138 [doi] PST - epublish SO - PLoS One. 2026 Aug 24;21(8):e0356138. doi: 10.1371/journal.pone.0356138. eCollection 2026. PMID- 42632459 OWN - NLM STAT- MEDLINE DCOM- 20260907 LR - 20260907 IS - 1872-8227 (Electronic) IS - 0168-8227 (Linking) VI - 240 DP - 2026 Oct TI - BMI trajectories and their relation to medication, comorbidities, and healthcare service use among people with type 2 diabetes mellitus. PG - 113515 LID - S0168-8227(26)00435-3 [pii] LID - 10.1016/j.diabres.2026.113515 [doi] AB - AIMS: To identify BMI trajectories after type 2 diabetes (T2D) diagnosis and examine associations with laboratory measures, medication use, comorbidities, and healthcare utilization. METHODS: We analyzed BMI trajectories in 3,539 adults with T2D in North Karelia (2011-2014) and followed until 2024. BMI trajectory classes were estimated using growth mixture modeling. Regression models were used to assess differences in measurement activity, treatment intensity and diabetes medication use between the classes. RESULTS: Three BMI trajectories were identified: stable (77.7 %), increasing (14.6 %), and decreasing (7.7 %). HbA1c and LDL cholesterol measurement activity was lowest in the decreasing class. Use of glucagon-like peptide-1 agonists varied over time, peaking in the decreasing class in 2015 and in the increasing class in 2024. Comorbidities increased in all classes but differed in pattern: the increasing class accumulated more chronic kidney and urinary tract diseases, obesity related diagnoses, sleep disorders, and chronic lower respiratory diseases, whereas the decreasing class had higher prevalence of dementia and cardiovascular and pulmonary diseases. Healthcare utilization was highest in the decreasing class. CONCLUSIONS: These findings reveal considerable heterogeneity in long-term outcomes among people with T2D and highlight the need for continuous monitoring and targeted support to maintain metabolic control and manage comorbidity burden. CI - Copyright (c) 2026 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Koivunen, Suvi AU - Koivunen S AD - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland. Electronic address: suvi.koivunen@uef.fi. FAU - Lamidi, Marja-Leena AU - Lamidi ML AD - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland. FAU - Wang, Zhiting AU - Wang Z AD - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. FAU - Lavikainen, Piia AU - Lavikainen P AD - School of Pharmacy, University of Eastern Finland, Kuopio, Finland. FAU - Wikstrom, Katja AU - Wikstrom K AD - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland. FAU - Storvik, Suchetana De AU - Storvik S AD - Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland; School of Pharmacy, University of Eastern Finland, Kuopio, Finland. FAU - Kivinen, Petri AU - Kivinen P AD - Wellbeing Services County of Central Finland, Jyvaskyla, Finland. FAU - Rautiainen, Paivi AU - Rautiainen P AD - Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland. FAU - Laatikainen, Tiina AU - Laatikainen T AD - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Wellbeing Services County of North Karelia (Siun Sote), Joensuu, Finland. LA - eng PT - Journal Article DEP - 20260822 PL - Ireland TA - Diabetes Res Clin Pract JT - Diabetes research and clinical practice JID - 8508335 RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - Comorbidity MH - Female MH - *Body Mass Index MH - Male MH - Middle Aged MH - *Patient Acceptance of Health Care/statistics & numerical data MH - Aged MH - *Obesity/epidemiology MH - *Hypoglycemic Agents/therapeutic use MH - Glycated Hemoglobin/analysis/metabolism OTO - NOTNLM OT - BMI trajectory OT - Electronic health records OT - Health care utilization OT - Type 2 diabetes mellitus OT - Weight management COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/08/22 23:43 MHDA- 2026/09/07 23:34 CRDT- 2026/08/22 19:11 PHST- 2026/06/11 00:00 [received] PHST- 2026/08/20 00:00 [revised] PHST- 2026/08/20 00:00 [accepted] PHST- 2026/09/07 23:34 [medline] PHST- 2026/08/22 23:43 [pubmed] PHST- 2026/08/22 19:11 [entrez] AID - S0168-8227(26)00435-3 [pii] AID - 10.1016/j.diabres.2026.113515 [doi] PST - ppublish SO - Diabetes Res Clin Pract. 2026 Oct;240:113515. doi: 10.1016/j.diabres.2026.113515. Epub 2026 Aug 22. PMID- 42631802 OWN - NLM STAT- Publisher LR - 20260822 IS - 1865-8652 (Electronic) IS - 0741-238X (Linking) DP - 2026 Aug 22 TI - Glucose-Lowering Therapies and Cognitive Decline: From Molecular Mechanisms to Clinical Evidence and Future Perspectives. LID - 10.1007/s12325-026-03760-8 [doi] AB - Several lines of evidence suggest the relationship between diabetes and cognitive decline. Patients with a diagnosis of type 2 diabetes (T2D) present an increased risk of Alzheimer's disease (AD) development than the general population, and it is known that brain insulin resistance (IR) plays a key role in the conversion from mild cognitive impairment (MCI) into AD. During recent years, emerging therapeutic perspectives have been proposed with the aim of targeting T2D-related cognitive impairment, and glucose-lowering drug classes, especially glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium glucose cotransporter inhibitors (SGLT2is), demonstrated neuroprotective effects and a positive effects on cognitive function acting by several molecular mechanisms including anti-inflammatory activity, modulation of insulin signaling, and promoting the neurogenesis process. Different clinical trials showed their ability in preventing neurodegenerative decline, with numerous phase II and III trials underway in populations with AD; however, although preclinical evidence is promising and some clinical data are encouraging, translating these results into established therapeutic strategies requires larger, randomized, and controlled clinical trials with extended follow-up period, standardized cognitive assessments, and inclusion of molecular and imaging biomarkers. Addressing these gaps will be essential to determine whether glucose-lowering drug classes can be introduced into clinical practice to prevent or slow cognitive decline in patients with T2D, exerting neuroprotective activity beyond their effect on glycemic control. CI - (c) 2026. The Author(s). FAU - Grasso, Margherita AU - Grasso M AD - Oasi Research Institute-IRCCS, Troina, Italy. FAU - Maggio, Viviana AU - Maggio V AUID- ORCID: 0009-0006-2211-8482 AD - School of Medicine, Department of Health Promotion, Mother and Childcare, Internal Medicine and Medical Specialties, University of Palermo, 90127, Palermo, Italy. viviana.maggio01@unipa.it. FAU - Caraci, Filippo AU - Caraci F AD - Oasi Research Institute-IRCCS, Troina, Italy. AD - Department of Drug and Health Sciences, University of Catania, Catania, Italy. FAU - Rizzo, Manfredi AU - Rizzo M AD - School of Medicine, Department of Health Promotion, Mother and Childcare, Internal Medicine and Medical Specialties, University of Palermo, 90127, Palermo, Italy. AD - College of Medicine, Ras Al Khaimah Medical and Health Sciences University, 11172, Ras Al Khaimah, United Arab Emirates. LA - eng PT - Journal Article PT - Review DEP - 20260822 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 SB - IM OTO - NOTNLM OT - Antidiabetic drugs OT - Brain insulin resistance OT - Cognitive decline OT - Diabetes OT - Neuroprotection COIS- Declarations. Conflict of Interest: Margherita Grasso, Viviana Maggio, and Filippo Caraci declare that they have no conflicts of interest. Manfredi Rizzo is an Editorial Board member of Advances in Therapy. Manfredi Rizzo was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics/Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. EDAT- 2026/08/22 22:41 MHDA- 2026/08/22 22:41 CRDT- 2026/08/22 11:07 PHST- 2026/04/22 00:00 [received] PHST- 2026/07/15 00:00 [accepted] PHST- 2026/08/22 22:41 [medline] PHST- 2026/08/22 22:41 [pubmed] PHST- 2026/08/22 11:07 [entrez] AID - 10.1007/s12325-026-03760-8 [pii] AID - 10.1007/s12325-026-03760-8 [doi] PST - aheadofprint SO - Adv Ther. 2026 Aug 22. doi: 10.1007/s12325-026-03760-8. PMID- 42629262 OWN - NLM STAT- Publisher LR - 20260821 IS - 1879-0828 (Electronic) IS - 0953-6205 (Linking) DP - 2026 Aug 21 TI - Comparative risks of dementia and Parkinson's disease with GLP-1 RAs versus other oral glucose-lowering medications in obese patients with type 2 diabetes: a large real-world cohort study. PG - 107164 LID - S0953-6205(26)00469-3 [pii] LID - 10.1016/j.ejim.2026.107164 [doi] AB - OBJECTIVE: This study evaluates dementia and Parkinson's disease (PD) risk among patients with type 2 diabetes (T2D) and obesity initiating GLP-1 receptor agonists (GLP-1 RAs) compared with other oral glucose-lowering medications, addressing the unclear comparative neurocognitive effects despite GLP-1 RAs' neuroprotective potential in preclinical studies. RESEARCH DESIGN AND METHODS: This historical prospective cohort study used electronic health records from Clalit Health Services. Adults with T2D and obesity (body mass index [BMI] >/=30 kg/m(2)) initiating non-insulin glucose-lowering medications between 2008-2021 were included. After exclusions and 1:1 nearest-neighbor matching, the final cohort comprised 46,962 patients. Associations were assessed using Cox proportional hazards models. RESULTS: Among 46,962 matched participants (mean age, 62.8 years; 52.6% women), median follow-up period was 7 years. Dementia occurred in 1125 GLP-1 RA users (4.8%) and 1822 non-GLP-1 users (7.8%) (adjusted hazard ratio [HR], 0.86 (0.75-0.99)). PD occurred in 231 GLP-1 RA users (1.0%) and 338 non-GLP-1 users (1.4%) (0.90 (0.67-1.22)). In the secondary analysis, GLP-1 RA use was associated with lower risks of dementia compared with sulfonylureas (0.75 (0.61-0.93)) and PD (0.56 (0.36-0.86)). No significant differences were observed compared with DPP-4 inhibitors or SGLT2 inhibitors. Subgroup analyses showed stronger protective associations for dementia among women (0.78 (0.65-0.94)) and participants aged >/=65 years (0.82 (0.69-0.97)). CONCLUSIONS: The use of GLP-1 RAs was associated with a lower risk of dementia compared with other glucose-lowering therapies. These findings support the neuroprotective potential of GLP-1 RAs and highlight the importance of incorporating brain health into diabetes management strategies. CI - Copyright (c) 2026 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Abu Ahmad, Wiessam AU - Abu Ahmad W AD - Braun School of Public Health, Hebrew University-Hadassah, Jerusalem, Israel; Branch of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel. Electronic address: wiessam.abuahmad@mail.huji.ac.il. FAU - Wolff Sagy, Yael AU - Wolff Sagy Y AD - Branch of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel. FAU - Arbel, Ronen AU - Arbel R AD - Maximizing Health Outcomes Research Lab, Sapir College, Sderot, Israel; Community Medical Services Division, Clalit Health Services, Tel Aviv, Israel. FAU - Battat, Erez AU - Battat E AD - Branch of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel. FAU - Dicker, Dror AU - Dicker D AD - Gray Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Internal Medicine Department D and Obesity Clinic, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel. FAU - Lavie, Gil AU - Lavie G AD - Branch of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. FAU - Reges, Orna AU - Reges O AD - Branch of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel; Department of Health Systems Management, Ariel University, Ariel, Israel. LA - eng PT - Journal Article DEP - 20260821 PL - Netherlands TA - Eur J Intern Med JT - European journal of internal medicine JID - 9003220 SB - IM OTO - NOTNLM OT - Dementia OT - GLP-1 receptor agonists OT - Neurodegenerative disease OT - Neuroprotection OT - Type 2 diabetes COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/08/21 23:37 MHDA- 2026/08/21 23:37 CRDT- 2026/08/21 21:53 PHST- 2025/11/04 00:00 [received] PHST- 2026/07/16 00:00 [revised] PHST- 2026/08/18 00:00 [accepted] PHST- 2026/08/21 23:37 [medline] PHST- 2026/08/21 23:37 [pubmed] PHST- 2026/08/21 21:53 [entrez] AID - S0953-6205(26)00469-3 [pii] AID - 10.1016/j.ejim.2026.107164 [doi] PST - aheadofprint SO - Eur J Intern Med. 2026 Aug 21:107164. doi: 10.1016/j.ejim.2026.107164. PMID- 42624955 OWN - NLM STAT- MEDLINE DCOM- 20260821 LR - 20260823 IS - 1535-1645 (Electronic) IS - 1523-3812 (Print) IS - 1523-3812 (Linking) VI - 28 IP - 1 DP - 2026 Aug 21 TI - GLP-1 and dual GIP/GLP-1 receptor agonists' psychopharmacology and putative neuropsychiatric associated effects: a Bradford Hill-informed, systematic, evaluation. LID - 10.1007/s11920-026-01709-w [doi] LID - 65 AB - PURPOSE OF REVIEW: This review evaluates evidence linking both GLP-1 and GIP/GLP-1RAs' exposure to a range of neuropsychiatric outcomes using the Bradford Hill criteria for causal inference. RECENT FINDINGS: Glucagon-like peptide-1 (GLP-1) and the dual glucose-dependent insulinotropic polypeptide-GIP/GLP-1 receptor agonists (RAs) are incretin-based medications widely prescribed for type 2 diabetes mellitus and obesity, with demonstrated cardiometabolic benefit and rapidly expanding population exposure. In parallel, post-marketing surveillance and emerging translational research have raised questions regarding potential central nervous system effects, including neuropsychiatric adverse events and psychopharmacological properties. Integrating data from receptor pharmacology, preclinical neuroscience, randomized controlled trials, and observational and pharmacovigilance studies, the strength, consistency, biological plausibility, and experimental support for reported associations with depression, anxiety, suicidality, reward-related behaviour, cognitive effects and retinal/ocular related disturbances were here assessed. Implications for clinical risk-benefit assessment were discussed as well. Current evidence supports potential biological plausibility of a relationship between GLP-1 RAs and a range of psychopathological disorders but remains insufficient to establish causality for most neuropsychiatric outcomes, suggesting the need for prospective, mechanism-informed clinical studies. CI - (c) 2026. The Author(s). FAU - Schifano, F AU - Schifano F AD - Drug Misuse and Novel Psychoactive Substances Research Unit, University of Hertfordshire Medical School, Psychopharmacology, Hatfield, UK. FAU - De Luca, M A AU - De Luca MA AD - Drug Misuse and Novel Psychoactive Substances Research Unit, University of Hertfordshire Medical School, Psychopharmacology, Hatfield, UK. AD - Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. FAU - Bonaccorso, S AU - Bonaccorso S AD - North London NHS Foundation Trust, St Pancras Hospital, London, UK. FAU - Arillotta, Davide AU - Arillotta D AUID- ORCID: 0000-0002-8843-0595 AD - Drug Misuse and Novel Psychoactive Substances Research Unit, University of Hertfordshire Medical School, Psychopharmacology, Hatfield, UK. davide.arillotta@yahoo.it. AD - Department of Neurosciences, Psychology, Drug Research, and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy. davide.arillotta@yahoo.it. FAU - Floresta, G AU - Floresta G AD - Department of Drug and Health Sciences, University of Catania, Catania, Italy. giuseppe.floresta@unict.it. FAU - Martinotti, G AU - Martinotti G AD - Department of Neurosciences, Imaging and Clinical Sciences, Universita degli Studi G. D'Annunzio Chieti-Pescara, Chieti, Italy. FAU - Papanti, G D AU - Papanti GD AD - Tolmezzo Community Mental Health Centre, ASUFC Mental Health and Addiction Department, Tolmezzo, Italy. FAU - Corkery, J M AU - Corkery JM AD - Drug Misuse and Novel Psychoactive Substances Research Unit, University of Hertfordshire Medical School, Psychopharmacology, Hatfield, UK. FAU - Chiappini, S AU - Chiappini S AD - UniCamillus International University of Medical Sciences, Rome, Italy. FAU - Guirguis, A AU - Guirguis A AD - University of Swansea Medical School, Swansea, UK. LA - eng PT - Journal Article PT - Review DEP - 20260821 PL - United States TA - Curr Psychiatry Rep JT - Current psychiatry reports JID - 100888960 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Receptors, Gastrointestinal Hormone) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Gastric Inhibitory Polypeptide/agonists MH - *Glucagon-Like Peptide 1/agonists MH - *Mental Disorders/chemically induced MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Receptors, Gastrointestinal Hormone/agonists MH - *Hypoglycemic Agents/adverse effects MH - *Incretins/adverse effects PMC - PMC13493456 OTO - NOTNLM OT - Anxiety OT - Bradford-Hill evaluation OT - Cognitive dysfunction OT - Depression OT - Dulaglutide OT - GLP-1 RAs OT - GLP-1 receptor agonists OT - Liraglutide OT - Psychopathology OT - Psychopharmacology OT - Retatrutide OT - Semaglutide OT - Suicidal ideation OT - Tirzepatide OT - dual GIP/GLP-1 RAs OT - triple GIP/GLP-1/glucagon RAs COIS- Declarations. Competing Interests: The authors declare no competing interests. EDAT- 2026/08/21 05:35 MHDA- 2026/08/21 05:36 PMCR- 2026/08/21 CRDT- 2026/08/21 00:09 PHST- 2026/05/21 00:00 [received] PHST- 2026/07/31 00:00 [accepted] PHST- 2026/08/21 05:36 [medline] PHST- 2026/08/21 05:35 [pubmed] PHST- 2026/08/21 00:09 [entrez] PHST- 2026/08/21 00:00 [pmc-release] AID - 10.1007/s11920-026-01709-w [pii] AID - 1709 [pii] AID - 10.1007/s11920-026-01709-w [doi] PST - epublish SO - Curr Psychiatry Rep. 2026 Aug 21;28(1):65. doi: 10.1007/s11920-026-01709-w. PMID- 42622752 OWN - NLM STAT- Publisher LR - 20260820 IS - 1970-9366 (Electronic) IS - 1828-0447 (Linking) DP - 2026 Aug 20 TI - Oral semaglutide vs DPP-4 inhibitors in reducing risk of cognitive impairment in elderly patients with HFpEF and obesity. LID - 10.1007/s11739-026-04499-4 [doi] AB - Heart failure with preserved ejection fraction (HFpEF), obesity, type 2 diabetes mellitus are common in elderly patients and are associated with an increased risk of cognitive impairment (CoI). In these patients, the protective metabolic and vascular effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established. The aim of this study was to evaluate effects of one-year treatment with oral semaglutide versus DPP-4 inhibitors (DPP4i), as an add-on to the hypoglycaemic therapy, on the incidence of CoI in patients with HFpEF, obesity, and type 2 diabetes. 246 elderly outpatients were recruited and divided into two groups (oral semaglutide vs. DPP4i), accurately matched for age, sex, and body mass index (BMI). At one-year follow-up, 106 new cases of CoI were observed in the entire study population (43.1 events/100 patients/year). A significant difference was found between the two groups: 33 cases with oral semaglutide (26.8 events/100 patients/year) versus 73 cases with DPP4i (59.3 events/100 patients/year), p<0.0001. Logistic regression analysis indicated a 77% reduced risk of incident CoI with oral semaglutide compared to DPP4i. In elderly patients with HFpEF, obesity and type 2 diabetes, oral semaglutide seems to have a positive effect in reducing the incidence of cognitive impairment. CI - (c) 2026. The Author(s). FAU - Armentaro, Giuseppe AU - Armentaro G AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, 88100, Catanzaro, Italy. FAU - Vitale, Cristiana AU - Vitale C AD - Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open, University of Rome, Rome, Italy. AD - IRCCS San Raffaele, Rome, Italy. FAU - Cassano, Velia AU - Cassano V AUID- ORCID: 0000-0002-0793-1225 AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. velia.cassano@unicz.it. FAU - Panza, Marilisa AU - Panza M AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. FAU - Gareri, Ilaria AU - Gareri I AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. FAU - Mirabelli, Maria AU - Mirabelli M AD - Department of Health Sciences, University "Magna Graecia" of Catanzaro, 88100, Catanzaro, Italy. FAU - Succurro, Elena AU - Succurro E AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. FAU - Andreozzi, Francesco AU - Andreozzi F AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR‑METDIS), University Magna Graecia, 88100, Catanzaro, Italy. FAU - Brunetti, Antonio AU - Brunetti A AD - Department of Health Sciences, University "Magna Graecia" of Catanzaro, 88100, Catanzaro, Italy. FAU - Savarese, Gianluigi AU - Savarese G AD - Division of Cardiology, Department of Medicine, Karolinska Institutet, and Heart and Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden. FAU - Volterrani, Maurizio AU - Volterrani M AD - Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open, University of Rome, Rome, Italy. AD - IRCCS San Raffaele, Rome, Italy. FAU - Sesti, Giorgio AU - Sesti G AD - Division of Cardiology, Department of Medicine, Karolinska Institutet, and Heart and Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden. FAU - Rosano, Giuseppe Massimo Claudio AU - Rosano GMC AD - Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open, University of Rome, Rome, Italy. AD - Department of Clinical and Molecular Medicine, University of Rome-Sapienza, 00185, Rome, Italy. FAU - Sciacqua, Angela AU - Sciacqua A AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, 88100, Catanzaro, Italy. AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR‑METDIS), University Magna Graecia, 88100, Catanzaro, Italy. LA - eng PT - Journal Article DEP - 20260820 PL - Italy TA - Intern Emerg Med JT - Internal and emergency medicine JID - 101263418 SB - IM OTO - NOTNLM OT - Cognitive impairment OT - Elderly OT - HFpEF OT - Obesity OT - Type 2 diabetes COIS- Declarations. Conflicts of interest: The authors declare no conflicts of interest. Institutional review board: The study was approved on 17/10/2012 by the local Institutional Ethics Committees of University "Magna Graecia" of Catanzaro (code protocol number 2012.63) for CATAnzaro Metabolic Risk factors (CATAMERI) Study; and on 20/10/2022 by Comitato Etico "Area Centro" (2022.304) for the "MAgna GraecIa evaluation of Comorbidities in patients with Heart Failure (MAGIC-HF) study; ClinicalTrials.gov Identifier: NCT05915364. All investigations were made in accordance with the principles of the Declaration of Helsinki. Informed consent: Informed written consent was obtained from all participants. EDAT- 2026/08/20 17:35 MHDA- 2026/08/20 17:35 CRDT- 2026/08/20 11:09 PHST- 2025/12/13 00:00 [received] PHST- 2026/08/11 00:00 [accepted] PHST- 2026/08/20 17:35 [medline] PHST- 2026/08/20 17:35 [pubmed] PHST- 2026/08/20 11:09 [entrez] AID - 10.1007/s11739-026-04499-4 [pii] AID - 10.1007/s11739-026-04499-4 [doi] PST - aheadofprint SO - Intern Emerg Med. 2026 Aug 20. doi: 10.1007/s11739-026-04499-4. PMID- 42618557 OWN - NLM STAT- MEDLINE DCOM- 20260819 LR - 20260822 IS - 2041-4889 (Electronic) VI - 17 IP - 1 DP - 2026 Aug 19 TI - Exendin-4 improves neurodevelopmental outcome after neonatal germinal matrix hemorrhage. LID - 10.1038/s41419-026-09189-9 [doi] LID - 743 AB - Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to evaluate whether exendin-4 exerts neuroprotective effects in this setting. Our results show that in the acute phase, exendin-4 reduced microglial activation, caspase-3 activation, p53 expression, AIF-associated cell death, MMP-9 expression, and neutrophil infiltration into the hemorrhage site. Exendin-4 treatment improved neurodevelopmental outcomes in both negative geotaxis and eye-opening latency when compared to saline-treated GMH controls, and conferred gray and white matter protection as early as 48 h after injury, with persistent neuroprotection observed at 5, 11, and 35 days after GMH. Exendin-4-treated animals also showed significant recovery of motor function in the rotarod test. In summary, this study demonstrates that exendin-4 reduces brain injury in a rat model of GMH in both the short and long term and is associated with improved neurological outcome. CI - (c) 2026. The Author(s). FAU - Jonsdotter, Andrea AU - Jonsdotter A AD - Department of Obstetrics and Gynecology, Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden. AD - Centre of Perinatal Medicine and Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Leverin, Anna-Lena AU - Leverin AL AD - Centre of Perinatal Medicine and Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Svedin, Pernilla AU - Svedin P AD - Centre of Perinatal Medicine and Health, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Lindstrom, Michelle AU - Lindstrom M AD - Centre of Perinatal Medicine and Health, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Ebefors, Kerstin AU - Ebefors K AD - Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Carlsson, Ylva AU - Carlsson Y AUID- ORCID: 0000-0002-1414-7279 AD - Department of Obstetrics and Gynecology, Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden. AD - Centre of Perinatal Medicine and Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Hagberg, Henrik AU - Hagberg H AD - Department of Obstetrics and Gynecology, Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden. AD - Centre of Perinatal Medicine and Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Rocha-Ferreira, Eridan AU - Rocha-Ferreira E AUID- ORCID: 0000-0002-9342-4691 AD - Centre of Perinatal Medicine and Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. eridan.rocha.ferreira@gu.se. LA - eng GR - 2023-02035/Vetenskapsradet (Swedish Research Council)/ GR - 2021-0056/Hjarnfonden (Swedish Brain Foundation)/ PT - Journal Article DEP - 20260819 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 9P1872D4OL (Exenatide) RN - 0 (Neuroprotective Agents) RN - EC 3.4.22.- (Caspase 3) RN - 0 (Peptides) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - 0 (Venoms) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Animals MH - *Exenatide/pharmacology MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - Rats MH - Animals, Newborn MH - Neurodevelopment/drug effects MH - Caspase 3/metabolism MH - *Peptides/pharmacology/therapeutic use MH - Matrix Metalloproteinase 9/metabolism MH - Rats, Sprague-Dawley MH - *Venoms/pharmacology/therapeutic use MH - Disease Models, Animal MH - Microglia/drug effects/metabolism/pathology MH - Tumor Suppressor Protein p53/metabolism MH - Female PMC - PMC13490559 COIS- Competing interests: The authors declare no competing interests. EDAT- 2026/08/20 05:43 MHDA- 2026/08/20 05:44 PMCR- 2026/08/19 CRDT- 2026/08/19 23:13 PHST- 2026/03/16 00:00 [received] PHST- 2026/08/07 00:00 [accepted] PHST- 2026/07/17 00:00 [revised] PHST- 2026/08/20 05:44 [medline] PHST- 2026/08/20 05:43 [pubmed] PHST- 2026/08/19 23:13 [entrez] PHST- 2026/08/19 00:00 [pmc-release] AID - 10.1038/s41419-026-09189-9 [pii] AID - 9189 [pii] AID - 10.1038/s41419-026-09189-9 [doi] PST - epublish SO - Cell Death Dis. 2026 Aug 19;17(1):743. doi: 10.1038/s41419-026-09189-9. PMID- 42608657 OWN - NLM STAT- MEDLINE DCOM- 20260818 LR - 20260820 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 25 IP - 8 DP - 2026 Aug TI - The GLP-1-Mitochondria Axis in Metabolic Aging. PG - e70676 LID - 10.1111/acel.70676 [doi] LID - e70676 AB - Metabolic aging underlies a cluster of chronic conditions-type 2 diabetes, cardiovascular disease, sarcopenia, and neurodegeneration-that account for a substantial share of global morbidity and mortality. A common feature is progressive mitochondrial dysfunction: impaired bioenergetics, disrupted quality control, and loss of metabolic resilience. Reduced mitochondrial DNA copy number in peripheral blood leukocytes is associated with cardiometabolic disease and mortality, but pre-analytical variability, dependence on blood-cell composition, and uncertain relationship to tissue-level function mean it should be regarded as a candidate risk-associated biomarker rather than a validated measure of mitochondrial integrity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control, engage pathways implicated in mitochondrial biogenesis, dynamics, and mitophagy; whether these effects reflect direct receptor signaling, indirect consequences of weight loss, or secondary mediators such as interleukin-6 remains debated and appears tissue-dependent. In SELECT, semaglutide reduced major adverse cardiovascular events by 20% in obesity without diabetes, and a 2025 multi-omic study in aged male mice found GLP-1 RA treatment attenuated age-associated molecular signatures despite only modest changes in food intake and body weight. No trial, however, has incorporated a prespecified mitochondrial endpoint, human mechanistic evidence remains limited, and access to these therapies remains uneven worldwide. Here we synthesize mechanistic, preclinical, and clinical evidence for a proposed GLP-1-mitochondria axis, classify this evidence by receptor dependence and translational stage, distinguish disease-specific treatment effects from evidence for aging modification, examine four major controversies, and outline a research and policy agenda for responsible, evidence-graded development of GLP-1-based geroscience interventions. CI - (c) 2026 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. FAU - Chang, Renin AU - Chang R AUID- ORCID: 0000-0003-1016-2233 AD - Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. AD - Center of General Education, Cheng Shiu University, Kaohsiung, Taiwan. AD - Center of General Education, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan. FAU - Tsai, Andy P AU - Tsai AP AUID- ORCID: 0000-0001-6400-544X AD - Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. FAU - Wang, Boyang AU - Wang B AD - Sundial Initiative, Palo Alto, California, USA. FAU - Li, Chia-Jung AU - Li CJ AUID- ORCID: 0000-0002-3773-9015 AD - Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. AD - Center of General Education, Cheng Shiu University, Kaohsiung, Taiwan. AD - Center of General Education, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan. AD - Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. AD - Institute of Biopharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. LA - eng GR - 114-2628-B075-B-001-MY3/National Science and Technology Council/ GR - KSVGH-114-056/Kaohsiung Veterans General Hospital/ PT - Journal Article PT - Review PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Aging/metabolism MH - Animals MH - *Mitochondria/metabolism MH - *Glucagon-Like Peptide 1/metabolism MH - Semaglutide PMC - PMC13481478 OTO - NOTNLM OT - GLP-1 receptor agonists OT - geroscience OT - healthy aging OT - metabolic aging OT - mitochondrial dysfunction OT - mitochondrial resilience OT - population health COIS- The authors declare no conflicts of interest. EDAT- 2026/08/18 07:46 MHDA- 2026/08/18 07:47 PMCR- 2026/08/17 CRDT- 2026/08/18 00:15 PHST- 2026/08/11 00:00 [revised] PHST- 2026/06/09 00:00 [received] PHST- 2026/08/12 00:00 [accepted] PHST- 2026/08/18 07:47 [medline] PHST- 2026/08/18 07:46 [pubmed] PHST- 2026/08/18 00:15 [entrez] PHST- 2026/08/17 00:00 [pmc-release] AID - ACEL70676 [pii] AID - 10.1111/acel.70676 [doi] PST - ppublish SO - Aging Cell. 2026 Aug;25(8):e70676. doi: 10.1111/acel.70676. PMID- 42594928 OWN - NLM STAT- MEDLINE DCOM- 20260908 LR - 20260930 IS - 2213-8595 (Electronic) IS - 2213-8587 (Linking) VI - 14 IP - 10 DP - 2026 Oct TI - Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial. PG - 831-840 LID - S2213-8587(26)00136-1 [pii] LID - 10.1016/S2213-8587(26)00136-1 [doi] AB - BACKGROUND: Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications. METHODS: COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries. Adults (aged >/=18 years) with type 2 diabetes (HbA(1c) >/=8.0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100. The titration target was 3.9-5.0 mmol/L (70-90 mg/dL). The primary endpoint was change in HbA(1c) and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants. Adverse events were recorded during weeks 0-45. This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete. FINDINGS: Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100. Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82). For HbA(1c), from baseline (9.57% for IcoSema and 9.50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3.32 vs -2.44 percentage points; estimated treatment difference [ETD] -0.88 percentage points [95% CI -1.12 to -0.63]), confirming superiority of IcoSema (p<0.001). From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0.79 vs 3.81 kg; ETD -4.61 kg [95% CI -5.46 to -3.75]), confirming superiority of IcoSema (p<0.001). Rate of combined clinically significant (blood glucose <3.0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0.29 vs 0.59 episodes per person-year of exposure; estimated rate ratio 0.56 [95% CI 0.32 to 0.97]; p=0.04). Gastrointestinal disorders were the most frequently reported adverse events with IcoSema. INTERPRETATION: Once-weekly IcoSema demonstrated superior HbA(1c) reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications. FUNDING: Novo Nordisk. CI - Copyright (c) 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. FAU - Ji, Linong AU - Ji L AD - Department of Endocrinology and Metabolism, Peking University Diabetes Centre, Peking University People's Hospital, Beijing, China. Electronic address: jiln@bjmu.edu.cn. FAU - Benamar, Malik AU - Benamar M AD - Novo Nordisk, Soborg, Denmark. FAU - Mohan, Viswanathan AU - Mohan V AD - Madras Diabetes Research Foundation (ICMR-Collaborating Centre of Excellence) and Dr Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), Chennai, India. FAU - Pletsch-Borba, Laura AU - Pletsch-Borba L AD - Novo Nordisk, Soborg, Denmark. FAU - Porcellati, Francesca AU - Porcellati F AD - Department of Medicine and Surgery, University of Perugia, Perugia, Italy. FAU - Wang, Ni AU - Wang N AD - Novo Nordisk, Soborg, Denmark. FAU - Watada, Hirotaka AU - Watada H AD - Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan. FAU - Rea, Rosangela R AU - Rea RR AD - Internal Medicine Department, Endocrine Division (SEMPR), Universidade Federal do Parana, Curitiba, Brazil. LA - eng SI - ClinicalTrials.gov/NCT06269107 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20260813 PL - England TA - Lancet Diabetes Endocrinol JT - The lancet. Diabetes & endocrinology JID - 101618821 RN - 2ZM8CX04RZ (Insulin Glargine) RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) RN - 53AXN4NNHX (Semaglutide) RN - 0 (Blood Glucose) RN - 62340-29-8 (Glucagon-Like Peptides) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Female MH - *Insulin Glargine/administration & dosage/therapeutic use MH - Male MH - Middle Aged MH - *Hypoglycemic Agents/administration & dosage/therapeutic use MH - Aged MH - Glycated Hemoglobin/analysis MH - Semaglutide MH - Blood Glucose/analysis MH - Drug Administration Schedule MH - Adult MH - *Glucagon-Like Peptides/administration & dosage/therapeutic use MH - Treatment Outcome MH - Drug Therapy, Combination COIS- Declaration of interests LJ has received research support and consultant fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Gan & Lee, Haisco Pharmaceutical, Innovent Biologics, Merck, MSD, Novo Nordisk, Sanofi-Aventis, Sibionics, and Sinocare; has served on advisory panels for Haisco Pharmaceutical and received honoraria from Eli Lilly, Innovent Biologics, Novo Nordisk and Sanofi-Aventis. MB, LP-B, and NW are employees of Novo Nordisk and hold stock options. VM has acted as consultant and speaker for, and received research or educational grants from Abbott, Alembic Pharmaceuticals, Apex Pharma, Aventis, Bayer, Biocon, Boehringer Ingelheim, Cipla, Dr Reddy's, Eli Lilly, Emcure, Fourrts India, Franco Indian, Glenmark Pharmaceuticals, GSK, Intas Pharmaceuticals, Ipca Laboratories, Johnson & Johnson, LifeScan, Lupin, Mankind Pharma, Medtronic, MSD, Novartis, Novo Nordisk, Primus Pharmaceuticals, Roche, Sanofi, Servier, Sun Pharma, Torrent Pharma, USV, Wockhardt, and Zydus Lifesciences. FP has received research support or consultant and speaker fees from, or has participated on advisory panels for Abbott, AstraZeneca, Eli Lilly, Laboratori Guidotti, Novo Nordisk, Roche, and Sanofi. HW has received research support from Kowa Company, Lifescan Japan, Nippon Boehringer Ingelheim, Sanwa Kagaku Kenkyusho, SBI Pharma, Sumitomo Pharma and Taisho Pharma; and has acted as a speaker for Abbott Japan, Bayer Yakuhin, Daiichi Sankyo, Eli Lilly Japan, Embecta, GSK, Kowa Company, Kyowa Kirin, MSD, Nippon Boehringer Ingelheim, Novo Nordisk, Roche DC Japan, Sanwa Kagaku Kenkyusho, Sumitomo Pharma, Tanabe Pharma, Taisho Pharma and Teijin. RRR is an advisory board member for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; has participated in speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, and Novo Nordisk; and has received research grants from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. EDAT- 2026/08/13 23:36 MHDA- 2026/09/08 23:35 CRDT- 2026/08/13 18:53 PHST- 2026/03/04 00:00 [received] PHST- 2026/05/29 00:00 [revised] PHST- 2026/05/29 00:00 [accepted] PHST- 2026/09/08 23:35 [medline] PHST- 2026/08/13 23:36 [pubmed] PHST- 2026/08/13 18:53 [entrez] AID - S2213-8587(26)00136-1 [pii] AID - 10.1016/S2213-8587(26)00136-1 [doi] PST - ppublish SO - Lancet Diabetes Endocrinol. 2026 Oct;14(10):831-840. doi: 10.1016/S2213-8587(26)00136-1. Epub 2026 Aug 13. PMID- 42591537 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260813 LR - 20260814 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 20 DP - 2026 TI - Research hotspots and trends of GLP-1 receptor agonists in the treatment of Parkinson's disease: a bibliometric analysis. PG - 1894856 LID - 10.3389/fnins.2026.1894856 [doi] LID - 1894856 AB - BACKGROUND: PD is still managed symptomatically with levodopa, and no disease-modifying therapy is available, making effective treatment difficult. In recent years, preclinical and some clinical evidence have shown that glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists, GLP-1 RAs) can cross to varying degrees the blood-brain barrier and exert neuroprotective effects, including anti-inflammatory, antioxidant, and insulin-sensitizing actions. They also reduce pathological protein aggregation, regulate mitochondrial function, and enhance autophagy, demonstrating their therapeutic potential for PD. Therefore, systematically reviewing the research status, hotspots, and trends of GLP-1 receptor agonists in PD is crucial for understanding the dynamic development of this field. METHODS: Systematic searches were performed in the Web of Science Core Collection and Scopus databases to identify literature on GLP-1 receptor agonists and PD. Bibliometric analyses were conducted using CiteSpace and VOSviewer to evaluate publication trends, collaborative networks, co-citation patterns, and research hotspots. The search period spanned from database inception to April 14, 2026. RESULTS: A total of 282 articles from WoS and Scopus were included for bibliometric analysis. The top three countries are China, the United States, and the United Kingdom. Major institutions include University College London, Shanxi Medical University, Henan University of Chinese Medicine, and Lancaster University, with authors Holscher, Athauda, Aviles-Olmos, and Li. Hotspots focus on oxidative stress, insulin resistance, alpha-synuclein, blood-brain barrier, and exendin-4. Emerging themes with increasing research attention include mild cognitive impairment, GIP/GLP-1 dual agonists, and blood-brain barrier. CONCLUSION: PD is a multifactorial neurodegenerative disorder characterized by complex and heterogeneous pathological mechanisms, supporting the exploration of multi-target therapeutic strategies. GLP-1 receptor signaling is widely distributed in the central nervous system and peripheral metabolic tissues, suggesting a potential link between metabolic regulation and neurodegenerative processes. Bibliometric analysis indicates that GLP-1 receptor agonists have attracted increasing research attention in PD, particularly in relation to metabolic dysfunction, neuroinflammation, and mitochondrial pathways. However, current clinical evidence remains inconsistent, with findings influenced by drug heterogeneity, study populations, and methodological differences. Overall, GLP-1 receptor-related mechanisms represent an emerging and evolving research direction in PD, warranting further experimental and clinical investigation. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/u7wdy. CI - Copyright (c) 2026 Yu, Mai, Wang, Pan, Xiong, Kuang and Liu. FAU - Yu, Ting AU - Yu T AD - Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China. AD - School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. FAU - Mai, Qingxin AU - Mai Q AD - Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China. AD - School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. AD - Shenzhen Clinical College of Integrated Traditional Chinese and Western Medicine, Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China. FAU - Wang, Qian AU - Wang Q AD - Shenzhen Clinical College of Integrated Traditional Chinese and Western Medicine, Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China. FAU - Pan, Mingxia AU - Pan M AD - Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China. FAU - Xiong, Yuanfang AU - Xiong Y AD - School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. FAU - Kuang, Lingyu AU - Kuang L AD - Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China. FAU - Liu, Hanjiao AU - Liu H AD - Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, China. AD - School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. AD - Shenzhen Clinical College of Integrated Traditional Chinese and Western Medicine, Affiliated to Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China. LA - eng PT - Journal Article PT - Systematic Review DEP - 20260729 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC13462061 OTO - NOTNLM OT - GLP-1 OT - GLP-1 receptor agonists OT - Parkinson's disease OT - bibliometric analysis OT - type 2 diabetes mellitus COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/08/13 12:42 MHDA- 2026/08/13 12:43 PMCR- 2026/07/29 CRDT- 2026/08/13 06:00 PHST- 2026/05/29 00:00 [received] PHST- 2026/06/29 00:00 [revised] PHST- 2026/06/30 00:00 [accepted] PHST- 2026/08/13 12:43 [medline] PHST- 2026/08/13 12:42 [pubmed] PHST- 2026/08/13 06:00 [entrez] PHST- 2026/07/29 00:00 [pmc-release] AID - 10.3389/fnins.2026.1894856 [doi] PST - epublish SO - Front Neurosci. 2026 Jul 29;20:1894856. doi: 10.3389/fnins.2026.1894856. eCollection 2026. PMID- 42573983 OWN - NLM STAT- MEDLINE DCOM- 20261001 LR - 20261001 IS - 1473-6519 (Electronic) IS - 1363-1950 (Linking) VI - 29 IP - 6 DP - 2026 Nov 1 TI - Choline and metabolic health, a missing link in a critical chain. PG - 519-526 LID - 10.1097/MCO.0000000000001252 [doi] AB - PURPOSE OF REVIEW: Emerging evidence suggests that choline plays a significant role in mediating metabolic disease beyond the regulation of hepatic triglycerides. The aim of this article is to present a current, brief synthesis focused on the impact of choline intake on metabolic health and to identify future directions in this research space. RECENT FINDINGS: Recent work has linked low choline intake to obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), type 2 diabetes, and obesity-associated cognitive decline. A new methodology now enables more precise discrimination of choline intake in clinical populations. Emerging evidence reframes circulating trimethylamine N-oxide (TMAO) as a marker of metabolic dysfunction driven by obesity and a high-fat diet, rather than a direct consequence of dietary choline intake. Preclinical and clinical studies further suggest that adequate choline intake may be protective against obesity-related disease progression, particularly when established early in life. SUMMARY: Choline is emerging as an important mediator of metabolic health and disease progression. A deeper understanding of the mechanisms regulating choline metabolism is critical to tailor nutritional therapies and mitigate metabolic disease progression. The impact of new antiobesity medications, including GLP-1 receptor agonists, on choline requirements also warrants investigation. CI - Copyright (c) 2026 The Author(s). Published by Wolters Kluwer Health, LLC. FAU - Paules, Evan M AU - Paules EM AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis. AD - Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. LA - eng PT - Journal Article PT - Review DEP - 20260810 PL - England TA - Curr Opin Clin Nutr Metab Care JT - Current opinion in clinical nutrition and metabolic care JID - 9804399 RN - N91BDP6H0X (Choline) RN - 0 (Methylamines) RN - 0 (Biomarkers) RN - FLD0K1SJ1A (trimethyloxamine) SB - IM MH - Humans MH - *Choline/metabolism/administration & dosage MH - Obesity MH - Diabetes Mellitus, Type 2 MH - *Metabolic Diseases/etiology MH - Methylamines/blood MH - Biomarkers/blood MH - Animals MH - Fatty Liver MH - Diet, High-Fat/adverse effects OTO - NOTNLM OT - choline OT - glucagon-like peptide-1 receptor agonists OT - metabolic dysfunction-associated steatotic liver disease OT - obesity OT - trimethylamine OT - trimethylamine oxide OT - type 2 diabetes EDAT- 2026/08/10 12:36 MHDA- 2026/10/01 05:30 CRDT- 2026/08/10 11:23 PHST- 2026/10/01 05:30 [medline] PHST- 2026/08/10 12:36 [pubmed] PHST- 2026/08/10 11:23 [entrez] AID - 00075197-990000000-00305 [pii] AID - 10.1097/MCO.0000000000001252 [doi] PST - ppublish SO - Curr Opin Clin Nutr Metab Care. 2026 Nov 1;29(6):519-526. doi: 10.1097/MCO.0000000000001252. Epub 2026 Aug 10. PMID- 42570467 OWN - NLM STAT- MEDLINE DCOM- 20261015 LR - 20261015 IS - 2426-0266 (Electronic) IS - 2274-5807 (Print) IS - 2274-5807 (Linking) VI - 13 IP - 9 DP - 2026 Nov TI - Risk of Dementia after initiation of GLP-1 RA versus long-acting insulin in patients with type 2 Diabetes mellitus. PG - 100645 LID - S2274-5807(26)00169-X [pii] LID - 10.1016/j.tjpad.2026.100645 [doi] LID - 100645 AB - BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort DESIGN: A population-based retrospective cohort study SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021). MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models. RESULTS: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia. CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials. CI - Copyright (c) 2026 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Lin, Chien-Hung AU - Lin CH AD - Division of Pediatric Immunology and Nephrology, Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; College of Science and Engineering, Fu Jen Catholic University, New Taipei, Taiwan. FAU - Hung, Peir-Haur AU - Hung PH AD - Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan. FAU - Chung, Mu-Chi AU - Chung MC AD - Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Clinical Toxicology, Department of Medical Toxicology, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung City, 402, Taiwan. FAU - Wu, Laing-You AU - Wu LY AD - Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan. FAU - Chung, Chi-Jung AU - Chung CJ AD - Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. Electronic address: cjchung@mail.cmu.edu.tw. LA - eng PT - Journal Article DEP - 20260808 PL - United States TA - J Prev Alzheimers Dis JT - The journal of prevention of Alzheimer's disease JID - 101638820 RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Insulin, Long-Acting) RN - 62340-29-8 (Glucagon-Like Peptides) RN - WTT295HSY5 (dulaglutide) RN - 53AXN4NNHX (Semaglutide) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Immunoglobulin Fc Fragments) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Female MH - Male MH - Retrospective Studies MH - *Dementia/epidemiology/prevention & control MH - Aged MH - Taiwan/epidemiology MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Insulin, Long-Acting/therapeutic use/adverse effects MH - Incidence MH - Glucagon-Like Peptides/analogs & derivatives/therapeutic use MH - Semaglutide MH - Recombinant Fusion Proteins/therapeutic use MH - Immunoglobulin Fc Fragments PMC - PMC13476480 OTO - NOTNLM OT - Basal insulin OT - Dementia OT - Diabetes mellitus OT - Glucagon-like peptide-1 receptor agonist OT - Propensity score-matching OT - Retrospective cohort study COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/08/09 00:43 MHDA- 2026/10/15 23:30 PMCR- 2026/08/08 CRDT- 2026/08/08 18:04 PHST- 2025/12/29 00:00 [received] PHST- 2026/06/24 00:00 [revised] PHST- 2026/07/03 00:00 [accepted] PHST- 2026/10/15 23:30 [medline] PHST- 2026/08/09 00:43 [pubmed] PHST- 2026/08/08 18:04 [entrez] PHST- 2026/08/08 00:00 [pmc-release] AID - S2274-5807(26)00169-X [pii] AID - 100645 [pii] AID - 10.1016/j.tjpad.2026.100645 [doi] PST - ppublish SO - J Prev Alzheimers Dis. 2026 Nov;13(9):100645. doi: 10.1016/j.tjpad.2026.100645. Epub 2026 Aug 8. PMID- 42528342 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260730 LR - 20260813 IS - 1738-1088 (Print) IS - 2093-4327 (Electronic) IS - 1738-1088 (Linking) VI - 24 IP - 3 DP - 2026 Aug 31 TI - Neurovascular Actions of Dipeptidyl Peptidase-4 Inhibitors and Their Implications for Cognitive Dysfunction in Type 2 Diabetes Mellitus. PG - 480-489 LID - 10.9758/cpn.26.1403 [doi] AB - Type 2 diabetes mellitus is a major contributor to cognitive dysfunction and neurodegeneration, driven by complex metabolic, vascular, and inflammatory disturbances. Although conventional antidiabetic therapies primarily focus on glycemic control, few effectively preserve the integrity of the neurovascular unit (NVU), a critical determinant of brain health. This review examines the neuroprotective potential of dipeptidyl peptidase-4 (DPP-4) inhibitors, highlighting their unique ability to link metabolic regulation with neural and vascular preservation. A literature search was conducted in PubMed and Google Scholar for English-language articles published up to December 2025, using keywords related to cognitive dysfunction, DPP-4 inhibitors, incretins, glucagon-like peptide-1, and the nervous system. Eligible studies included original research, randomized trials, meta-analyses, animal studies, reviews, and mechanistic investigations addressing the effects of DPP-4 inhibitors on NVU stability. Editorials and studies lacking relevance to diabetes-related cognitive impairment or clear biological mechanisms were excluded. Evidence indicates that DPP-4 inhibitors exert dual neuroprotective actions by enhancing incretin signaling (GLP-1/GIP), which supports synaptic plasticity and attenuates neuroinflammation, and by preserving stromal cell-derived factor-1alpha, thereby activating the CXCR4 pathway to promote endothelial repair. Additional benefits include modulation of the Nrf2/GPX4 axis, reducing oxidative stress and ferroptosis in neural tissue. Comparative analyses suggest potential advantages over other antidiabetic classes, although clinical data on dementia risk remain heterogeneous. Overall, DPP-4 inhibitors emerge as promising agents for stabilizing the NVU beyond glucose lowering, supporting their repositioning in the management of diabetes-associated cognitive dysfunction. FAU - Mohammad, Aseel H AU - Mohammad AH AUID- ORCID: 0009-0008-0578-5392 AD - Nineveh Health Directorate, Mosul, Iraq. AD - Department of Pharmacology, College of Medicine, University of Mosul, Mosul, Iraq. FAU - Mohammad, Shatha H AU - Mohammad SH AUID- ORCID: 0000-0002-2873-8846 AD - Department of Pharmacology, College of Medicine, University of Mosul, Mosul, Iraq. FAU - Alsaaty, Mohammad H AU - Alsaaty MH AUID- ORCID: 0000-0003-1853-939X AD - Department of Medicine, College of Medicine, University of Mosul, Mosul, Iraq. LA - eng PT - Journal Article PT - Review DEP - 20260512 PL - Korea (South) TA - Clin Psychopharmacol Neurosci JT - Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology JID - 101207332 PMC - PMC13429761 OTO - NOTNLM OT - Cognitive dysfunction OT - Diabetes mellitus OT - Dipeptidyl-peptidase IV inhibitors OT - Glucagon-like peptide 1 OT - Incretins OT - Nervous system COIS- Conflicts of Interest No potential conflict of interest relevant to this article was reported. EDAT- 2026/07/30 06:41 MHDA- 2026/07/30 06:42 PMCR- 2026/05/12 CRDT- 2026/07/30 03:23 PHST- 2026/01/08 00:00 [received] PHST- 2026/02/15 00:00 [revised] PHST- 2026/03/03 00:00 [accepted] PHST- 2026/07/30 06:42 [medline] PHST- 2026/07/30 06:41 [pubmed] PHST- 2026/07/30 03:23 [entrez] PHST- 2026/05/12 00:00 [pmc-release] AID - cpn.26.1403 [pii] AID - cpn-24-3-480 [pii] AID - 10.9758/cpn.26.1403 [doi] PST - ppublish SO - Clin Psychopharmacol Neurosci. 2026 Aug 31;24(3):480-489. doi: 10.9758/cpn.26.1403. Epub 2026 May 12. PMID- 42493728 OWN - NLM STAT- Publisher LR - 20260723 IS - 1970-9366 (Electronic) IS - 1828-0447 (Linking) DP - 2026 Jul 23 TI - Impact of semaglutide on cognitive function in patients with type 2 diabetes and mild cognitive impairment: a 24-month observational study. LID - 10.1007/s11739-026-04468-x [doi] AB - Type 2 diabetes mellitus (T2DM) is associated with an increased risk of mild cognitive impairment (MCI) and dementia. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide cardiovascular and metabolic benefits, and emerging data suggest neurocognitive effects. We conducted a 24-month prospective observational study of 72 adults (>/= 50 years) with T2DM and MCI treated with semaglutide (subcutaneous [SC] or oral) and assessed at baseline (T0) and every 6 months (T1-T4). Outcomes included anthropometrics, fasting glucose, HbA1c, LDL-c, and neuropsychological tests (Montreal Cognitive Assessment [MoCA], Digit Symbol Substitution Test [DSST], Beck Depression Inventory [BDI]). A control cohort of 60 patients with T2DM and MCI not receiving semaglutide was evaluated with the same protocol. Semaglutide was associated with significant reductions in body weight, BMI, waist circumference, fasting glucose, and HbA1c (all p < 0.05). Cognitive performance improved, as shown by MoCA scores (median Delta approximately + 4 points, p < 0.001) at T4 compared with T0; at T4, semaglutide recipients also had higher MoCA scores than controls (+ 4.0 vs - 1.5, p < 0.001). DSST and BDI scores also improved (p = 0.001 and p = 0.044, respectively). MoCA improved similarly with both formulations, whereas DSST improvement reached significance only with SC semaglutide. In multivariable regression, semaglutide independently predicted MoCA improvement (+ 4.76 points, p < 0.001). No semaglutide-treated patient progressed to dementia versus 14 in controls (p = 0.002). In adults with T2DM and MCI, semaglutide was associated with improved cognition and a lower risk of progression to dementia. Differences between formulations may reflect distinct central nervous system engagement. Randomized trials are warranted. CI - (c) 2026. The Author(s), under exclusive licence to Societa Italiana di Medicina Interna (SIMI). FAU - Cassataro, Giuliano AU - Cassataro G AUID- ORCID: 0000-0001-8511-3589 AD - Medicine and Pulmonology Ward, Fondazione Istituto "G. Giglio", Cefalu, Italy. giuliano.cassat@gmail.com. AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy. giuliano.cassat@gmail.com. FAU - Scriffignano, Silvia AU - Scriffignano S AD - Medicine and Pulmonology Ward, Fondazione Istituto "G. Giglio", Cefalu, Italy. FAU - Geraci, Giulio AU - Geraci G AD - Internal Medicine Unit, Hospital Umberto I, Enna, Italy. AD - Department of Medicine and Surgery, "Kore" University of Enna, Enna, Italy. FAU - Augello, Giuseppa AU - Augello G AD - Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy. FAU - Grasso, Maria Angela AU - Grasso MA AD - Clinical Laboratory and Microbiology Unit, Fondazione Istituto "G. Giglio", Cefalu, Italy. FAU - D'Ippolito, Maria Enza AU - D'Ippolito ME AD - Clinical Laboratory and Microbiology Unit, Fondazione Istituto "G. Giglio", Cefalu, Italy. FAU - Puleo, Maria Grazia AU - Puleo MG AD - Internal Medicine and Stroke Care Ward, University Hospital, Policlinico "Paolo Giaccone", Palermo, Italy. FAU - Cadelo, Marcello AU - Cadelo M AD - Fondazione Istituto "G. Giglio", Cefalu, Italy. FAU - Renda, Maurizio AU - Renda M AD - Medicine and Pulmonology Ward, Fondazione Istituto "G. Giglio", Cefalu, Italy. FAU - Tuttolomondo, Antonino AU - Tuttolomondo A AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy. AD - Internal Medicine and Stroke Care Ward, University Hospital, Policlinico "Paolo Giaccone", Palermo, Italy. LA - eng PT - Journal Article DEP - 20260723 PL - Italy TA - Intern Emerg Med JT - Internal and emergency medicine JID - 101263418 SB - IM OTO - NOTNLM OT - Cognition OT - GLP-1 receptor agonist OT - Mild cognitive impairment OT - Semaglutide OT - Type 2 diabetes mellitus COIS- Declarations. Conflict of interest: The authors have no conflicts of interest to declare. Ethics approval: The study was approved by the Ethics Committee Palermo 1. Informed consent: Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki. EDAT- 2026/07/24 00:37 MHDA- 2026/07/24 00:37 CRDT- 2026/07/23 23:42 PHST- 2026/02/07 00:00 [received] PHST- 2026/07/10 00:00 [accepted] PHST- 2026/07/24 00:37 [medline] PHST- 2026/07/24 00:37 [pubmed] PHST- 2026/07/23 23:42 [entrez] AID - 10.1007/s11739-026-04468-x [pii] AID - 10.1007/s11739-026-04468-x [doi] PST - aheadofprint SO - Intern Emerg Med. 2026 Jul 23. doi: 10.1007/s11739-026-04468-x. PMID- 42440082 OWN - NLM STAT- MEDLINE DCOM- 20260903 LR - 20260906 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 69 IP - 10 DP - 2026 Oct TI - Dementia in type 2 diabetes: risk factors, disease processes and opportunities for prevention across the lifespan. PG - 2659-2671 LID - 10.1007/s00125-026-06795-2 [doi] AB - People with type 2 diabetes have a 60-70% higher risk of developing dementia than those without diabetes. Given the increasing number of older people living with diabetes, preventing dementia in this population is becoming increasingly important. However, dementia in individuals with type 2 diabetes is not a single entity and no diabetes-specific pathologies contributing to dementia have been identified yet. Here, we suggest that the relation between type 2 diabetes and dementia may be best understood through a probabilistic model that considers the context in which type 2 diabetes develops and the involvement of multiple dementia-related pathologies. Within this model, type 2 diabetes alters both the probability of dementia-related pathologies occurring and their downstream consequences. Opportunities for prevention of dementia evolve across the lifespan and comprise reducing cumulative exposures to dementia risk factors through a holistic approach rather than through targeting a single factor. Accordingly, beyond preventing type 2 diabetes itself, glucose-lowering medications with effects beyond glycaemic management (e.g. multihormone receptor modulators, such as glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors), alongside traditional multi-domain cardiovascular risk management, may be most effective at lowering excess dementia risk in individuals with type 2 diabetes. CI - (c) 2026. The Author(s). FAU - de Leijer, Jan F AU - de Leijer JF AUID- ORCID: 0000-0003-4254-8923 AD - Department of Vascular Medicine & Endocrinology, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - Biessels, Geert Jan AU - Biessels GJ AUID- ORCID: 0000-0001-6862-2496 AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - Visseren, Frank L J AU - Visseren FLJ AUID- ORCID: 0000-0003-3951-5223 AD - Department of Vascular Medicine & Endocrinology, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - van Sloten, Thomas T AU - van Sloten TT AUID- ORCID: 0000-0003-2870-482X AD - Department of Vascular Medicine & Endocrinology, University Medical Center Utrecht, Utrecht, the Netherlands. t.t.vansloten@umcutrecht.nl. LA - eng PT - Journal Article PT - Review DEP - 20260713 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Dementia/prevention & control/etiology MH - Risk Factors MH - Hypoglycemic Agents/therapeutic use PMC - PMC13541823 OTO - NOTNLM OT - Dementia OT - Prevention OT - Probabilistic model OT - Review OT - Risk factors OT - Type 2 diabetes COIS- Funding: JdL and TvS are supported by grants from the European Foundation for the Study of Diabetes (EFSD) and the Dutch Diabetes Association. GJB is supported by the Timely, Accurate, and Personalized Diagnosis of Dementia (TAP-dementia) program, which receives funding from ZonMw (no. 10510032120003). Authors' relationships and activities: GJB consults for Nestle Health Science for the COGNIKET-MCI trial. All financial compensation for these services is transferred to his employer, University Medical Center Utrecht. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: All authors were responsible for drafting the article and reviewing it critically for important intellectual content. All authors approved the final version to be published. EDAT- 2026/07/13 16:10 MHDA- 2026/09/03 17:36 PMCR- 2026/07/13 CRDT- 2026/07/13 11:13 PHST- 2026/02/17 00:00 [received] PHST- 2026/05/05 00:00 [accepted] PHST- 2026/09/03 17:36 [medline] PHST- 2026/07/13 16:10 [pubmed] PHST- 2026/07/13 11:13 [entrez] PHST- 2026/07/13 00:00 [pmc-release] AID - 10.1007/s00125-026-06795-2 [pii] AID - 6795 [pii] AID - 10.1007/s00125-026-06795-2 [doi] PST - ppublish SO - Diabetologia. 2026 Oct;69(10):2659-2671. doi: 10.1007/s00125-026-06795-2. Epub 2026 Jul 13. PMID- 42432163 OWN - NLM STAT- MEDLINE DCOM- 20260711 LR - 20261008 IS - 1590-3478 (Electronic) IS - 1590-1874 (Linking) VI - 47 IP - 8 DP - 2026 Jul 11 TI - Glucagon-like peptide-1 agonists in Parkinson's disease: a meta-analysis. LID - 620 [pii] LID - 10.1007/s10072-026-09238-3 [doi] AB - BACKGROUND: Type 2 diabetes and Parkinson's disease (PD) share underlying pathways, including insulin resistance and neuroinflammation. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show neuroprotective promise in preclinical models, clinical trials have produced conflicting results. This meta-analysis systematically evaluates the efficacy and safety of GLP-1 RAs in PD, specifically distinguishing between symptomatic relief and potential disease modification. METHODS: We searched PubMed, Scopus, Web of Science, Cochrane Library, and Embase through November 2025 for randomized, double-blind, placebo-controlled trials of GLP-1 RAs in idiopathic PD. The primary motor outcome, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (motor examination), was analyzed using a random-effects model and strictly stratified by "ON" versus "OFF" medication states. RESULTS: We included four high-quality trials comprising 667 patients. GLP-1 RAs failed to significantly improve motor function in either the OFF-medication state (mean difference [MD] - 0.69; 95% confidence interval [CI] - 2.81 to 1.43; p = 0.52) or ON-medication state (MD - 0.86; 95% CI - 3.35 to 1.63; p = 0.50). Furthermore, no meaningful benefits emerged for non-motor symptoms, cognition, or quality of life. Conversely, treatment significantly increased gastrointestinal adverse events, including nausea (risk ratio [RR] = 2.48), vomiting (RR = 4.53), and clinically concerning weight loss (RR = 3.32). CONCLUSIONS: Synthesizing the latest phase 3 data, current GLP-1 RAs offer neither disease-modifying nor symptomatic motor benefits for the broader PD population. Given the pronounced risk of weight loss, their routine use is unwarranted. Future trials must shift focus toward biologically enriched subgroups or newer-generation incretin analogs. CI - (c) 2026. Fondazione Societa Italiana di Neurologia. FAU - Abdallah, Amr Khalid AU - Abdallah AK AD - Faculty of Medicine, Menoufia University, Menoufia, Egypt. FAU - Harb, Ahmed AU - Harb A AD - Faculty of Medicine, Al-Azhar University, Cairo, Egypt. FAU - Mansour, Anas AU - Mansour A AD - Faculty of Medicine, Al-Azhar University, Cairo, Egypt. FAU - Nasreldin, Asmaa AU - Nasreldin A AD - Qena Faculty of Medicine, South Valley University, Qena, Egypt. FAU - Hamdy, Rofida AU - Hamdy R AD - Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Hatem, Nourhan AU - Hatem N AD - Faculty of Medicine, Suez Canal University, Ismailia, Egypt. FAU - Mosad, Nada AU - Mosad N AD - Faculty of Medicine, Al-Azhar University, Damietta, Egypt. FAU - Hamouda, Mohamed AU - Hamouda M AD - Faculty of Medical Sciences, Galala University, Ataka, Suez, Egypt. FAU - Hamouda, Abdelrahman AU - Hamouda A AD - Department of Neurosurgery, Mayo Clinic, Rochester, MN, 55905, USA. Hamouda.abdelrahman@mayo.edu. FAU - Arumaithurai, Kogulavadanan AU - Arumaithurai K AD - Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review DEP - 20260711 PL - Italy TA - Neurol Sci JT - Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology JID - 100959175 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Antiparkinson Agents) SB - IM MH - Humans MH - *Parkinson Disease/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Antiparkinson Agents/therapeutic use MH - Randomized Controlled Trials as Topic OTO - NOTNLM OT - Disease modification OT - Glucagon-like peptide-1 receptor agonists OT - Meta-analysis OT - Neuroprotection OT - Parkinson's disease COIS- Declarations. Ethics approval: Not applicable. This study is a meta-analysis of previously published literature and does not involve new studies with human participants or animals performed by any of the authors. Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interests: The authors have no relevant financial or non-financial interests to disclose. EDAT- 2026/07/11 05:38 MHDA- 2026/07/12 04:11 CRDT- 2026/07/10 23:22 PHST- 2026/03/06 00:00 [received] PHST- 2026/07/05 00:00 [accepted] PHST- 2026/07/12 04:11 [medline] PHST- 2026/07/11 05:38 [pubmed] PHST- 2026/07/10 23:22 [entrez] AID - 10.1007/s10072-026-09238-3 [pii] AID - 10.1007/s10072-026-09238-3 [doi] PST - epublish SO - Neurol Sci. 2026 Jul 11;47(8):620. doi: 10.1007/s10072-026-09238-3. PMID- 42416049 OWN - NLM STAT- MEDLINE DCOM- 20260708 LR - 20260813 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 17 DP - 2026 TI - GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection. PG - 1839620 LID - 10.3389/fimmu.2026.1839620 [doi] LID - 1839620 AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit. CI - Copyright (c) 2026 Yang and Liang. FAU - Yang, Mengting AU - Yang M AD - Second Clinical Medical College, Binzhou Medical University, Yantai, China. AD - Qingdao University Affiliated Yantai Yuhuangding Hospital, Yantai, China. FAU - Liang, Zhigang AU - Liang Z AD - Qingdao University Affiliated Yantai Yuhuangding Hospital, Yantai, China. AD - Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China. AD - National Clinical Medical Research Center for Neurological Diseases Regional Subcenter, Yantai, China. LA - eng PT - Journal Article PT - Review DEP - 20260623 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (GLP1R protein, human) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Neuroprotective Agents/therapeutic use/pharmacology MH - *Nervous System Diseases/drug therapy/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Neuroprotection/drug effects MH - Oxidative Stress/drug effects PMC - PMC13337448 OTO - NOTNLM OT - GLP-1 receptor agonists OT - blood-brain barrier OT - metabolic dysfunction OT - neuroinflammation OT - neuroprotection COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/07/08 06:51 MHDA- 2026/07/08 20:01 PMCR- 2026/06/23 CRDT- 2026/07/08 04:38 PHST- 2026/03/26 00:00 [received] PHST- 2026/05/26 00:00 [revised] PHST- 2026/06/02 00:00 [accepted] PHST- 2026/07/08 20:01 [medline] PHST- 2026/07/08 06:51 [pubmed] PHST- 2026/07/08 04:38 [entrez] PHST- 2026/06/23 00:00 [pmc-release] AID - 10.3389/fimmu.2026.1839620 [doi] PST - epublish SO - Front Immunol. 2026 Jun 23;17:1839620. doi: 10.3389/fimmu.2026.1839620. eCollection 2026. PMID- 42410298 OWN - NLM STAT- MEDLINE DCOM- 20260903 LR - 20260908 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 28 IP - 10 DP - 2026 Oct TI - Epidemiological Studies on Type 2 Diabetes Using the German Disease Analyser Database: A Narrative Review. PG - 8795-8800 LID - 10.1111/dom.71089 [doi] AB - BACKGROUND: The German IQVIA Disease Analyser (DA) database provides longitudinal, anonymised outpatient data from a large network of German general practices and specialist offices, including ICD-10 diagnoses, ATC-coded prescriptions, consultation dates and selected clinical measurements (HbA1c, BMI). AIMS: This narrative review synthesises DA-based research in patients with type 2 diabetes (T2D) published between 2020 and 2025, with a focus on studies examining glucose-lowering drug effectiveness, real-world prescribing patterns, pharmacoepidemiological associations and relevant comorbidities. METHODS: A structured PubMed search was used to identify eligible studies, and methodological limitations of the included observational studies are discussed. RESULTS: Key findings include observational associations between SGLT2 inhibitor therapy and lower incidence of iron deficiency anaemia and dementia in patients with T2D, a decline in cardiovascular event incidence among patients with newly diagnosed T2D over a 17-years period, a gap between guideline recommendations and real-world use of GLP-1 receptor agonists and SGLT2 inhibitors in patients with established cardiovascular disease, and associations between glucose-lowering drug classes and cerebrovascular outcomes. DISCUSSION: Given the observational design of all included studies, these associations should be regarded as hypothesis-generating rather than causal. The DA database complements randomised trial evidence by capturing large, heterogeneous populations in routine care. Limitations include underestimation of hypoglycaemia, absence of lifestyle and socioeconomic variables, and incomplete inpatient data, as well as reliance on a single data source to which several included studies and authors of this review have contributed. CONCLUSION: DA-based pharmacoepidemiological evidence is a valuable, albeit methodologically constrained, addition to the evidence base for contemporary diabetes management. CI - (c) 2026 John Wiley & Sons Ltd. FAU - Kostev, Karel AU - Kostev K AUID- ORCID: 0000-0002-2124-7227 AD - Marburg University, University Clinic, Marburg, Germany. AD - Epidemiology, IQVIA, Frankfurt, Germany. FAU - Sievert, Henning AU - Sievert H AD - Epidemiology, IQVIA, Frankfurt, Germany. FAU - Konrad, Marcel AU - Konrad M AUID- ORCID: 0000-0001-6798-5092 AD - Health & Social, FOM University of Applied Sciences for Economics and Management, Frankfurt am Main, Germany. FAU - Sarabhai, Theresia AU - Sarabhai T AD - Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen, Germany. LA - eng PT - Journal Article PT - Review DEP - 20260706 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/epidemiology/drug therapy MH - *Hypoglycemic Agents/therapeutic use MH - Germany/epidemiology MH - Databases, Factual MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Epidemiologic Studies MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Observational Studies as Topic MH - Pharmacoepidemiology PMC - PMC13538734 OTO - NOTNLM OT - GLP-1 receptor agonists OT - Germany OT - SGLT2 inhibitors OT - disease analyser OT - pharmacoepidemiology OT - real-world evidence OT - type 2 diabetes COIS- K.K. and H.S. are employees of IQVIA. M.K. and T.S. have no conflicts of interest to declare. EDAT- 2026/07/07 00:40 MHDA- 2026/09/03 05:37 PMCR- 2026/09/03 CRDT- 2026/07/06 23:41 PHST- 2026/06/28 00:00 [revised] PHST- 2026/06/14 00:00 [received] PHST- 2026/06/29 00:00 [accepted] PHST- 2026/09/03 05:37 [medline] PHST- 2026/07/07 00:40 [pubmed] PHST- 2026/07/06 23:41 [entrez] PHST- 2026/09/03 00:00 [pmc-release] AID - DOM71089 [pii] AID - 10.1111/dom.71089 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Oct;28(10):8795-8800. doi: 10.1111/dom.71089. Epub 2026 Jul 6. PMID- 42389857 OWN - NLM STAT- MEDLINE DCOM- 20260702 LR - 20260709 IS - 1419-8711 (Print) IS - 1419-8711 (Linking) VI - 28 IP - 2 DP - 2026 Jun TI - Adipokine dysregulation and oxidative stress in type 2 diabetes: Implications for neurodegeneration and neuroprotective eff ects of antidiabetic therapies. PG - 102-114 AB - BACKGROUND: Neurodegeneration is accelerated by Type 2 diabetes mellitus through adipokine dysregulation, insulin resistance, oxidative stress, and neuroinflammation. This could link metabolic imbalance to Alzheimer's disease, Parkinson's disease, and cognitive decline. The aim of this review is to clarify the roles of adipokines in type 2 diabetes-induced neurodegeneration, their molecular pathways, and the possible neuroprotective potential of antidiabetic agents. METHODS: Literature was searched in PubMed, Google Scholar, and Scopus for Englishlanguage articles published up to November 2025, using keywords like adipokines, diabetes mellitus, neurodegeneration, neuroinfl ammation, and antidiabetics. RESULTS: Results highlight those elevated levels of pro-infl ammatory adipokines, such as TNF-alpha, IL-6, and resistin, together with reduced levels of neuroprotective adipokines, including adiponectin and leptin, may drive NF-kB activation, suppression of Nrf2 signaling, and amyloid and tau pathology. This is further exacerbated by oxidative stress and mitochondrial dysfunction. Antidiabetic agents like metformin, GLP-1 agonists, thiazolidinediones, and SGLT2 inhibitors restore adipokine balance, enhance AMPK/PPARgamma signaling, and show cognitive benefits in mild cognitive impairment cohorts per clinical trials. DISCUSSION: In conclusion, repurposing antidiabetics via biomarker-guided multiple therapies offers disease-modifying promise for type 2 diabetes-linked neurodegeneration, necessitating large randomized controlled trials in prediabetic populations. SOURCE: (Neuropsychopharmacol Hung 2026; 28(2): 102-114) FAU - Kashmoola, Israa O AU - Kashmoola IO AD - Nineveh Health Directorate, Mosul, Nineveh Province, 41006, Iraq. AD - University of Mosul, College of Medicine, Department of Pharmacology, Mosul, Nineveh Province, 41002, Iraq. FAU - Mohammad, Shatha H AU - Mohammad SH AD - University of Mosul, College of Medicine, Department of Pharmacology, Mosul, Nineveh Province, 41002, Iraq. FAU - Alsaaty, Mohammad H AU - Alsaaty MH AD - University of Mosul, College of Medicine, Department of Medicine, Mosul, Nineveh Province, 41002, Iraq LA - eng PT - Journal Article PT - Review TT - Adipokinek diszregulacioja es oxidativ stressz 2-es tipusu cukorbetegsegben: a neurodegeneraciora gyakorolt hatasok es az antidiabetikus terapiak neuroprotektiv potencialja. PL - Hungary TA - Neuropsychopharmacol Hung JT - Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology JID - 100961631 RN - 0 (Adipokines) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (PPAR-gamma Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/metabolism MH - *Oxidative Stress/drug effects MH - *Adipokines/metabolism MH - *Hypoglycemic Agents/pharmacology/therapeutic use MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - PPAR-gamma Agonists MH - *Neurodegenerative Diseases/etiology/metabolism MH - Animals MH - Alzheimer Disease/metabolism OTO - NOTNLM OT - Adipokines OT - Type 2 diabetes mellitus OT - Neurodegeneration OT - Neuroinfl ammation OT - Antidiabetic agents EDAT- 2026/07/02 06:40 MHDA- 2026/07/02 16:09 CRDT- 2026/07/02 05:23 PHST- 2026/07/02 16:09 [medline] PHST- 2026/07/02 06:40 [pubmed] PHST- 2026/07/02 05:23 [entrez] PST - ppublish SO - Neuropsychopharmacol Hung. 2026 Jun;28(2):102-114. PMID- 42385950 OWN - NLM STAT- MEDLINE DCOM- 20260812 LR - 20260812 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 514 DP - 2026 Oct 2 TI - Effects of retatrutide on learning and memory in streptozotocin-induced male diabetic rats. PG - 116343 LID - S0166-4328(26)00319-0 [pii] LID - 10.1016/j.bbr.2026.116343 [doi] AB - Diabetes mellitus is associated with cognitive impairment and neurodegenerative changes, partly through hyperglycaemia-driven neuroinflammation and disrupted neuronal signalling. Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, has shown strong metabolic efficacy, but its effects on diabetes-associated cognitive dysfunction remain unclear. The present study investigated whether Retatrutide attenuates learning- and memory-related impairments in a streptozotocin-induced, insulin-deficient diabetic rat model. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced with streptozotocin, and spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while hippocampal cytokine levels (IL-1beta, TNF-alpha), BDNF, CREB, and AKT mRNA expression, Tau protein levels, and cortical and hippocampal histopathology were evaluated using biochemical, molecular, and histological methods. Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, and impaired behavioural performance, particularly prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose levels but did not prevent diabetes-associated weight loss. In behavioural testing, Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects were accompanied by a significant reduction in hippocampal TNF-alpha, a non-significant trend toward lower IL-1beta, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioural performance beyond control levels, although BDNF and CREB mRNA expression were increased in the non-diabetic Retatrutide group. These findings indicate that Retatrutide is associated with a partial attenuation of streptozotocin-induced behavioural and neuroinflammatory alterations in male rats. The observed effects are consistent with actions extending beyond glycaemic control alone, although direct central exposure of Retatrutide was not established in the present study. Further studies in insulin-resistant and type 2 diabetes-like models are needed to clarify the underlying mechanisms and translational relevance. CI - Copyright (c) 2026 Elsevier B.V. All rights reserved. FAU - Keskin, Ulya AU - Keskin U AD - Kutahya Health Sciences University, School of Medicine, Department of Medical Pharmacology, Turkiye. FAU - Altin, Eslem AU - Altin E AD - Kutahya Health Sciences University, School of Medicine, Turkiye. FAU - Kara, Melkan Kagan AU - Kara MK AD - Kutahya Health Sciences University, School of Medicine, Turkiye. Electronic address: melkankkara@hotmail.com. FAU - Tekin, Burak AU - Tekin B AD - Kutahya Health Sciences University, School of Medicine, Turkiye. FAU - Cakircoban, Kerime Nur AU - Cakircoban KN AD - Kutahya Health Sciences University, School of Medicine, Turkiye. FAU - Ozatik, Fikriye Yasemin AU - Ozatik FY AD - Kutahya Health Sciences University, School of Medicine, Department of Medical Pharmacology, Turkiye. FAU - Ari, Neziha Senem AU - Ari NS AD - Kutahya Health Sciences University, School of Medicine, Department of Histology and Embryology, Turkiye. FAU - Sezgin, Ayse Kocak AU - Sezgin AK AD - Kutahya Health Sciences University, School of Medicine, Department of Biochemistry, Turkiye. FAU - Gungor, Emre AU - Gungor E AD - Kutahya Health Sciences University, Faculty of Engineering and Natural Sciences, Computer Engineering, Turkiye. LA - eng PT - Journal Article DEP - 20260701 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Hypoglycemic Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (retatrutide) RN - 0 (Fatty Acids) RN - 0 (Peptides) SB - IM MH - Animals MH - Male MH - *Diabetes Mellitus, Experimental/drug therapy/metabolism/complications MH - Rats, Sprague-Dawley MH - Rats MH - Hippocampus/drug effects/metabolism/pathology MH - Maze Learning/drug effects MH - *Hypoglycemic Agents/pharmacology MH - *Memory/drug effects MH - Avoidance Learning/drug effects MH - Cognitive Enhancement MH - Brain-Derived Neurotrophic Factor/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Fatty Acids MH - Peptides OTO - NOTNLM OT - Behavioural neuroscience OT - Diabetes-related cognitive impairment OT - Learning and memory OT - Retatrutide OT - Triple incretin receptor agonists COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/07/02 04:10 MHDA- 2026/08/12 23:34 CRDT- 2026/07/01 19:31 PHST- 2026/01/23 00:00 [received] PHST- 2026/05/18 00:00 [revised] PHST- 2026/06/22 00:00 [accepted] PHST- 2026/08/12 23:34 [medline] PHST- 2026/07/02 04:10 [pubmed] PHST- 2026/07/01 19:31 [entrez] AID - S0166-4328(26)00319-0 [pii] AID - 10.1016/j.bbr.2026.116343 [doi] PST - ppublish SO - Behav Brain Res. 2026 Oct 2;514:116343. doi: 10.1016/j.bbr.2026.116343. Epub 2026 Jul 1. PMID- 42376874 OWN - NLM STAT- MEDLINE DCOM- 20260630 LR - 20260813 IS - 1752-8984 (Electronic) IS - 1479-1641 (Print) IS - 1479-1641 (Linking) VI - 23 IP - 3 DP - 2026 May-Jun TI - Comparative real-world outcomes of tirzepatide vs semaglutide in patients with obesity and type2 diabetes: A retrospective propensity-matched cohort study. PG - 14791641261465360 LID - 10.1177/14791641261465360 [doi] LID - 14791641261465360 AB - BackgroundWith the increasing use of GLP-1 receptor agonists and dual GIP/GLP-1 agonists for managing obesity and type 2 diabetes, understanding their real-world effectiveness and safety is essential. This TriNetX analysis directly compares clinical outcomes among patients treated with tirzepatide vs semaglutide.MethodWe utilized data from the TriNetX Research Network, identifying patients aged > 40 years or with obesity ("BMI >/= 30 kg/m2") and type 2 diabetes (HbA1c >/= 6.5% or fasting glucose.>/= 125 mg/dL). Qualifying events were restricted to May 1, 2022, through November 21, 2024. We established two cohorts: one initiating tirzepatide and another semaglutide, ensuring each patient had at least three prescriptions and no prior exposure to the comparator drug or other GLP-1 receptor agonists. The index date was defined as the first co-occurrence of the obesity/diabetes criteria and the respective drug prescription. To ensure comparability, we performed 1:1 propensity matching, resulting in 47,804 patients in each cohort. Outcomes, including all-cause mortality, MACE, heart failure exacerbation, ischemic stroke/TIA, hospitalization/ED use, dementia, UTI, adverse Gastrointestinal (GI) effects, and changes in HbA1c, were assessed within a 1-year window after the index date.ResultsOur matched cohort had a mean age of 75 years, with 45% male patients and 74% identified as white. Patients treated with tirzepatide experienced a significantly lower incidence of MACE at "("3.7% vs 4.1% (RR 0.918, 95% CI 0.862-0.978). All-cause mortality was also lower with tirzepatide (0.2% vs. 0.4%; Risk Ratio 0.436, 95% CI 0.338-0.562). The tirzapetide group achieved better glycemic control with a lower mean HbA1c (6.565% vs. 6.848%; p < 0.001) during the follow-up. There was no significant difference in heart failure exacerbation or UTI incidence. GI side effects were slightly less frequent in the tirzepatide cohort (9.8% vs. 10.2%; Risk Ratio 0.959, 95% CI 0.924-0.997), while hospitalization or emergency visits were comparable between the two groups.ConclusionIn this propensity matched cohort of patients with obesity and type 2 diabetes, tirzepatide demonstrated improved cardiometabolic outcomes compared to semaglutide, including lower all-cause mortality and lower HbA1c. These findings support the cardiovascular safety and efficacy of tirzapetide and highlight the need for further studies to evaluate its effectiveness in broader clinical populations. FAU - Qadeer, Abdul AU - Qadeer A AUID- ORCID: 0009-0005-8478-7086 AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Khalid, Marwah Bintay AU - Khalid MB AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. RINGGOLD: 123683 FAU - Syed, Ridwan AU - Syed R AD - Department of Cardiovascular Medicine, The University of Texas Medical Branch, Galveston, TX, USA. FAU - Jain, Samiksha AU - Jain S AD - Department of Medicine, Mobile Infirmary Medical Center, Mobile, AL, USA. RINGGOLD: 76093 FAU - Zakaria, Faiza AU - Zakaria F AD - Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, Michigan, USA. FAU - Khan, Muhammad Huzaifa Ahmed AU - Khan MHA AD - Department of Internal Medicine, Prime South GME Consortium Harlingen Medical Center, TX, USA. FAU - Gohar, Najam AU - Gohar N AD - Department of Internal Medicine, Ameer-ud-Din Medical College, Lahore, Pakistan. FAU - Shoukat, Ashraf AU - Shoukat A AD - Department of Medicine, Nishtar Medical University, Multan, Pakistan. RINGGOLD: 619131 FAU - Mortada, Ibrahim AU - Mortada I AUID- ORCID: 0009-0006-9215-880X AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Hamza, Izhan AU - Hamza I AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Motiwala, Afaq AU - Motiwala A AUID- ORCID: 0000-0002-4750-7090 AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Raja, Muhammad Waheed AU - Raja MW AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Blackwell, Thomas AU - Blackwell T AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA. FAU - Jneid, Hani AU - Jneid H AD - Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston, TX, USA. LA - eng PT - Comparative Study PT - Journal Article PT - Observational Study DEP - 20260630 PL - England TA - Diab Vasc Dis Res JT - Diabetes & vascular disease research JID - 101234011 RN - 53AXN4NNHX (Semaglutide) RN - OYN3CCI6QE (Tirzepatide) RN - 0 (Blood Glucose) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Biomarkers) RN - 0 (Incretins) RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Humans MH - Semaglutide MH - *Tirzepatide/therapeutic use/adverse effects MH - *Diabetes Mellitus, Type 2/drug therapy/diagnosis/mortality/blood MH - Male MH - Female MH - Treatment Outcome MH - Middle Aged MH - Retrospective Studies MH - *Obesity/drug therapy/diagnosis/mortality MH - Aged MH - Time Factors MH - Blood Glucose/drug effects/metabolism MH - *Glucagon-Like Peptides/therapeutic use/adverse effects MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Diabesity/mortality MH - Biomarkers/blood MH - *Incretins/therapeutic use/adverse effects MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Glycated Hemoglobin/metabolism MH - Risk Factors MH - Risk Assessment MH - Glycemic Control/adverse effects PMC - PMC13319829 OTO - NOTNLM OT - obesity diabetes mellitus OT - semaglutide OT - tirzepatide COIS- Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2026/06/30 16:10 MHDA- 2026/06/30 16:11 PMCR- 2026/06/30 CRDT- 2026/06/30 07:03 PHST- 2026/06/30 16:11 [medline] PHST- 2026/06/30 16:10 [pubmed] PHST- 2026/06/30 07:03 [entrez] PHST- 2026/06/30 00:00 [pmc-release] AID - 10.1177_14791641261465360 [pii] AID - 10.1177/14791641261465360 [doi] PST - ppublish SO - Diab Vasc Dis Res. 2026 May-Jun;23(3):14791641261465360. doi: 10.1177/14791641261465360. Epub 2026 Jun 30. PMID- 42364723 OWN - NLM STAT- Publisher LR - 20260727 IS - 1878-4216 (Electronic) IS - 0278-5846 (Linking) VI - 148 DP - 2026 Jul 13 TI - GLP-1 receptor agonists in addiction and affective disorders: Implications for dual disorders. PG - 111802 LID - S0278-5846(26)00200-9 [pii] LID - 10.1016/j.pnpbp.2026.111802 [doi] AB - Substance use disorders and affective disorders frequently coexist and share overlapping neurobiological mechanisms involving reward processing, stress regulation, neuroinflammation, and metabolic dysfunction. However, few pharmacological approaches currently target these interconnected pathways simultaneously. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for the treatment of type 2 diabetes and obesity, have recently attracted interest because of their central nervous system effects extending beyond metabolic regulation. This narrative review summarizes preclinical, translational, and emerging clinical evidence regarding the potential role of GLP-1 receptor signalling in addiction and affective disorders. Experimental studies suggest that GLP-1 receptor activation may influence dopaminergic, glutamatergic, and GABAergic neurotransmission within mesolimbic and corticolimbic circuits involved in reward-related behaviours. In animal models, GLP-1 RAs have been associated with reductions in drug-seeking behaviours and cue-induced reinstatement across several substances. Early clinical studies, particularly in alcohol use disorders, have reported reductions in alcohol intake, craving, and cue-reactivity. Additional preliminary evidence from metabolic and psychiatric populations suggests possible effects on depressive symptoms, cognitive function, and neuroinflammatory pathways, although findings remain heterogeneous and direct evidence in dual-disorder populations involving co-occurring substance use and affective disorders remains limited. Overall, current evidence supports further investigation of GLP-1 receptor signalling as a potential mechanistic link between metabolic, reward, and affective processes. Nevertheless, the available clinical literature remains preliminary, and adequately powered randomized controlled trials specifically targeting populations with co-occurring substance use and affective disorders are needed to clarify clinical efficacy, underlying mechanisms, and patient subgroups most likely to benefit. CI - Copyright (c) 2026 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Seijas-Amigo, Jose AU - Seijas-Amigo J AD - Cardiology Department, Complejo Hospitalario Universidad de Santiago de Compostela, Santiago de Compostela, Spain; Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela (FIDIS), Spain; Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Universidade de Santiago de Compostela, Spain. Electronic address: jose.seijas.amigo@sergas.es. FAU - Salgado-Barreira, Angel AU - Salgado-Barreira A AD - Universidade de Santiago de Compostela, Spain; Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiologia y Salud Publica CIBERESP), Carlos III Health Institute, Madrid, Spain. FAU - Eiras, Sonia AU - Eiras S AD - Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Translational Cardiology Group, Health Research Institute, Santiago de Compostela, Spain. FAU - Arias-Rivas, Susana AU - Arias-Rivas S AD - Neurology Department, Complejo Hospitalario Universidad de Santiago de Compostela, Santiago de Compostela, Spain. FAU - Rodriguez-Carnero, Gemma AU - Rodriguez-Carnero G AD - Endocrinology Department, Complejo Hospitalario Universidad de Santiago de Compostela, Santiago de Compostela, Spain. FAU - Gonzalez-Juanatey, Jose Ramon AU - Gonzalez-Juanatey JR AD - Cardiology Department, Complejo Hospitalario Universidad de Santiago de Compostela, Santiago de Compostela, Spain; Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela (FIDIS), Spain. LA - eng PT - Journal Article PT - Review DEP - 20260627 PL - England TA - Prog Neuropsychopharmacol Biol Psychiatry JT - Progress in neuro-psychopharmacology & biological psychiatry JID - 8211617 SB - IM OTO - NOTNLM OT - Affective disorders OT - Dual disorder OT - GLP-1 receptor agonists OT - Neuroinflammation OT - Reward circuitry OT - Substance use disorder COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/06/28 00:37 MHDA- 2026/06/28 00:37 CRDT- 2026/06/27 19:29 PHST- 2026/05/23 00:00 [received] PHST- 2026/06/21 00:00 [revised] PHST- 2026/06/22 00:00 [accepted] PHST- 2026/06/28 00:37 [pubmed] PHST- 2026/06/28 00:37 [medline] PHST- 2026/06/27 19:29 [entrez] AID - S0278-5846(26)00200-9 [pii] AID - 10.1016/j.pnpbp.2026.111802 [doi] PST - ppublish SO - Prog Neuropsychopharmacol Biol Psychiatry. 2026 Jul 13;148:111802. doi: 10.1016/j.pnpbp.2026.111802. Epub 2026 Jun 27. PMID- 42353761 OWN - NLM STAT- MEDLINE DCOM- 20260626 LR - 20260830 IS - 2073-4425 (Electronic) IS - 2073-4425 (Linking) VI - 17 IP - 6 DP - 2026 May 25 TI - Molecular Basis of Synergistic Causal Effect of Dual GLP-1R and GIPR Agonists for Risk Reduction in Diabetic Retinopathy, Alzheimer Disease, and Coronary Artery Disease in Diabetic Patients. LID - 10.3390/genes17060602 [doi] LID - 602 AB - Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 x 10(-17)] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 x 10(-8)]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients. FAU - Xu, Jiehui AU - Xu J AD - Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Ashebir, Yibeltal A AU - Ashebir YA AD - Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Shao, Yongzhao AU - Shao Y AUID- ORCID: 0000-0003-0641-6755 AD - Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA. LA - eng GR - U01OH012486/CC/CDC HHS/United States GR - P30AG066512/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20260525 PL - Switzerland TA - Genes (Basel) JT - Genes JID - 101551097 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (GLP1R protein, human) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Coronary Artery Disease/genetics/drug therapy/prevention & control MH - *Alzheimer Disease/genetics/drug therapy/prevention & control MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetic Retinopathy/genetics/drug therapy/prevention & control MH - *Diabetes Mellitus, Type 2/drug therapy/genetics/complications MH - *Receptors, Gastrointestinal Hormone/agonists/genetics MH - Glucagon-Like Peptide-1 Receptor/genetics MH - Glycated Hemoglobin/metabolism MH - Male MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - Female PMC - PMC13298441 OTO - NOTNLM OT - Alzheimer's diseases OT - PC-GMM OT - antidiabetic drug OT - cis-MR OT - coronary artery disease OT - diabetic retinopathy OT - multivariate Mendelian Randomization OT - synergistic causal effect COIS- The authors declare no conflicts of interest. EDAT- 2026/06/26 10:10 MHDA- 2026/06/27 04:10 PMCR- 2026/05/25 CRDT- 2026/06/26 01:08 PHST- 2026/03/17 00:00 [received] PHST- 2026/05/01 00:00 [revised] PHST- 2026/05/03 00:00 [accepted] PHST- 2026/06/27 04:10 [medline] PHST- 2026/06/26 10:10 [pubmed] PHST- 2026/06/26 01:08 [entrez] PHST- 2026/05/25 00:00 [pmc-release] AID - genes17060602 [pii] AID - genes-17-00602 [pii] AID - 10.3390/genes17060602 [doi] PST - epublish SO - Genes (Basel). 2026 May 25;17(6):602. doi: 10.3390/genes17060602. PMID- 42328044 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260622 LR - 20260813 IS - 2590-1125 (Electronic) IS - 2590-1125 (Linking) VI - 15 DP - 2026 TI - Glucagon-like peptide-1 receptor agonists in movement disorders: From Parkinson's disease to the broader spectrum - Mechanisms, evidence, and future directions. PG - 100461 LID - 10.1016/j.prdoa.2026.100461 [doi] LID - 100461 AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have emerged as potential neuroprotective agents in neurodegenerative disorders. GLP-1 signaling modulates key pathogenic pathways relevant to movement disorders, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with receptors widely expressed in motor-related brain regions. This narrative reviewaimed to summarize current mechanistic, preclinical, and clinical evidence regarding the role of GLP-1RAs across the spectrum of movement disorders. METHODS: A narrative review of the literature was conducted, including preclinical studies, randomized clinical trials, observational data, and pharmacovigilance analyses evaluating GLP-1RAs in movement disorders. RESULTS: Preclinical studies consistently demonstrate neuroprotective effects of GLP-1RAs, including preservation of dopaminergic neurons, reduction of alpha-synuclein aggregation, and improvement in motor function. Clinical evidence is most advanced in Parkinson's disease, where early randomized trials of exenatide and lixisenatide suggested modest motor benefits and possible disease-modifying effects. However, subsequent larger studies, including the phase III Exenatide-PD3 trial, failed to demonstrate significant clinical benefit. Preliminary signals have been reported in multiple system atrophy, whereas evidence in Huntington's disease, essential tremor, and other movement disorders remains largely preclinical. CONCLUSIONS: GLP-1RAs represents a biologically plausible but as yet unproven disease-modifying strategy in movement disorders. Translational challenges, including pharmacologic heterogeneity, variability in central nervous system exposure, and clinical trial design limitations-must be addressed. Future research should focus on biomarker-guided patient selection, optimized CNS-penetrant agents, and rigorously designed clinical trials. CI - (c) 2026 Published by Elsevier Ltd. FAU - Dahshan, Ahmed AU - Dahshan A AD - Neurology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. FAU - Khalil, Marwa Ibrahim Mahfouz AU - Khalil MIM AD - Geriatric Nursing Department, Faculty of Nursing, Alexandria university, Alexandria, Egypt. FAU - El-Jaafary, Shaimaa I AU - El-Jaafary SI AD - Neurology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. FAU - Al Yamani, Ahmed AU - Al Yamani A AD - Neurology Department, Thamar University, Dhamar, Yemen. LA - eng PT - Journal Article PT - Review DEP - 20260603 PL - England TA - Clin Park Relat Disord JT - Clinical parkinsonism & related disorders JID - 101761473 PMC - PMC13279746 OTO - NOTNLM OT - Current evidence OT - GLP-1 RAs OT - Movement disorders OT - Parkinson's disease OT - Trials COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/06/22 13:42 MHDA- 2026/06/22 13:43 PMCR- 2026/06/03 CRDT- 2026/06/22 07:21 PHST- 2026/04/19 00:00 [received] PHST- 2026/05/28 00:00 [revised] PHST- 2026/06/02 00:00 [accepted] PHST- 2026/06/22 13:43 [medline] PHST- 2026/06/22 13:42 [pubmed] PHST- 2026/06/22 07:21 [entrez] PHST- 2026/06/03 00:00 [pmc-release] AID - S2590-1125(26)00041-1 [pii] AID - 100461 [pii] AID - 10.1016/j.prdoa.2026.100461 [doi] PST - epublish SO - Clin Park Relat Disord. 2026 Jun 3;15:100461. doi: 10.1016/j.prdoa.2026.100461. eCollection 2026. PMID- 42320781 OWN - NLM STAT- MEDLINE DCOM- 20260916 LR - 20260922 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 100 IP - 8 DP - 2026 Oct 15 TI - Glucagon-Like Peptide-1 Signaling in Learning and Memory: Evidence, Mechanisms, and Therapeutic Implications. PG - 850-861 LID - S0006-3223(26)01344-2 [pii] LID - 10.1016/j.biopsych.2026.06.006 [doi] AB - Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for type 2 diabetes and obesity treatment in humans. Beyond these functions, the GLP-1 receptor (GLP-1R) is widely expressed throughout the brain, including in the hippocampus (HPC) and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that manifest with HPC dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and HPC neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms by which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on HPC GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's disease and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches toward maximizing bioavailability and brain penetrance. CI - Copyright (c) 2026 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Bashaw, Alexander G AU - Bashaw AG AD - Neuroscience Graduate Program, University of Southern California, Los Angeles, California. FAU - Roman-Ortiz, Ciorana AU - Roman-Ortiz C AD - Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California. FAU - Gao, Serena X AU - Gao SX AD - Neuroscience Graduate Program, University of Southern California, Los Angeles, California. FAU - Schier, Lindsey A AU - Schier LA AD - Neuroscience Graduate Program, University of Southern California, Los Angeles, California; Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California. FAU - Borner, Tito AU - Borner T AD - Neuroscience Graduate Program, University of Southern California, Los Angeles, California. Electronic address: tborner@usc.edu. FAU - Kanoski, Scott E AU - Kanoski SE AD - Neuroscience Graduate Program, University of Southern California, Los Angeles, California; Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California. Electronic address: kanoski@usc.edu. LA - eng GR - F31 DK142526/DK/NIDDK NIH HHS/United States GR - R01 DC018562/DC/NIDCD NIH HHS/United States GR - R01 DK104897/DK/NIDDK NIH HHS/United States GR - R01 DK123423/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Review DEP - 20260619 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - Animals MH - *Memory/physiology/drug effects MH - *Learning/physiology/drug effects MH - *Glucagon-Like Peptide 1/metabolism MH - *Signal Transduction/physiology MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - *Hippocampus/metabolism MH - *Memory Disorders/drug therapy/metabolism PMC - PMC13587819 MID - NIHMS2201004 OTO - NOTNLM OT - Alzheimer's disease OT - Dementia OT - GLP-1 OT - Hippocampus OT - Memory OT - Obesity EDAT- 2026/06/20 00:37 MHDA- 2026/09/16 23:34 PMCR- 2026/09/18 CRDT- 2026/06/19 19:36 PHST- 2026/02/23 00:00 [received] PHST- 2026/05/06 00:00 [revised] PHST- 2026/06/09 00:00 [accepted] PHST- 2026/09/16 23:34 [medline] PHST- 2026/06/20 00:37 [pubmed] PHST- 2026/06/19 19:36 [entrez] PHST- 2026/09/18 00:00 [pmc-release] AID - S0006-3223(26)01344-2 [pii] AID - 10.1016/j.biopsych.2026.06.006 [doi] PST - ppublish SO - Biol Psychiatry. 2026 Oct 15;100(8):850-861. doi: 10.1016/j.biopsych.2026.06.006. Epub 2026 Jun 19. PMID- 42316561 OWN - NLM STAT- Publisher LR - 20260619 IS - 1996-3181 (Electronic) IS - 1871-5273 (Linking) DP - 2026 Jun 18 TI - Role of Cholesterol Metabolism in the Link Between Diabetes and Alzheimer's Disease. LID - 10.2174/0118715273444881260119053309 [doi] AB - INTRODUCTION: Type 2 Diabetes Mellitus (T2DM) and Alzheimer's Disease (AD) share complex metabolic disturbances, with cholesterol dysregulation emerging as a central mechanistic link. Although brain cholesterol metabolism operates largely independently of peripheral lipid pools, it is highly susceptible to disruption, particularly in the insulin-resistant ApoE4 genotype. METHODS: This review follows a structured literature approach using PubMed, Scopus, and Web of Science (2000-2025) to critically evaluate mechanistic and translational evidence on cholesterol- T2DM-AD interplay. It critically evaluates current evidence on cholesterol production, transport, and elimination in the Central Nervous System (CNS), focusing on the roles of astrocytes, neurons, and transporters such as ATP-binding cassette transporter A1 (ABCA1). It also explores how peripheral metabolic stress in T2DM affects central cholesterol homeostasis and contributes to amyloid- beta (Abeta) accumulation and neurodegeneration. Pharmacological approaches targeting cholesterol regulation, including statins, liver X receptor (LXR) modulators, and glucagon-like peptide-1 (GLP-1) receptor agonists, are discussed. RESULTS: Findings indicate that impaired cholesterol regulation disrupts neuron-astrocyte interactions, enhances Abeta deposition, and accelerates neurodegeneration. Controversies remain regarding the relative impact of peripheral vs. central cholesterol imbalance and Blood-Brain Barrier (BBB) permeability in therapy. In T2DM, peripheral insulin resistance and hypercholesterolemia exacerbate central cholesterol imbalance, thereby intensifying AD pathology. Emerging therapeutic studies suggest that modulation of cholesterol pathways may reduce neuroinflammation, promote Abeta clearance, and slow cognitive decline. DISCUSSION: The overlap between T2DM and AD highlights cholesterol metabolism as a pivotal pathogenic axis. While peripheral factors worsen central dysregulation, CNS-specific disturbances independently drive disease progression. Targeted modulation of cholesterol pathways, through statins, LXR modulators, and GLP-1 agonists, shows promise but demands precision approaches tailored to genotype and BBB permeability. CONCLUSION: The cholesterol-AD-T2DM axis represents a promising therapeutic target. Addressing cholesterol dysregulation could enable novel, personalized strategies to mitigate neurodegeneration and cognitive decline. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Sharma, Pratishtha AU - Sharma P AD - Department of Pharmacology, LJ Institute of Pharmacy, LJ University, Ahmedabad, Gujarat, 382210, India. AD - School of Pharmacy, Indrashil University, Rajpur, Kadi, Gujarat, 382715, India. FAU - Dodiya, Rohinee AU - Dodiya R AD - Department of Pharmacology, LJ Institute of Pharmacy, LJ University, Ahmedabad, Gujarat, 382210, India. FAU - Israni, Dipa K AU - Israni DK AD - Department of Pharmacology, LJ Institute of Pharmacy, LJ University, Ahmedabad, Gujarat, 382210, India. FAU - Kapoor, Devesh U AU - Kapoor DU AD - Dr. Dayaram Patel Pharmacy College, Bardoli, Gujarat, India. AD - Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India. LA - eng PT - Journal Article DEP - 20260618 PL - United Arab Emirates TA - CNS Neurol Disord Drug Targets JT - CNS & neurological disorders drug targets JID - 101269155 SB - IM OTO - NOTNLM OT - Alzheimer's disease OT - ApoE4 OT - GLP-1 receptor agonists. OT - LXR modulators OT - amyloid-beta (Abeta) OT - blood-brain barrier OT - type 2 diabetes mellitus EDAT- 2026/06/19 06:33 MHDA- 2026/06/19 06:33 CRDT- 2026/06/19 00:53 PHST- 2025/10/05 00:00 [received] PHST- 2025/11/10 00:00 [revised] PHST- 2025/11/18 00:00 [accepted] PHST- 2026/06/19 06:33 [medline] PHST- 2026/06/19 06:33 [pubmed] PHST- 2026/06/19 00:53 [entrez] AID - CNSNDDT-EPUB-156477 [pii] AID - 10.2174/0118715273444881260119053309 [doi] PST - aheadofprint SO - CNS Neurol Disord Drug Targets. 2026 Jun 18. doi: 10.2174/0118715273444881260119053309. PMID- 42311464 OWN - NLM STAT- MEDLINE DCOM- 20260618 LR - 20260813 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 20 DP - 2026 TI - GLP-1 Receptor Agonists in Neurological Disorders: From Mechanisms to Clinical Translation. PG - 613616 LID - 10.2147/DDDT.S613616 [doi] LID - 613616 AB - Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, have been used for years to treat type 2 diabetes and obesity. More recently, it has become clear that these receptors are widely distributed throughout the central nervous system (CNS), which has raised the possibility of repurposing these drugs for neurological disorders. In this review we go through the evidence across a range of neurological conditions, discuss the main mechanisms thought to explain their neuroprotective effects, and point out the hurdles that still need to be cleared before they can be used in the clinic. Preclinical work has been fairly consistent. These drugs activate the cAMP/PKA/CREB pathway to boost BDNF expression. They also turn on the PI3K/Akt pathway, which reins in GSK-3beta and cuts down tau hyperphosphorylation. At the same time, they put the brakes on NLRP3 inflammasome activation in microglia and get AMPK dependent mitochondrial biogenesis and autophagy going. In animal models of Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI), these cellular changes add up to less protein aggregation, less neuron loss, and better functional outcomes. Clinical data are harder to interpret. Some trials have shown modest improvements in cognition or motor function, but others have found no meaningful effect on disease progression. One thing that does not get enough attention is that different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, and these differences could well explain why trial results have been so mixed. Looking ahead, getting these drugs into the clinic will depend on choosing the ones that actually reach the CNS, developing biomarkers that can predict who will respond, and designing trials that take disease heterogeneity into account. Seen this way, this review offers a practical framework for turning mechanistic insights into real patient benefit. CI - (c) 2026 Li et al. FAU - Li, Pengpeng AU - Li P AUID- ORCID: 0009-0008-4744-625X AD - Department of Neurosurgery, Xi'an Aerospace Hospital of Northwest University, Xi'an, Shanxi, 710000, People's Republic of China. FAU - Gao, Yangyang AU - Gao Y AD - Department of Neurosurgery, Xi'an Aerospace Hospital of Northwest University, Xi'an, Shanxi, 710000, People's Republic of China. FAU - Liu, Wei AU - Liu W AD - Department of Neurosurgery, Xi'an Aerospace Hospital of Northwest University, Xi'an, Shanxi, 710000, People's Republic of China. LA - eng PT - Journal Article PT - Review DEP - 20260612 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Nervous System Diseases/drug therapy/metabolism MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism PMC - PMC13271144 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Parkinson's disease OT - neuroinflammation OT - neuroprotection COIS- The authors declare that they have no competing interests. EDAT- 2026/06/18 06:32 MHDA- 2026/06/18 06:33 PMCR- 2026/06/12 CRDT- 2026/06/18 04:37 PHST- 2026/04/01 00:00 [received] PHST- 2026/06/02 00:00 [accepted] PHST- 2026/06/18 06:33 [medline] PHST- 2026/06/18 06:32 [pubmed] PHST- 2026/06/18 04:37 [entrez] PHST- 2026/06/12 00:00 [pmc-release] AID - 613616 [pii] AID - 10.2147/DDDT.S613616 [doi] PST - epublish SO - Drug Des Devel Ther. 2026 Jun 12;20:613616. doi: 10.2147/DDDT.S613616. eCollection 2026. PMID- 42298987 OWN - NLM STAT- Publisher LR - 20260616 IS - 2211-9132 (Print) IS - 2211-9132 (Linking) DP - 2025 Dec 12 TI - Real-world trends in glucagon-like peptide-1 receptor agonists prescribing in acute kidney disease: a global federated-network study of dialysis-requiring acute kidney injury survivors. LID - 10.23876/j.krcp.25.104 [doi] AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) confer cardiovascular and renal benefits in type 2 diabetes mellitus (T2DM). However, their real-world utilization in acute kidney disease (AKD) remains underexplored. METHODS: Using the TriNetX Global Network, we identified adults who survived dialysis-requiring acute kidney injury and met Acute Disease Quality Initiative 16 criteria for AKD (2012-2022). Prescribing trends and determinants of GLP-1 RAs were analyzed with logistic regression. RESULTS: Among 1,095,318 post-dialysis AKD patients, 8,334 (0.8%) received GLP-1 RAs. Prescription rates reached 4.5% in patients with T2DM and rose steeply after 2018, largely driven by long-acting agents. Independent positive predictors (odds ratio [OR], 95% confidence interval [CI]) were T2DM (6.6, 6.01-7.27), chronic kidney disease (CKD) stage 3 (1.7, 1.61-1.85), obesity (1.5, 1.46-1.63), and hypertension (1.4, 1.31-1.49). Liver or cerebrovascular disease and anticoagulant use were negative predictors. Co-medication with insulin, metformin or sodium-glucose cotransporter 2 inhibitor was common. GLP-1 RA users had higher risks of hypoglycemia (5.4, 4.87-5.99), depression (2.6, 2.51-2.80), gastroparesis (2.6, 2.37-2.83) and other gastrointestinal events, but a lower risk of dementia (0.7, 0.60-0.81), with values representing OR and 95% CI, respectively. Nausea/vomiting declined over the decade, whereas constipation increased. Other adverse event rates were stable. CONCLUSION: Real-world use of GLP-1 RAs in AKD remains modest but is accelerating, especially in patients with T2DM, CKD stage 3 and obesity. Given the elevated rates of hypoglycemia, mood disorders and gastrointestinal intolerance, careful monitoring is warranted when prescribing these agents in the post-dialysis AKD setting. FAU - Pan, Heng-Chih AU - Pan HC AD - Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. AD - Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan. AD - Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan. AD - Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan. AD - Kidney Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan. FAU - Wang, Chung-An AU - Wang CA AD - Department of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Chen, Jui-Yi AU - Chen JY AD - Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan. AD - Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. FAU - Peng, Kang-Yung AU - Peng KY AD - Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Wu, Vin-Cent AU - Wu VC AD - Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. q91421028@ntu.edu.tw. AD - Primary Aldosteronism Center, National Taiwan University Hospital, Taipei, Taiwan. q91421028@ntu.edu.tw. AD - National Taiwan University Hospital Study Group of Acute Renal Failure (NARF), Taipei, Taiwan. q91421028@ntu.edu.tw. AD - Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. q91421028@ntu.edu.tw. LA - eng PT - Journal Article DEP - 20251212 PL - Korea (South) TA - Kidney Res Clin Pract JT - Kidney research and clinical practice JID - 101586778 OTO - NOTNLM OT - Acute kidney injury; Drug prescriptions/trends; Electronic health records; Glucagon-like peptide 1 receptor agonists; Renal replacement therapy OT - Type 2 diabetes mellitus EDAT- 2026/06/16 06:35 MHDA- 2026/06/16 06:35 CRDT- 2026/06/16 03:02 PHST- 2025/04/14 00:00 [received] PHST- 2025/09/15 00:00 [accepted] PHST- 2026/06/16 06:35 [medline] PHST- 2026/06/16 06:35 [pubmed] PHST- 2026/06/16 03:02 [entrez] AID - j.krcp.25.104 [pii] AID - 10.23876/j.krcp.25.104 [doi] PST - aheadofprint SO - Kidney Res Clin Pract. 2025 Dec 12. doi: 10.23876/j.krcp.25.104. PMID- 42261705 OWN - NLM STAT- MEDLINE DCOM- 20260804 LR - 20260831 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 112 IP - 3 DP - 2026 Aug TI - Semaglutide showed limited improvements in patients with Alzheimer's disease: Revisiting the evoke and evoke + clinical trials. PG - 1377-1381 LID - 10.1177/13872877261458402 [doi] AB - BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the drug in patients with Alzheimer's disease. The trial management presented results of the intermediate readout at week 104 of the CDR-SB scores, which were negative. On the basis of that, the management decided to declare the trials a failure. However, data from week 130 and 156 had not been statistically analyzed.ObjectiveWhen evaluating time points 130 and 156, several results show a separation between drug group and placebo group with semaglutide showing better results.MethodsUsing the means, converting the SEMs to SDs and numbers of patients per group, I analyzed the results using the Welch T-test (two-tailed), which does not assume equal SD.ResultsThe ADCS-ADL-MCI test, Evoke trial, week 130, did show a significant difference, p = 0.0039. Other test such as the ADAS-cog-13 results show trends towards improvement by semaglutide at week 156. Cerebrospinal fluid biomarker analyses showed significant differences in some AD markers, too.ConclusionsThe results did show some limited drug effects at later time points of the trials. However, Semaglutide has been designed to stay in the blood for a long time and therefore does not cross the blood-brain barrier readily. Novel GLP-1 type drugs that can cross the blood-brain barrier easily may show superior protective effects in AD patients. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - Neurology Department, Second Associated Hospital, Shanxi Medical University, Taiyuan, Shanxi province, PR China. AD - Kariya Pharmaceuticals Ltd, Copenhagen, Denmark. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20260609 PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - *Alzheimer Disease/drug therapy MH - *Glucagon-Like Peptides/therapeutic use MH - *Hypoglycemic Agents/therapeutic use MH - Semaglutide MH - Treatment Outcome MH - Randomized Controlled Trials as Topic MH - Clinical Trials, Phase III as Topic OTO - NOTNLM OT - Alzheimer's disease OT - dementia OT - incretin OT - insulin OT - memory OT - mild cognitive impairment COIS- Declaration of conflicting interestsThe author declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CH is a named inventor on patents that cover GLP-1, GIP or dual GLP-1/GIP receptor agonists as treatments for AD and PD. He is the CSO of the biotech company Kariya Pharmaceuticals Ltd, Denmark. EDAT- 2026/06/09 06:35 MHDA- 2026/08/04 06:37 CRDT- 2026/06/09 05:23 PHST- 2026/08/04 06:37 [medline] PHST- 2026/06/09 06:35 [pubmed] PHST- 2026/06/09 05:23 [entrez] AID - 10.1177/13872877261458402 [doi] PST - ppublish SO - J Alzheimers Dis. 2026 Aug;112(3):1377-1381. doi: 10.1177/13872877261458402. Epub 2026 Jun 9. PMID- 42247872 OWN - NLM STAT- MEDLINE DCOM- 20260725 LR - 20260725 IS - 1090-2120 (Electronic) IS - 0045-2068 (Linking) VI - 180 DP - 2026 Sep 15 TI - Shared pathophysiology and therapeutic repurposing in Alzheimer's disease and type 2 diabetes: a critical review of convergent mechanisms and clinical challenges. PG - 110044 LID - S0045-2068(26)00580-8 [pii] LID - 10.1016/j.bioorg.2026.110044 [doi] AB - Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent age-related disorders that share striking pathophysiological similarities, leading to the conceptualization of AD as a metabolic disorder often termed "type 3 diabetes." While numerous reviews have documented the epidemiological association between these diseases, a critical synthesis of the underlying molecular convergence-and its implications for therapeutic repurposing-remains fragmented. This review provides a comprehensive and critical analysis of the shared signaling pathways that underpin both AD and T2DM, including insulin resistance, oxidative stress, the AGE-RAGE axis, amyloidogenic protein misfolding (Abeta in AD and IAPP in T2DM), endoplasmic reticulum stress, and vasculopathy. By systematically examining each pathway, we highlight not only their disease-specific manifestations but also their intricate interconnections and the critical unresolved questions that hinder translational progress. We then critically evaluate the current evidence for repurposing major antidiabetic drug classes-insulin and its analogues, metformin, sulfonylureas, thiazolidinediones, incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors), and amylin receptor modulators-for AD treatment. Through this analysis, we identify key sources of clinical inconsistency, including patient heterogeneity (particularly APOE epsilon4 genotype), disease stage dependency, blood-brain barrier integrity, and off-target safety concerns. By integrating mechanistic insights with a rigorous assessment of clinical evidence, this review advances the understanding of AD as a metabolic disorder and provides a framework for future precision medicine approaches in cross-disease intervention. The synthesis presented here underscores that realizing the therapeutic potential of antidiabetic drugs in AD will require mechanism-guided patient stratification, early-stage intervention, and the development of brain-selective agents with improved efficacy and safety profiles. CI - Copyright (c) 2026 Elsevier Inc. All rights reserved. FAU - Fu, Wenling AU - Fu W AD - Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. FAU - Lu, Roujun AU - Lu R AD - Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. FAU - Wang, Dongdong AU - Wang D AD - Centre for Metabolism, Obesity and Diabetes Research, Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada. Electronic address: wangd123@mcmaster.ca. FAU - Sang, Zhipei AU - Sang Z AD - Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. Electronic address: sangzhipei@hainanu.edu.cn. LA - eng PT - Journal Article PT - Review DEP - 20260601 PL - United States TA - Bioorg Chem JT - Bioorganic chemistry JID - 1303703 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/metabolism/physiopathology MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism/physiopathology MH - *Hypoglycemic Agents/therapeutic use/pharmacology/chemistry MH - *Drug Repositioning MH - Animals OTO - NOTNLM OT - Alzheimer's disease (AD) OT - Abeta OT - Insulin OT - Type 2 diabetes mellitus (T2DM) COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zhipei Sang reports financial support was provided by National Natural Science Foundation of China. NO has patent NO pending to NO. NO If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/06/06 00:35 MHDA- 2026/07/25 06:36 CRDT- 2026/06/05 18:06 PHST- 2026/01/06 00:00 [received] PHST- 2026/03/12 00:00 [revised] PHST- 2026/05/25 00:00 [accepted] PHST- 2026/07/25 06:36 [medline] PHST- 2026/06/06 00:35 [pubmed] PHST- 2026/06/05 18:06 [entrez] AID - S0045-2068(26)00580-8 [pii] AID - 10.1016/j.bioorg.2026.110044 [doi] PST - ppublish SO - Bioorg Chem. 2026 Sep 15;180:110044. doi: 10.1016/j.bioorg.2026.110044. Epub 2026 Jun 1. PMID- 42227394 OWN - NLM STAT- Publisher LR - 20260602 IS - 1875-6190 (Electronic) IS - 1570-159X (Linking) DP - 2026 May 20 TI - GLP-1 Receptor Agonists in Neuropathic Pain and Neurodegenerative Diseases: Mechanisms, Therapeutic Potentials, and Future Perspectives. LID - 10.2174/011570159X450007260305034049 [doi] AB - Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), originally developed for type 2 diabetes mellitus, have demonstrated significant neuroprotective and analgesic properties in preclinical and early clinical studies. This review examines the role of GLP-1RAs and their therapeutic potential in neuropathic pain and neurodegenerative diseases, which share several overlapping pathophysiological mechanisms. These include chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired insulin signaling, and altered synaptic plasticity. In neuropathic pain, GLP-1RAs attenuate neuroinflammation and reduce central sensitization. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, they promote neuronal survival, restore metabolic homeostasis, and counteract protein aggregation and autophagic dysfunction. The convergence of these mechanisms supports the exploration of GLP-1RAs as a unified therapeutic approach across neuroinflammatory and neurodegenerative fields. GLP-1RAs exert multifaceted neuroprotective, anti-inflammatory, and autophagy-enhancing effects, highlighting their potential as disease-modifying agents in neuropathic pain and neurodegenerative disorders. Further studies are needed to optimize CNS delivery, refine patient selection, and evaluate long-term safety. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Grasso, Margherita AU - Grasso M AD - Oasi Research Institute-IRCCS, Unit of Neuropharmacology and Translational Neurosciences, Troina, Italy. FAU - Fidilio, Annamaria AU - Fidilio A AUID- ORCID: 0000-0002-9279-0171 AD - Oasi Research Institute-IRCCS, Unit of Neuropharmacology and Translational Neurosciences, Troina, Italy. AD - Department of Drug and Health Sciences, University of Catania, Catania, Italy. FAU - Varrasi, Sofia AU - Varrasi S AD - Oasi Research Institute-IRCCS, Unit of Neuropharmacology and Translational Neurosciences, Troina, Italy. AD - Department of Drug and Health Sciences, University of Catania, Catania, Italy. FAU - Chiechio, Santina AU - Chiechio S AUID- ORCID: 0000-0003-4648-391X AD - Oasi Research Institute-IRCCS, Unit of Neuropharmacology and Translational Neurosciences, Troina, Italy. AD - Department of Drug and Health Sciences, University of Catania, Catania, Italy. LA - eng PT - Journal Article DEP - 20260520 PL - United Arab Emirates TA - Curr Neuropharmacol JT - Current neuropharmacology JID - 101157239 SB - IM OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Parkinson's disease. OT - neurodegenerative diseases OT - neuroinflammation OT - neuropathic pain EDAT- 2026/06/02 12:45 MHDA- 2026/06/02 12:45 CRDT- 2026/06/02 06:53 PHST- 2025/09/23 00:00 [received] PHST- 2025/12/24 00:00 [revised] PHST- 2026/01/08 00:00 [accepted] PHST- 2026/06/02 12:45 [medline] PHST- 2026/06/02 12:45 [pubmed] PHST- 2026/06/02 06:53 [entrez] AID - CN-EPUB-155875 [pii] AID - 10.2174/011570159X450007260305034049 [doi] PST - aheadofprint SO - Curr Neuropharmacol. 2026 May 20. doi: 10.2174/011570159X450007260305034049. PMID- 42219869 OWN - NLM STAT- MEDLINE DCOM- 20260812 LR - 20260812 IS - 1945-7197 (Electronic) IS - 0021-972X (Linking) VI - 111 IP - 9 DP - 2026 Aug 13 TI - Anti-inflammatory effects of GLP1-RA drugs. PG - e2076-e2085 LID - 10.1210/clinem/dgag218 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RA) are established treatment options for type 2 diabetes and obesity. This class of medications has redefined care by lowering glucose, reducing body weight, and improving cardiovascular outcomes. Beyond metabolic benefits, accumulating evidence indicates that GLP-1RA exert direct anti-inflammatory effects across multiple organ systems. Chronic inflammation is a driving force behind many prevalent diseases, including diabetes, cardiovascular disease, neurodegenerative disorders, and inflammatory bowel disease. This review summarizes the current evidence of the anti-inflammatory effects of GLP-1RA, highlighting data from preclinical models and clinical trials across different diseases. By targeting both metabolic and inflammatory pathways, GLP-1RA may offer dual cardiometabolic and immunomodulatory protection, positioning these agents as promising candidates for broader therapeutic applications. However, several key questions remain regarding causality, the precise molecular mechanisms involved, and the extent to which these anti-inflammatory effects can be translated into effective therapies for nonmetabolic inflammatory diseases. CI - (c) The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. See the journal About page for additional terms. FAU - Quintana, Luis AU - Quintana L AD - Department of Internal Medicine I-Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen D-52074, Germany. FAU - Tabaza, Nadim AU - Tabaza N AD - Department of Internal Medicine I-Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen D-52074, Germany. FAU - Kurt, Berkan AU - Kurt B AUID- ORCID: 0009-0006-1313-152X AD - Department of Internal Medicine I-Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen D-52074, Germany. FAU - Kahles, Florian AU - Kahles F AUID- ORCID: 0000-0001-6343-2562 AD - Department of Internal Medicine I-Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen D-52074, Germany. LA - eng GR - Deutsche Forschungsgemeinschaft/ GR - 520275106/German Research Foundation/ GR - SFB TRR 219-322900939-M-07/Emmy Noether Research Group/ GR - European Research Area Network on Cardiovascular Diseases/ GR - JTC-2019/BMBF/ GR - MyPenPath-01KL2004/BMBF/ GR - European Foundation for the Study of Diabetes (EFSD)/ GR - NNF2OSA0066111/Novo Nordisk Foundation/ GR - Interdisciplinary Centre for Clinical Research/ GR - PTD 1-11/RWTH Aachen University/ PT - Journal Article PT - Review PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Anti-Inflammatory Agents/therapeutic use/pharmacology MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Inflammation/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy/immunology MH - Cardiovascular Diseases/drug therapy MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Neurodegenerative Diseases/drug therapy OTO - NOTNLM OT - GLP-1 receptor agonists OT - autoimmune diseases OT - cardiometabolic disease OT - cardiovascular disease OT - immunomodulation OT - infectious diseases OT - inflammation OT - inflammatory bowel disease OT - neurodegeneration OT - sepsis EDAT- 2026/06/01 08:04 MHDA- 2026/08/12 23:34 CRDT- 2026/06/01 02:03 PHST- 2025/12/19 00:00 [received] PHST- 2026/05/25 00:00 [accepted] PHST- 2026/08/12 23:34 [medline] PHST- 2026/06/01 08:04 [pubmed] PHST- 2026/06/01 02:03 [entrez] AID - 8698993 [pii] AID - 10.1210/clinem/dgag218 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2026 Aug 13;111(9):e2076-e2085. doi: 10.1210/clinem/dgag218. PMID- 42213027 OWN - NLM STAT- MEDLINE DCOM- 20260717 LR - 20260803 IS - 2162-5239 (Electronic) IS - 0094-6354 (Linking) VI - 94 IP - 3 DP - 2026 Jun 1 TI - AANA Journal Course-GLP-1 Receptor Agonists: What CRNAs Need to Know About Their Expanding Role. PG - 225-233 LID - 10.70278/AANAJ/.0000001093 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were developed to treat type 2 diabetes mellitus and later became widely used for the management of obesity. Recent evidence includes off-label uses for substance use disorders; nicotine and alcohol dependence; neurodegenerative diseases; and cardiovascular, kidney, and liver diseases. Certified registered nurse anesthetists (CRNAs) are likely to encounter patients using GLP-1RAs for both Food and Drug Administration-approved and nontraditional purposes. This review explores the pharmacology and mechanisms of action of GLP-1RAs, with a focus on their relevance in the perioperative period. It covers their effects on blood glucose control, gastric motility, and central nervous system pathways. Special attention is given to delayed gastric emptying, concerns about pulmonary aspiration, and the metabolic benefits of glucose-dependent insulin secretion and reduced blood glucose fluctuations. Current professional guidelines emphasize personalized, patient-centered perioperative care. The increasing use of GLP-1RAs, combined with more off-label prescribing and unregulated peptide use, emphasizes the need for thorough preoperative screening, clear medication reconciliation, and effective interdisciplinary communication. As more evidence emerges, CRNAs must remain vigilant while recognizing that the expanding role of GLP-1RAs is important for optimizing perioperative safety and achieving optimal patient outcomes in modern anesthesia practice. CI - Copyright (c) 2026 by the American Association of Nurse Anesthesiology. FAU - Davies, Adam AU - Davies A AD - Assistant Professor at the University of South Florida, Tampa, Florida. FAU - Maldonado, Karla AU - Maldonado K AD - Assistant Professor at the University of South Florida, Tampa, Florida. FAU - Diaz, Mayte AU - Diaz M AD - Assistant Professor at the University of South Florida, Tampa, Florida. FAU - Rawson, Eleanor AU - Rawson E AD - Assistant Professor at the University of South Florida, Tampa, Florida. FAU - Canale, Michelle AU - Canale M AD - Assistant Professor at the University of South Florida, Tampa, Florida. FAU - Zhang, Sarah AU - Zhang S AD - Associate Professor at the University of South Florida, Tampa, Florida. FAU - Dabney, Cynthia AU - Dabney C AD - Assistant Professor at the University of South Florida, Tampa, Florida. Email: Cdabney1@usf.edu. LA - eng PT - Journal Article PT - Review PL - United States TA - AANA J JT - AANA journal JID - 0431420 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Nurse Anesthetists/education MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy MH - United States MH - *Nurse's Role OTO - NOTNLM OT - anesthesia OT - glucagon-like peptide-1 OT - glucagon-like peptide-1 receptor agonist OT - guidelines OT - off-label use COIS- Name: Adam Davies, DNP, CRNA, APRN; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Karla Maldonado, DrAP, CRNA, APRN, FAANA; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Mayte Diaz, DNP, CRNA, APRN; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Eleanor Rawson, DNP, CRNA, APRN, FAANA; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Michelle Canale, DNP, CRNA, APRN, FAANA; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Sarah Zhang, PhD, CRNA, APRN; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Cynthia Dabney, PhD, DNP, CRNA; Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author; she is the corresponding author for this article. Disclosures: None.The authors did not discuss off-label use within the article. Disclosure statements are available upon request. EDAT- 2026/05/29 15:42 MHDA- 2026/05/29 15:43 CRDT- 2026/05/29 10:33 PHST- 2026/05/29 15:43 [medline] PHST- 2026/05/29 15:42 [pubmed] PHST- 2026/05/29 10:33 [entrez] AID - 10.70278/AANAJ/.0000001093 [doi] PST - ppublish SO - AANA J. 2026 Jun 1;94(3):225-233. doi: 10.70278/AANAJ/.0000001093. PMID- 42208956 OWN - NLM STAT- MEDLINE DCOM- 20260715 LR - 20260930 IS - 2213-8595 (Electronic) IS - 2213-8587 (Linking) VI - 14 IP - 8 DP - 2026 Aug TI - Beyond weight loss: multisystem benefits of obesity medications. PG - 678-692 LID - S2213-8587(26)00100-2 [pii] LID - 10.1016/S2213-8587(26)00100-2 [doi] AB - Obesity is increasingly managed with medications as disease-modifying therapies, reflecting its role as a gateway disease driving metabolic, cardiovascular, reproductive, neuropsychiatric, and mechanical conditions. This Review synthesises evidence from randomised controlled trials and high-quality meta-analyses on approved and late-stage investigational obesity medications, including phentermine-topiramate, naltrexone-bupropion, glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide, semaglutide, subcutaneously and orally), and newer GLP-1 receptor agonist-based agents (eg, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). We evaluated the effects of obesity medications across major obesity-related conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea syndrome, polycystic ovary syndrome (recently named polyendocrine metabolic ovarian syndrome), osteoarthritis, muscle mass, depression, quality of life, and food cravings, along with binge-eating disorders, substance use disorders, and neurodegenerative diseases. Overall, GLP-1-based and multiagonist therapies show beneficial effects across these comorbid conditions. While many benefits of obesity medications are mediated by weight loss, accumulating evidence indicates important weight loss-independent effects, particularly with GLP-1 receptor agonist-based therapies. A broader understanding of these pleiotropic effects is essential to inform personalised obesity management and optimise long-term clinical outcomes. CI - Copyright (c) 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. FAU - Savas, Mesut AU - Savas M AD - Obesity Center CGG (Centrum Gezond Gewicht), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.savas@erasmusmc.nl. FAU - Kuckuck, Susanne AU - Kuckuck S AD - Obesity Center CGG (Centrum Gezond Gewicht), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Epidemiology and Biostatistics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. FAU - Boon, Mariette R AU - Boon MR AD - Obesity Center CGG (Centrum Gezond Gewicht), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. FAU - van Rossum, Elisabeth F C AU - van Rossum EFC AD - Obesity Center CGG (Centrum Gezond Gewicht), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. LA - eng PT - Journal Article PT - Review DEP - 20260528 PL - England TA - Lancet Diabetes Endocrinol JT - The lancet. Diabetes & endocrinology JID - 101618821 RN - 0 (Anti-Obesity Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Obesity/drug therapy/complications MH - *Anti-Obesity Agents/therapeutic use MH - *Weight Loss/drug effects MH - Diabetes Mellitus, Type 2/drug therapy MH - Female MH - Semaglutide MH - Cardiovascular Diseases/drug therapy COIS- Declaration of interests MS received honoraria for lectures and educational events from Obesitas Platform-MedOnline, SCEM, Health Investment, Public Eyes Healthcare Communications, BSL, Medische Scholing, and MedClass-Boehringer Ingelheim; and support for attending a meeting from Rhythm Pharmaceuticals. MRB received honoraria for lectures and educational events from Obesitas Platform-MedOnline, SCEM, Health Investment, Public Eyes Healthcare Communications, Goodlife, and Eli Lilly; support for attending a meeting from Rhythm Pharmaceuticals; and receives royalties from Ambo Anthos for a book for lay and professional audiences: FAT, the secret organ (Dutch: VET Belangrijk, 2019; VET Belangrijk 2.0, 2026). EFCvR reports speaker fees from the Dutch Obesity Academy, Medische Scholing, Medscape-WebMD, Radcliffe CVRM, BSL, and Prevents (most payments to institution); was involved in (primarily providing medical care for) clinical trials funded by Rhythm Pharmaceuticals (payments to institution; present Review is independent of these trials); serves as a member of the guideline committee on obesity pharmacotherapy of the Endocrine Society; chaired the Dutch multidisciplinary guideline on overweight and obesity in adults (2023) and Partnership Overweight Netherlands; was the clinical lead of focus area obesity, diabetes, nutrition, and metabolism of the European Society of Endocrinology (2021-25); and received royalties from Ambo Anthos for the book: Fat, the secret organ, 2020 (Dutch: VET Belangrijk, 2019; VET Belangrijk 2.0, 2026). MRB and EFCVR are co-developers of the screening and monitoring tool CheckCausesObesity.com. SK declares no competing interests. EDAT- 2026/05/29 15:45 MHDA- 2026/07/15 12:35 CRDT- 2026/05/28 20:08 PHST- 2026/01/16 00:00 [received] PHST- 2026/03/31 00:00 [revised] PHST- 2026/04/10 00:00 [accepted] PHST- 2026/07/15 12:35 [medline] PHST- 2026/05/29 15:45 [pubmed] PHST- 2026/05/28 20:08 [entrez] AID - S2213-8587(26)00100-2 [pii] AID - 10.1016/S2213-8587(26)00100-2 [doi] PST - ppublish SO - Lancet Diabetes Endocrinol. 2026 Aug;14(8):678-692. doi: 10.1016/S2213-8587(26)00100-2. Epub 2026 May 28. PMID- 42177747 OWN - NLM STAT- MEDLINE DCOM- 20260729 LR - 20260813 IS - 1720-8319 (Electronic) IS - 1594-0667 (Print) IS - 1594-0667 (Linking) VI - 38 IP - 1 DP - 2026 May 24 TI - Angiogenic T cells and cognitive function in older adults with type 2 diabetes treated with GLP-1 receptor agonists. LID - 10.1007/s40520-026-03417-0 [doi] LID - 165 AB - BACKGROUND: Older adults with type 2 diabetes mellitus (T2DM) are at high risk of both cardiovascular complications and cognitive decline, with major implications for independence and self-management. Endothelial dysfunction and impaired angiogenic capacity may play a key role. This study investigated the association between circulating angiogenic T cells (Tang cells) and cognitive function in older adults with T2DM and explored the potential impact of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. METHODS: A cross-sectional study was conducted on 154 T2DM patients aged 60-80 years, treated either with GLP-1 receptor agonist (GLP-1RA) plus metformin or metformin alone. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Circulating CD3+CD31+CXCR4+ Tang cells were quantified by flow cytometry. Propensity score matching was applied to control for age, body weight and HbA1c. RESULTS: In the overall cohort, higher Tang cell levels were significantly associated with better cognitive performance (MoCA, r = 0.423; MMSE, r = 0.428; both P < 0.001). After matching, 35 patients in each treatment group were included in the comparative analysis. The GLP-1RA + MET group showed significantly higher circulating Tang cell levels than the MET group, both in absolute counts and as percentage of CD3+ T cells (P < 0.001). CONCLUSIONS: Circulating Tang cell levels are positively associated with cognitive function in older adults with T2DM. GLP-1RA therapy is associated with higher Tang cell levels compared with metformin alone, suggesting a potential association with mechanisms related to endothelial repair in diabetes-related cognitive impairment in older age. CI - (c) 2026. The Author(s). FAU - Longo, Miriam AU - Longo M AD - Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy. miriam.longo@unicampania.it. AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. miriam.longo@unicampania.it. FAU - Caruso, Paola AU - Caruso P AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Auriemma, Maria Chiara AU - Auriemma MC AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Geriatrics and Internal Medicine, AOU University of Campania : "Luigi Vanvitelli", Naples, Italy. FAU - Maio, Antonietta AU - Maio A AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Di Meo, Irene AU - Di Meo I AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Geriatrics and Internal Medicine, AOU University of Campania : "Luigi Vanvitelli", Naples, Italy. FAU - Scappaticcio, Lorenzo AU - Scappaticcio L AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Maiorino, Maria Ida AU - Maiorino MI AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Bellastella, Giuseppe AU - Bellastella G AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Rizzo, Maria Rosaria AU - Rizzo MR AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Geriatrics and Internal Medicine, AOU University of Campania : "Luigi Vanvitelli", Naples, Italy. FAU - Paolisso, Giuseppe AU - Paolisso G AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Geriatrics and Internal Medicine, AOU University of Campania : "Luigi Vanvitelli", Naples, Italy. FAU - Esposito, Katherine AU - Esposito K AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. LA - eng PT - Journal Article DEP - 20260524 PL - Germany TA - Aging Clin Exp Res JT - Aging clinical and experimental research JID - 101132995 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/psychology/immunology MH - Aged MH - Female MH - Male MH - *Cognition/drug effects/physiology MH - Cross-Sectional Studies MH - Middle Aged MH - Aged, 80 and over MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use MH - *T-Lymphocytes/drug effects MH - Metformin/therapeutic use MH - *Angiogenesis PMC - PMC13415266 OTO - NOTNLM OT - Angiogenic T cells OT - Cognitive function OT - Endothelial dysfunction OT - GLP-1RA OT - Type 2 diabetes COIS- Declarations. Competing interests: The authors declare no competing interests. EDAT- 2026/05/24 13:39 MHDA- 2026/07/29 18:38 PMCR- 2026/05/24 CRDT- 2026/05/24 11:04 PHST- 2026/02/07 00:00 [received] PHST- 2026/05/11 00:00 [accepted] PHST- 2026/07/29 18:38 [medline] PHST- 2026/05/24 13:39 [pubmed] PHST- 2026/05/24 11:04 [entrez] PHST- 2026/05/24 00:00 [pmc-release] AID - 10.1007/s40520-026-03417-0 [pii] AID - 3417 [pii] AID - 10.1007/s40520-026-03417-0 [doi] PST - epublish SO - Aging Clin Exp Res. 2026 May 24;38(1):165. doi: 10.1007/s40520-026-03417-0. PMID- 42163663 OWN - NLM STAT- Publisher LR - 20260521 IS - 1875-6190 (Electronic) IS - 1570-159X (Linking) DP - 2026 May 15 TI - The Efficacy of Glucagon-like Peptide-1 Receptor Agonists on Different Cognitive Domains: A Meta-analysis of Randomized Controlled Trials. LID - 10.2174/011570159X439787260312090015 [doi] AB - INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely studied for cognitive enhancement. However, their clinical efficacy remains inconclusive in patients with Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes mellitus (T2DM). We therefore conducted a domain-specific meta-analysis to evaluate their cognitive effects. METHODS: The PubMed, Web of Science, and Cochrane Library were searched for studies published up to January 2026. Eligible randomized controlled trials comparing GLP‑1 RAs to control groups, with baseline and post‑intervention cognitive scores, were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random‑effects model across six cognitive domains. RESULTS: Eleven trials met the inclusion criteria. GLP-1 RAs demonstrated no significant benefit across all cognitive domains: pooled SMD for overall cognition was 0.03 (95% CI, -0.11 to 0.18; P =  0.64); memory, 0.21 (95% CI, -0.19 to 0.60; P = 0.30); attention, 0.23 (95% CI, -0.19 to 0.65; P =  0.28); executive function, 0.14 (95% CI, -0.28 to 0.56; P =  0.51); visuospatial ability, 0.04 (95% CI, -0.43 to 0.50; P =  0.88); and motor function, 0.20 (95% CI, -0.19 to 0.59; P = 0.31). Subgroup analyses by disease type and drug class also revealed no statistically significant differences. DISCUSSION: Our findings suggest that the cognitive benefits of GLP‑1 RAs may be limited in patients with established disease. This may be attributable to irreversible neuropathological alterations in AD, PD, and T2DM patients, which hinder the translation of GLP‑1 RA-mediated neuroprotective actions into measurable symptomatic improvements. A key limitation of the present study is the relatively small sample size for several specific cognitive domains, which may affect the robustness of the results. CONCLUSIONS: The available evidence from this meta-analysis does not support significant benefits across six cognitive domains with GLP‑1 RAs in patients with AD, PD, and T2DM. Future largescale trials with domain-specific assessments are needed to evaluate their potential in earlier disease stages or specific subgroups. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Xu, Hong AU - Xu H AUID- ORCID: 0009-0007-7290-5916 AD - Department of Cardiology, Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, Nanjing 211198, China. FAU - Zhang, Jing AU - Zhang J AD - Child Mental Health Department, Children's Hospital of Nanjing Medical University, Nanjing, China. FAU - Wang, Yuqing AU - Wang Y AD - Department of Cardiology, Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, Nanjing 211198, China. FAU - Ma, Gaoxiang AU - Ma G AD - Department of Cardiology, Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, Nanjing 211198, China. FAU - Zhao, Yi-Jing AU - Zhao YJ AD - Department of Cardiology, Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, Nanjing 211198, China. LA - eng PT - Journal Article PT - Meta-Analysis DEP - 20260515 PL - United Arab Emirates TA - Curr Neuropharmacol JT - Current neuropharmacology JID - 101157239 SB - IM OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Parkinson's disease OT - cognitive function OT - type-2 diabetes EDAT- 2026/05/21 06:32 MHDA- 2026/05/21 06:32 CRDT- 2026/05/21 03:42 PHST- 2025/09/25 00:00 [received] PHST- 2026/01/11 00:00 [revised] PHST- 2026/02/04 00:00 [accepted] PHST- 2026/05/21 06:32 [medline] PHST- 2026/05/21 06:32 [pubmed] PHST- 2026/05/21 03:42 [entrez] AID - CN-EPUB-155708 [pii] AID - 10.2174/011570159X439787260312090015 [doi] PST - aheadofprint SO - Curr Neuropharmacol. 2026 May 15. doi: 10.2174/011570159X439787260312090015. PMID- 42159155 OWN - NLM STAT- In-Process LR - 20260726 IS - 1758-2032 (Electronic) IS - 1758-2024 (Print) IS - 1758-2024 (Linking) VI - 16 IP - 4 DP - 2026 Aug TI - Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease. PG - 381-390 LID - 10.1080/17582024.2026.2666332 [doi] FAU - Cummings, Jeffrey L AU - Cummings JL AD - aChambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Las Vegas, NV, USA. FAU - Atri, Alireza AU - Atri A AD - bBanner Sun Health Research Institute, Sun City, AZ, USA. AD - cBanner Alzheimer's Institute, Phoenix, AZ, USA. AD - dDepartment of Neurology, Mass General Brigham and Harvard Medical School, Boston, MA, USA. FAU - Sano, Mary AU - Sano M AD - eIcahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Zetterberg, Henrik AU - Zetterberg H AD - fDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden. AD - gClinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden. AD - hDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. AD - iUK Dementia Research Institute at UCL, London, UK. AD - jDepartment of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. AD - kWisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. AD - lCentre for Brain Research, Indian Institute of Science, Bangalore, India. FAU - Scheltens, Philip AU - Scheltens P AD - mAlzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands. AD - nEQT Life Sciences, Amsterdam, Netherlands. FAU - Knop, Filip K AU - Knop FK AD - oNovo Nordisk A/S, Soborg, Denmark. FAU - Johannsen, Peter AU - Johannsen P AD - oNovo Nordisk A/S, Soborg, Denmark. FAU - Wichmann, Christian A AU - Wichmann CA AD - oNovo Nordisk A/S, Soborg, Denmark. FAU - Abschneider, Rikke Mortensen AU - Abschneider RM AD - oNovo Nordisk A/S, Soborg, Denmark. FAU - Leon, Teresa AU - Leon T AD - oNovo Nordisk A/S, Soborg, Denmark. FAU - Taylor, Jim AU - Taylor J AD - pVoices of Alzheimer's, New York, NY, USA. FAU - Feldman, Howard H AU - Feldman HH AD - qAlzheimer's Disease Cooperative Study, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. LA - eng PT - Journal Article DEP - 20260520 PL - England TA - Neurodegener Dis Manag JT - Neurodegenerative disease management JID - 101517977 SB - IM CIN - Neurodegener Dis Manag. PMC - PMC13390525 OAB - What is this summary about?This article presents a plain language summary of the results from the evoke and evoke+ phase 3 clinical studies, collectively known as the evoke(+) studies, which were published in The Lancet in March 2026.The primary goal of the evoke(+) studies was to understand if oral treatment with up to 14 mg of the drug semaglutide (normally used for the treatment of type 2 diabetes and/or obesity) delayed decline of memory and thinking in people with the early stages of Alzheimer's disease.A delay in the onset of Alzheimer's disease has been observed in some previous studies among patients with type 2 diabetes treated with semaglutide, suggesting that this could be a potential treatment for Alzheimer's disease.The evoke(+) studies compared the effects of semaglutide treatment taken once per day by mouth with a placebo group using clinical tests and blood and cerebral fluid samples that can measure the course of Alzheimer's disease. People in the trial did not know if they were receiving semaglutide or placebo (e.g. the trials were 'blinded').The main test used was change in Clinical Dementia Rating-Sum of Boxes score which assesses thinking, memory, and everyday activities.Change in Alzheimer's Disease Cooperative Study Activities of Daily Living-Mild Cognitive Impairment score, a measure of activities of daily living in everyday life, was also included in the study. Activities of daily living include those inside and outside the home.What are the key takeaways?Oral semaglutide taken once per day by mouth up to 14 mg did not slow cognitive or functional decline in people with the early stage of Alzheimer's disease. Therefore, it is not effective as a treatment for the early stages of Alzheimer's disease.Safety information collected during the studies showed that adverse effects are similar to those observed when semaglutide is taken for other diseases and no new adverse effects were identified.The evoke(+) studies provide information on disease progression and safety that could be used in the future. OABL- eng OTO - NOTNLM OT - Alzheimer's disease OT - cognitive function OT - early-stage AD OT - evoke OT - evoke(+) OT - evoke+ OT - glucagon-like peptide-1 receptor agonist OT - phase 3 trial OT - semaglutide OT - small vessel pathology COIS- Jeffrey L. Cummings has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, Bio X Cel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He is supported by National Institute of General Medical Sciences grant P20GM109025, National Institute on Aging (NIA) grant R35AG71476, NIA grant R25 AG083721-01, Alzheimer's Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment. Alireza Atri has, in the last 10 years, served as a consultant or received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programmes, and materials; and serving on advisory boards for AbbVie, Acadia, Allergan, Alzheimer's Disease International, the Alzheimer's Association, AriBio, Axovant, Axsome, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Johnson & Johnson, Life Molecular Imaging/Lantheus, Lundbeck, Merck, Michael J Fox Foundation, Novo Nordisk, ONO, Otsuka, Prothena, Qynapse, Roche/Genentech, Sunovion, Suven, Synexus, and Vaxxinity. He receives book royalties from Oxford University Press for a medical book on dementia. He receives institutional research grant or contract funding from the NIA/National Institutes of Health (NIH; 1P30AG072980, U24AG057437, 1P30AG072980, R01AG070883, R01AG086363, U01AG082350, U24AG057437), Arizona Department of Health Services (CTR040636), Foundation for the NIH, Washington University in St. Louis, Michael J. Fox Foundation, and Gates Ventures. His institution receives or has received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves or has served as a contracted site principal investigator. He has received or receives honoraria from Novo Nordisk for consulting activities, including for service on the evoke(+) program Steering Committee. Mary Sano has served on the Scientific Advisory Board for Medication and as a consultant for Eisai, Avenir, vTv, Biogen, Bio X Cel, F. Hoffman LaRoche, Merck, Novo Nordisk, Novartis, Otsuka, Genentech, and BioVie. She is a member of the Alzheimer Association Medical and Scientific Advisory Group and Chair of the data safety monitoring board for the Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD; sponsor: University of Colorado). Henrik Zetterberg reports a relationship with AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, NervGen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, ReMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave that includes consulting or advisory services. He reports a relationship with AlzeCure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD that includes speaking and lecture fees. He reports a relationship with Brain Biomarker Solutions in Gothenburg AB that includes equity or stocks. Philip Scheltens is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam UMC. He is co-Chair of the Steering Committee for the phase 3 trials evoke and evoke+ with Novo Nordisk. Filip K. Knop, Peter Johannsen, Rikke Mortensen Abschneider, and Christian A. Wichmann are employees and minor shareholders of Novo Nordisk. Teresa Leon was an employee and minor shareholder of Novo Nordisk at the time of the analysis. Jim Taylor is Chief Executive Officer at Voices of Alzheimer's, New York, New York, USA. Howard H. Feldman reports a consulting service agreement with Novo Nordisk for serving on the evoke + Steering Committee with funds including travel support for its meetings paid to UC San Diego. He receives no financial support for the present manuscript. Other disclosures include his receiving grants for UC San Diego from Allyx Therapeutics and Vivoryon Therapeutics (Probiodrug). He holds service agreements through UC San Diego for consulting with Biosplice Therapeutics, Arrowhead Pharmaceuticals, Axon Neuroscience, and LuMind Foundation. He provides service as a member of data and safety monitoring boards for Janssen Research & Development and Roche/Genentech and is a Scientific Advisory Board Chair for the Tau Consortium Rainwater Charitable Foundation through a UC San Diego service agreement. He has received travel support from Royal Society of Canada, Translating Research for Elder Care (TREC), Association for Frontotemporal Dementia (AFTD), Rainwater Charitable Foundation, Banner Health, Invictus, Summeet, and Novo Nordisk. He receives philanthropic support for Alzheimer's disease therapeutic research through the Epstein Family Alzheimer's Research Collaboration as well as personal funds for Detecting and Treating Dementia (Serial Number 12/3- 2691 US Patent Number PCT/US2007/07008, Washington DC, US Patent and Trademark Office). The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing support was provided by Amy Bray and Liam Gillies from Apollo, OPEN Health Communications, and was funded by Novo Nordisk A/S. Patient reviewers on this PLSP have received honorarium from Neurodegenerative Disease Management for their review work but have no other relevant financial relationships to disclose. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. EDAT- 2026/05/20 12:38 MHDA- 2026/05/20 12:38 PMCR- 2026/05/20 CRDT- 2026/05/20 06:53 PHST- 2026/05/20 12:38 [pubmed] PHST- 2026/05/20 12:38 [medline] PHST- 2026/05/20 06:53 [entrez] PHST- 2026/05/20 00:00 [pmc-release] AID - 2666332 [pii] AID - 10.1080/17582024.2026.2666332 [doi] PST - ppublish SO - Neurodegener Dis Manag. 2026 Aug;16(4):381-390. doi: 10.1080/17582024.2026.2666332. Epub 2026 May 20. PMID- 42136854 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260515 LR - 20260813 IS - 2296-858X (Print) IS - 2296-858X (Electronic) IS - 2296-858X (Linking) VI - 13 DP - 2026 TI - Mechanisms of interaction between type 2 diabetes and psychological disorders and therapeutic interventions: a narrative review. PG - 1777797 LID - 10.3389/fmed.2026.1777797 [doi] LID - 1777797 AB - Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia, having become one of the most prevalent diseases globally. Type 2 diabetes constitutes the most common form amongst diabetic patients. As the condition progresses, patients typically require long-term medication, imposing significant burdens on daily life. Prolonged treatment is liable to trigger psychological problems such as anxiety, depression and cognitive impairment, which exerts an adverse impact on the long-term management and prognosis of the condition. In recent years, the association between the gut microbiota and diabetes has been increasingly recognised, with the microbiota-gut-brain axis (MGBA) playing a significant role. Consequently, this review primarily explores the role of gut microbiota in psychological disorders amongst patients with type 2 diabetes (T2DM), briefly outlines the association between T2DM and psychological disorders. This article also discusses various therapeutic interventions aimed at alleviating psychological symptoms in patients with Type 2 Diabetes Mellitus (T2DM), including pharmacological treatments such as GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors, which not only show potential in regulating blood glucose but also have beneficial effects on mood health. Furthermore, we emphasise lifestyle interventions as an adjunctive approach, which provides a positive impact on improving psychological well-being. This review comprehensively outlines the mechanisms linking T2DM and psychological disorders, offering clinicians a thorough overview of the subject and valuable reference material. CI - Copyright (c) 2026 Sui, Sun, Yu, Han, Li, Wan and Chi. FAU - Sui, Haoxuan AU - Sui H AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Sun, Yujie AU - Sun Y AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Yu, Haoming AU - Yu H AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Han, Shengyu AU - Han S AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Li, Jihong AU - Li J AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Wan, Lei AU - Wan L AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. FAU - Chi, Yuhua AU - Chi Y AD - Department of General Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China. AD - College of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. LA - eng PT - Journal Article PT - Review DEP - 20260429 PL - Switzerland TA - Front Med (Lausanne) JT - Frontiers in medicine JID - 101648047 PMC - PMC13168012 OTO - NOTNLM OT - gut microbiota OT - intervention measures OT - mechanism of action OT - psychological disorders OT - type 2 diabetes COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/05/15 06:29 MHDA- 2026/05/15 06:30 PMCR- 2026/04/29 CRDT- 2026/05/15 04:46 PHST- 2025/12/30 00:00 [received] PHST- 2026/03/24 00:00 [revised] PHST- 2026/04/09 00:00 [accepted] PHST- 2026/05/15 06:30 [medline] PHST- 2026/05/15 06:29 [pubmed] PHST- 2026/05/15 04:46 [entrez] PHST- 2026/04/29 00:00 [pmc-release] AID - 10.3389/fmed.2026.1777797 [doi] PST - epublish SO - Front Med (Lausanne). 2026 Apr 29;13:1777797. doi: 10.3389/fmed.2026.1777797. eCollection 2026. PMID- 42123553 OWN - NLM STAT- MEDLINE DCOM- 20260716 LR - 20260813 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 27 IP - 9 DP - 2026 Apr 29 TI - The Role of Antidiabetic Therapies in Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review of Metformin, Pioglitazone, and GLP-1 Receptor Agonists. LID - 10.3390/ijms27093967 [doi] LID - 3967 AB - Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major causes of cognitive decline. Antidiabetic medications such as metformin, pioglitazone, and GLP-1 receptor agonists have been proposed as potential neuroprotective therapies. We assessed whether these agents slow cognitive decline or disease progression in people with AD or MCI. PubMed, Embase, and Cochrane Central were searched for randomized controlled trials and observational studies of metformin, pioglitazone, or GLP-1 receptor agonists in AD/MCI. Results were synthesized narratively by drug class. Eleven studies met the inclusion criteria. Metformin, particularly in early-stage disease and metabolically vulnerable groups, demonstrated improvements in episodic memory and selective executive outcomes. Observational data in diabetic MCI suggested improved cognition and preservation of hippocampal and cortical structure, with limited amyloid-beta and tau changes. Pioglitazone findings varied. Benefits were mainly reported in mild AD with type-2 diabetes, but not in non-diabetic AD/MCI. GLP-1 receptor agonists demonstrated preserved cerebral glucose metabolism and improved blood-to-brain glucose transport but did not improve cognitive function. Current evidence does not support antidiabetic therapies as effective treatments in AD/MCI. Any benefits appear to depend on disease stage and metabolic status, with metformin being the most promising candidate. Larger, longer-duration biomarker-defined trials are needed to determine whether any sustained clinical benefit is observed. FAU - Mahoon, Dina A AU - Mahoon DA AUID- ORCID: 0009-0007-3090-5803 AD - School of Medicine, Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain. FAU - Hamad, Omar AU - Hamad O AD - Research Department, Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain. FAU - Butler, Alexandra E AU - Butler AE AUID- ORCID: 0000-0002-5762-3917 AD - Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain. LA - eng PT - Journal Article PT - Systematic Review DEP - 20260429 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 9100L32L2N (Metformin) RN - X4OV71U42S (Pioglitazone) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (PPAR-gamma Agonists) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - Humans MH - *Metformin/therapeutic use MH - *Pioglitazone/therapeutic use MH - *Cognitive Dysfunction/drug therapy/metabolism MH - *Hypoglycemic Agents/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Diabetes Mellitus, Type 2/drug therapy/complications MH - PPAR-gamma Agonists MH - Animals PMC - PMC13163320 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - antidiabetic therapy OT - metformin OT - mild cognitive impairment OT - pioglitazone COIS- The authors declare no conflicts of interest. EDAT- 2026/05/13 06:31 MHDA- 2026/05/13 06:32 PMCR- 2026/04/29 CRDT- 2026/05/13 01:11 PHST- 2026/03/10 00:00 [received] PHST- 2026/04/15 00:00 [revised] PHST- 2026/04/16 00:00 [accepted] PHST- 2026/05/13 06:32 [medline] PHST- 2026/05/13 06:31 [pubmed] PHST- 2026/05/13 01:11 [entrez] PHST- 2026/04/29 00:00 [pmc-release] AID - ijms27093967 [pii] AID - ijms-27-03967 [pii] AID - 10.3390/ijms27093967 [doi] PST - epublish SO - Int J Mol Sci. 2026 Apr 29;27(9):3967. doi: 10.3390/ijms27093967. PMID- 42101745 OWN - NLM STAT- Publisher LR - 20260508 IS - 2509-2723 (Electronic) IS - 2509-2723 (Linking) DP - 2026 May 8 TI - Comparative effectiveness of SGLT-2 inhibitors and GLP-1 receptor agonists on the risk of incident dementia after acute kidney injury: a target-trial emulation. LID - 10.1007/s11357-026-02300-0 [doi] AB - Patients with type 2 diabetic mellitus (T2DM) who recover from acute kidney injury (AKI) face substantial risks of cognitive decline and kidney disease progression. Whether sodium-glucosecotransporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) differentially affect incident dementia in this setting is uncertain. We conducted a target trial emulation using TriNetX electronic health records (2015-2024). Adults with T2DM hospitalized for AKI requiring emergent dialysis (AKI-D) were indexed 90 days post-discharge and classified as users of SGLT2i or GLP-1 RAs within that window (intention-to-treat). One-to-one (1:1) propensity score matching (PSM) was performed to control for potential confounding factors. The primary outcome was incident degenerative and vascular dementia. The prespecified secondary outcomes included all-cause mortality, kidney events, and major adverse cardiovascular events (MACE). Among 14,460 eligible patients, SGLT2i users showed a lower risk of degenerative dementia (2.8% vs. 3.9%, aHR 0.78, 95% CI 0.63-0.97; p = 0.028; E value 2.58) and adverse kidney events (7.2% vs. 9.2%, aHR 0.82, 95% CI 0.71-0.95; p = 0.006; E value 2.15) than GLP-1 RAs users. No significant differences were observed for vascular dementia, mortality, or MACE. Safety profiles were similar, with fewer gastrointestinal adverse events in the SGLT2i group. In patients with T2DM recovering from AKI, SGLT2i therapy was associated with reduced risks of degenerative dementia and kidney disease progression compared with GLP-1 RAs. These results suggest that SGLT2i may be a favorable option for cognition during AKI recovery, though further prospective studies are needed to confirm these findings. CI - (c) 2026. The Author(s), under exclusive licence to American Aging Association. FAU - Chen, Ying-Ru AU - Chen YR AD - Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan. FAU - Jiang, Zheng-Hong AU - Jiang ZH AD - Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. AD - Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan. FAU - Chen, Jui-Yi AU - Chen JY AD - Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan. FAU - Wu, Vin-Cent AU - Wu VC AUID- ORCID: 0000-0001-7935-0991 AD - Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. q91421028@ntu.edu.tw. AD - NSARF (National Taiwan University Hospital Study Group of ARF), TAIPAI, (Taiwan Primary Aldosteronism Investigators), and Division of Nephrology, Primary Aldosteronism Center (PAC) of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. q91421028@ntu.edu.tw. LA - eng PT - Journal Article DEP - 20260508 PL - Switzerland TA - Geroscience JT - GeroScience JID - 101686284 SB - IM OTO - NOTNLM OT - AKI OT - Dementia OT - GLP-1 receptor agonists OT - SGLT-2 inhibitor OT - Type 2 diabetes COIS- Declarations. Competing interests: The authors declare no competing interests. EDAT- 2026/05/08 12:38 MHDA- 2026/05/08 12:38 CRDT- 2026/05/08 11:18 PHST- 2026/01/26 00:00 [received] PHST- 2026/04/29 00:00 [accepted] PHST- 2026/05/08 12:38 [medline] PHST- 2026/05/08 12:38 [pubmed] PHST- 2026/05/08 11:18 [entrez] AID - 10.1007/s11357-026-02300-0 [pii] AID - 10.1007/s11357-026-02300-0 [doi] PST - aheadofprint SO - Geroscience. 2026 May 8. doi: 10.1007/s11357-026-02300-0. PMID- 42100768 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260508 LR - 20260813 IS - 1664-0640 (Print) IS - 1664-0640 (Electronic) IS - 1664-0640 (Linking) VI - 17 DP - 2026 TI - Managing metabolic syndrome in bipolar disorder: multidisciplinary monitoring and treatment strategies. PG - 1699908 LID - 10.3389/fpsyt.2026.1699908 [doi] LID - 1699908 AB - BACKGROUND: Bipolar disorder (BD) is a chronic psychiatric illness associated with high rates of medical comorbidities, among which metabolic syndrome (MetS) is particularly prevalent and consequential. Affecting nearly half of individuals with BD, MetS compounds the risk of cardiovascular disease, type 2 diabetes, and premature mortality, while also undermining psychiatric stability and cognitive functioning. Despite these outcomes, metabolic health remains underrecognized and undertreated in psychiatric care. OBJECTIVE: This narrative review aims to examine the bidirectional relationship between BD and metabolic syndrome and to highlight multidisciplinary strategies for metabolic monitoring and clinical management in this population. METHODS: A targeted literature search was conducted using PubMed (2000-2025), covering studies on the epidemiology, behavioral and biological mechanisms, pharmacologic and lifestyle interventions, and clinical care integration related to BD and MetS. The review followed established quality guidance for narrative synthesis and was structured using the Population-Concept-Context framework to improve transparency in the selection and synthesis of the literature. RESULTS: The comorbidity between BD and MetS is shaped by multiple interacting factors, including shared behavioral risk factors, inflammatory pathways, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and the metabolic effects of psychotropic medications. While pharmacological treatment remains essential for mood stabilization, systematic metabolic monitoring is crucial to mitigate treatment-related risks. Evidence supports the central role of lifestyle interventions, including nutritional strategies and physical activity in reducing cardiometabolic risk. Emerging therapeutic approaches such as GLP-1 receptor agonists and ketogenic metabolic therapy show potential benefits but require careful clinical integration. In selected individuals with severe or refractory obesity, bariatric surgery may be considered. Therapeutic patient education (TPE) represents the cornerstone of care by supporting self-management, treatment adherence, and shared decision-making. CONCLUSION: Addressing the dual burden of BD and MetS requires a multidisciplinary and patient-centered approach integrating metabolic monitoring, lifestyle interventions, pharmacological strategies, and therapeutic patient education. Strengthening collaboration between psychiatry, primary care, and metabolic specialists is essential to reduce cardiometabolic risk and improve long-term health outcomes in this vulnerable population. CI - Copyright (c) 2026 Correia, Richard-Lepouriel, Chalut-Carpentier and Pataky. FAU - Correia, Jorge C AU - Correia JC AD - Unit of Therapeutic Patient Education, WHO Collaborating Centre, Service of Primary Care Medicine, Geneva University Hospitals, Geneva, Switzerland. AD - Faculty Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Richard-Lepouriel, Helene AU - Richard-Lepouriel H AD - Mood Disorder and Anxiety Unit, Psychiatric Specialties Service, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland. AD - Department of Psychiatry, University of Geneva, Geneva, Switzerland. FAU - Chalut-Carpentier, Anne AU - Chalut-Carpentier A AD - Centre Metabolique Nutrition et Mouvement, Geneva, Switzerland. FAU - Pataky, Zoltan AU - Pataky Z AD - Unit of Therapeutic Patient Education, WHO Collaborating Centre, Service of Primary Care Medicine, Geneva University Hospitals, Geneva, Switzerland. AD - Faculty Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland. LA - eng PT - Journal Article PT - Review DEP - 20260422 PL - Switzerland TA - Front Psychiatry JT - Frontiers in psychiatry JID - 101545006 PMC - PMC13144086 OTO - NOTNLM OT - bipolar disorder OT - inflammation OT - integrated care OT - lifestyle intervention OT - metabolic syndrome OT - psychotropic medications OT - therapeutic education COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/05/08 06:32 MHDA- 2026/05/08 06:33 PMCR- 2026/04/22 CRDT- 2026/05/08 05:09 PHST- 2025/09/05 00:00 [received] PHST- 2026/03/23 00:00 [revised] PHST- 2026/03/25 00:00 [accepted] PHST- 2026/05/08 06:33 [medline] PHST- 2026/05/08 06:32 [pubmed] PHST- 2026/05/08 05:09 [entrez] PHST- 2026/04/22 00:00 [pmc-release] AID - 10.3389/fpsyt.2026.1699908 [doi] PST - epublish SO - Front Psychiatry. 2026 Apr 22;17:1699908. doi: 10.3389/fpsyt.2026.1699908. eCollection 2026. PMID- 42074266 OWN - NLM STAT- MEDLINE DCOM- 20260716 LR - 20260813 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 27 IP - 8 DP - 2026 Apr 18 TI - Glucagon-like Peptide-1 and Dual GIP/GLP-1 Receptor Agonists in Brain: Exploring the Expanding Role and Safety in Neuropsychiatry. LID - 10.3390/ijms27083628 [doi] LID - 3628 AB - Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. FAU - Tudosie, Ana Cristina AU - Tudosie AC AD - Department of Endocrinology, University of Medicine and Pharmacy, 200349 Craiova, Romania. FAU - Marin, Loredana-Maria AU - Marin LM AD - Department of Pharmaceutical Physics, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 020956 Bucharest, Romania. FAU - Popa, Simona Georgiana AU - Popa SG AD - Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy, 200349 Craiova, Romania. FAU - Golli, Andreea Loredana AU - Golli AL AUID- ORCID: 0000-0002-1802-3601 AD - Department of Public Health and Healthcare Management, University of Medicine and Pharmacy, 200349 Craiova, Romania. LA - eng PT - Journal Article PT - Review DEP - 20260418 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Receptors, Gastrointestinal Hormone) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Glucagon-Like Peptide 1/metabolism/agonists MH - *Brain/metabolism/drug effects MH - *Receptors, Gastrointestinal Hormone/agonists/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Neuropsychiatry/methods MH - Mental Disorders/drug therapy/metabolism PMC - PMC13115786 OTO - NOTNLM OT - GLP-1/GIP receptor agonists OT - dopamine OT - neuroprotection OT - neuropsychiatry OT - safety OT - serotonin COIS- The authors declare no conflicts of interest. EDAT- 2026/05/04 06:32 MHDA- 2026/05/04 06:33 PMCR- 2026/04/18 CRDT- 2026/05/04 01:13 PHST- 2026/03/22 00:00 [received] PHST- 2026/04/08 00:00 [revised] PHST- 2026/04/16 00:00 [accepted] PHST- 2026/05/04 06:33 [medline] PHST- 2026/05/04 06:32 [pubmed] PHST- 2026/05/04 01:13 [entrez] PHST- 2026/04/18 00:00 [pmc-release] AID - ijms27083628 [pii] AID - ijms-27-03628 [pii] AID - 10.3390/ijms27083628 [doi] PST - epublish SO - Int J Mol Sci. 2026 Apr 18;27(8):3628. doi: 10.3390/ijms27083628. PMID- 42072284 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260504 LR - 20260813 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 14 IP - 4 DP - 2026 Mar 24 TI - Integrating GLP-1 Receptor Agonists into Modern Stroke Prevention: Evidence, Mechanisms, and Clinical Consideration-A Narrative Review. LID - 10.3390/biomedicines14040743 [doi] LID - 743 AB - Stroke remains a major cause of morbidity and mortality worldwide. Although reperfusion therapies and secondary prevention have advanced, the global stroke burden continues to rise, driven by increasing rates of hypertension and diabetes mellitus. Type 2 diabetes (T2DM) increases the risk of acute ischemic stroke (AIS) through mechanisms involving chronic hyperglycemia, endothelial dysfunction, inflammation, and accelerated atherogenesis. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents for cardiovascular and cerebrovascular risk reduction in patients with T2DM. Beyond their glucose-lowering properties, GLP-1RAs improve blood pressure regulation and lipid metabolism, as mentioned in the 2025 AHA Journal guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults. Emerging preclinical and clinical evidence indicates that GLP-1RAs also provide direct neurovascular protection by stabilizing the blood-brain barrier, modulating neuroinflammation, and promoting neuronal survival. These mechanisms may reduce ischemic injury, improve recovery after stroke, and protect against cognitive decline. Major cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events and, to a lesser degree, non-fatal stroke among patients receiving GLP-1RAs. This narrative review evaluates current evidence on the neurovascular, cardiometabolic, and anti-inflammatory actions of GLP-1RAs and their potential role in mitigating stroke risk and promoting cerebrovascular health. Additionally, it highlights gaps in the literature, explores clinical and guideline implications, and outlines future directions for integrating GLP-1RA therapy into comprehensive stroke prevention and recovery strategies. FAU - Khan, Shayan AU - Khan S AUID- ORCID: 0009-0008-0084-8542 AD - Department of Neurology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. FAU - Herbst, William AU - Herbst W AD - Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. FAU - Tajrishi, Farbod Zahedi AU - Tajrishi FZ AUID- ORCID: 0000-0003-3860-884X AD - Department of Internal Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. FAU - Notani, Sonali AU - Notani S AUID- ORCID: 0009-0003-4527-1023 AD - Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. FAU - Knight, Alexander AU - Knight A AD - Department of Internal Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. FAU - Jamil, Zina AU - Jamil Z AUID- ORCID: 0009-0003-9609-045X AD - Department of Trauma and Orthopedics, Craigavon Area Hospital, 68 Lurgen Rd, Portadown, BT63 5QQ Craigavon, Ireland. FAU - Ferdinand, Keith C AU - Ferdinand KC AD - Department of Cardiology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. LA - eng PT - Journal Article PT - Review DEP - 20260324 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC13113324 OTO - NOTNLM OT - GLP-1 receptor agonist OT - acute ischemic stroke OT - cardiovascular outcomes OT - cerebrovascular disease OT - endothelial dysfunction OT - inflammation OT - neurovascular protection OT - type 2 diabetes mellitus COIS- Dr. Keith C. Ferdinand has served as a consultant for Amgen, Novartis, Eli Lilly, Janssen, and Medtronic. The remaining authors declare no conflicts of interest. EDAT- 2026/05/04 06:33 MHDA- 2026/05/04 06:34 PMCR- 2026/03/24 CRDT- 2026/05/04 01:06 PHST- 2026/03/04 00:00 [received] PHST- 2026/03/19 00:00 [revised] PHST- 2026/03/21 00:00 [accepted] PHST- 2026/05/04 06:34 [medline] PHST- 2026/05/04 06:33 [pubmed] PHST- 2026/05/04 01:06 [entrez] PHST- 2026/03/24 00:00 [pmc-release] AID - biomedicines14040743 [pii] AID - biomedicines-14-00743 [pii] AID - 10.3390/biomedicines14040743 [doi] PST - epublish SO - Biomedicines. 2026 Mar 24;14(4):743. doi: 10.3390/biomedicines14040743. PMID- 42068584 OWN - NLM STAT- MEDLINE DCOM- 20260702 LR - 20260702 IS - 2191-0200 (Electronic) IS - 0334-1763 (Linking) VI - 37 IP - 5 DP - 2026 Jul 24 TI - Metformin in T2DM: neurocognitive mechanisms and precision pharmacotherapy. PG - 491-504 LID - 10.1515/revneuro-2026-0013 [doi] AB - Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that significantly predisposes individuals to delirium and dementia through multifaceted neurobiological pathways. The essence of this neurocognitive decline involves mechanisms such as central insulin resistance, chronic low-grade inflammation, and mitochondrial dysfunction. While metformin remains the cornerstone of T2DM management, its impact on the central nervous system exhibits a "double-edged sword" nature, balancing intrinsic neuroprotective properties against the potential neurotoxicity associated with vitamin B12 deficiency. This review aims to systematically synthesize epidemiological and clinical evidence linking metformin to neurocognitive outcomes, contrasting its efficacy with newer glucose-lowering agents such as GLP-1 receptor agonists and SGLT2 inhibitors. In addition, it sheds light on the reciprocal connectivity between systemic metabolic regulation and direct CNS modulation, specifically elucidating AMPK activation, the autophagy-lysosome axis, and the gut-brain and liver-brain axes. We review these molecular mechanisms to delineate the delicate trade-off between neuroprotection and risk, providing a framework for precision pharmacotherapy and biomarker-guided stratification in high-risk T2DM populations. CI - (c) 2026 the author(s), published by De Gruyter, Berlin/Boston. FAU - Tang, ZeZhong AU - Tang Z AD - Yan'an Medical College, Yan'an University, Baota District, Yan'an 716000, China. FAU - Li, PeiHeng AU - Li P AD - Xi'an Medical University, Xi'an, P.R. 710003, China. FAU - Huang, XiZhou AU - Huang X AD - Xi'an Medical University, Xi'an, P.R. 710003, China. FAU - Long, QianFa AU - Long Q AD - Department of Neurosurgery, Xi'an Central Hospital, West Fifth Street, Xi'an 710003, China. FAU - Niu, Jinyun AU - Niu J AD - Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710000, China. AD - Department of Nuclear Medicine, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an P.R.710003, China. FAU - Yin, SongNa AU - Yin S AD - Yan'an Medical College, Yan'an University, Baota District, Yan'an 716000, China. FAU - Hu, MingJun AU - Hu M AD - Department of Neurosurgery, Xi'an Central Hospital, West Fifth Street, Xi'an 710003, China. LA - eng PT - Journal Article PT - Review DEP - 20260504 PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 9100L32L2N (Metformin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Metformin/therapeutic use/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - Animals MH - *Precision Medicine/methods MH - Brain/drug effects/metabolism OTO - NOTNLM OT - delirium OT - dementia OT - metformin OT - neuroprotection OT - precision prescribing OT - type 2 diabetes mellitus EDAT- 2026/05/03 05:26 MHDA- 2026/07/02 12:34 CRDT- 2026/05/02 15:02 PHST- 2026/01/15 00:00 [received] PHST- 2026/03/27 00:00 [accepted] PHST- 2026/07/02 12:34 [medline] PHST- 2026/05/03 05:26 [pubmed] PHST- 2026/05/02 15:02 [entrez] AID - revneuro-2026-0013 [pii] AID - 10.1515/revneuro-2026-0013 [doi] PST - epublish SO - Rev Neurosci. 2026 May 4;37(5):491-504. doi: 10.1515/revneuro-2026-0013. Print 2026 Jul 24. PMID- 42064764 OWN - NLM STAT- MEDLINE DCOM- 20260716 LR - 20260921 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 17 DP - 2026 TI - The impact of antidiabetic drugs on dementia risk: a Bayesian network meta-analysis. PG - 1780676 LID - 10.3389/fendo.2026.1780676 [doi] LID - 1780676 AB - BACKGROUND: Diabetes is significantly associated with cognitive impairment, particularly the risk of developing dementia. However, the impact of antidiabetic drugs on dementia risk remains unclear. This study aims to comprehensively evaluate the effects of different antidiabetic drugs on dementia risk using Bayesian network analysis. METHODS: The study systematically searched databases including PubMed, Embase, and the Cochrane Library to identify relevant publications up to September 5, 2025. Eligible randomized controlled trials, cohort studies, and case-control studies were selected. We employed a Bayesian network meta-analysis model to quantitatively assess the relationship between antidiabetic drugs and dementia risk. Data analysis was performed using R version 4.4.1. RESULTS: A total of 28 articles (involving 4,382,897 patients), network meta-analysis results indicates that compared with placebo, Insulin [OR = 0.11, 95% CrI (0.1, 0.12)], Metformin [OR = 0.79, 95% CrI (0.77, 0.81)], and Pioglitazone [OR = 0.69, 95% CrI (0.56, 0.86)] all reduced the incidence of dementia compared to placebo, a higher incidence of Alzheimer's dementia[OR = 1.78, 95% CrI (1.66, 1.91)] and Vascular dementia[OR = 2.59, 95% CrI (2.33, 2.88)] with DPP4i compared to SGLT_2i. CONCLUSION: This study indicate that insulin demonstrates the most pronounced efficacy in reducing the incidence risk of dementia and vascular dementia. Furthermore, SGLT_2i and GLP1 exhibit certain therapeutic benefits in the management of Alzheimer's disease. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251172386. CI - Copyright (c) 2026 Yu, Peng, Su, Bai and Hou. FAU - Yu, Yang AU - Yu Y AD - Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China. FAU - Peng, Xu AU - Peng X AD - Department of Pathology and Lab Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. FAU - Su, Chang AU - Su C AD - College of Pharmacy, Dalian Medical University, Dalian, China. FAU - Bai, Yangguang AU - Bai Y AD - Department of Pharmacy and Shandong Provincial Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. FAU - Hou, Dan AU - Hou D AD - Department of Pharmacy and Shandong Provincial Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. LA - eng PT - Journal Article PT - Network Meta-Analysis PT - Systematic Review DEP - 20260415 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Insulin) RN - X4OV71U42S (Pioglitazone) SB - IM MH - Humans MH - *Hypoglycemic Agents/therapeutic use MH - Bayes Theorem MH - *Dementia/epidemiology/prevention & control MH - Metformin/therapeutic use MH - Insulin/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Pioglitazone/therapeutic use MH - Risk Factors PMC - PMC13124527 OTO - NOTNLM OT - Alzheimer's disease OT - Bayesian network analysis OT - antidiabetic drugs OT - dementia risk OT - meta-analysis OT - systematic review COIS- The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/05/01 06:34 MHDA- 2026/05/01 06:35 PMCR- 2026/04/15 CRDT- 2026/05/01 05:18 PHST- 2026/01/04 00:00 [received] PHST- 2026/02/17 00:00 [revised] PHST- 2026/02/23 00:00 [accepted] PHST- 2026/05/01 06:35 [medline] PHST- 2026/05/01 06:34 [pubmed] PHST- 2026/05/01 05:18 [entrez] PHST- 2026/04/15 00:00 [pmc-release] AID - 10.3389/fendo.2026.1780676 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2026 Apr 15;17:1780676. doi: 10.3389/fendo.2026.1780676. eCollection 2026. PMID- 42055924 OWN - NLM STAT- Publisher LR - 20260429 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) DP - 2026 Apr 28 TI - Neuroprotective strategies for cognitive decline in type 2 diabetes. LID - S1043-2760(26)00095-0 [pii] LID - 10.1016/j.tem.2026.04.003 [doi] AB - Type 2 diabetes (T2D) is increasingly associated with cognitive impairment and dementia, reflecting the combined impact of metabolic dysregulation, vascular injury, neuroinflammation, and defective brain insulin signaling. While this link is now well recognized, it remains unclear whether cognitive decline in T2D is modifiable. This review focuses on emerging neuroprotective strategies, highlighting both pharmacological and lifestyle-based interventions. Recent evidence indicates that some glucose-lowering agents, notably metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists, may exert pleiotropic effects on brain metabolism, inflammation, and vascular integrity beyond glycemic control. We propose a conceptual shift in T2D management in which cognitive preservation becomes an explicit therapeutic objective, integrating metabolic control with targeted brain-protective approaches. CI - Copyright (c) 2026. Published by Elsevier Ltd. FAU - Cimini, Flavia A AU - Cimini FA AD - Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. FAU - Cuenca-Royo, Aida AU - Cuenca-Royo A AD - Integrative Pharmacology and Systems Neurosciences Research Group, Hospital del Mar Research Institute, Barcelona, Spain. FAU - Gomis-Gonzalez, Maria AU - Gomis-Gonzalez M AD - Integrative Pharmacology and Systems Neurosciences Research Group, Hospital del Mar Research Institute, Barcelona, Spain. FAU - Forcano, Laura AU - Forcano L AD - Integrative Pharmacology and Systems Neurosciences Research Group, Hospital del Mar Research Institute, Barcelona, Spain. FAU - Barchetta, Ilaria AU - Barchetta I AD - Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. FAU - Barone, Eugenio AU - Barone E AD - Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy. FAU - Cavallo, Maria G AU - Cavallo MG AD - Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. FAU - De La Torre, Rafael AU - De La Torre R AD - Integrative Pharmacology and Systems Neurosciences Research Group, Hospital del Mar Research Institute, Barcelona, Spain; Faculty of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Physiopathology of Obesity and Nutrition Networking Center (CIBEROBN), Madrid, Spain. Electronic address: Rtorre2@researchmar.net. LA - eng PT - Journal Article PT - Review DEP - 20260428 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 SB - IM OTO - NOTNLM OT - brain insulin resistance OT - cognitive impairment OT - cognitive prevention strategies OT - metabolic-cognitive axis OT - neuroprotection OT - type 2 diabetes COIS- Declaration of interests All the authors declare that they have no conflicts of interest related to this work. EDAT- 2026/04/30 00:30 MHDA- 2026/04/30 00:30 CRDT- 2026/04/29 21:55 PHST- 2026/02/09 00:00 [received] PHST- 2026/03/20 00:00 [revised] PHST- 2026/04/08 00:00 [accepted] PHST- 2026/04/30 00:30 [medline] PHST- 2026/04/30 00:30 [pubmed] PHST- 2026/04/29 21:55 [entrez] AID - S1043-2760(26)00095-0 [pii] AID - 10.1016/j.tem.2026.04.003 [doi] PST - aheadofprint SO - Trends Endocrinol Metab. 2026 Apr 28:S1043-2760(26)00095-0. doi: 10.1016/j.tem.2026.04.003. PMID- 42042580 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260427 LR - 20260813 IS - 2075-4426 (Print) IS - 2075-4426 (Electronic) IS - 2075-4426 (Linking) VI - 16 IP - 4 DP - 2026 Apr 13 TI - Personalised Approach to the Management of Older People with Type 2 Diabetes Mellitus-A Comprehensive Narrative Review. LID - 10.3390/jpm16040213 [doi] LID - 213 AB - The global population is ageing due to increased life expectancy, and the prevalence of diabetes is proportionally increasing. With advancing age, diabetes in older people is a complex condition due to associated morbidities and geriatric syndromes. As a result, the management of diabetes in old age is challenging. Due to the wide heterogeneity of older people, diabetes management in this age group should be personalised. While strict targets are accepted in fit individuals, relaxed targets should be considered in patients with multiple morbidities and a high risk of hypoglycaemia. The development of frailty changes the metabolic profile of older people, and their insulin resistance and diabetes trajectory, which will have an impact on the choice of glucose-lowering agents and the goals of therapy. For example, intensive therapy, the use of SGLT-2 inhibitors and GLP-1RA, and tight targets should be continued in frail, sarcopenic, obese individuals due to their increased insulin resistance and cardiovascular risk. On the other hand, relaxed targets and deintensification of therapy should be considered in anorexic, malnourished, frail individuals with significant weight loss due to their low insulin resistance, low prevalence of cardiovascular risk factors, and high risk of hypoglycaemia. Annual reviews of older people with diabetes should include screening for frailty, depression and dementia for early diagnosis, and appropriate interventions. The introduction of continuous glucose monitoring is increasingly used in older people with diabetes and has the potential to reduce the incidence of hypoglycaemia. With the expectation of a continued increase in the prevalence of older people with diabetes, the use of mobile health may allow care delivery on a wider scale without the need for face-to-face appointments. In addition, there is a promising scope for artificial intelligence to achieve better diabetes outcomes. Future research is still required to expand the use of these technologies in older age groups. FAU - Sinclair, Alan AU - Sinclair A AD - King's College, London WC2R 2LS, UK. AD - Foundation for Diabetes Research in Older People (fDROP), Droitwich Spa WR9 0QH, UK. FAU - Al-Banna, Mohammed AU - Al-Banna M AD - Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2UD, UK. FAU - Tutunariu, Roxana AU - Tutunariu R AD - Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2UD, UK. FAU - Abdelhafiz, Ahmed H AU - Abdelhafiz AH AD - Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2UD, UK. LA - eng PT - Journal Article PT - Review DEP - 20260413 PL - Switzerland TA - J Pers Med JT - Journal of personalized medicine JID - 101602269 PMC - PMC13117061 OTO - NOTNLM OT - diabetes mellitus OT - frailty OT - management OT - older people OT - personalised COIS- The authors declare no conflict of interest. EDAT- 2026/04/27 12:34 MHDA- 2026/04/27 12:35 PMCR- 2026/04/13 CRDT- 2026/04/27 09:29 PHST- 2026/02/10 00:00 [received] PHST- 2026/03/27 00:00 [revised] PHST- 2026/04/08 00:00 [accepted] PHST- 2026/04/27 12:35 [medline] PHST- 2026/04/27 12:34 [pubmed] PHST- 2026/04/27 09:29 [entrez] PHST- 2026/04/13 00:00 [pmc-release] AID - jpm16040213 [pii] AID - jpm-16-00213 [pii] AID - 10.3390/jpm16040213 [doi] PST - epublish SO - J Pers Med. 2026 Apr 13;16(4):213. doi: 10.3390/jpm16040213. PMID- 42035861 OWN - NLM STAT- MEDLINE DCOM- 20260916 LR - 20261004 IS - 1873-2402 (Electronic) IS - 0006-3223 (Linking) VI - 100 IP - 8 DP - 2026 Oct 15 TI - From the Discovery of GLP-1 to Today's Diabetes/Obesity Therapy and Beyond. PG - 805-813 LID - S0006-3223(26)01195-9 [pii] LID - 10.1016/j.biopsych.2026.04.010 [doi] AB - Glucagon-like peptide-1 (GLP-1) was discovered as an insulinotropic peptide from the gut during a search for candidates for the incretin effect. It was found to also inhibit glucagon secretion and is now considered an important regulator of glucose metabolism. In further investigations of its physiological effects, GLP-1 also inhibited gastrointestinal secretion and motility and inhibited appetite and food intake. Because of these effects, GLP-1 was eventually shown to be able to improve glucose control and beta cell function in patients with type 2 diabetes mellitus (T2DM) and was even associated with weight loss. Because of a very short half-life in the circulation due to renal clearance and enzymatic degradation, stable analogs were developed allowing long-term treatment. Analogs suitable for weekly administration proved highly effective in improving glycemic control in patients with T2DM, and the analogs showed efficacy with respect to weight loss. Moreover, in cardiovascular outcome trials, the agonists were protective against major cardiovascular events and showed renoprotection and neuroprotection. Several observational studies also indicated protection against psychiatric illnesses and dementia. Thus, GLP-1 receptor agonists seem to be an effective weapon against the obesity-associated cardiovascular-kidney-metabolic syndrome affecting millions of patients. CI - Copyright (c) 2026 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Holst, Jens Juul AU - Holst JJ AD - Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: jjholst@sund.ku.dk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20260424 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/therapeutic use/metabolism/analogs & derivatives MH - *Obesity/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy MH - Animals MH - *Hypoglycemic Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Appetite regulation OT - cardiovascular outcome trials OT - gut hormone OT - obesity OT - reward mechanisms OT - weight loss agents EDAT- 2026/04/27 00:30 MHDA- 2026/09/16 23:34 CRDT- 2026/04/26 19:12 PHST- 2026/01/20 00:00 [received] PHST- 2026/04/08 00:00 [revised] PHST- 2026/04/14 00:00 [accepted] PHST- 2026/09/16 23:34 [medline] PHST- 2026/04/27 00:30 [pubmed] PHST- 2026/04/26 19:12 [entrez] AID - S0006-3223(26)01195-9 [pii] AID - 10.1016/j.biopsych.2026.04.010 [doi] PST - ppublish SO - Biol Psychiatry. 2026 Oct 15;100(8):805-813. doi: 10.1016/j.biopsych.2026.04.010. Epub 2026 Apr 24. PMID- 42021007 OWN - NLM STAT- MEDLINE DCOM- 20260715 LR - 20260806 IS - 1538-8662 (Electronic) IS - 0361-1817 (Linking) VI - 51 IP - 5 DP - 2026 May 1 TI - GLP-1 receptor agonists: The good, the bad, and the ugly-A comprehensive guide for NPs. PG - 22-30 LID - 10.1097/01.NPR.0000000000000430 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in primary care for diabetes, obesity, and other conditions, offering glycemic control, weight loss, and cardioprotection. This article explores the indications, benefits, risks, and prescribing considerations of GLP-1RAs for nurse practitioners (NPs). Although effective, GLP-1RAs present challenges, including gastrointestinal side effects, accessibility issues, and serious risks like pancreatitis. NPs play a key role in patient education, monitoring, and advocacy to ensure equitable access and safe prescribing. Emerging research suggests expanded indications for cardiovascular, hepatic, and neurocognitive benefits. This review provides a comprehensive guide for NPs to optimize GLP-1RA therapy in clinical practice. CI - Copyright (c) 2026 Wolters Kluwer Health, Inc. All rights reserved. FAU - Rodriguez, Megan E AU - Rodriguez ME FAU - Lavell, Julia AU - Lavell J FAU - Foreman, Ruth Madden AU - Foreman RM LA - eng PT - Journal Article PT - Review DEP - 20260423 PL - United States TA - Nurse Pract JT - The Nurse practitioner JID - 7603663 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/nursing MH - *Glucagon-Like Peptide-1 Receptor Agonists/adverse effects/therapeutic use MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Nurse Practitioners MH - Obesity/drug therapy MH - *Practice Guidelines as Topic OTO - NOTNLM OT - GLP-1 receptor agonists OT - accessibility OT - cardioprotection OT - chronic kidney disease OT - diabetes OT - obesity OT - obstructive sleep apnea EDAT- 2026/04/23 06:32 MHDA- 2026/04/23 06:33 CRDT- 2026/04/23 00:13 PHST- 2026/04/23 06:33 [medline] PHST- 2026/04/23 06:32 [pubmed] PHST- 2026/04/23 00:13 [entrez] AID - 00006205-202605000-00004 [pii] AID - 10.1097/01.NPR.0000000000000430 [doi] PST - ppublish SO - Nurse Pract. 2026 May 1;51(5):22-30. doi: 10.1097/01.NPR.0000000000000430. Epub 2026 Apr 23. PMID- 42019901 OWN - NLM STAT- MEDLINE DCOM- 20260814 LR - 20260922 IS - 2320-2890 (Electronic) IS - 2319-4170 (Print) IS - 2319-4170 (Linking) VI - 49 IP - 4 DP - 2026 Aug TI - The hidden link between diabetes and dementia: Findings from recent epidemiological studies. PG - 100985 LID - S2319-4170(26)00041-7 [pii] LID - 10.1016/j.bj.2026.100985 [doi] LID - 100985 AB - Recent epidemiological studies investigating the link between diabetes mellitus and dementia or Alzheimer's disease are narratively reviewed. Diabetes mellitus is associated with a significantly higher risk of dementia by 56%, more predominant for vascular dementia than Alzheimer's disease and tau pathology is more remarkable than amyloid beta deposition. The increased risk is related to the burden of microvascular and macrovascular diseases in a dose-response pattern; and a threshold effect between glycemic control and dementia risk is observed. A treatment target of hemoglobin A1c < 7% may be optimal for reducing the risk of dementia but hypoglycemia should be avoided. Antidiabetic drugs such as metformin, pioglitazone, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists may show beneficial effects on dementia in observational studies. In a Taiwanese cohort study acarbose is also associated with a lower risk of dementia in female diabetes patients. When considering the repurposing of antidiabetic drugs in the treatment of patients with Alzheimer's disease, low-dose insulin detemir shows a promising effect in a network meta-analysis. A phase 3 clinical trial (MET-FINGER) is being conducted to investigate whether metformin plus lifestyle intervention can be effective in the prevention of Alzheimer's disease. Hyperuricemia, though considered a potential component of metabolic syndrome, seems to be associated with a lower risk of dementia. Sex hormones play some roles in cognitive function and females present a higher risk of dementia than males. However, additional studies are required to explore the impacts of sex and sex hormones on the development of dementia and Alzheimer's disease. CI - Copyright (c) 2026 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Tseng, Chin-Hsiao AU - Tseng CH AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, Far Eastern Polyclinic, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: tsengchinhsiao@gmail.com. LA - eng PT - Journal Article PT - Review DEP - 20260420 PL - United States TA - Biomed J JT - Biomedical journal JID - 101599820 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Dementia/epidemiology MH - Hypoglycemic Agents/therapeutic use MH - *Alzheimer Disease/epidemiology MH - Female MH - *Diabetes Mellitus/epidemiology/drug therapy MH - *Diabetes Mellitus, Type 2/complications PMC - PMC13452960 OTO - NOTNLM OT - Alzheimer's disease OT - Apolipoprotein E OT - Dementia OT - Insulin resistance OT - Type 3 diabetes mellitus EDAT- 2026/04/23 00:31 MHDA- 2026/08/14 23:37 PMCR- 2026/04/20 CRDT- 2026/04/22 19:17 PHST- 2025/11/24 00:00 [received] PHST- 2026/03/26 00:00 [revised] PHST- 2026/04/19 00:00 [accepted] PHST- 2026/08/14 23:37 [medline] PHST- 2026/04/23 00:31 [pubmed] PHST- 2026/04/22 19:17 [entrez] PHST- 2026/04/20 00:00 [pmc-release] AID - S2319-4170(26)00041-7 [pii] AID - 100985 [pii] AID - 10.1016/j.bj.2026.100985 [doi] PST - ppublish SO - Biomed J. 2026 Aug;49(4):100985. doi: 10.1016/j.bj.2026.100985. Epub 2026 Apr 20. PMID- 42014236 OWN - NLM STAT- MEDLINE DCOM- 20260612 LR - 20260709 IS - 1095-9327 (Electronic) IS - 1044-7431 (Linking) VI - 137 DP - 2026 Jun TI - The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review. PG - 104091 LID - S1044-7431(26)00021-7 [pii] LID - 10.1016/j.mcn.2026.104091 [doi] AB - BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Abeta) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Abeta. METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Abeta and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified. RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Abeta plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Abeta and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Abeta accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Abeta or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Abeta42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Abeta burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited. CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Abeta levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive. REGISTRATION: PROSPERO CRD420251029748. CI - Copyright (c) 2026 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Corcoran, Eve AU - Corcoran E AD - School of Medicine, Anglia Ruskin University, Bishop Hall Road, Chelmsford, CM1 1SQ, UK. FAU - Kettlety, Michael AU - Kettlety M AD - School of Medicine, Anglia Ruskin University, Bishop Hall Road, Chelmsford, CM1 1SQ, UK. FAU - Mogul, Urwa AU - Mogul U AD - School of Medicine, Anglia Ruskin University, Bishop Hall Road, Chelmsford, CM1 1SQ, UK. FAU - Azah, Jennifer Ndiforngwah AU - Azah JN AD - School of Medicine, Anglia Ruskin University, Bishop Hall Road, Chelmsford, CM1 1SQ, UK. FAU - Cork, Simon C AU - Cork SC AD - School of Medicine, Anglia Ruskin University, Bishop Hall Road, Chelmsford, CM1 1SQ, UK. Electronic address: simon.cork@aru.ac.uk. LA - eng PT - Journal Article PT - Systematic Review DEP - 20260420 PL - United States TA - Mol Cell Neurosci JT - Molecular and cellular neurosciences JID - 9100095 RN - 0 (Amyloid beta-Peptides) RN - WTT295HSY5 (dulaglutide) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Immunoglobulin Fc Fragments) RN - 839I73S42A (Liraglutide) RN - 0 (Recombinant Fusion Proteins) RN - 53AXN4NNHX (Semaglutide) RN - 0 (tau Proteins) SB - IM MH - Animals MH - Humans MH - *Alzheimer Disease/drug therapy/metabolism/physiopathology MH - Amyloid beta-Peptides/metabolism MH - Exenatide/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptides/analogs & derivatives/therapeutic use/analogs & derivatives MH - Immunoglobulin Fc Fragments/therapeutic use MH - Liraglutide/therapeutic use MH - Recombinant Fusion Proteins/therapeutic use MH - Semaglutide/therapeutic use MH - tau Proteins/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid OT - Beta-amyloid OT - Dulaglutide OT - Exenatide OT - GLP-1 receptor agonists OT - Hyperphosphorylated tau OT - Liraglutide OT - Neuroprotection OT - Semaglutide COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. There is no funding associated with this work. EDAT- 2026/04/22 00:35 MHDA- 2026/06/12 13:02 CRDT- 2026/04/21 21:52 PHST- 2026/01/28 00:00 [received] PHST- 2026/03/26 00:00 [revised] PHST- 2026/03/31 00:00 [accepted] PHST- 2026/06/12 13:02 [medline] PHST- 2026/04/22 00:35 [pubmed] PHST- 2026/04/21 21:52 [entrez] AID - S1044-7431(26)00021-7 [pii] AID - 10.1016/j.mcn.2026.104091 [doi] PST - ppublish SO - Mol Cell Neurosci. 2026 Jun;137:104091. doi: 10.1016/j.mcn.2026.104091. Epub 2026 Apr 20. PMID- 41995965 OWN - NLM STAT- MEDLINE DCOM- 20260628 LR - 20260813 IS - 1590-3478 (Electronic) IS - 1590-1874 (Print) IS - 1590-1874 (Linking) VI - 47 IP - 5 DP - 2026 Apr 17 TI - Efficacy of GLP-1 receptor agonists in Parkinson's disease: a systematic review and exploratory network meta-analysis of randomized controlled trials. LID - 10.1007/s10072-026-08929-1 [doi] LID - 432 AB - BACKGROUND: Current therapies for Parkinson's disease lack proven disease-modifying effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), developed for type 2 diabetes, have shown potential neuroprotective properties. Their comparative efficacy in Parkinson's disease remains unclear. METHODS: A systematic search (inception-February 2026) identified randomized controlled trials evaluating GLP-1RAs in Parkinson's disease. Pairwise and frequentist random-effects network meta-analyses were performed. The primary outcome was MDS-UPDRS Part III (ON state). RESULTS: Five trials (n = 708) were included. Pairwise meta-analysis showed no significant overall improvement in MDS-UPDRS Part III (MD -2.00; 95% CI -5.46 to 1.46; I(2) = 80.5%). Network meta-analysis demonstrated significant ON-state motor improvement with Exenatide 20 microg/day (MD -9.80; 95% CI -14.47 to -5.13) and Lixisenatide 20 microg/day (MD -3.08; 95% CI -5.31 to -0.85). No significant effects were observed for MDS-UPDRS Part III (OFF-state) or other domains (Parts I, II, and IV; ON-state). NLY01 at 5 mg/week improved PDQ-39, while NMSS showed dose-dependent divergence. Gastrointestinal adverse events were more frequent with GLP-1RAs. CONCLUSION: GLP-1 receptor agonists may provide dose-specific motor benefits in Parkinson's disease, but evidence for broader clinical improvement is limited. Larger, longer-duration trials are needed. FAU - Ali, Muaz AU - Ali M AD - Cleveland Clinic Florida, Weston, FL, United States of America. FAU - Sharma, Arkansh AU - Sharma A AUID- ORCID: 0009-0001-7472-5966 AD - Government Medical College, Omandurar, Chennai, Tamil Nadu, India. FAU - Paruchuri, Amith AU - Paruchuri A AD - All India Institute of Medical Sciences, New Delhi, India. FAU - Shahzad, Faizan AU - Shahzad F AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Khalid, Marwah Bintay AU - Khalid MB AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - B, Karthik N AU - B KN AD - Government Medical College, Omandurar, Chennai, Tamil Nadu, India. FAU - Avanaki, Mona AU - Avanaki M AD - Cleveland Clinic Florida, Weston, FL, United States of America. FAU - Nithyanandam, Allimuthu AU - Nithyanandam A AD - Department of Neurology, Tamil Nadu Government Multi-Super Speciality Hospital, Omandurar Government Estate, Chennai, Tamil Nadu, India. FAU - Khan, Tarannum AU - Khan T AD - Cleveland Clinic Florida, Weston, FL, United States of America. FAU - Suresh, Vinay AU - Suresh V AUID- ORCID: 0000-0002-1401-9154 AD - University of Oxford, Oxford, UK. vinay.suresh@bnc.ox.ac.uk. LA - eng PT - Journal Article PT - Network Meta-Analysis PT - Systematic Review DEP - 20260417 PL - Italy TA - Neurol Sci JT - Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology JID - 100959175 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 9P1872D4OL (Exenatide) RN - 0 (Antiparkinson Agents) RN - 74O62BB01U (lixisenatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - *Parkinson Disease/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Randomized Controlled Trials as Topic MH - Exenatide/therapeutic use MH - *Antiparkinson Agents/therapeutic use MH - Glucagon-Like Peptide 1/analogs & derivatives PMC - PMC13090280 OTO - NOTNLM OT - Cognition OT - GLP-1 receptor agonist (GLP-1RA) OT - Parkinson's disease OT - Quality of life COIS- Declarations. Competing interest: The authors declare that there are no competing financial or personal relationships that could influence the work reported in this article. Generative AI and AI assisted technologies in writing process: During the preparation of this work the author(s) used ChatGPT-5(OpenAI) for language refinement, summarisation, and converting statistical outputs into written text. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. EDAT- 2026/04/18 07:10 MHDA- 2026/06/28 06:35 PMCR- 2026/04/17 CRDT- 2026/04/17 11:23 PHST- 2025/11/08 00:00 [received] PHST- 2026/02/21 00:00 [accepted] PHST- 2026/06/28 06:35 [medline] PHST- 2026/04/18 07:10 [pubmed] PHST- 2026/04/17 11:23 [entrez] PHST- 2026/04/17 00:00 [pmc-release] AID - 10.1007/s10072-026-08929-1 [pii] AID - 8929 [pii] AID - 10.1007/s10072-026-08929-1 [doi] PST - epublish SO - Neurol Sci. 2026 Apr 17;47(5):432. doi: 10.1007/s10072-026-08929-1. PMID- 41994910 OWN - NLM STAT- MEDLINE DCOM- 20260613 LR - 20260827 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 28 IP - 7 DP - 2026 Jul TI - Use of Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson's Disease: Scandinavian Cohort Study. PG - 5767-5778 LID - 10.1111/dom.70760 [doi] AB - AIMS: To investigate the association between use of GLP-1 receptor agonists and incident Parkinson's disease. MATERIAL AND METHODS: Cohort study using data from nationwide registers in Denmark, Norway and Sweden and an active-comparator, new-user design. We included 158 961 new users of GLP-1 receptor agonists and 188 065 new users of sulfonylureas, aged 45 years or older. Liraglutide accounted for 72.9% of GLP-1 receptor agonist follow-up time, followed by semaglutide (13.4%), exenatide (7.3%), dulaglutide (5.1%) and lixisenatide (1.3%). The primary outcome was incident Parkinson's disease, defined as a first-ever diagnosis of Parkinson's disease (ICD-10 G20) or Parkinson's disease dementia (ICD-10 F02.3) in national patient registers. Cox regression with propensity score weighting was used to estimate hazard ratios (HRs) and control for confounding. RESULTS: Mean age was 65 years and 43% were female. Incidence rates for Parkinson's disease were 5.2 and 8.0 per 10 000 person-years among GLP-1 receptor agonist and sulfonylurea users, respectively (adjusted HR 0.81 [95% CI 0.68-0.96]). Results were consistent in a 2-year lag-time analysis (HR 0.84 [95% CI 0.70-1.02]) after excluding or censoring users of DPP-4 inhibitors at cohort entry or during follow-up (HR 0.74 [95% CI 0.60-0.93]) and in subgroup analyses by sex and age. CONCLUSION: In this large observational cohort study, use of GLP-1 receptor agonists compared with sulfonylureas was associated with a lower risk of incident Parkinson's disease. These findings support a potential neuroprotective role of GLP-1 receptor agonists, though replication in additional studies is needed. CI - (c) 2026 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Engstrom, Arvid AU - Engstrom A AUID- ORCID: 0000-0001-7047-0217 AD - Clinical Epidemiology Division, Department of Medicine, Centre for Pharmacoepidemiology, Solna, Karolinska Institutet, Stockholm, Sweden. FAU - Svanstrom, Henrik AU - Svanstrom H AD - Clinical Epidemiology Division, Department of Medicine, Centre for Pharmacoepidemiology, Solna, Karolinska Institutet, Stockholm, Sweden. AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. FAU - Hviid, Anders AU - Hviid A AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. AD - Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Pharmacovigilance Research Center, University of Copenhagen, Copenhagen, Denmark. FAU - Eliasson, Bjorn AU - Eliasson B AD - Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. AD - The Swedish National Diabetes Register, Vastra Gotalandsregionen, Gothenburg, Sweden. FAU - Gudbjornsdottir, Soffia AU - Gudbjornsdottir S AD - The Swedish National Diabetes Register, Vastra Gotalandsregionen, Gothenburg, Sweden. AD - Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. FAU - Wintzell, Viktor AU - Wintzell V AD - Clinical Epidemiology Division, Department of Medicine, Centre for Pharmacoepidemiology, Solna, Karolinska Institutet, Stockholm, Sweden. FAU - Hveem, Kristian AU - Hveem K AD - Department of Public Health and Nursing, Faculty of Medicine and Health Science, HUNT Center for Molecular and Clinical Epidemiology, NTNU-Norwegian University of Science and Technology, Trondheim, Norway. AD - Faculty of Medicine, HUNT Research Center, NTNU-Norwegian University of Science and Technology, Levanger, Norway. FAU - Jonasson, Christian AU - Jonasson C AD - Department of Public Health and Nursing, Faculty of Medicine and Health Science, HUNT Center for Molecular and Clinical Epidemiology, NTNU-Norwegian University of Science and Technology, Trondheim, Norway. AD - Faculty of Medicine, HUNT Research Center, NTNU-Norwegian University of Science and Technology, Levanger, Norway. FAU - Melbye, Mads AU - Melbye M AD - Department of Public Health and Nursing, Faculty of Medicine and Health Science, HUNT Center for Molecular and Clinical Epidemiology, NTNU-Norwegian University of Science and Technology, Trondheim, Norway. AD - Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. AD - Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA. AD - Danish Cancer Institute, Copenhagen, Denmark. FAU - Ueda, Peter AU - Ueda P AUID- ORCID: 0000-0002-3275-8743 AD - Clinical Epidemiology Division, Department of Medicine, Centre for Pharmacoepidemiology, Solna, Karolinska Institutet, Stockholm, Sweden. FAU - Pasternak, Bjorn AU - Pasternak B AD - Clinical Epidemiology Division, Department of Medicine, Centre for Pharmacoepidemiology, Solna, Karolinska Institutet, Stockholm, Sweden. LA - eng GR - Vetenskapsradet/ GR - Lundbeck Foundation/ GR - Region Stockholm/ GR - Novo Nordisk Fonden/ GR - Dr. Margaretha Nilsson's Foundation for Medical Research/ GR - Karolinska Institutet/ GR - Strategic Research Area Epidemiology programme/ GR - Independent Research Foundation Denmark/ GR - Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ GR - Danish Cancer Society/ PT - Journal Article DEP - 20260417 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - WTT295HSY5 (dulaglutide) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Insulin Secretagogues) RN - 839I73S42A (Liraglutide) RN - 74O62BB01U (lixisenatide) RN - 0 (Recombinant Fusion Proteins) RN - 53AXN4NNHX (Semaglutide) RN - 0 (Sulfonylurea Compounds) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - Cohort Studies MH - Denmark/epidemiology MH - *Diabetes Mellitus, Type 2/drug therapy MH - Exenatide/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists/therapeutic use MH - Glucagon-Like Peptides/analogs & derivatives/therapeutic use/adverse effects/analogs & derivatives MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Immunoglobulin Fc Fragments/therapeutic use MH - Incidence MH - Insulin Secretagogues MH - Liraglutide/therapeutic use MH - Norway/epidemiology MH - *Parkinson Disease/epidemiology/prevention & control MH - Recombinant Fusion Proteins/therapeutic use MH - Registries MH - Semaglutide/therapeutic use MH - Sulfonylurea Compounds/therapeutic use MH - Sweden/epidemiology MH - Glucagon-Like Peptide 1/analogs & derivatives PMC - PMC13243990 OTO - NOTNLM OT - GLP-1 analogue OT - disease prevention OT - observational study OT - pharmaco-epidemiology COIS- The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and have the following declarations. Dr. Christian Jonasson is an employee of NordicRWE. Dr. Bjorn Eliasson reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mundipharma, Navamedic, Novo Nordisk and Sanofi outside the submitted work. Dr. Henrik Svanstrom is a former employee of IQVIA. Prof. Anders Hviid is a scientific advisory board member of VAC4EU. The other authors declare no conflicts of interest. EDAT- 2026/04/17 13:25 MHDA- 2026/06/15 11:33 PMCR- 2026/06/08 CRDT- 2026/04/17 06:03 PHST- 2026/03/26 00:00 [revised] PHST- 2025/12/19 00:00 [received] PHST- 2026/03/27 00:00 [accepted] PHST- 2026/06/15 11:33 [medline] PHST- 2026/04/17 13:25 [pubmed] PHST- 2026/04/17 06:03 [entrez] PHST- 2026/06/08 00:00 [pmc-release] AID - DOM70760 [pii] AID - 10.1111/dom.70760 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Jul;28(7):5767-5778. doi: 10.1111/dom.70760. Epub 2026 Apr 17. PMID- 41971071 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260413 LR - 20260813 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 17 DP - 2026 TI - Molecular mechanisms underlying Parkinson's disease and role of phytochemicals, alpha-synuclein, sirtuins, and incretin mimetics in potential therapy. PG - 1798309 LID - 10.3389/fphar.2026.1798309 [doi] LID - 1798309 AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by dopaminergic neuronal loss in the substantia nigra and intracellular accumulation of misfolded alpha-synuclein aggregates. Despite being extensively studied, current pharmacological and surgical interventions remain mostly symptomatic, leaving limited efficacy in halting or reversing disease progression. The complicated pathogenesis of PD involves oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, and proteostasis imbalance, altogether contributing to neuronal vulnerability. In addition to established drugs such as levodopa, other medications affecting dopamine pathways and incretin mimetics, numerous studies have highlighted the therapeutic potential of phytomolecules to target these processes. This includes resveratrol, curcumin, quercetin, baicalein, berberine and epigallocatechin gallate (EGCG), which have demonstrated pleiotropic neuroprotective effects by mitigating oxidative and inflammatory cascades, improving mitochondrial biogenesis, preventing proteostasis imbalance, and/or blocking alpha-synuclein aggregation. Some phytomolecules may also act through the sirtuin and PI3K/Akt signaling pathways, linking neuroprotection with metabolic regulation. Some phytomolecules may additionally alleviate insulin resistance and stimulate incretin (GLP-1/GIP) secretion, potentially enhancing their neuroprotective. The exact relationship between alphaS, sirtuins, insulin signaling and phytomolecules is not yet fully understood. Nevertheless, increasing evidence suggests that phytomolecules can modulate brain insulin resistance and enhance incretin signaling, which contribute to their neuroprotective effects in PD. This review highlights the interconnected metabolic and neuronal mechanisms in Parkinson's disease encompassing alpha-synuclein pathology, sirtuin imbalance, and disrupted insulin signaling role in PD and explores incretin and phytomolecules molecule based therapies, often utilized for type 2 diabetes management as complementary multi-target neuroprotective strategies. CI - Copyright (c) 2026 Juthi, Ansari, Ahmed, Khan, Seidel, Kumar, Kumari, McKillop, Abdel-Wahab and Flatt. FAU - Juthi, Sanjida Shahid AU - Juthi SS AD - Behavioral Services, Anderson Center for Autism, Staatsburg, NY, United States. FAU - Ansari, Prawej AU - Ansari P AD - Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. AD - Department of Pharmacology, National Medical College and Teaching Hospital, Birgunj, Nepal. AD - Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka, Bangladesh. AD - Department of Genetics, Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama, Birmingham, AL, United States. FAU - Ahmed, Md Ferdos AU - Ahmed MF AD - Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka, Bangladesh. FAU - Khan, Joyeeta T AU - Khan JT AD - Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka, Bangladesh. FAU - Seidel, Veronique AU - Seidel V AD - Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom. FAU - Kumar, Sandeep AU - Kumar S AD - Department of Microbiology and Immunology, Tulane University, New Orleans, LA, United States. FAU - Kumari, Reena AU - Kumari R AD - Department of Genetics, Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama, Birmingham, AL, United States. FAU - McKillop, Aine AU - McKillop A AD - Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Abdel-Wahab, Yasser H A AU - Abdel-Wahab YHA AD - Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Flatt, Peter R AU - Flatt PR AD - Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. LA - eng PT - Journal Article PT - Review DEP - 20260326 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC13062330 OTO - NOTNLM OT - GLP-1 OT - Parkinson's disease OT - incretin mimetics OT - neurodegeneration OT - phytoconstituents OT - sirtuins OT - alpha-synuclein COIS- The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author VS declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2026/04/13 18:17 MHDA- 2026/04/13 18:18 PMCR- 2026/03/26 CRDT- 2026/04/13 06:38 PHST- 2026/01/28 00:00 [received] PHST- 2026/02/27 00:00 [revised] PHST- 2026/02/28 00:00 [accepted] PHST- 2026/04/13 18:18 [medline] PHST- 2026/04/13 18:17 [pubmed] PHST- 2026/04/13 06:38 [entrez] PHST- 2026/03/26 00:00 [pmc-release] AID - 1798309 [pii] AID - 10.3389/fphar.2026.1798309 [doi] PST - epublish SO - Front Pharmacol. 2026 Mar 26;17:1798309. doi: 10.3389/fphar.2026.1798309. eCollection 2026. PMID- 41967915 OWN - NLM STAT- MEDLINE DCOM- 20261004 LR - 20261006 IS - 1460-2156 (Electronic) IS - 0006-8950 (Linking) VI - 149 IP - 10 DP - 2026 Oct 5 TI - GLP1R expression and Parkinson's disease and related disorders in GLP-1 receptor agonist-treated type 2 diabetes. PG - 3431-3439 LID - 10.1093/brain/awag130 [doi] AB - Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, raising the possibility of biologically meaningful heterogeneity. We tested whether interindividual differences in systemic GLP1R expression are associated with PDRD risk among adults with type 2 diabetes initiating GLP-1RAs. We conducted an electronic health record-based new-user cohort study in the National Institutes of Health All of Us Research Program, focusing on adults with type 2 diabetes aged 50 years or older who initiated a GLP-1RA between 2005 and 2023 and had no prior PDRD or Alzheimer's disease and related dementias (ADRD). Systemic GLP1R expression was genetically proxied by a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score dichotomized at the cohort median. Follow-up ended at the earliest of incident PDRD, death or 1 October 2023. Hazard ratios (HR) were estimated using multivariable Cox proportional hazards models adjusting for baseline covariates, and incidence rates and rate differences per 1000 person-years were estimated using Poisson models. Prespecified sensitivity analyses excluded early outcome events and short drug exposure; an exploratory analysis evaluated incident ADRD. The cohort included 7039 initiators (3520 high versus 3519 low genetic score; mean age 61.7 +/- 8.4 years; 59.8% female; mean follow-up 3.8 +/- 3.1 years). Compared with the low-score group, the high-score group had a lower hazard of incident PDRD [HR 0.78; 95% confidence interval (CI) 0.62 to 0.98] and a lower incidence rate (rate difference -1.36 per 1000 person-years; 95% CI -2.51 to -0.20). Associations were consistent across sensitivity analyses. No association was observed for incident ADRD (HR 1.02; 95% CI 0.81 to 1.28). These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among GLP-1RA-treated adults with type 2 diabetes. Systemic GLP1R-mediated pathways may be relevant to interindividual differences in observed PDRD risk, and genetic instruments for GLP1R expression may inform hypotheses for future PDRD trial design. CI - (c) The Author(s) 2026. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. FAU - Woo, Kyung Ah AU - Woo KA AUID- ORCID: 0000-0001-5457-7348 AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. AD - Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea. AD - Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. FAU - Jang, Yoonhyuk AU - Jang Y AUID- ORCID: 0009-0004-5991-7822 AD - Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea. AD - Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. AD - Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. FAU - Kim, Han-Joon AU - Kim HJ AUID- ORCID: 0000-0001-8219-9663 AD - Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. FAU - Park, Peter J AU - Park PJ AUID- ORCID: 0000-0001-9378-960X AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. LA - eng GR - Korea Health Industry Development Institute/ GR - RS-2024-00403047/Ministry of Health & Welfare/ PT - Journal Article PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (GLP1R protein, human) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/genetics/complications MH - Female MH - *Glucagon-Like Peptide-1 Receptor/genetics/biosynthesis/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Parkinson Disease/genetics/epidemiology MH - Male MH - Middle Aged MH - Aged MH - Cohort Studies MH - *Hypoglycemic Agents/therapeutic use OTO - NOTNLM OT - GLP1R OT - Parkinson's disease OT - genetics OT - glucagon-like peptide-1 receptor agonist OT - type 2 diabetes EDAT- 2026/04/13 00:31 MHDA- 2026/10/04 23:29 CRDT- 2026/04/12 21:14 PHST- 2025/12/23 00:00 [received] PHST- 2026/03/11 00:00 [revised] PHST- 2026/03/21 00:00 [accepted] PHST- 2026/10/04 23:29 [medline] PHST- 2026/04/13 00:31 [pubmed] PHST- 2026/04/12 21:14 [entrez] AID - 8651260 [pii] AID - 10.1093/brain/awag130 [doi] PST - ppublish SO - Brain. 2026 Oct 5;149(10):3431-3439. doi: 10.1093/brain/awag130. PMID- 41931123 OWN - NLM STAT- MEDLINE DCOM- 20260628 LR - 20260813 IS - 1573-6830 (Electronic) IS - 0272-4340 (Print) IS - 0272-4340 (Linking) VI - 46 IP - 1 DP - 2026 Apr 3 TI - Narrative Review "Dual Frontiers in Neurodegeneration: Pharmacological Synergies and Divergences in Parkinson's Disease and Type 2 Diabetes Mellitus". LID - 10.1007/s10571-026-01702-0 [doi] LID - 86 AB - Diabetes mellitus (DM) and Parkinson's disease (PD) are both chronic diseases that have a bidirectional relationship, wherein DM increases the risk of developing PD. Both diseases are related through overlapping pathways, insulin resistance, oxidative stress, and chronic inflammation, which can potentially lead to neurodegeneration. Insulin resistance and impaired insulin signalling present in DM may exacerbate neurodegeneration in PD. Current treatments for PD and DM can interact, such that dopaminergic drugs used to manage PD may increase the risk of altering glucose uptake, leading to exacerbated insulin resistance. Conversely, anti-diabetic drugs like GLP-1 receptor agonists and metformin may even be neuroprotective. However, not all anti-diabetic drugs provide utility in managing PD symptoms; some merely provide general metabolic change. The interplay between PD and DM remains largely uncharacterized, and due to the overlapping nature of these conditions, expanding the scope of research into novel and/or personalized causes of their combined effects may improve treatment efficacy. FAU - Sharallah, Omnya A AU - Sharallah OA AUID- ORCID: 0000-0001-7046-6680 AD - Faculty of Pharmacy (PharmD), Egypt-Japan University of Science and Technology (E-JUST), New Borg El Arab, Alexandria, 21934, Egypt. FAU - Malakar, Vishnu AU - Malakar V AUID- ORCID: 0000-0003-2772-364X AD - Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education and Research, The Nilgiris, Ooty, Tamil Nadu, 643001, India. FAU - Salama, Ahmed E AU - Salama AE AUID- ORCID: 0000-0002-9503-2149 AD - Faculty of Medicine, Misr University for Science and Technology (MUST), 6th of October City, Giza, 12566, Egypt. FAU - Elmaaz, Salma M AU - Elmaaz SM AUID- ORCID: 0009-0003-1081-6126 AD - Faculty of Science, Menoufia University, Shebin el Koom, 32511, Egypt. FAU - Daba, Salma A AU - Daba SA AUID- ORCID: 0009-0006-5031-8414 AD - Faculty of Medicine, Menoufia University, Shebin el Koom, 32511, Egypt. FAU - Poddar, Nitesh Kumar AU - Poddar NK AUID- ORCID: 0000-0002-2162-9110 AD - Biochemistry & Molecular Biology Laboratory, Department of Biosciences, Manipal University Jaipur, Jaipur-Ajmer Express Highway, Dehmi Kalan, Near GVK Toll Plaza, Jaipur, Rajasthan, 303007, India. niteshkumar.poddar@jaipur.manipal.edu. LA - eng PT - Journal Article PT - Review DEP - 20260403 PL - Netherlands TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Parkinson Disease/drug therapy/metabolism/pathology MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Animals MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - *Nerve Degeneration/drug therapy/pathology MH - Oxidative Stress/drug effects MH - Drug Synergism PMC - PMC13172232 OTO - NOTNLM OT - Anti-Parkinson's drugs OT - Antidiabetic OT - Diabetes mellitus OT - Parkinson COIS- Declarations. Competing interests: The authors declare no competing interests. EDAT- 2026/04/03 13:47 MHDA- 2026/06/28 00:38 PMCR- 2026/04/03 CRDT- 2026/04/03 11:02 PHST- 2025/06/29 00:00 [received] PHST- 2026/02/13 00:00 [accepted] PHST- 2026/06/28 00:38 [medline] PHST- 2026/04/03 13:47 [pubmed] PHST- 2026/04/03 11:02 [entrez] PHST- 2026/04/03 00:00 [pmc-release] AID - 10.1007/s10571-026-01702-0 [pii] AID - 1702 [pii] AID - 10.1007/s10571-026-01702-0 [doi] PST - epublish SO - Cell Mol Neurobiol. 2026 Apr 3;46(1):86. doi: 10.1007/s10571-026-01702-0. PMID- 41925713 OWN - NLM STAT- MEDLINE DCOM- 20260907 LR - 20260907 IS - 2724-6116 (Electronic) IS - 2724-6116 (Linking) VI - 51 IP - 3 DP - 2026 Sep TI - Impact of hypoglycemic agents on glycemic control and cognitive decline in older adults with type 2 diabetes: real-world evidence on glucagon like peptide 1 receptor agonists. PG - 257-265 LID - 10.23736/S2724-6507.26.04501-X [doi] AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is frequently associated with cognitive decline in the older population. Although optimal glycemic control is known to be essential for disease management, the impact of hypoglycemic agents on cognitive function remains poorly investigated. METHODS: This retrospective study included 93 geriatric outpatients with T2DM. Hypoglycemic treatments consisted of metformin, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors, and insulin. Patient evaluations included glycated hemoglobin (HbA1c) measurements, Standardized Mini-Mental State Examination (MMSE), and Mini Nutritional Assessment (MNA). RESULTS: After one year of treatment, patients exhibited a significant reduction in HbA1c levels (from 8.06% [+/-1.19] to 7.19% [+/-0.84], P<0.001), improvement of MMSE scores (from 25.87 [+/-3.09] to 27.47 [+/-2.9], P<0.001). Regression analysis identified GLP-1RAs as the most effective agent in improving glycemic control (P<0.001) and cognitive function (P=0.016). Treatment with GLP-1RAs was associated with a reduction in MNA scores (P<0.001), though these remained above the malnutrition threshold. CONCLUSIONS: Our findings suggest that improved glycemic control may help slow cognitive decline in older patients with T2DM. Among the drug classes examined, GLP-1RAs showed the largest reductions in HbA1c and were linked to greater MMSE score gains. FAU - DI Marzio, Benedetta AU - DI Marzio B AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. AD - PhD Program in Translation Specialistic Medicine, "G.B. Morgagni" Curriculum "Endocrine and Metabolic Sciences", University of Padua, Padua, Italy. FAU - Gasparini, Giulia AU - Gasparini G AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Ambrosio, Andrea AU - Ambrosio A AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy - andrea.ambrosio@studenti.unipd.it. FAU - Coin, Alessandra AU - Coin A AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Filipponi, Luca AU - Filipponi L AD - Department of General Psychology (DPG), University of Padua, Padua, Italy. FAU - Sartore, Giovanni AU - Sartore G AD - Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Ferra, Elisabetta AU - Ferra E AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Papa, Mario V AU - Papa MV AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Ravelli, Adele AU - Ravelli A AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Ceolin, Chiara AU - Ceolin C AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. AD - Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Aging Research Center, University of Stockholm, Stockholm, Sweden. FAU - DE Rui, Marina AU - DE Rui M AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Zanforlini, Bruno M AU - Zanforlini BM AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Curreri, Chiara AU - Curreri C AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Bertocco, Anna AU - Bertocco A AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. FAU - Devita, Maria AU - Devita M AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. AD - Department of General Psychology (DPG), University of Padua, Padua, Italy. FAU - Sergi, Giuseppe AU - Sergi G AD - Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy. LA - eng PT - Journal Article DEP - 20260402 PL - Italy TA - Minerva Endocrinol (Torino) JT - Minerva endocrinology JID - 101777342 RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glycated Hemoglobin) RN - 0 (Blood Glucose) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/blood/complications/psychology MH - Female MH - *Hypoglycemic Agents/therapeutic use MH - Male MH - Retrospective Studies MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Aged MH - *Glycemic Control/methods MH - *Cognitive Dysfunction/etiology/prevention & control MH - Glycated Hemoglobin/analysis MH - Aged, 80 and over MH - Blood Glucose/drug effects MH - Cognition/drug effects EDAT- 2026/04/02 12:36 MHDA- 2026/09/07 11:37 CRDT- 2026/04/02 10:45 PHST- 2026/09/07 11:37 [medline] PHST- 2026/04/02 12:36 [pubmed] PHST- 2026/04/02 10:45 [entrez] AID - S2724-6507.26.04501-X [pii] AID - 10.23736/S2724-6507.26.04501-X [doi] PST - ppublish SO - Minerva Endocrinol (Torino). 2026 Sep;51(3):257-265. doi: 10.23736/S2724-6507.26.04501-X. Epub 2026 Apr 2. PMID- 41920344 OWN - NLM STAT- MEDLINE DCOM- 20260627 LR - 20261010 IS - 1573-7365 (Electronic) IS - 0885-7490 (Linking) VI - 41 IP - 1 DP - 2026 Apr 1 TI - GLP-1 and the brain's powerhouse: a new perspective on the role of mitochondria in neuroprotection. LID - 72 [pii] LID - 10.1007/s11011-026-01839-3 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are emerging as potential neuroprotective drugs in neurodegenerative diseases. These drugs were initially developed to manage type 2 diabetes (T2D) and obesity. In addition to GLP-1RAs having an impact on metabolic pathways, growing evidences suggests that GLP-1RAs also positively regulate mitochondrial homeostasis in several neuronal cell types such as hippocampal, cortical, dopaminergic and hypothalamic. These modulatory effect of activated GLP-1R in the brain might be playing a crucial role which ultimately leads to neuronal cell survival, synaptic function, and improve in neuroinflammation in case neurodegenerative diseases. Although GLP-1RAs show promise in enhancing mitochondrial health, major gaps remain in understanding cell-type-specific responses, sex- and age-related differences, and the precise mechanistic links between GLP-1 signaling in mitochondrial biogenesis, dynamics, and mitophagy. This review summarises current understanding of GLP-1RA-induced mitochondrial regulation in the central nervous system. It also highlights key knowledge gaps, including cell type specificity and the lack of mechanistic as well as translational studies linking GLP-1RA signalling to mitochondrial regulation in the human CNS, which must be addressed to harness their full neuroprotective potential. FAU - Dasgupta, Tiasha AU - Dasgupta T AD - Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. Tiasha.S.Dasgupta@ZydusLife.com. FAU - Bhayani, Hitesh AU - Bhayani H AD - Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. FAU - Ghoshdastidar, Krishnarup AU - Ghoshdastidar K AD - Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. FAU - Viswanathan, Kasinath AU - Viswanathan K AD - Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. FAU - Jain, Mukul AU - Jain M AD - Zydus Research Centre, Zydus Life Sciences, Ahmedabad, Gujarat, 382210, India. LA - eng PT - Journal Article PT - Review DEP - 20260401 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Mitochondria/metabolism/drug effects MH - Animals MH - *Brain/metabolism/drug effects MH - *Neuroprotection/physiology/drug effects MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - *Glucagon-Like Peptide 1/metabolism MH - *Neurodegenerative Diseases/metabolism/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Signal Transduction MH - Neurons/metabolism/drug effects OTO - NOTNLM OT - AD OT - GLP-1RAs OT - Mitochondria OT - PD OT - Type 2 diabetes COIS- Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Competing interests: The authors declare no competing interests. EDAT- 2026/04/01 12:31 MHDA- 2026/06/28 00:36 CRDT- 2026/04/01 11:14 PHST- 2026/01/12 00:00 [received] PHST- 2026/03/24 00:00 [accepted] PHST- 2026/06/28 00:36 [medline] PHST- 2026/04/01 12:31 [pubmed] PHST- 2026/04/01 11:14 [entrez] AID - 10.1007/s11011-026-01839-3 [pii] AID - 10.1007/s11011-026-01839-3 [doi] PST - epublish SO - Metab Brain Dis. 2026 Apr 1;41(1):72. doi: 10.1007/s11011-026-01839-3. PMID- 41880197 OWN - NLM STAT- MEDLINE DCOM- 20260713 LR - 20260813 IS - 2162-3279 (Electronic) VI - 16 IP - 4 DP - 2026 Apr TI - Efficacy and Safety of Glucagon-Like Peptide 1 Receptor Agonists in Parkinson Disease: A Systematic Review and Meta-Analysis. PG - e71344 LID - 10.1002/brb3.71344 [doi] LID - e71344 AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with no currently approved disease-modifying treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally used in type 2 diabetes, have demonstrated neuroprotective and anti-inflammatory effects in preclinical PD models. This systematic review and meta-analysis evaluated the efficacy and safety of GLP-1RAs in patients with PD. METHODS: A systematic search of MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov was conducted through July 2025 for randomized controlled trials (RCTs) comparing GLP-1RAs to placebo in PD. Primary outcomes included MDS-UPDRS Part III (motor examination) both on and off medication. Secondary outcomes included MDS-UPDRS Parts I, II, IV, PDQ-39, NMSS, and adverse effects. Data were pooled using a random-effects model with results reported as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). RESULTS: Five RCTs involving 708 participants were included. No statistically significant differences were found in MDS-UPDRS Part III scores off medication (MD: -2.00, 95% CI: -4.12 to 0.11, p = 0.06) or on medication (MD: -1.40, 95% CI: -3.42 to 0.62, p = 0.17). Secondary outcomes also showed no significant benefits with GLP-1RA use. However, GLP-1RAs were associated with increased gastrointestinal side effects, including nausea (RR: 2.09), vomiting (RR: 4.53), constipation (RR: 1.60), and weight loss (RR: 1.83). CONCLUSION: Current evidence does not demonstrate a statistically significant overall benefit of GLP-1RAs on efficacy outcomes in PD, while gastrointestinal adverse events are increased. More trials are needed to clarify their disease-modifying potential. CI - (c) 2026 The Author(s). Brain and Behavior published by Wiley Periodicals LLC. FAU - Raza, Hassan AU - Raza H AD - Department of Medicine, Lahore Medical and Dental College, Lahore, Pakistan. FAU - Nizam, Bakhtmeena AU - Nizam B AD - Department of Medicine, Women Medical College, Abbotabad, Pakistan. FAU - Padaniya, Arif AU - Padaniya A AD - Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA. FAU - Farid, Muhammad Aqib AU - Farid MA AD - Department of Geriatrics, Oxleas NHS Trust, London, UK. FAU - Nabi, Amber AU - Nabi A AD - Department of Medicine, Ziauddin University, Karachi, Pakistan. FAU - Hasan, Muhammad Qasim AU - Hasan MQ AD - Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan. FAU - Salih, Muhammad AU - Salih M AD - Department of Medicine, Dow University Hospital, Karachi, Pakistan. FAU - Patel, Apurva Hiteshkumar AU - Patel AH AD - Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Inam, Noora AU - Inam N AD - Department of Medicine, Gajju Khan Medical College, Swabi, Pakistan. FAU - Rehman, Mohammad Ebad Ur AU - Rehman MEU AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Khan, Usman AU - Khan U AD - Department of Neurology, Geisinger Hospital, Scranton, Pennsylvania, USA. FAU - Alsubari, Asma'a Munasar Ali AU - Alsubari AMA AD - Department of Medicine, Sana'a University, Sana'a, Yemen. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - United States TA - Brain Behav JT - Brain and behavior JID - 101570837 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Antiparkinson Agents) SB - IM MH - Humans MH - *Parkinson Disease/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Antiparkinson Agents/adverse effects/pharmacology/therapeutic use PMC - PMC13109035 COIS- The authors declare no conflicts of interest. EDAT- 2026/03/25 19:36 MHDA- 2026/03/25 19:37 PMCR- 2026/03/25 CRDT- 2026/03/25 12:42 PHST- 2026/03/06 00:00 [revised] PHST- 2025/10/25 00:00 [received] PHST- 2026/03/09 00:00 [accepted] PHST- 2026/03/25 19:37 [medline] PHST- 2026/03/25 19:36 [pubmed] PHST- 2026/03/25 12:42 [entrez] PHST- 2026/03/25 00:00 [pmc-release] AID - BRB371344 [pii] AID - 10.1002/brb3.71344 [doi] PST - ppublish SO - Brain Behav. 2026 Apr;16(4):e71344. doi: 10.1002/brb3.71344. PMID- 41865758 OWN - NLM STAT- MEDLINE DCOM- 20260528 LR - 20261002 IS - 1474-547X (Electronic) IS - 0140-6736 (Linking) VI - 407 IP - 10544 DP - 2026 May 30 TI - Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. PG - 2167-2179 LID - S0140-6736(26)00459-9 [pii] LID - 10.1016/S0140-6736(26)00459-9 [doi] AB - BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease. METHODS: evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome. FINDINGS: Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72.2 years (SD 7.1), and mean CDR-SB score was 3.7 (SD 1.6) at baseline. In evoke+, 54 (2.8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2.3 (SE 0.1) and 2.2 (0.1) with semaglutide, compared with 2.3 (0.1) and 2.1 (0.1) with placebo (estimated difference -0.08 [95% CI -0.35 to 0.20], p=0.57 in evoke and 0.10 [-0.17 to 0.38], p=0.46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91.2%) of 1896 participants receiving semaglutide versus 1613 (84.8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). INTERPRETATION: Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications. FUNDING: Novo Nordisk. CI - Copyright (c) 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. FAU - Cummings, Jeffrey L AU - Cummings JL AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Las Vegas, NV, USA. FAU - Atri, Alireza AU - Atri A AD - Banner Sun Health Research Institute, Sun City, AZ, USA; Banner Alzheimer's Institute, Phoenix, AZ, USA; Department of Neurology, Mass General Brigham and Harvard Medical School, Boston, MA, USA. FAU - Sano, Mary AU - Sano M AD - Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Zetterberg, Henrik AU - Zetterberg H AD - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Dementia Research Institute at UCL, London, UK; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Centre for Brain Research, Indian Institute of Science, Bangalore, India. FAU - Scheltens, Philip AU - Scheltens P AD - Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; EQT Life Sciences, Amsterdam, Netherlands. FAU - Knop, Filip K AU - Knop FK AD - Novo Nordisk, Soborg, Denmark. FAU - Johannsen, Peter AU - Johannsen P AD - Novo Nordisk, Soborg, Denmark. FAU - Wichmann, Christian A AU - Wichmann CA AD - Novo Nordisk, Soborg, Denmark. FAU - Abschneider, Rikke Mortensen AU - Abschneider RM AD - Novo Nordisk, Soborg, Denmark. FAU - Leon, Teresa AU - Leon T AD - Novo Nordisk, Soborg, Denmark. FAU - Feldman, Howard H AU - Feldman HH AD - Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. Electronic address: howardfeldman@health.ucsd.edu. LA - eng SI - ClinicalTrials.gov/NCT04777396 SI - ClinicalTrials.gov/NCT04777409 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20260319 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R RN - 53AXN4NNHX (Semaglutide) RN - 62340-29-8 (Glucagon-Like Peptides) SB - IM MH - Humans MH - Semaglutide MH - *Glucagon-Like Peptides/administration & dosage/adverse effects/therapeutic use MH - *Alzheimer Disease/drug therapy MH - Female MH - Male MH - Aged MH - Double-Blind Method MH - Aged, 80 and over MH - Middle Aged MH - Administration, Oral MH - Treatment Outcome MH - Cognitive Dysfunction/drug therapy COIS- Declaration of interests JLC has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, Bio X Cel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He is supported by National Institute of General Medical Sciences grant P20GM109025, National Institute on Aging (NIA) grant R35AG71476, NIA grant R25 AG083721-01, Alzheimer's Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment. AA has, in the last 10 years, served as a consultant or received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programmes, and materials; and serving on advisory boards for AbbVie, Acadia, Allergan, Alzheimer's Disease International, the Alzheimer's Association, AriBio, Axovant, Axsome, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Johnson & Johnson, Life Molecular Imaging/Lantheus, Lundbeck, Merck, Michael J Fox Foundation, Novo Nordisk, ONO, Otsuka, Prothena, Qynapse, Roche/Genentech, Sunovion, Suven, Synexus, and Vaxxinity. He receives book royalties from Oxford University Press for a medical book on dementia. He receives institutional research grant or contract funding from the NIA/National Institutes of Health (NIH; 1P30AG072980, U24AG057437, 1P30AG072980, R01AG070883, R01AG086363, U01AG082350, U24AG057437), Arizona Department of Health Services (CTR040636), Foundation for the NIH, Washington University in St. Louis, Michael J. Fox Foundation, and Gates Ventures. His institution receives or has received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves or has served as a contracted site principal investigator. He has received or receives honoraria from Novo Nordisk for consulting activities, including for service on the evoke(+) program Steering Committee. MS has served on the Scientific Advisory Board for Medication and as a consultant for Eisai, Avenir, vTv, Biogen, Bio X Cel, F. Hoffman LaRoche, Merck, Novo Nordisk, Novartis, Otsuka, Genentech, and BioVie. She is a member of the Alzheimer Association Medical and Scientific Advisory Group and Chair of the data safety monitoring board for the Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD; sponsor: University of Colorado). HZ reports a relationship with AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, NervGen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, ReMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave that includes consulting or advisory services. He reports a relationship with AlzeCure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD that includes speaking and lecture fees. He reports a relationship with Brain Biomarker Solutions in Gothenburg AB that includes equity or stocks. FKK, PJ, RMA, and CAW are employees and minor shareholders of Novo Nordisk. TL was an employee and minor shareholder of Novo Nordisk at the time of the analysis. PS is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam UMC. He is co-Chair of the Steering Committee for the phase 3 trials evoke and evoke+ with Novo Nordisk. HHF reports a consulting service agreement with Novo Nordisk for serving on the evoke + Steering Committee with funds including travel support for its meetings paid to UC San Diego. He receives no financial support for the present manuscript. Other disclosures include his receiving grants for UC San Diego from Allyx Therapeutics and Vivoryon Therapeutics (Probiodrug). He holds service agreements through UC San Diego for consulting with Biosplice Therapeutics, Arrowhead Pharmaceuticals, Axon Neuroscience, and LuMind Foundation. He provides service as a member of data and safety monitoring boards for Janssen Research & Development and Roche/Genentech and is a Scientific Advisory Board Chair for the Tau Consortium Rainwater Charitable Foundation through a UC San Diego service agreement. He has received travel support from Royal Society of Canada, Translating Research for Elder Care (TREC), Association for Frontotemporal Dementia (AFTD), Rainwater Charitable Foundation, Banner Health, Invictus, Summeet, and Novo Nordisk. He receives philanthropic support for Alzheimer's disease therapeutic research through the Epstein Family Alzheimer's Research Collaboration as well as personal funds for Detecting and Treating Dementia (Serial Number 12/3- 2691 US Patent Number PCT/US2007/07008, Washington DC, US Patent and Trademark Office). EDAT- 2026/03/23 01:33 MHDA- 2026/05/29 15:45 CRDT- 2026/03/22 19:54 PHST- 2026/02/06 00:00 [received] PHST- 2026/02/27 00:00 [revised] PHST- 2026/03/03 00:00 [accepted] PHST- 2026/05/29 15:45 [medline] PHST- 2026/03/23 01:33 [pubmed] PHST- 2026/03/22 19:54 [entrez] AID - S0140-6736(26)00459-9 [pii] AID - 10.1016/S0140-6736(26)00459-9 [doi] PST - ppublish SO - Lancet. 2026 May 30;407(10544):2167-2179. doi: 10.1016/S0140-6736(26)00459-9. Epub 2026 Mar 19. PMID- 41862354 OWN - NLM STAT- MEDLINE DCOM- 20260711 LR - 20260730 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 48 IP - 4 DP - 2026 Apr TI - Effect of Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA) on Neuropsychiatric Outcomes: A Systematic Review and Meta-Analysis. PG - 347-384 LID - S0149-2918(26)00044-5 [pii] LID - 10.1016/j.clinthera.2026.02.010 [doi] AB - PURPOSE: Type 2 diabetes mellitus (T2D) is associated with an increased burden of neuropsychiatric disorders, including cognitive decline, affective disorders, and substance use disorders. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control and weight reduction, have been hypothesized to confer neuroprotective and psychotropic benefits via central and peripheral mechanisms. However, evidence across individual studies remains inconsistent. METHODS: We conducted a systematic review and meta-analysis (PROSPERO CRD420251025534) of randomized controlled trials (RCTs) and observational studies assessing the effect of GLP-1 RAs on neuropsychiatric outcomes. Searches were performed in MEDLINE, SCOPUS, CENTRAL, and Web of Science up to 30(th) October 2025. Eligible comparators included placebo, standard care, or alternative glucose-lowering agents. Data were synthesized using random-effects models, and risk of bias was assessed using RoB2 and ROBINS-I. Evidence certainty was graded using GRADE methodology. FINDINGS: From 10,037 records, 82 studies were included. GLP-1 RAs were associated with a reduced risk of idiopathic Parkinson's disease (PD) (pooled HR 0.70, 95% CI: 0.53-0.92, I(2) = 38%) but no improvements in motor symptoms in established PD (MDS-UPDRS Part III off-medication: mean difference -3.29, 95% CI: -7.84, 1.26, I(2) = 80%). No consistent improvements in non-motor symptoms, quality of life, or dyskinesia scores were seen. GLP-1 RAs were associated with a reduced risk of cannabis use disorder (pooled HR 0.55, 95% CI: 0.39-0.77, I(2) = 71%) but showed no significant effect on opioid use disorder (pooled HR 0.61, 95% CI: 0.24-1.52, I(2) = 91%). Liraglutide reduced binge frequency in binge eating disorder (mean difference -1.28, 95% CI: -1.67, -0.89, I(2) = 53%) compared to placebo. In observational studies versus non-user controls, GLP-1 RA use was associated with a lower reported risk of suicidality (pooled OR 0.34, 95% CI: 0.18-0.63, I(2) = 99%), but no such association was seen with Semaglutide alone (pooled OR 0.71, 95% CI: 0.29-1.73, I(2) = 99%), active-comparator studies (pooled HR 0.96, 95% CI: 0.81-1.15, I(2)=0%) or RCTs (pooled RR 1.13, 95% CI: 0.53-2.41, I(2)=0%). No associations were observed for depression or anxiety. For dementia, findings were mixed: no benefit versus SGLT2 inhibitors (pooled RR 1.07, 95% CI: 0.73-1.56, I(2) = 78%), but there was a reduced risk of Alzheimer's disease when compared to unmatched or non-exposed controls (pooled RR 0.37, 95% CI: 0.14-0.96, I(2) = 98%). Certainty of evidence ranged from moderate to very low. IMPLICATIONS: Current evidence, largely of low to very low certainty, suggests potential selective neuropsychiatric associations of GLP-1 RAs, particularly in Parkinson's disease risk reduction and binge eating disorder. Benefits for dementia risk reduction were observed primarily in comparisons with non-exposed or DPP4i, whereas no advantage was seen versus other active comparators, such as SGLT2 inhibitors. Our findings should be interpreted as hypothesis-generating due to significant heterogeneity and wide confidence intervals, indicating imprecision. Longer-term studies with neuropsychiatric outcomes as the primary endpoint are required. CI - Copyright (c) 2026 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Choudhury, Ishraq AU - Choudhury I AD - Salford Royal Hospital, Northern Care Alliance, Salford, UK. FAU - Ward, John Headly AU - Ward JH AD - Department of Psychiatry, University of Cambridge, Cambridge, UK. FAU - Mahesh, Sahana AU - Mahesh S AD - Diabetes & Endocrinology Research, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK. FAU - Alam, Uazman AU - Alam U AD - Diabetes & Endocrinology Research, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; Centre for Biomechanics and Rehabilitation Technologies, Staffordshire University, Stoke-on-Trent, UK. FAU - Azmi, Shazli AU - Azmi S AD - Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Anson, Matthew AU - Anson M AD - Diabetes & Endocrinology Research, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. Electronic address: manson1@liverpool.ac.uk. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20260319 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - *Mental Disorders/prevention & control MH - Randomized Controlled Trials as Topic MH - Parkinson Disease/prevention & control OTO - NOTNLM OT - Addiction OT - GLP-1 OT - Glucagon-like-peptide-1 OT - Neurology OT - Psychiatiry OT - Type 2 diabetes COIS- Declaration of competing interest MA receives a fellowship from the Novo Nordisk UK research foundation and Breakthrough T1D. UA has received honoraria from Eli Lilly, Theras, Procter & Gamble, Viatris, Grunenthal and Sanofi for educational meetings and funding for attendance to an educational meeting from Sanofi and Diiachi Sankyo. UA has also received investigator-led funding by Procter & Gamble and is a council member of the Royal Society of Medicine's Vascular, Lipid & Metabolic Medicine Section. EDAT- 2026/03/21 00:34 MHDA- 2026/04/21 17:43 CRDT- 2026/03/20 22:54 PHST- 2025/12/06 00:00 [received] PHST- 2026/02/10 00:00 [revised] PHST- 2026/02/23 00:00 [accepted] PHST- 2026/04/21 17:43 [medline] PHST- 2026/03/21 00:34 [pubmed] PHST- 2026/03/20 22:54 [entrez] AID - S0149-2918(26)00044-5 [pii] AID - 10.1016/j.clinthera.2026.02.010 [doi] PST - ppublish SO - Clin Ther. 2026 Apr;48(4):347-384. doi: 10.1016/j.clinthera.2026.02.010. Epub 2026 Mar 19. PMID- 41830037 OWN - NLM STAT- MEDLINE DCOM- 20260711 LR - 20260813 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 18 IP - 5 DP - 2026 Mar 8 TI - Effects of Laurocerasus Officinalis Roem (Cherry Laurel) on Cognitive Function and Neurobiochemical Pathways in a Streptozotocin-Induced Nontransgenic Alzheimer's Disease Model. LID - 10.3390/nu18050867 [doi] LID - 867 AB - Background: This study investigated the effects of Laurocerasus officinalis Roem (cherry laurel; CL), a traditionally consumed fruit, on cognitive performance and selected neurobiochemical and metabolic pathways in a nontransgenic streptozotocin (STZ)-induced Alzheimer's disease (i.c.v. STZ) model and an STZ-induced type 2 diabetes mellitus (T2DM; i.p. STZ) model. Method: Fifty-seven adult male Sprague-Dawley rats were allocated to control, T2DM, and Alzheimer (ALZ) model groups, with subgroup interventions including CL supplementation and, in the T2DM model, metformin as a comparator. Spatial learning and memory were assessed using the Morris Water Maze. Serum and brain tissue levels of GSK3-beta, glutathione (GSH), interleukin-1 (IL-1), GLUT4, GLP-1, beta-amyloid (Abeta), and acetylcholinesterase (AChE) were quantified. Results: Serum GSK3-beta levels did not differ significantly between groups, whereas brain tissue GSK3-beta showed significant between-group differences. CL increased GSH levels in both models, with significant elevations in serum and brain tissue GSH in the ALZ model following CL administration; in the T2DM model, GSH increased after both CL and metformin. In the ALZ model, CL was associated with decreased serum Abeta and AChE levels and improved Morris Water Maze performance, reflected by reduced escape latencies. Conclusions: CL supplementation was associated with antioxidant enhancement and modulation of amyloid- and cholinergic-related measures, alongside improved spatial learning performance in the STZ-induced nontransgenic ALZ model. In addition, CL reduced blood glucose in the T2DM model. Given the likely contribution of fruit phytochemicals (including total phenolics), further studies are warranted to better define the bioactive composition and mechanisms underlying these effects. FAU - Ozsoy, Fulya AU - Ozsoy F AD - Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey. AD - Medical Laboratory Techniques Programme, Vacotinial School and Isik University, 34980 Istanbul, Turkey. FAU - Yanar, Karolin AU - Yanar K AUID- ORCID: 0000-0001-6571-415X AD - Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey. FAU - Sayili, Ugurcan AU - Sayili U AUID- ORCID: 0000-0002-5925-2128 AD - Department of Public Health, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey. FAU - Atukeren, Pinar AU - Atukeren P AD - Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey. FAU - Uzun, Hafize AU - Uzun H AUID- ORCID: 0000-0002-1347-8498 AD - Department of Medical Biochemistry, Faculty of Medicine, Istanbul Atlas University, 34303 Istanbul, Turkey. LA - eng PT - Journal Article DEP - 20260308 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 5W494URQ81 (Streptozocin) RN - 0 (Plant Extracts) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - GAN16C9B8O (Glutathione) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - 0 (Amyloid beta-Peptides) RN - EC 3.1.1.7 (Acetylcholinesterase) RN - 0 (Interleukin-1) SB - IM MH - Animals MH - *Alzheimer Disease/chemically induced/drug therapy/psychology/metabolism MH - Male MH - Rats, Sprague-Dawley MH - Streptozocin MH - *Cognition/drug effects MH - Disease Models, Animal MH - Brain/metabolism/drug effects MH - Rats MH - *Plant Extracts/pharmacology MH - Glycogen Synthase Kinase 3 beta/metabolism/blood MH - Glutathione/metabolism MH - Maze Learning/drug effects MH - *Diabetes Mellitus, Experimental/drug therapy MH - Metformin/pharmacology MH - Diabetes Mellitus, Type 2/drug therapy MH - Fruit/chemistry MH - Memory/drug effects MH - Amyloid beta-Peptides/metabolism MH - Acetylcholinesterase/metabolism MH - Interleukin-1/metabolism PMC - PMC12986940 OTO - NOTNLM OT - Alzheimer's disease OT - GSK3-beta OT - Moris Water Maze OT - cherry laurel OT - type 2 diabetes COIS- The authors declare no potential conflicts of interest. EDAT- 2026/03/14 06:32 MHDA- 2026/03/14 06:33 PMCR- 2026/03/08 CRDT- 2026/03/14 01:11 PHST- 2026/01/29 00:00 [received] PHST- 2026/03/02 00:00 [revised] PHST- 2026/03/06 00:00 [accepted] PHST- 2026/03/14 06:33 [medline] PHST- 2026/03/14 06:32 [pubmed] PHST- 2026/03/14 01:11 [entrez] PHST- 2026/03/08 00:00 [pmc-release] AID - nu18050867 [pii] AID - nutrients-18-00867 [pii] AID - 10.3390/nu18050867 [doi] PST - epublish SO - Nutrients. 2026 Mar 8;18(5):867. doi: 10.3390/nu18050867. PMID- 41825212 OWN - NLM STAT- MEDLINE DCOM- 20260711 LR - 20260831 IS - 1873-460X (Electronic) IS - 1056-8727 (Linking) VI - 40 IP - 5 DP - 2026 May TI - Tirzepatide versus semaglutide for the prevention of mild cognitive impairment, dementia, and Alzheimer's disease in type 2 diabetes: A real-world, retrospective cohort study. PG - 109306 LID - S1056-8727(26)00051-6 [pii] LID - 10.1016/j.jdiacomp.2026.109306 [doi] AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in managing type 2 diabetes mellitus (T2DM) and provide metabolic and cardiovascular benefits. Their associations with neurocognitive outcomes in clinical populations remain uncertain. METHODS: We conducted a retrospective, population-based cohort study using de-identified electronic health records from the global TriNetX research network, predominantly comprising U.S.-based healthcare organizations. Adults with T2DM who initiated tirzepatide or semaglutide were included. Propensity score matching (1:1) was applied to balance baseline characteristics, including age, sex, race, and cardiometabolic and psychiatric comorbidities. Incident diagnoses of mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD) occurring at least 12 months after treatment initiation were assessed using risk ratios (RRs) and time-to-event analyses with Kaplan-Meier estimators. FINDINGS: A total of 290,606 patients initiated semaglutide and 44,471 initiated tirzepatide. After propensity score matching, each group included 44,470 patients. Compared with semaglutide, initiation of tirzepatide was associated with a lower risk of MCI (RR 0.12; 95% CI 0.06-0.22), dementia (RR 0.15; 95% CI 0.09-0.26), and AD (RR 0.48; 95% CI 0.22-1.01). Absolute risks were low for all outcomes, and separation of survival curves was more consistent for MCI than for dementia or AD. INTERPRETATION: In this real-world observational analysis of adults with T2DM, initiation of tirzepatide was associated with a lower incidence of MCI compared with semaglutide, whereas associations for dementia and AD were less consistent. These findings should be interpreted descriptively and as hypothesis-generating. Prospective randomized trials with longer follow-up and systematic neurocognitive assessment are needed to clarify whether, and under which conditions, incretin-based therapies influence neurocognitive outcomes. CI - Copyright (c) 2026 Elsevier Inc. All rights reserved. FAU - da Silva, Anderson Matheus Pereira AU - da Silva AMP AD - Division of Biostatistics and Clinical Epidemiology, MemoryHub, Cognitive and Neurodegenerative Disorders Research Group, Sao Paulo, SP, Brazil. Electronic address: anderson.mhps@icloud.com. FAU - Januario Campos Cardoso, Leonardo AU - Januario Campos Cardoso L AD - Department of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. FAU - Batista, Savio AU - Batista S AD - Department of Neurology, Grady Memorial Hospital, Emory University, Atlanta, GA, USA. FAU - Goncalves, Ocilio Ribeiro AU - Goncalves OR AD - Department of Medicine, Federal University of Piaui, Teresina, PI, Brazil. FAU - Paranhos, Thiago AU - Paranhos T AD - Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Teixeira, Ivan Petterson Santana AU - Teixeira IPS AD - Department of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. FAU - Guimaraes, Pedro Duarte AU - Guimaraes PD AD - Faculty of Medicine, Faculdade de Ciencias Medicas de Santos, Santos, Sao Paulo, SP, Brazil. FAU - Espinosa Franco, Beatriz AU - Espinosa Franco B AD - Department of Endocrinology, Hospital Alemao Oswaldo Cruz, Sao Paulo, SP, Brazil; Department of Endocrinology, Federal University of Sao Paulo, Sao Paulo, SP, Brazil. FAU - Cal, Henrique AU - Cal H AD - Division of Neurology, MemoryHub, Cognitive and Neurodegenerative Disorders Research Group, Sao Paulo, SP, Brazil. FAU - Salles, Joao Eduardo Nunes AU - Salles JEN AD - Division of Endocrinology, Department of Internal Medicina of Santa Casa of Sao Paulo Scholl of Medical Science, Sao Paulo, SP, Brazil. FAU - Perry, George AU - Perry G AD - Department of Neurosciences, Developmental and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA. FAU - Hoilund-Carlsen, Poul F AU - Hoilund-Carlsen PF AD - Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark. FAU - Santos, Diogo Haddad AU - Santos DH AD - Department of Neurology, Hospital Alemao Oswaldo Cruz, Sao Paulo, SP, Brazil; Division of Neurology, MemoryHub, Cognitive and Neurodegenerative Disorders Research Group, Sao Paulo, SP, Brazil. Electronic address: dhaddadsantos@gmail.com. LA - eng PT - Comparative Study PT - Journal Article DEP - 20260225 PL - United States TA - J Diabetes Complications JT - Journal of diabetes and its complications JID - 9204583 RN - 53AXN4NNHX (Semaglutide) RN - OYN3CCI6QE (Tirzepatide) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Semaglutide MH - Tirzepatide/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - *Alzheimer Disease/prevention & control/epidemiology MH - Female MH - Retrospective Studies MH - *Cognitive Dysfunction/prevention & control/epidemiology/etiology MH - *Glucagon-Like Peptides/therapeutic use MH - Male MH - Aged MH - *Dementia/prevention & control/epidemiology MH - *Hypoglycemic Agents/therapeutic use MH - Middle Aged MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - Dementia OT - Mild cognitive impairment OT - Semaglutide OT - Tirzepatide OT - Type 2 diabetes mellitus COIS- Declaration of competing interest The authors declare that they have no financial or personal relationships with individuals or organizations that could inappropriately influence, or be perceived to influence, the work reported in this manuscript. EDAT- 2026/03/14 00:31 MHDA- 2026/04/12 04:37 CRDT- 2026/03/13 19:08 PHST- 2025/11/18 00:00 [received] PHST- 2026/01/06 00:00 [revised] PHST- 2026/02/22 00:00 [accepted] PHST- 2026/04/12 04:37 [medline] PHST- 2026/03/14 00:31 [pubmed] PHST- 2026/03/13 19:08 [entrez] AID - S1056-8727(26)00051-6 [pii] AID - 10.1016/j.jdiacomp.2026.109306 [doi] PST - ppublish SO - J Diabetes Complications. 2026 May;40(5):109306. doi: 10.1016/j.jdiacomp.2026.109306. Epub 2026 Feb 25. PMID- 41815886 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260312 LR - 20260312 IS - 2190-1678 (Print) IS - 2190-1686 (Electronic) IS - 2190-1678 (Linking) VI - 17 IP - 2 DP - 2026 Apr TI - Baseline characteristics of patients with type 1 and type 2 diabetes in the Asahi Diabetes Complications Study (Asahi Study): a clinic-based prospective observational study. PG - 30 LID - 10.1007/s13340-026-00881-x [doi] LID - 30 AB - BACKGROUND: It is becoming increasingly important to investigate not only micro-/macrovascular complications, but also comorbidities associated with diabetes. In the Asahi Diabetes Complications Study (Asahi Study), in addition to micro-/macrovascular complications, the onset and progression of dementia and sarcopenia were also investigated in patients with diabetes. METHODS: The Asahi Study is a prospective 8-year observational cohort study of subjects with diabetes receiving outpatient care at the Institute of Medical Science, Asahi Life Foundation. Participants were enrolled between November 2014 and December 2017. The baseline data include the age, HbA1c level, and median duration of diabetes. In addition, medication use, prevalence of micro-/macrovascular complications, and presence/absence of malignant neoplasms were also assessed. RESULTS: A total of 49 patients with type 1 DM (T1DM group) and 791 patients with type 2 DM (T2DM group) were enrolled in the study. The mean age was 58.4 years in the T1DM group and 64.9 years in the T2DM group. Other baseline characteristics (T1DM/T2DM) were: mean HbA1c 7.5%/7.0%; median duration of diabetes 23 years/18 years. In regard to medication history, in the T2DM group, 57.3% were receiving oral hypoglycemic agents, 5.6% were receiving injectable GLP-1 receptor agonists, and 28.4% were receiving insulin therapy. The prevalences of microvascular complications, macrovascular complications, and malignant neoplasms were approximately 30-50%, 10%, and 7%, respectively, in the study participants. CONCLUSION: This 8-year observation study may offer valuable insights into the relationship between risk factor management and development of diabetic complications/comorbidities in persons with diabetes. CI - (c) The Japan Diabetes Society 2026. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. FAU - Yoshida, Yoko AU - Yoshida Y AUID- ORCID: 0000-0003-3888-8132 AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Onishi, Yukiko AU - Onishi Y AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Kubota, Tetsuya AU - Kubota T AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Takao, Toshiko AU - Takao T AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 AD - JR East Health Promotion Center, East Japan Railway Company, Tokyo, 140-0005 Japan. ROR: https://ror.org/00mh5ga26. GRID: grid.497069.5. ISNI: 0000 0001 2181 997X AD - Department of Public Health and Environmental Medicine, Jikei University School of Medicine, Tokyo, 105-8461 Japan. ROR: https://ror.org/039ygjf22. GRID: grid.411898.d. ISNI: 0000 0001 0661 2073 FAU - Tahara, Tazu AU - Tahara T AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Iwamoto, Masahiko AU - Iwamoto M AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Kawazu, Shoji AU - Kawazu S AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Iwamoto, Yasuhiko AU - Iwamoto Y AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 FAU - Noda, Mitsuhiko AU - Noda M AD - Department of Diabetes, Metabolism and Endocrinology Ichikawa Hospital, International University of Health and Welfare, Chiba, 272-0827 Japan. ROR: https://ror.org/053d3tv41. GRID: grid.411731.1. ISNI: 0000 0004 0531 3030 AD - Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, 350-0495 Japan. ROR: https://ror.org/04zb31v77. GRID: grid.410802.f. ISNI: 0000 0001 2216 2631 FAU - Kasuga, Masato AU - Kasuga M AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, 2-2-6 Nihonbashi Bakurocho, Chuo-ku, Tokyo, 103-0002 Japan. ROR: https://ror.org/027x43420. GRID: grid.471899.a. ISNI: 0000 0004 0632 0371 LA - eng PT - Journal Article DEP - 20260309 PL - Japan TA - Diabetol Int JT - Diabetology international JID - 101553224 PMC - PMC12972451 OTO - NOTNLM OT - Comorbidities in diabetes OT - Macrovascular complications OT - Microvascular complications OT - Prospective observational study OT - Type 1 diabetes OT - Type 2 diabetes COIS- Conflict of interestThe authors have no personal conflicts of interest to declare in relation to this study. EDAT- 2026/03/12 07:04 MHDA- 2026/03/12 07:05 PMCR- 2027/03/09 CRDT- 2026/03/12 05:12 PHST- 2025/09/30 00:00 [received] PHST- 2026/02/09 00:00 [accepted] PHST- 2026/03/12 07:05 [medline] PHST- 2026/03/12 07:04 [pubmed] PHST- 2026/03/12 05:12 [entrez] PHST- 2027/03/09 00:00 [pmc-release] AID - 881 [pii] AID - 10.1007/s13340-026-00881-x [doi] PST - epublish SO - Diabetol Int. 2026 Mar 9;17(2):30. doi: 10.1007/s13340-026-00881-x. eCollection 2026 Apr. PMID- 41760788 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260409 LR - 20260813 IS - 2730-664X (Electronic) IS - 2730-664X (Linking) VI - 6 IP - 1 DP - 2026 Feb 27 TI - Metformin provides superior neuroprotective potential compared to semaglutide in preventing diabetes-associated Alzheimer's disease via dual actions. LID - 10.1038/s43856-026-01471-3 [doi] LID - 196 AB - BACKGROUND: Alzheimer's disease (AD) and Diabetes Mellitus Type II (DM2) share overlapping biological mechanisms, and diabetes increases the risk of developing AD. Treatments that modify the course of diabetes, such as metformin and semaglutide, have been proposed to protect the brain, but their effectiveness in preventing AD remains uncertain. This study aimed to systematically compare the potential of diabetes therapies to reduce the risk of AD. METHODS: We developed an integrative framework combining comparative network pharmacology to evaluate 39 diabetes therapies in relation to AD. The analysis examined how each treatment influenced shared molecular pathways between the two conditions and measured their comparative impact score and validated key findings using gene expression data. RESULTS: Here we show that metformin is the most promising therapy for protection against AD, while semaglutide ranks among the least effective, based on comparative analysis within the DM2-AD pathway-pathway comorbidity network. Metformin's effects are mediated through AMPK, insulin, and adipocytokine signaling, that influence key Alzheimer's-related processes. In contrast, semaglutide, despite its growing clinical prominence as a weight loss therapy, exhibits minimal engagement with core neurodegenerative pathways within the DM2-AD comorbidity network. Certain combination therapies, such as insulin glargine with lixisenatide and insulin degludec with liraglutide, display effects comparable to metformin. CONCLUSIONS: These findings reveal that diabetes therapies differ in their ability to protect against AD. Metformin shows the strongest potential, supporting its prioritization for targeted studies in people with diabetes who are at high risk of AD, and highlighting the importance of precision medicine in future prevention trials. CI - (c) 2026. The Author(s). FAU - Georgiou, Andrea AU - Georgiou A AD - Department of Psychology, University of Cyprus, Nicosia, Cyprus. AD - Center of Applied Neuroscience, Nicosia, Cyprus. FAU - Zanos, Panos AU - Zanos P AD - Department of Psychology, University of Cyprus, Nicosia, Cyprus. AD - Center of Applied Neuroscience, Nicosia, Cyprus. FAU - Onisiforou, Anna AU - Onisiforou A AUID- ORCID: 0000-0003-3380-7356 AD - Department of Psychology, University of Cyprus, Nicosia, Cyprus. onisiforou.anna@ucy.ac.cy. AD - Center of Applied Neuroscience, Nicosia, Cyprus. onisiforou.anna@ucy.ac.cy. LA - eng PT - Journal Article DEP - 20260227 PL - England TA - Commun Med (Lond) JT - Communications medicine JID - 9918250414506676 PMC - PMC13066627 OAB - Type 2 diabetes increases the risk of developing Alzheimer's disease (AD), a brain disorder that slowly damages memory, thinking, and the ability to carry out everyday activities. However, the biological reasons for this link are not fully understood. Some diabetes medicines may help protect the brain, yet it is unclear which ones are most effective.In this study, we used computer-based methods to compare 39 diabetes treatments and examined how they affect biological pathways related to AD and ranked them using a comparative effectiveness score. Our analysis found that metformin showed the strongest potential to protect the brain, while semaglutide was among the least effective.These results suggest that not all diabetes medicines provide the same brain benefits. Understanding how specific treatments like metformin work may help doctors choose therapies that reduce Alzheimer's risk in people with diabetes and may also inform the potential repurposing of diabetes drugs for AD prevention. OABL- eng COIS- Competing interests: The authors declare no competing interests. EDAT- 2026/02/28 00:41 MHDA- 2026/02/28 00:42 PMCR- 2026/02/27 CRDT- 2026/02/27 23:21 PHST- 2025/07/18 00:00 [received] PHST- 2026/02/16 00:00 [accepted] PHST- 2026/02/28 00:42 [medline] PHST- 2026/02/28 00:41 [pubmed] PHST- 2026/02/27 23:21 [entrez] PHST- 2026/02/27 00:00 [pmc-release] AID - 10.1038/s43856-026-01471-3 [pii] AID - 1471 [pii] AID - 10.1038/s43856-026-01471-3 [doi] PST - epublish SO - Commun Med (Lond). 2026 Feb 27;6(1):196. doi: 10.1038/s43856-026-01471-3. PMID- 41752021 OWN - NLM STAT- MEDLINE DCOM- 20260709 LR - 20260813 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 27 IP - 4 DP - 2026 Feb 15 TI - The Multifaceted Nature of GLP-1: Molecular Mechanisms and Signaling Pathways in Metabolic and Neurodegenerative Diseases. LID - 10.3390/ijms27041886 [doi] LID - 1886 AB - The aim of this article is to present the current state of knowledge regarding the use of GLP-1 agonists in the treatment of type 2 diabetes, obesity, and other potential clinical indications, including neurodegenerative conditions. The article describes the characteristics of the diseases discussed, with particular emphasis on the pathophysiological mechanisms and the impact of metabolic disorders on the course of the diseases. In addition, the specific role of GLP-1 receptor agonists and their mechanisms of action leading to improved clinical outcomes were discussed, including their impact on molecular pathways involved in glucose metabolism regulation, inflammatory processes, carcinogenesis, and neuroprotection. Based on meta-analyses of available clinical trials, the evidence supporting the effectiveness of GLP-1 agonist therapy in glycemic control, weight loss, and improvement of metabolic parameters was synthesized. Additionally, potential benefits beyond the metabolic system are discussed, including neuroprotective effects and impact on patients' cardiovascular profiles, as well as risks and adverse effects associated with the use of GLP-1 agonists. The collected data indicate the growing role of GLP-1 agonists as an innovative and effective therapeutic strategy, while emphasizing the need for further research in the context of new clinical indications. FAU - Kowalska, Malgorzata Katarzyna AU - Kowalska MK AUID- ORCID: 0000-0001-8947-2861 AD - Department of Applied Chemistry, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. FAU - El-Mallul, Ahmed AU - El-Mallul A AD - Department of Health Sciences and Physical Culture, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. FAU - Hudecka, Weronika AU - Hudecka W AD - Department of Health Sciences and Physical Culture, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. FAU - Lubojanska, Joanna Elzbieta AU - Lubojanska JE AD - Department of Health Sciences and Physical Culture, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. FAU - Lubojanski, Piotr Jan AU - Lubojanski PJ AD - Specialist Hospital Named Dr. Tytus Chalubinski, 1 Adolfa Tochtermana Street, 26-600 Radom, Poland. FAU - Orlowska, Sara Malgorzata AU - Orlowska SM AUID- ORCID: 0009-0008-2785-4985 AD - Department of Health Sciences and Physical Culture, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. FAU - Bednarczyk, Lukasz AU - Bednarczyk L AUID- ORCID: 0009-0002-9211-6264 AD - Department of Health Sciences and Physical Culture, Casimir Pulaski Radom University, Street Chrobrego 27, 26-600 Radom, Poland. LA - eng PT - Journal Article PT - Review DEP - 20260215 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Neurodegenerative Diseases/metabolism/drug therapy MH - *Signal Transduction MH - *Glucagon-Like Peptide 1/metabolism/agonists MH - Animals MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Metabolic Diseases/metabolism/drug therapy MH - Diabetes Mellitus, Type 2/metabolism/drug therapy MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Obesity/metabolism/drug therapy PMC - PMC12941302 OTO - NOTNLM OT - GLP-1 OT - GLP-1 receptor agonists OT - appetite regulation OT - cardiometabolic risk OT - mesolimbic reward pathway OT - molecular pathways OT - obesity OT - type 2 diabetes mellitus COIS- The authors declare no conflicts of interest. EDAT- 2026/02/27 06:31 MHDA- 2026/03/06 19:44 PMCR- 2026/02/15 CRDT- 2026/02/27 01:10 PHST- 2025/12/21 00:00 [received] PHST- 2026/02/07 00:00 [revised] PHST- 2026/02/13 00:00 [accepted] PHST- 2026/03/06 19:44 [medline] PHST- 2026/02/27 06:31 [pubmed] PHST- 2026/02/27 01:10 [entrez] PHST- 2026/02/15 00:00 [pmc-release] AID - ijms27041886 [pii] AID - ijms-27-01886 [pii] AID - 10.3390/ijms27041886 [doi] PST - epublish SO - Int J Mol Sci. 2026 Feb 15;27(4):1886. doi: 10.3390/ijms27041886. PMID- 41737324 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260225 LR - 20260813 IS - 2666-6758 (Electronic) IS - 2666-6758 (Linking) VI - 7 IP - 1 DP - 2026 Jan 5 TI - Recent advances and ongoing challenges in diabetes prevention and control in China. PG - 101083 LID - 10.1016/j.xinn.2025.101083 [doi] LID - 101083 AB - Diabetes, particularly type 2 diabetes, poses a significant public health challenge globally, with an especially pronounced impact in China. The prevalence of diabetes in China has surged from 2.5% in 1994 to 13.0% in 2021, with projections indicating a continued upward trend. This review provides a comprehensive overview of the diabetes burden in China and underscores the urgent need for effective prevention and control measures. We examine the epidemiology of diabetes, highlighting the rising prevalence of prediabetes, type 1 and type 2 diabetes, youth-onset diabetes, and gestational diabetes mellitus, as well as diabetes-related complications, including both macrovascular and microvascular complications, and emerging conditions like cancer, infectious disease, fatty liver disease, and dementia. Key risk factors, including genetic susceptibility, obesity, dietary factors, and physical activity, are discussed, with particular attention to how these factors manifest differently in Chinese versus western populations. The review highlights advancements in national prevention efforts, innovative diabetes management models, and emerging technological innovations. The review also addresses advancements in pharmacological therapies, including the introduction of novel glucose-lowering agents such as GLP-1 receptor agonists, and SGLT2 inhibitors, which offer both metabolic and cardio-renal benefits. However, significant challenges remain, including the underrepresentation of the Chinese population in current research, persistent regional disparities, gaps in primary healthcare capacity, and the need for better integration of new technologies into clinical practice. CI - (c) 2025 The Author(s). FAU - Geng, Tingting AU - Geng T AD - Union Hospital & School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China. AD - Centre for Obesity and Diabetes Research, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Yin, Xiaoxu AU - Yin X AD - Centre for Obesity and Diabetes Research, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. AD - Department of Social Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Guo, Yanjun AU - Guo Y AD - Centre for Obesity and Diabetes Research, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. AD - Department of Occupational Health and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Liu, Gang AU - Liu G AD - Centre for Obesity and Diabetes Research, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. AD - Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Pan, An AU - Pan A AD - Union Hospital & School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China. AD - Centre for Obesity and Diabetes Research, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Liao, Yunfei AU - Liao Y AD - Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China. LA - eng PT - Journal Article PT - Review DEP - 20250821 PL - United States TA - Innovation (Camb) JT - Innovation (Cambridge (Mass.)) JID - 101771342 PMC - PMC12925905 OTO - NOTNLM OT - diabetes OT - diabetes complications OT - epidemiology OT - management OT - prevention OT - risk factors COIS- The authors declare no competing interests. EDAT- 2026/02/25 10:21 MHDA- 2026/02/25 10:22 PMCR- 2025/08/21 CRDT- 2026/02/25 04:49 PHST- 2025/05/09 00:00 [received] PHST- 2025/08/18 00:00 [accepted] PHST- 2026/02/25 10:22 [medline] PHST- 2026/02/25 10:21 [pubmed] PHST- 2026/02/25 04:49 [entrez] PHST- 2025/08/21 00:00 [pmc-release] AID - S2666-6758(25)00286-3 [pii] AID - 101083 [pii] AID - 10.1016/j.xinn.2025.101083 [doi] PST - epublish SO - Innovation (Camb). 2025 Aug 21;7(1):101083. doi: 10.1016/j.xinn.2025.101083. eCollection 2026 Jan 5. PMID- 41710720 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260219 LR - 20260813 IS - 1178-7007 (Print) IS - 1178-7007 (Electronic) IS - 1178-7007 (Linking) VI - 19 DP - 2026 TI - Revitalizing GIP: Therapeutic Potential in Metabolic and Neurodegenerative Disorders. PG - 559587 LID - 10.2147/DMSO.S559587 [doi] LID - 559587 AB - Glucose-dependent insulinotropic polypeptide (GIP), once the overlooked sibling of the incretin family, is now experiencing a research renaissance. Historically, its therapeutic development was hindered by a seemingly diminished insulinotropic effect in type 2 diabetes (T2DM), its paradoxical stimulation of glucagon during hyperglycemia, and translational gaps between rodent and human physiology. This review highlights the renewed interest in GIP, driven by a deeper understanding of its pleiotropic actions. GIP stimulates glucose-dependent insulin secretion and, uniquely, also stimulates glucagon secretion during hyperglycemia. Emerging evidence suggests this glucagon release may subsequently enhance insulin secretion through intra-islet alpha-beta cell communication, revealing a more complex role in glucose homeostasis than previously appreciated. Beyond the pancreas, GIP promotes lipid storage in adipose tissue, reduces ectopic fat deposition, modulates bone remodeling, influences cardiovascular lipid metabolism, and exhibits neuroprotective properties. Preclinical and clinical studies indicate that GIP-based therapies can improve glycemic control, alleviate obesity-related inflammation, and enhance insulin sensitivity. Notably, GIP exhibits synergistic effects with GLP-1, exemplified by the dual receptor agonist Tirzepatide, which has demonstrated superior efficacy in clinical trials. Compared to the selective GLP-1 receptor agonist semaglutide (1 mg), the highest dose (15 mg) of tirzepatide achieved a greater reduction in glycated hemoglobin (-2.30 vs -1.86 percentage points) and body weight (an additional 5.5 kg reduction) over 40 weeks. Furthermore, GIP and its analogs show promise in ameliorating pathology and cognitive deficits in neurodegenerative models like Alzheimer's disease, suggesting a potential new therapeutic avenue for central nervous system disorders. This review synthesizes the evolving narrative of GIP from a challenging target to a multifaceted therapeutic agent and identifies key research gaps, particularly in understanding its tissue-specific signaling and optimizing its synergy within multi-agonist therapies for metabolic and neurodegenerative diseases. CI - (c) 2026 Qiao et al. FAU - Qiao, Yingdan AU - Qiao Y AD - Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China. FAU - Zhou, Fen AU - Zhou F AUID- ORCID: 0009-0000-3444-4564 AD - Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China. FAU - Mao, Tuohua AU - Mao T AUID- ORCID: 0000-0002-5514-121X AD - Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China. FAU - Gao, Ling AU - Gao L AUID- ORCID: 0000-0003-0714-7200 AD - Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China. LA - eng PT - Journal Article PT - Review DEP - 20260210 PL - New Zealand TA - Diabetes Metab Syndr Obes JT - Diabetes, metabolic syndrome and obesity : targets and therapy JID - 101515585 PMC - PMC12912186 OTO - NOTNLM OT - Alzheimer's disease OT - GIP OT - GLP-1/GIP dual agonists OT - obesity OT - type 2 diabetes COIS- The authors declare that there is no conflict of interest. EDAT- 2026/02/19 07:03 MHDA- 2026/02/19 07:04 PMCR- 2026/02/10 CRDT- 2026/02/19 04:53 PHST- 2025/08/15 00:00 [received] PHST- 2026/01/28 00:00 [accepted] PHST- 2026/02/19 07:04 [medline] PHST- 2026/02/19 07:03 [pubmed] PHST- 2026/02/19 04:53 [entrez] PHST- 2026/02/10 00:00 [pmc-release] AID - 559587 [pii] AID - 10.2147/DMSO.S559587 [doi] PST - epublish SO - Diabetes Metab Syndr Obes. 2026 Feb 10;19:559587. doi: 10.2147/DMSO.S559587. eCollection 2026. PMID- 41697753 OWN - NLM STAT- MEDLINE DCOM- 20260708 LR - 20260813 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 136 IP - 4 DP - 2026 Feb 16 TI - The promise of GLP-1 receptor agonists for neurodegenerative diseases. LID - 10.1172/JCI194745 [doi] LID - e194745 AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs), established therapies for type 2 diabetes and obesity, are increasingly recognized for their potential in neurodegenerative diseases. Preclinical studies across diverse neurodegenerative conditions consistently demonstrate neuroprotective effects of GLP-1RAs, including reduced protein aggregation, enhanced autophagy, improved mitochondrial function, suppression of neuroinflammation, and preservation of synaptic integrity. Epidemiological analyses further suggest reduced incidence of dementia, Parkinson disease, and multiple sclerosis among long-term GLP-1RA users. Early human trials provide signals of target engagement, such as preserved cerebral glucose metabolism, altered inflammatory biomarkers, and slowed brain atrophy, although clinical outcomes to date remain mixed and trials in rarer disorders are sparse. Translation is constrained by uncertainty around optimal molecule choice, CNS penetrance, tolerability, adherence, and heterogeneity of response. Furthermore, next-generation dual and triple agonists may offer enhanced efficacy but remain untested in neurodegeneration. Conceptually, GLP-1RAs share pleiotropic effects with exercise - one of the few interventions with proven disease-modifying potential - by enhancing insulin signaling, stabilizing mitochondria, reducing inflammation, and promoting synaptic plasticity. This overlap highlights their promise as "pharmacological analogues of exercise," and underscores the need for biomarker-driven, disease-specific trials to establish whether GLP-1RAs can deliver durable disease modification across the spectrum of neurodegenerative diseases. FAU - Athauda, Dilan AU - Athauda D AD - The Francis Crick Institute, London, United Kingdom. AD - Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. FAU - Greig, Nigel H AU - Greig NH AD - Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA. FAU - Meissner, Wassilios G AU - Meissner WG AD - CHU Bordeaux, Service de Neurologie des Maladies Neurodegeneratives, IMNc, Bordeaux, France. AD - University de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France. AD - Department of Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand. FAU - Foltynie, Thomas AU - Foltynie T AD - Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. FAU - Gandhi, Sonia AU - Gandhi S AD - The Francis Crick Institute, London, United Kingdom. AD - Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. LA - eng PT - Journal Article PT - Review DEP - 20260216 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Neurodegenerative Diseases/drug therapy/metabolism/pathology MH - Animals MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Neuroprotective Agents/therapeutic use MH - Mitochondria/metabolism/pathology PMC - PMC12904716 COIS- Conflict of interest: TF has served on advisory boards for Peptron, Abbvie, Eli Lilly, Bluerock, Bayer, and Bial. He has received honoraria for talks sponsored by Bayer, Bial, Boston Scientific, and Novo Nordisk. Outside the present manuscript, WGM has received consultancy fees from Lundbeck, Inhibikase, Koneksa, Ferrer, TreeFrog, Takeda, and BioArctic. He has also received fees for lecturing from Lundbeck. EDAT- 2026/02/16 12:30 MHDA- 2026/02/16 18:34 PMCR- 2026/02/16 CRDT- 2026/02/16 11:52 PHST- 2026/02/16 18:34 [medline] PHST- 2026/02/16 12:30 [pubmed] PHST- 2026/02/16 11:52 [entrez] PHST- 2026/02/16 00:00 [pmc-release] AID - 194745 [pii] AID - 10.1172/JCI194745 [doi] PST - epublish SO - J Clin Invest. 2026 Feb 16;136(4):e194745. doi: 10.1172/JCI194745. eCollection 2026 Feb 16. PMID- 41697144 OWN - NLM STAT- MEDLINE DCOM- 20260827 LR - 20260827 IS - 1460-2385 (Electronic) IS - 0931-0509 (Linking) VI - 41 IP - 9 DP - 2026 Aug 27 TI - GLP-1 receptor agonists reduce dementia and Alzheimer disease risk in diabetic patients with CKD. PG - 1673-1685 LID - 10.1093/ndt/gfag032 [doi] AB - BACKGROUND: Patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia and Alzheimer's disease due to vascular dysfunction, insulin resistance and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective properties; however, their impact on dementia risk in diabetic patients with CKD remains uncertain. This study evaluated the association between GLP-1RA use and dementia risk in patients with CKD stage 3 or later, compared with dipeptidyl peptidase-4 inhibitors (DPP4is). METHODS: This retrospective cohort study analyzed data from the TriNetX global research network, comprising electronic medical records from 67 healthcare organizations in the US Collaborative Network. We identified patients with CKD stage 3 or later and T2DM who were newly prescribed GLP-1RAs or DPP4is between 1 January 2015 and 31 December 2020. Patients with prior GLP-1RAs or DPP4i use, a dementia diagnosis within 12 months before the index date or recent hospitalization were excluded. The primary outcome was the incidence of dementia, Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, and dementia with Lewy bodies, assessed over a follow-up period ranging from 90 days to 5 years. Statistical analyses included Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: GLP-1RA use was associated with a significantly lower risk of dementia [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.71-0.91, P = .001] and Alzheimer's disease (HR 0.76, 95% CI 0.59-0.98, P = .033) compared with DPP4i use. However, no significant differences were observed in vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, or dementia with Lewy bodies. CONCLUSIONS: GLP-1RA therapy may reduce the risk of dementia and Alzheimer's disease in patients with CKD stage 3 or later, offering potential neuroprotective benefits beyond glycemic control. Research is needed to confirm these findings and optimize treatment strategies for this vulnerable population. CI - (c) The Author(s) 2026. Published by Oxford University Press on behalf of the ERA. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. FAU - Lee, Wen-Teng AU - Lee WT AD - Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC. FAU - Wang, Jing-Tong AU - Wang JT AD - Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC. FAU - Tsai, Ming-Hsien AU - Tsai MH AUID- ORCID: 0000-0003-3561-4689 AD - Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC. AD - Department of Medicine, Fu-Jen Catholic University School of Medicine, Taipei, Taiwan, ROC. FAU - Fang, Yu-Wei AU - Fang YW AUID- ORCID: 0000-0002-1302-1885 AD - Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC. AD - Department of Medicine, Fu-Jen Catholic University School of Medicine, Taipei, Taiwan, ROC. LA - eng GR - 2025SKHADR009/Shin-Kong Wu Ho-Su Memorial Hospital/ PT - Journal Article PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) SB - IM MH - Humans MH - Female MH - Male MH - *Alzheimer Disease/prevention & control/etiology/epidemiology MH - Retrospective Studies MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Aged MH - *Renal Insufficiency, Chronic/complications MH - *Dementia/prevention & control/etiology/epidemiology MH - Follow-Up Studies MH - Risk Factors MH - *Hypoglycemic Agents/therapeutic use MH - Prognosis MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Middle Aged MH - Aged, 80 and over OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - chronic kidney disease OT - dementia OT - type 2 diabetes EDAT- 2026/02/16 12:32 MHDA- 2026/08/27 05:35 CRDT- 2026/02/16 10:13 PHST- 2025/08/12 00:00 [received] PHST- 2026/01/26 00:00 [accepted] PHST- 2026/08/27 05:35 [medline] PHST- 2026/02/16 12:32 [pubmed] PHST- 2026/02/16 10:13 [entrez] AID - 8487645 [pii] AID - 10.1093/ndt/gfag032 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2026 Aug 27;41(9):1673-1685. doi: 10.1093/ndt/gfag032. PMID- 41683853 OWN - NLM STAT- MEDLINE DCOM- 20260707 LR - 20260707 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 27 IP - 3 DP - 2026 Jan 31 TI - Glucagon-like Peptide-1 Receptor Agonists and Ocular Disease: Mechanisms, Evidence and Therapeutic Perspectives. LID - 10.3390/ijms27031432 [doi] LID - 1432 AB - Ocular diseases, including glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), remain major global causes of irreversible vision loss. Despite advances in clinical management, current therapies insufficiently address the shared metabolic, inflammatory, vascular, and neurodegenerative mechanisms underlying these conditions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have emerged as multi-target candidates for ocular therapeutics due to their pleiotropic anti-inflammatory, antioxidant, vasculoprotective, and neuroprotective properties. Preclinical studies consistently demonstrate that GLP-1RAs preserve blood-retina barrier integrity, suppress pathological angiogenesis, mitigate oxidative and inflammatory stress, and protect retinal neurons from degeneration. Complementary clinical and real-world evidence shows a robust and reproducible reduction in glaucoma risk among GLP-1RA users across diabetic and non-diabetic populations. By contrast, findings for DR and AMD are more heterogeneous and appear context-dependent, with potential benefits most evident in early or non-exudative disease stages. Emerging safety considerations-including reports of nonarteritic anterior ischemic optic neuropathy and early DR worsening in the setting of rapid glycemic improvement-highlight the need for careful interpretation, individualized risk assessment, and appropriate ophthalmic monitoring. This review synthesizes molecular mechanisms, experimental data, clinical and pharmacoepidemiologic evidence, and safety signals to critically evaluate the therapeutic potential of GLP-1RAs in ocular disease. We also outline key translational challenges, including the need for ocular-targeted delivery strategies, prospective ophthalmology-specific trials, and precision-medicine approaches to determine when and how GLP-1RAs can be safely advanced as disease-modifying treatments in ophthalmology. FAU - Gong, Xiaoming AU - Gong X AUID- ORCID: 0009-0009-8687-0763 AD - Vision Center, Akron Children's Hospital, Akron, OH 44308, USA. AD - Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, OH 44308, USA. FAU - Orge, Faruk H AU - Orge FH AD - Vision Center, Akron Children's Hospital, Akron, OH 44308, USA. AD - Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, OH 44308, USA. LA - eng PT - Journal Article PT - Review DEP - 20260131 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Eye Diseases/drug therapy/metabolism MH - Diabetic Retinopathy/drug therapy/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Diabetes Mellitus, Type 2/drug therapy PMC - PMC12897703 OTO - NOTNLM OT - age-related macular degeneration OT - diabetic retinopathy OT - glaucoma OT - glucagon-like peptide-1 receptor agonists OT - nonarteritic anterior ischemic optic neuropathy COIS- The authors declare no conflicts of interest. EDAT- 2026/02/13 06:32 MHDA- 2026/02/13 06:33 PMCR- 2026/01/31 CRDT- 2026/02/13 01:10 PHST- 2026/01/08 00:00 [received] PHST- 2026/01/28 00:00 [revised] PHST- 2026/01/30 00:00 [accepted] PHST- 2026/02/13 06:33 [medline] PHST- 2026/02/13 06:32 [pubmed] PHST- 2026/02/13 01:10 [entrez] PHST- 2026/01/31 00:00 [pmc-release] AID - ijms27031432 [pii] AID - ijms-27-01432 [pii] AID - 10.3390/ijms27031432 [doi] PST - epublish SO - Int J Mol Sci. 2026 Jan 31;27(3):1432. doi: 10.3390/ijms27031432. PMID- 41670429 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260220 LR - 20260920 IS - 2049-3614 (Print) IS - 2049-3614 (Electronic) IS - 2049-3614 (Linking) VI - 15 IP - 2 DP - 2026 Feb 1 TI - Impact of ethnicity and antihyperglycemic medications on dementia incidence in older adults with type 2 diabetes. LID - 10.1530/EC-25-0593 [doi] LID - e250593 AB - BACKGROUND: Type 2 diabetes increases the risk of cognitive decline and dementia. Data on ethnic differences in dementia prevalence among patients with diabetes remain limited. METHODS: We conducted a retrospective matched case-control study of Clalit Health Services members aged 60 or older. Matching (1:3) was based on age, sex, language, and socioeconomic status. Ethnicity was determined by spoken language or place of birth. Prescriptions and refills for antidiabetic medications were recorded for the two years preceding the index date. Clinical, anthropometric, and comorbidity data were analyzed. RESULTS: During follow-up, 39% of participants were diagnosed with dementia over a maximum observation period of 20 years (crude proportion). However, given a median follow-up of 9.6 years, dementia incidence was primarily evaluated using time-specific competing-risk analyses. When accounting for death as a competing event, the 10-year cumulative incidence of dementia was approximately 9-10%, varying across ethnic groups. However, in multivariable competing-risk models adjusting for age, sex, socioeconomic status, and comorbidities, ethnicity was no longer independently associated with dementia incidence. In matched analyses, the use of SGLT-2 inhibitors and DPP-4 inhibitors was associated with a lower probability of dementia. In time-to-event analyses of dementia-related mortality, treatment with SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors was associated with significantly reduced mortality risk. CONCLUSION: Ethnic differences in dementia incidence were attenuated after adjustment for demographic and clinical factors. SGLT-2 and DPP-4 inhibitors were associated with a lower risk of dementia, whereas GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were associated with reduced dementia-related mortality. FAU - Chertok Shacham, Elena AU - Chertok Shacham E AUID- ORCID: 0000-0001-9013-1271 AD - Endocrinology Unit, Haemek Medical Center, Afula, Israel. AD - Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. FAU - Sharif, Sireen AU - Sharif S AD - Statistics Department, Haemek Medical Center, Afula, Israel. FAU - Kadah, Muhammad AU - Kadah M AD - Internal Medicine, Haemek Medical Center, Afula, Israel. FAU - Ayalon, Snait AU - Ayalon S AD - Statistics Department, Haemek Medical Center, Afula, Israel. AD - Research Authority, Emek Medical Center, Afula, Israel. LA - eng PT - Journal Article DEP - 20260220 PL - England TA - Endocr Connect JT - Endocrine connections JID - 101598413 PMC - PMC12926960 OTO - NOTNLM OT - aging OT - diabetes COIS- The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported. EDAT- 2026/02/11 13:08 MHDA- 2026/02/11 13:09 PMCR- 2026/02/20 CRDT- 2026/02/11 09:42 PHST- 2025/09/10 00:00 [received] PHST- 2026/02/10 00:00 [accepted] PHST- 2026/02/11 13:09 [medline] PHST- 2026/02/11 13:08 [pubmed] PHST- 2026/02/11 09:42 [entrez] PHST- 2026/02/20 00:00 [pmc-release] AID - EC-25-0593 [pii] AID - 10.1530/EC-25-0593 [doi] PST - epublish SO - Endocr Connect. 2026 Feb 20;15(2):e250593. doi: 10.1530/EC-25-0593. Print 2026 Feb 1. PMID- 41667890 OWN - NLM STAT- In-Process LR - 20260316 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 28 IP - 4 DP - 2026 Apr TI - RETRACTION: Effects of GLP-1 Receptor Agonists on Cognitive Function in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials. PG - 3451 LID - 10.1111/dom.70552 [doi] AB - S. Wan , H. Yan , Q.-Y. Sun , J.-Q. Zhu , H.-H. Wang , K.-Y. Qu , and X. Yi , "Effects of GLP-1 Receptor Agonists on Cognitive Function in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials," Diabetes, Obesity and Metabolism (Early View): https://doi.org/10.1111/dom.70201. The above article, published online on 17 October 2025 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Richard Donnelly; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties and upon the authors' request. It was brought to the journal's attention that the original studies forming the basis of the meta-analysis presented in the article contain inconsistencies that are prone to misinterpretation. As a result, these studies were found not to be directly comparable. Consequently, the conclusions drawn in the article were determined to be affected by these issues, and their reliability was considered compromised. To their credit, the authors have agreed with this determination and requested the retraction of the article. The authors have acted responsibly after concerns were raised and following their own internal investigations of the research. CI - (c) 2026 John Wiley & Sons Ltd. LA - eng PT - Journal Article PT - Retraction Notice DEP - 20260210 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 SB - IM ROF - Diabetes Obes Metab. 2026 Apr;28(4):3396-3407. doi: 10.1111/dom.70201. PMID: 41104525 EDAT- 2026/02/11 00:40 MHDA- 2026/02/11 00:40 CRDT- 2026/02/10 23:39 PHST- 2026/02/03 00:00 [accepted] PHST- 2026/02/11 00:40 [pubmed] PHST- 2026/02/11 00:40 [medline] PHST- 2026/02/10 23:39 [entrez] AID - 10.1111/dom.70552 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Apr;28(4):3451. doi: 10.1111/dom.70552. Epub 2026 Feb 10. PMID- 41631108 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260203 LR - 20260205 IS - 1756-2856 (Print) IS - 1756-2864 (Electronic) IS - 1756-2856 (Linking) VI - 19 DP - 2026 TI - Efficacy and safety of glucagon-like peptide-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis of randomized placebo-controlled clinical trials. PG - 17562864251408269 LID - 10.1177/17562864251408269 [doi] LID - 17562864251408269 AB - BACKGROUND: Converging lines of preclinical evidence support the neuroprotective properties of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Parkinson's disease (PD). Nevertheless, results from randomized-controlled clinical trials (RCTs) remain conflicting. OBJECTIVES: To assess the safety and efficacy of GLP-1 RAs in PD. DESIGN: Systematic review and meta-analysis of randomized placebo-controlled clinical trials. DATA SOURCES AND METHODS: A systematic search of MEDLINE and Scopus databases was conducted on October 7, 2025, for randomized placebo-controlled clinical trials investigating GLP-1 RAs in adults with PD. Risk of bias was evaluated using the Cochrane Collaboration risk-of-bias (RoB2) tool. RESULTS: Four RCTs comprising 667 PD patients (377 receiving GLP-1 RAs) were included. Between baseline and end-of-treatment, no differences were observed in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score change between GLP-1 RA- and placebo-treated patients in either off-medication (standardized mean difference (SMD): -0.16; 95% CI: -0.64 to 0.32; p = 0.52) or on-medication states (SMD: -0.13; 95% confidence interval (CI): -0.51 to 0.25; p = 0.49). No significant differences were uncovered in other MDS-UPDRS subscores, Non-Motor Symptoms Scale, Montreal Cognitive Assessment, or Parkinson's Disease Questionnaire scores. The risk of serious adverse events and odds of treatment discontinuation were similar between groups, but GLP-1 RAs were associated with an increased risk of weight loss compared to placebo (risk ratio: 1.44; 95% CI: 1.04-1.99; p = 0.03). CONCLUSION: GLP-1 RAs were not associated with improvements in motor or non-motor domains of PD. However, robust preclinical evidence and promising findings in select subpopulations warrant further RCTs to evaluate their neuroprotective potential, prioritizing long-acting and brain-penetrant agents that effectively engage central GLP-1 circuits for PD treatment. REGISTRATION: The pre-specified protocol of the present systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration ID: CRD420251008703). CI - (c) The Author(s), 2026. FAU - Stefanou, Maria-Ioanna AU - Stefanou MI AUID- ORCID: 0000-0002-2305-6627 AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. AD - Department of Neurology and Stroke, Eberhard-Karls University of Tubingen, Tubingen, Germany. FAU - Panagiotopoulos, Evangelos AU - Panagiotopoulos E AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Tentolouris, Anastasios AU - Tentolouris A AD - First Department of Propaedeutic Internal Medicine and Diabetes Center, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece. FAU - Theodorou, Aikaterini AU - Theodorou A AUID- ORCID: 0000-0001-7229-2610 AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Papagiannopoulou, Georgia AU - Papagiannopoulou G AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Athanasaki, Athanasia AU - Athanasaki A AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Tsalouchidou, Panagiota-Eleni AU - Tsalouchidou PE AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Peppa, Melpomeni AU - Peppa M AD - Diabetes Center, Second Department of Internal Medicine, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece. FAU - Lambadiari, Vaia AU - Lambadiari V AD - Diabetes Center, Second Department of Internal Medicine, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece. FAU - Konitsiotis, Spiridon AU - Konitsiotis S AD - Department of Neurology, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, Ioannina, Greece. FAU - Mengel, Annerose AU - Mengel A AUID- ORCID: 0000-0002-2399-3020 AD - Department of Neurology and Stroke, Eberhard-Karls University of Tubingen, Tubingen, Germany. FAU - Paraskevas, Georgios P AU - Paraskevas GP AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Tentolouris, Nikolaos AU - Tentolouris N AD - First Department of Propaedeutic Internal Medicine and Diabetes Center, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece. FAU - Tsivgoulis, Georgios AU - Tsivgoulis G AUID- ORCID: 0000-0002-0640-3797 AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Rimini 1, Chaidari, Athens 12462, Greece. LA - eng PT - Journal Article DEP - 20260131 PL - England TA - Ther Adv Neurol Disord JT - Therapeutic advances in neurological disorders JID - 101480242 PMC - PMC12861370 OAB - Efficacy and safety of glucagon-like peptide-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are medications approved for type 2 diabetes and obesity that have shown neuroprotective effects in preclinical models of Parkinson's disease (PD). However, clinical trial results have been inconsistent. In this systematic review and meta-analysis, we evaluated the overall safety and effectiveness of GLP-1 RAs in people with PD by analyzing data from all available randomized placebo-controlled clinical trials. Our findings indicate that GLP-1 RAs do not lead to measurable improvements in motor symptoms, cognitive performance, or quality of life when compared to placebo. Although the risk of serious adverse events was similar between treatment and placebo groups, GLP-1 RAs were associated with an increased risk of weight loss and gastrointestinal adverse events. Despite the lack of demonstrated clinical benefit, strong preclinical evidence and exploratory signals in specific patient subgroups support the need for further high-quality trials, particularly with long-acting and brain-penetrant GLP-1 RAs in early-stage PD populations. OABL- eng OTO - NOTNLM OT - GLP-1 OT - GLP-1 receptor agonist OT - Parkinson's disease OT - exenatide OT - lixisenatide COIS- All authors declare no financial or non-financial competing interests. G.T. is Associate Editor of Therapeutic Advances in Neurological Disorders, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process. EDAT- 2026/02/03 13:34 MHDA- 2026/02/03 13:35 PMCR- 2026/01/31 CRDT- 2026/02/03 04:18 PHST- 2025/07/02 00:00 [received] PHST- 2025/12/03 00:00 [accepted] PHST- 2026/02/03 13:35 [medline] PHST- 2026/02/03 13:34 [pubmed] PHST- 2026/02/03 04:18 [entrez] PHST- 2026/01/31 00:00 [pmc-release] AID - 10.1177_17562864251408269 [pii] AID - 10.1177/17562864251408269 [doi] PST - epublish SO - Ther Adv Neurol Disord. 2026 Jan 31;19:17562864251408269. doi: 10.1177/17562864251408269. eCollection 2026. PMID- 41621451 OWN - NLM STAT- MEDLINE DCOM- 20260706 LR - 20260730 IS - 1573-2517 (Electronic) IS - 0165-0327 (Linking) VI - 402 DP - 2026 Jun 1 TI - The effect of glucagon-like peptide 1 (GLP-1) receptor agonists on cognition: A systematic review of systematic reviews and meta-analyses. PG - 121310 LID - S0165-0327(26)00161-8 [pii] LID - 10.1016/j.jad.2026.121310 [doi] AB - BACKGROUND: Results from extant studies indicate that type 2 diabetes mellitus (T2DM) is associated with decreased cognitive function and increased risk for dementia, notably Alzheimer's Disease (AD). Herein, we aimed to evaluate the effect of glucacon-like peptide-1 receptor agonists (GLP-1 RAs) on cognitive measures in persons with cognitive impairment and T2DM from available systematic reviews and meta-analyses. METHODS: A literature search was conducted using Web of Science and MEDLINE from inception to July 15, 2025. Article screening and data extraction were conducted by three reviewers (H.B., C.D., S.L.). Primary research studies examining race, sex, children, animals and neurodegenerative diseases other than AD were excluded. RESULTS: Nine systematic reviews and meta-analyses examining the effect of GLP-1 RAs on cognitive function in adults with T2DM were included. Evidence suggests that GLP-1 RAs are associated with a reduction in overall cognitive decline in adults with T2DM and dementia/AD. Replicated findings from meta-analyses indicated that GLP-1 RAs improved performance on cognitive assessments (total learning; p = 0.039; p < 0.00001). Some meta-analyses observed a change in cognitive measures but lacked sufficient statistical significance (p > 0.05). CONCLUSIONS: GLP-1 RAs positively affect cognitive function in AD patients with T2DM. However, their efficacy on disparate cognitive domains requires further replication in larger scale controlled clinical trials. CI - Copyright (c) 2026 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Ballum, Hana AU - Ballum H AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: hana.ballum@mail.utoronto.ca. FAU - Dri, Christine AU - Dri C AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: christine.dri@mail.utoronto.ca. FAU - Liao, Sonya AU - Liao S AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: sonya.liao@mail.utoronto.ca. FAU - Yu, Minyi AU - Yu M AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: mindy.yu@mail.utoronto.ca. FAU - Le, Gia Han AU - Le GH AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: hanny.le@mail.utoronto.ca. FAU - Wong, Sabrina AU - Wong S AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address: sabrinal.wong@mail.utoronto.ca. FAU - Teopiz, Kayla M AU - Teopiz KM AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: kayla.teopiz@mail.utoronto.ca. FAU - Kwan, Angela T H AU - Kwan ATH AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: angela.kwan@mail.utoronto.ca. FAU - Ho, Roger AU - Ho R AD - Department of Psychological Medicine, Yong Loo Lin School of Medicine, Singapore; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore; Division of Life Science (LIFS), Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Hong Kong. Electronic address: rogercmho@ust.hk. FAU - Choi, Hayun AU - Choi H AD - Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Veteran Health Service Medical Center, Seoul, Republic of Korea. Electronic address: hayun.choi@utoronto.ca. FAU - Rosenblat, Joshua D AU - Rosenblat JD AD - Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: joshua.rosenblat@uhn.ca. FAU - Vinberg, Maj AU - Vinberg M AD - The Early Multimodular Prevention and Intervention Research Institution (EMPIRI), Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: maj.vinberg@regionh.dk. FAU - K Y Lo, Heidi AU - K Y Lo H AD - Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong. Electronic address: lokaying@hku.hk. FAU - McIntyre, Roger S AU - McIntyre RS AD - Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: roger.mcintyre@bcdf.org. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20260130 PL - Netherlands TA - J Affect Disord JT - Journal of affective disorders JID - 7906073 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/psychology MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Cognition/drug effects MH - *Cognitive Dysfunction/drug therapy MH - Alzheimer Disease MH - *Hypoglycemic Agents/therapeutic use MH - Cognitive Enhancement MH - Meta-Analysis as Topic OTO - NOTNLM OT - Alzheimer's Disease OT - Cognitive function OT - Dementia OT - Glucagon-like peptide 1 receptor agonist OT - Major neurocognitive disorders OT - Metabolic OT - Type 2 diabetes mellitus (T2DM) COIS- Declaration of competing interest Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Kayla M. Teopiz has received fees from Braxia Scientific Corp. Roger Ho received funding from the Institute for Health Innovation & Technology (iHeathtech) at the National University of Singapore (NUS, Other Operating Expenses: A-0001415-09-00). Maj Vinberg has received consultation fees from Lundbeck Pharma and Janssen Cilag. H.B., C.D., S.L., M.Y., G.H.L. and S.W. have no conflicts of interest to declare. EDAT- 2026/02/02 00:29 MHDA- 2026/02/24 00:29 CRDT- 2026/02/01 19:11 PHST- 2024/11/08 00:00 [received] PHST- 2026/01/26 00:00 [revised] PHST- 2026/01/28 00:00 [accepted] PHST- 2026/02/24 00:29 [medline] PHST- 2026/02/02 00:29 [pubmed] PHST- 2026/02/01 19:11 [entrez] AID - S0165-0327(26)00161-8 [pii] AID - 10.1016/j.jad.2026.121310 [doi] PST - ppublish SO - J Affect Disord. 2026 Jun 1;402:121310. doi: 10.1016/j.jad.2026.121310. Epub 2026 Jan 30. PMID- 41619622 OWN - NLM STAT- MEDLINE DCOM- 20260706 LR - 20260831 IS - 1873-460X (Electronic) IS - 1056-8727 (Linking) VI - 40 IP - 3 DP - 2026 Mar TI - Effects of GLP-1 receptor agonists on vascular dementia: a systematic review and meta-analysis. PG - 109271 LID - S1056-8727(26)00016-4 [pii] LID - 10.1016/j.jdiacomp.2026.109271 [doi] AB - BACKGROUND AND AIMS: Vascular dementia (VaD) is strongly associated with type 2 diabetes (T2DM), overweight, and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular risk and exhibit neuroprotective properties, yet their effects in incident VaD remain uncertain. This study evaluated whether GLP-1 RAs have preventive potential for VaD in adults with T2DM, overweight, or obesity. METHODS: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was conducted to estimate the risk of incident VaD among patients with T2DM or overweight/obesity treated with GLP-1 RAs versus placebo. Data were pooled using a random-effects model, with outcomes expressed as risk ratios (RRs) and 95% confidence intervals (CIs). Subgroup analysis was performed after stratification by population type (T2DM vs. overweight/obesity), and meta-regression assessed the association between RCT duration and effect size. RESULTS: Seven RCTs (six in T2DM, one in overweight/obesity) comprising 61,610 participants were included. GLP-1 RA treatment was not associated with a statistically significant difference in VaD incidence (RR: 0.50; 95% CI: 0.19-1.32; I(2) = 0%). Subgroup analysis revealed no significant between-group differences (p for subgroups = 0.612), although numerically lower VaD rates were observed in the T2DM subgroup (RR: 0.38; 95% CI: 0.13-1.11). Meta-regression did not demonstrate a significant association between follow-up duration and treatment effect (beta = -0.291; SE = 0.212; 95% CI: -0.843 to 0.262; p = 0.229). CONCLUSIONS: The pooled evidence did not confirm a statistically significant reduction in VaD risk with GLP-1 RA therapy. Numerically lower VaD incidence in T2DM populations warrants further investigation in adequately powered and systematically adjudicated trials. CI - Copyright (c) 2026 Elsevier Inc. All rights reserved. FAU - Stefanou, Maria-Ioanna AU - Stefanou MI AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Department of Neurology & Stroke, Eberhard-Karls University of Tubingen, Tubingen, Germany. FAU - Tentolouris, Anastasios AU - Tentolouris A AD - First Department of Propaedeutic Internal Medicine and Diabetes Center, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece. FAU - Panagiotopoulos, Evangelos AU - Panagiotopoulos E AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Theodorou, Aikaterini AU - Theodorou A AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Mengel, Annerose AU - Mengel A AD - Department of Neurology & Stroke, Eberhard-Karls University of Tubingen, Tubingen, Germany; Hertie Institute for Clinical Brain Research, Eberhard-Karls University of Tubingen, Tubingen, Germany. FAU - Athanasaki, Athanasia AU - Athanasaki A AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Lambadiari, Vaia AU - Lambadiari V AD - Second Department of Internal Medicine, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Peppa, Melpomeni AU - Peppa M AD - Second Department of Internal Medicine, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Papadopoulou, Marianna AU - Papadopoulou M AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Paraskevas, Georgios P AU - Paraskevas GP AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Giannopoulos, Sotirios AU - Giannopoulos S AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Siasos, Gerasimos AU - Siasos G AD - Third Department of Cardiology, Sotiria Thoracic Diseases General Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Sharma, Vijay K AU - Sharma VK AD - Division of Neurology, Department of Medicine, National University Hospital, Singapore; School of Medicine, National University of Singapore, Singapore. FAU - Ziemann, Ulf AU - Ziemann U AD - Department of Neurology & Stroke, Eberhard-Karls University of Tubingen, Tubingen, Germany; Hertie Institute for Clinical Brain Research, Eberhard-Karls University of Tubingen, Tubingen, Germany. FAU - Tsivgoulis, Georgios AU - Tsivgoulis G AD - Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: tsivgoulisgiorg@yahoo.gr. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20260126 PL - United States TA - J Diabetes Complications JT - Journal of diabetes and its complications JID - 9204583 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - *Dementia, Vascular/prevention & control/epidemiology/etiology MH - Obesity/complications/epidemiology/drug therapy MH - Randomized Controlled Trials as Topic MH - Overweight/complications MH - *Hypoglycemic Agents/therapeutic use MH - Incidence OTO - NOTNLM OT - Diabetes OT - GLP-1 OT - MACE OT - Obesity OT - Overweight OT - Vascular dementia COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2026/02/01 00:44 MHDA- 2026/02/14 05:30 CRDT- 2026/01/31 18:07 PHST- 2025/10/10 00:00 [received] PHST- 2025/12/08 00:00 [revised] PHST- 2026/01/24 00:00 [accepted] PHST- 2026/02/14 05:30 [medline] PHST- 2026/02/01 00:44 [pubmed] PHST- 2026/01/31 18:07 [entrez] AID - S1056-8727(26)00016-4 [pii] AID - 10.1016/j.jdiacomp.2026.109271 [doi] PST - ppublish SO - J Diabetes Complications. 2026 Mar;40(3):109271. doi: 10.1016/j.jdiacomp.2026.109271. Epub 2026 Jan 26. PMID- 41619567 OWN - NLM STAT- MEDLINE DCOM- 20260706 LR - 20260730 IS - 1876-2026 (Electronic) IS - 1876-2018 (Linking) VI - 117 DP - 2026 Mar TI - Molecular evidence associating GLP-1 receptor agonists and brain-derived neurotrophic factors in neurodegenerative and psychiatric disorders: A systematic review. PG - 104870 LID - S1876-2018(26)00043-2 [pii] LID - 10.1016/j.ajp.2026.104870 [doi] AB - BACKGROUND: A converging mechanistic theme across mental disorders involves impaired neuroplasticity and reduced brain-derived neurotrophic factor (BDNF). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), used for type 2 diabetes and obesity, have shown neuroprotective potential, but whether these effects are mediated by BDNF is unclear. OBJECTIVE: This systematic review synthesised molecular evidence linking GLP-1RA administration to BDNF changes and evaluated their contribution to illness progression in neurodegenerative and psychiatric disorders. METHODS: A systematic search of PubMed, Ovid and Google Scholar from inception to September 6, 2025, identified studies reporting BDNF-related outcomes following GLP-1RA treatment. Eligible studies included primary in vivo or in vitro research on GLP-1RAs in models of neurodegenerative or psychiatric disorders. Risk of bias was assessed using SYRCLE and QUIN tools. RESULTS: The initial search yielded 300 records, of which 18 met the inclusion criteria. Across these studies, GLP-1RAs consistently enhanced BDNF expression and signalling in models of diabetes, neurodegeneration and neurotoxicity, with diabetic models included for their relevance to GLP-1RA pharmacology and shared neuroinflammatory pathway. Reported increases in BDNF expression ranged from 76 % to 377 %, correlating with improved synaptic plasticity, cognition and neuronal survival. In vitro, GLP-1 and exendin-4 increased BDNF expression and axonal transport even under Abeta oligomer exposure. While most neuroprotection aligned with BDNF upregulation, some effects occurred independently through alternative pathways. CONCLUSION: GLP-1RAs upregulate BDNF in preclinical models, supporting its role as a key mediator of neuroprotection. Despite some BDNF-independent actions, the consistent restoration of neurotrophic support positions BDNF as a central pathway for disease modification. CI - Copyright (c) 2026 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Xu, Tianyi AU - Xu T AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, ON, Canada. Electronic address: anniee.xu@mail.utoronto.ca. FAU - Zheng, Yang Jing AU - Zheng YJ AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Institute of Medical Science, University of Toronto, Canada. Electronic address: yangjing.zheng@mail.utoronto.ca. FAU - Wong, Sabrina AU - Wong S AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, ON, Canada; Poul Hansen Family Centre for Depression, University Health Network, Toronto, Canada. Electronic address: sabrinal.wong@mail.utoronto.ca. FAU - Dri, Christine E AU - Dri CE AD - Brain and Cognition Discovery Foundation, Toronto, Canada. Electronic address: christine.dri@alumni.utoronto.ca. FAU - Zhou, Xin Tong AU - Zhou XT AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, ON, Canada. Electronic address: lisaxt.zhou@mail.utoronto.ca. FAU - Teopiz, Kayla M AU - Teopiz KM AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Institute of Medical Science, University of Toronto, Canada; Poul Hansen Family Centre for Depression, University Health Network, Toronto, Canada. Electronic address: kayla.teopiz@alumni.utoronto.ca. FAU - Le, Gia Han AU - Le GH AD - Brain and Cognition Discovery Foundation, Toronto, Canada; Institute of Medical Science, University of Toronto, Canada. Electronic address: hanny.le@mail.utoronto.ca. FAU - McIntyre, Roger S AU - McIntyre RS AD - Department of Psychiatry, University of Toronto, ON, Canada; Department of Pharmacology & Toxicology, University of Toronto, ON, Canada. Electronic address: roger.mcintyre@bcdf.org. LA - eng PT - Journal Article PT - Systematic Review DEP - 20260129 PL - Netherlands TA - Asian J Psychiatr JT - Asian journal of psychiatry JID - 101517820 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - *Brain-Derived Neurotrophic Factor/metabolism/drug effects MH - Humans MH - *Neurodegenerative Diseases/drug therapy/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Mental Disorders/drug therapy/metabolism MH - *Neuroprotective Agents/pharmacology OTO - NOTNLM OT - Brain-derived neurotrophic factor OT - Glucagon-like peptide-1 receptor agonists OT - Neurodegenerative disorders OT - Neuroplasticity OT - Neuroprotection OT - Psychiatric disorders COIS- Declaration of Competing Interest The authors declare no competing interests. EDAT- 2026/02/01 00:44 MHDA- 2026/02/21 00:56 CRDT- 2026/01/31 18:06 PHST- 2025/12/19 00:00 [received] PHST- 2026/01/14 00:00 [revised] PHST- 2026/01/21 00:00 [accepted] PHST- 2026/02/21 00:56 [medline] PHST- 2026/02/01 00:44 [pubmed] PHST- 2026/01/31 18:06 [entrez] AID - S1876-2018(26)00043-2 [pii] AID - 10.1016/j.ajp.2026.104870 [doi] PST - ppublish SO - Asian J Psychiatr. 2026 Mar;117:104870. doi: 10.1016/j.ajp.2026.104870. Epub 2026 Jan 29. PMID- 41582696 OWN - NLM STAT- MEDLINE DCOM- 20260630 LR - 20260815 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 28 IP - 4 DP - 2026 Apr TI - GLP-1RAs versus metformin and Parkinson's risk in type 2 diabetes. PG - 2815-2826 LID - 10.1111/dom.70459 [doi] AB - BACKGROUND: Parkinson's disease (PD) is an increasingly prevalent neurodegenerative condition, particularly among individuals with type 2 diabetes mellitus (T2DM). While prior studies have suggested that GLP-1 receptor agonists (GLP-1RAs) and metformin may confer neuroprotective effects, most were limited by small sample sizes, short follow-up, uncontrolled designs, or lacked direct comparisons between therapies-making their findings inconclusive for clinical decision-making. METHODS: Using the TriNetX Global Collaborative Network, we identified 92 485 patients with T2DM initiating GLP-1RA therapy and matched them 1:1 to new metformin users using propensity score matching. Patients with prior antidiabetic therapy, PD, or dementia were excluded. Incident PD was the primary outcome; all-cause mortality served as a secondary endpoint. Adjusted hazard ratios (aHRs) were estimated using Cox models. Competing risk and time-stratified (10 years) analyses were conducted. Positive and negative outcome/exposure controls were employed to validate internal consistency. RESULTS: The overall PD risk was comparable between GLP-1RA and metformin groups (aHR, 0.91; 95% CI, 0.79-1.05). However, between years 5 and 10, GLP-1RA use was associated with a significantly lower PD risk (aHR, 0.56; 95% CI, 0.34-0.93). Mortality risk did not differ significantly. Validation analyses confirmed the specificity of the findings. CONCLUSIONS: By addressing key limitations of earlier studies through a large-scale, active-comparator, new-user design, this study provides novel evidence of a delayed neuroprotective effect of GLP-1RAs. These findings support incorporating neurologic outcomes into long-term diabetes management and may inform therapy selection in high-risk populations. CI - (c) 2026 John Wiley & Sons Ltd. FAU - Sun, Mingyang AU - Sun M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Wang, Xiaoling AU - Wang X AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. AD - Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China. FAU - Lu, Zhongyuan AU - Lu Z AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. AD - Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China. FAU - Yang, Yitian AU - Yang Y AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Lv, Shuang AU - Lv S AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Miao, Mengrong AU - Miao M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Chen, Wan-Ming AU - Chen WM AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan. AD - Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan. FAU - Wu, Szu-Yuan AU - Wu SY AUID- ORCID: 0000-0001-5637-558X AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan. AD - Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan. AD - Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan. AD - Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan. AD - Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Taiwan. AD - Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan. AD - Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Taiwan. AD - Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Zhang, Jiaqiang AU - Zhang J AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. LA - eng GR - 2023YFC25069003/National Key Research and Development Program of China/ GR - 11403/Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital/ GR - 11404/Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital/ PT - Comparative Study PT - Journal Article DEP - 20260126 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 9100L32L2N (Metformin) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - *Metformin/therapeutic use MH - Female MH - *Hypoglycemic Agents/therapeutic use MH - Male MH - Aged MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Parkinson Disease/epidemiology/prevention & control MH - Middle Aged OTO - NOTNLM OT - GLP-1 receptor agonists OT - Parkinson's disease OT - comparative effectiveness research OT - metformin OT - type 2 diabetes mellitus EDAT- 2026/01/26 06:27 MHDA- 2026/03/17 06:48 CRDT- 2026/01/26 03:33 PHST- 2025/12/25 00:00 [revised] PHST- 2025/11/28 00:00 [received] PHST- 2026/01/01 00:00 [accepted] PHST- 2026/03/17 06:48 [medline] PHST- 2026/01/26 06:27 [pubmed] PHST- 2026/01/26 03:33 [entrez] AID - 10.1111/dom.70459 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Apr;28(4):2815-2826. doi: 10.1111/dom.70459. Epub 2026 Jan 26. PMID- 41564595 OWN - NLM STAT- MEDLINE DCOM- 20260630 LR - 20260806 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 177 DP - 2026 Apr TI - Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond. PG - 156494 LID - S0026-0495(26)00003-X [pii] LID - 10.1016/j.metabol.2026.156494 [doi] AB - While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions. CI - Copyright (c) 2026 Elsevier Inc. All rights reserved. FAU - Muzurovic, Emir AU - Muzurovic E AD - Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Podgorica, Montenegro. Electronic address: dremir@t-com.me. FAU - Katsiki, Niki AU - Katsiki N AD - Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus. FAU - Volcansek, Spela AU - Volcansek S AD - Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Zaloska 7, 1000, Ljubljana, Slovenia; Medical Faculty Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia. FAU - Plescia, Fulvio AU - Plescia F AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90100, Palermo, Italy. FAU - Rizzo, Manfredi AU - Rizzo M AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90100, Palermo, Italy; Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates. FAU - Mantzoros, Christos S AU - Mantzoros CS AD - Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Boston VA Healthcare System, Harvard Medical School, Boston, MA, 02115, USA. LA - eng PT - Journal Article PT - Review DEP - 20260120 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Incretins) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Incretins/therapeutic use MH - *Metabolic Diseases/drug therapy MH - *Liver Diseases/drug therapy MH - *Cardiovascular Diseases/drug therapy MH - *Kidney Diseases/drug therapy MH - Animals MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Obesity/drug therapy OTO - NOTNLM OT - Amylin receptor agonists OT - Cardio-kidney-liver-metabolic OT - Glucagon receptor agonists OT - Glucagon-like peptide-1 receptor agonists OT - Glucose-dependent insulinotropic polypeptide receptor agonists OT - Incretin-based therapies OT - Metabolic dysfunction-associated steatotic liver disease OT - Multi-agonist-based therapies OT - Obesity OT - Prediabetes COIS- Declaration of competing interest EM has given talks or attended conferences sponsored by Novo Nordisk, Boehringer Ingelheim, AstraZeneca, Medtronic, Merck Sharp & Dohme, Novartis, Sanofi, and Servier. NK has given talks, attended conferences and participated in trials sponsored by Amgen, Astra Zeneca, Boehringer Ingelheim, Elpen, Libytec, Menarini, Novartis, Novo Nordisk, Sanofi, Recordatti and Viatris. SV has given talks or attended conferences sponsored by Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Sanofi, Medtronic, and Abbott. MR has given lectures, received honoraria and research support, and participated in conferences, advisory boards, and clinical trials sponsored by several pharmaceutical companies including Amgen, Astra Zeneca, Boehringer Ingelheim, Kowa, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Novartis, Roche Diagnostics, Sanofi, and Servier. CSM reports grants through his institution from Merck and Boehringer Ingellheim, has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports personal fees from Novo Nordisk, reports personal fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal fees from Genfit, Lumos, Amgen, Corcept, Intercept, and Regeneron, reports support (educational activity meals through his institution or national conferences) from Amarin, Novo Nordisk, Astra Zeneca, Boehringer Ingelheim and travel support and fees from TMIOA, Elsevier, the California Walnut Commission, College Internationale Researche Servier, and the Cardio Metabolic Health Conference. None is directly related to the work presented herein. As EIC he was not involved in handling this manuscript which was handled by an Associate Editor overseeing the special issue. Other authors declare no conflict of interest. EDAT- 2026/01/22 01:09 MHDA- 2026/02/15 00:31 CRDT- 2026/01/21 18:04 PHST- 2024/07/04 00:00 [received] PHST- 2025/11/09 00:00 [revised] PHST- 2026/01/06 00:00 [accepted] PHST- 2026/02/15 00:31 [medline] PHST- 2026/01/22 01:09 [pubmed] PHST- 2026/01/21 18:04 [entrez] AID - S0026-0495(26)00003-X [pii] AID - 10.1016/j.metabol.2026.156494 [doi] PST - ppublish SO - Metabolism. 2026 Apr;177:156494. doi: 10.1016/j.metabol.2026.156494. Epub 2026 Jan 20. PMID- 41550266 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260119 LR - 20260121 IS - 2813-2890 (Electronic) IS - 2813-2890 (Linking) VI - 4 DP - 2025 TI - Multidisciplinary care of pediatric obesity and its impact on sleep: a review. PG - 1634185 LID - 10.3389/frsle.2025.1634185 [doi] LID - 1634185 AB - Pediatric obesity has emerged as a significant global health issue with multifaceted consequences, including its impact on sleep health. Obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) are among the serious sleep-related comorbidities in obese children, contributing to impaired quality of life, cognitive deficits, and cardiovascular risks. These conditions frequently coexist with other obesity-related complications such as insulin resistance, type 2 diabetes, hypertension, and non-alcoholic fatty liver disease (NAFLD). This review explores the importance of multidisciplinary care in addressing pediatric obesity, emphasizing early diagnosis, nutritional counseling, physical activity interventions, psychological support, and pharmacologic therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists. The role of global trends, academic performance, and wellbeing clinics are also discussed. Although promising, the use of GLP-1s and surgical interventions in pediatrics remains constrained by limited data, particularly concerning their impact on sleep disorders. Further research is essential to clarify the long-term effects of GLP-1 receptor agonists and bariatric surgery not only on obesity and sleep-related comorbidities such as OSA and OHS, but also on cognitive function, psychosocial wellbeing, and overall health outcomes-thereby informing evidence-based, multidisciplinary approaches to pediatric obesity management. CI - Copyright (c) 2026 Inja and Cielo. FAU - Inja, Ravali AU - Inja R AD - Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States. FAU - Cielo, Christopher AU - Cielo C AD - Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States. LA - eng PT - Journal Article PT - Review DEP - 20260102 PL - Switzerland TA - Front Sleep JT - Frontiers in sleep JID - 9918451286706676 PMC - PMC12807914 OTO - NOTNLM OT - multidisciplinary approach OT - obesity OT - obesity hypoventilation OT - pediatrics OT - sleep apnea OT - weight loss COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/01/19 12:51 MHDA- 2026/01/19 12:52 PMCR- 2026/01/02 CRDT- 2026/01/19 06:05 PHST- 2025/05/23 00:00 [received] PHST- 2025/08/04 00:00 [accepted] PHST- 2026/01/19 12:52 [medline] PHST- 2026/01/19 12:51 [pubmed] PHST- 2026/01/19 06:05 [entrez] PHST- 2026/01/02 00:00 [pmc-release] AID - 10.3389/frsle.2025.1634185 [doi] PST - epublish SO - Front Sleep. 2026 Jan 2;4:1634185. doi: 10.3389/frsle.2025.1634185. eCollection 2025. PMID- 41547366 OWN - NLM STAT- MEDLINE DCOM- 20260306 LR - 20260924 IS - 1474-547X (Electronic) IS - 0140-6736 (Linking) VI - 407 IP - 10531 DP - 2026 Feb 28 TI - Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits. PG - 892-908 LID - S0140-6736(25)02105-1 [pii] LID - 10.1016/S0140-6736(25)02105-1 [doi] AB - GLP-1 receptor agonists were initially developed to treat type 2 diabetes and have had a transformative effect on its therapy, and are highly effective for glycaemic control, with the added benefit of bodyweight reduction and a low risk of causing hypoglycaemia. GLP-1 receptor agonists reduce risks for major adverse cardiovascular events (eg, non-fatal myocardial infarction, stroke, and cardiovascular death), and the risk of admission to or treatment within hospital for heart failure. These drugs reduce albuminuria and slow the decline in estimated glomerular filtration rate over time, therefore delaying or preventing kidney failure. Furthermore, GLP-1 receptor agonists (eg, liraglutide and semaglutide) and the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist tirzepatide have been approved for treatment of obesity, with clinical trials establishing benefits for various obesity-related conditions: prevention of type 2 diabetes; risk for major adverse cardiovascular events; heart failure, especially with preserved ejection fraction; regression of steatosis and prevention of fibrosis in steatotic liver disease; and symptomatic improvements in obstructive sleep apnoea and knee osteoarthritis. Current developments include the exploration of novel indications (eg, neurodegenerative diseases and substance use disorders) with suggestive evidence of efficacy, and the development of small-molecule GLP-1 receptor agonists for oral treatment to improve convenience. Dual (ie, GLP-1-glucagon and GLP-1-amylin) and triple (ie, GIP-GLP-1-glucagon) receptor agonists activating multiple receptors promise greater efficacy than mono-agonists, especially for weight loss. However, some clinical development programmes have a high burden of adverse gastrointestinal events, and dose-escalation regimens should be optimised to reach acceptable tolerability. CI - Copyright (c) 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. FAU - Nauck, Michael A AU - Nauck MA AD - Diabetes, Endocrinology, Metabolism Section, Medical Department 1, St Josef-Hospital, Katholisches Klinikum Bochum gGmbH, Ruhr University Bochum, Bochum, Germany; Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. Electronic address: michael.nauck@rub.de. FAU - Tuttle, Katherine R AU - Tuttle KR AD - Providence Inland Northwest Health, Division of Nephrology and Kidney Research Institute, University of Washington School of Medicine, Spokane, WA, USA. FAU - Tschop, Matthias H AU - Tschop MH AD - Division of Metabolic Diseases, Technische Universitat Munchen, Helmholtz Diabetes Center, Helmholtz Zentrum Munchen, Munich, Germany. FAU - Bluher, Matthias AU - Bluher M AD - Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum Munchen, University of Leipzig and University Hospital Leipzig, Leipzig, Germany. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20260114 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 839I73S42A (Liraglutide) RN - OYN3CCI6QE (Tirzepatide) RN - 53AXN4NNHX (Semaglutide) SB - IM EIN - Lancet. 2026 Mar 14;407(10533):1058. doi: 10.1016/S0140-6736(26)00467-8. PMID: 41831846 MH - Humans MH - *Cardiovascular Diseases/prevention & control MH - *Diabetes Mellitus, Type 2/drug therapy MH - Gastric Inhibitory Polypeptide/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists/therapeutic use MH - *Hypoglycemic Agents/therapeutic use MH - *Incretins/therapeutic use MH - Liraglutide/therapeutic use MH - Obesity/drug therapy MH - Tirzepatide/therapeutic use MH - Semaglutide/therapeutic use COIS- Declaration of interests MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co, Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (Gasherbrum); has received grant support from Merck and Sharp & Dohme; has served on the speakers bureau of Eli Lilly & Co, Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk; and is on a Data Monitoring and Safety Board for Inventiva. KRT has received investigator-initiated grant support from Travere, Bayer, Benaroya Research Institute, the Doris Duke Charitable Foundation, and Breakthrough-T1D; reports consultancy fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, Alnylam, Bayer, and ProKidney; and reports speaker fees from Novo Nordisk, Bayer, and Boehringer Ingelheim. She reports US National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, OT2OD032581, and US Centers for Disease Control and Prevention project numbers 75D301-21-P-12254 and 75D301-23-C-18264. She reports being chair of Data Safety Monitoring boards for the US National Institutes of Health National Institute of Diabetes and Digestive and Kidney Disease, and the George Clinical Institute, and reports being a member of the Data Safety Monitoring Board for AstraZeneca. She reports leadership roles as chair for the Diabetic Kidney Disease Collaborative for the American Society of Nephrology, chair for Kidney Week 2025 Program Committee, member of the American Heart Association publication committee, and a member of the American Heart Association-American College of Cardiology Cardiovascular Kidney Metabolic Guideline Committee. MHT has delivered scientific lectures for Boehringer Ingelheim (2024), KG (2024), AstraZeneca (2024), Lilly Deutschland (2024), and Novo Nordisk (2024). He is co-founder of the biotech startup Bluewater Biotech (founded in 2024). As CEO and CSO of Helmholtz Munich, he is co-responsible for countless collaborations of the employees with a multitude of companies and institutions, worldwide. In this capacity, he discusses potential projects with and has signed/signs contracts for the centre's institute(s) related to research collaborations worldwide, including but not limited to pharmaceutical corporations such as Boehringer Ingelheim, Novo Nordisk, Roche Diagnostics, Arbormed, Eli Lilly, SCG Cell Therapy, and others. As the CEO of Helmholtz Munich, he was/is further overall responsible for commercial technology transfer activities. He confirms that, to the best of his knowledge, none of the above funding sources or collaborations were involved in or had an influence on the preparation of this manuscript. MB received honoraria as a consultant and speaker from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, MSD, Novo Nordisk, Novartis, Pfizer, and Sanofi; and reports chairing a Clinical Trial Data Safety Monitoring Board for Boehringer Ingelheim. EDAT- 2026/01/18 00:37 MHDA- 2026/03/06 08:57 CRDT- 2026/01/17 18:52 PHST- 2025/04/02 00:00 [received] PHST- 2025/10/13 00:00 [revised] PHST- 2025/10/13 00:00 [accepted] PHST- 2026/03/06 08:57 [medline] PHST- 2026/01/18 00:37 [pubmed] PHST- 2026/01/17 18:52 [entrez] AID - S0140-6736(25)02105-1 [pii] AID - 10.1016/S0140-6736(25)02105-1 [doi] PST - ppublish SO - Lancet. 2026 Feb 28;407(10531):892-908. doi: 10.1016/S0140-6736(25)02105-1. Epub 2026 Jan 14. PMID- 41544899 OWN - NLM STAT- MEDLINE DCOM- 20260626 LR - 20260626 IS - 1872-8227 (Electronic) IS - 0168-8227 (Linking) VI - 235 DP - 2026 May TI - Target trial emulations for tirzepatide, semaglutide and SGLT2-inhibitors for dementia in patients with type 2 diabetes: Real world evidence from a retrospective cohort study. PG - 113083 LID - S0168-8227(26)00002-1 [pii] LID - 10.1016/j.diabres.2026.113083 [doi] AB - AIMS: Evidence suggests sodium glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists may reduce the onset/progression of dementia. The effect of the dual GLP1/GIP receptor agonist tirzepatide on dementia outcomes remains unknown. We compared tirzepatide, semaglutide and SGLT2-i in relation to incident dementia in patients with type 2 diabetes. METHODS: Three target trial emulations (TTE) were conducted using real-world data from the TriNetX global federated network: TTE1: tirzepatide vs. SGLT2-i, TTE2: semaglutide vs. SGLT2-i and TTE3: tirzepatide vs. semaglutide. Eligible adults with type 2 diabetes without dementia at baseline were included. Follow-up was two years. First diagnosis of dementia, MACE, and all-cause mortality were analysed using survival analysis after propensity score matching. RESULTS: After matching, TTE1 included 14,462 patients; TTE2, 57,959; TTE3 12,246. Tirzepatide was associated with a lower risk of dementia versus semaglutide (HR 0.69, 95% CI 0.48-0.99, p = 0.04) and SGLT2-i (HR 0.66, 95% CI 0.47-0.93, p = 0.02), and lower mortality (HR 0.72, 95% CI 0.58-0.90, p < 0.01; HR 0.29, 95% CI 0.23-0.37, p < 0.01). Tirzepatide and semaglutide reduced MACE vs SGLT2-i. CONCLUSIONS: Tirzepatide is associated with a lower risk of dementia versus semaglutide and SGLT2-i in type 2 diabetes. Our findings are hypothesis generating, requiring confirmation in randomised controlled trials. CI - Copyright (c) 2026 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Younis, Alhena AU - Younis A AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK. FAU - Henney, Alex E AU - Henney AE AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK. FAU - Riley, David R AU - Riley DR AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK. FAU - Anson, Matthew AU - Anson M AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK. FAU - Zhao, Sizheng S AU - Zhao SS AD - Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. FAU - Ibarburu, Gema H AU - Ibarburu GH AD - TriNetX LLC, Cambridge, MA, USA. FAU - Malik, Rayaz A AU - Malik RA AD - Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar. FAU - Su, Li AU - Su L AD - Sheffield Institute of Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK. FAU - Lip, Gregory Y H AU - Lip GYH AD - Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK; Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Cardiology, Lipidology and Internal Medicine with Intensive Coronary Care Unit, Medical University of Bialystok, Bialystok, Poland. FAU - Cuthbertson, Daniel J AU - Cuthbertson DJ AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK. FAU - Alam, Uazman AU - Alam U AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK. Electronic address: Uazman.alam@liverpool.ac.uk. LA - eng PT - Journal Article DEP - 20260114 PL - Ireland TA - Diabetes Res Clin Pract JT - Diabetes research and clinical practice JID - 8508335 RN - 53AXN4NNHX (Semaglutide) RN - OYN3CCI6QE (Tirzepatide) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) SB - IM MH - Humans MH - Semaglutide MH - Tirzepatide/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Female MH - Male MH - Aged MH - Retrospective Studies MH - *Dementia/epidemiology/prevention & control/drug therapy MH - *Glucagon-Like Peptides/therapeutic use MH - *Hypoglycemic Agents/therapeutic use MH - Middle Aged MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Gastric Inhibitory Polypeptide/therapeutic use MH - Aged, 80 and over OTO - NOTNLM OT - Dementia OT - Diabetes OT - GLP1-RA OT - Tirzepatide COIS- Declaration of competing interest SSZ has received: (1) support for conference attendance from Novartis, UCB, AlfaSigma, Eli Lilly; (2) consultancy/speaker fees from Novartis, UCB, AlfaSigma, AbbVie, Jassen. GYHL is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos (No fees are received personally). He is co-PI of the AFFIRMO project on multimorbidity in AF (grant agreement No 899871), TARGET project on digital twins for personalised management of atrial fibrillation and stroke (grant agreement No 101136244) and ARISTOTELES project on artificial intelligence for management of chronic long term conditions (grant agreement No 101080189), which are all funded by the EU's Horizon Europe Research & Innovation programme. DJC has received investigator-initiated grants from Astra Zeneca and Novo Nordisk, support for education from Perspectum with any financial remuneration from pharmaceutical company consultation made to the University of Liverpool and serves as the Topic Advisor for Type 2 Diabetes medications for The National Institute for Health and Care Excellence (NICE), UK. UA has received honoraria from Procter & Gamble, Viatris, Grunenthal, Daiichi Sankyo, Eli Lilly, Theras and Sanofi for educational meetings and funding for attendance to an educational meeting from Sanofi and Daiichi Sankyo. UA has also received investigator-led funding by Procter & Gamble, consultancy fees from Axonis therapeutics and is a council member of the Royal Society of Medicine's Vascular, Lipid & Metabolic Medicine Section. EDAT- 2026/01/17 00:36 MHDA- 2026/04/12 04:37 CRDT- 2026/01/16 19:14 PHST- 2025/11/19 00:00 [received] PHST- 2025/12/28 00:00 [revised] PHST- 2026/01/05 00:00 [accepted] PHST- 2026/04/12 04:37 [medline] PHST- 2026/01/17 00:36 [pubmed] PHST- 2026/01/16 19:14 [entrez] AID - S0168-8227(26)00002-1 [pii] AID - 10.1016/j.diabres.2026.113083 [doi] PST - ppublish SO - Diabetes Res Clin Pract. 2026 May;235:113083. doi: 10.1016/j.diabres.2026.113083. Epub 2026 Jan 14. PMID- 41524953 OWN - NLM STAT- MEDLINE DCOM- 20260627 LR - 20261009 IS - 1590-3478 (Electronic) IS - 1590-1874 (Linking) VI - 47 IP - 1 DP - 2026 Jan 12 TI - The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or alzheimer's disease: a meta-analysis of randomized controlled trials. PG - 149 LID - 10.1007/s10072-025-08602-z [doi] AB - BACKGROUND: Currently, the cognitive impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remains unclear in non-diabetic patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), despite their widespread use for type 2 diabetes. This meta-analysis summarized cognitive outcomes from randomized controlled trials (RCTs) of GLP-1 RAs in non-diabetic patients with AD or MCI. METHODS: PubMed, Cochrane Library, and Embase were searched for studies through October 27, 2024. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random-effects models. Sensitivity analyses addressed variations in cognitive assessment methodologies. Between-study heterogeneity was evaluated using the I(2) index. RESULTS: Four RCTs comprising 112 patients (61 placebo, 51 treatment) were included. For cognitive tests where higher scores indicate better outcomes, no significant difference was observed between GLP-1 RA and placebo groups (pooled SMD: -0.10, 95% CI: -0.53, 0.34; I(2) = 23.9%). Sensitivity analyses yielded consistent results. Analysis of the Alzheimer's Disease Assessment Scale-Cognitive subscale from two studies, where lower scores indicate better outcomes, similarly showed no significant treatment effect (SMD: 0.07, 95% CI: -0.47, 0.62; I(2) = 0%). CONCLUSION: There was no evidence that GLP-1 RAs improved cognitive outcomes compared to placebo in non-diabetic patients with AD or MCI. Further research is needed to clarify their neuroprotective potential and explore alternative therapeutic strategies for cognitive decline. CI - (c) 2026. Fondazione Societa Italiana di Neurologia. FAU - O'Mara, Ashley AU - O'Mara A AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Mody, Bhakti Pradip AU - Mody BP AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Mammi, Marco AU - Mammi M AD - Neurosurgery Unit, "M. Bufalini" Hospital, Cesena, 47521, Italy. FAU - Simjian, Thomas AU - Simjian T AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Ghattas, Kyrellos AU - Ghattas K AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Kaliki, Srilekha AU - Kaliki S AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Le, Ngoc Phuong Mai AU - Le NPM AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. AD - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA. FAU - Liew, Aaron AU - Liew A AD - Department of Medicine, Portiuncula University Hospital and University of Galway, Galway, Ireland. FAU - Migliore, Mattia AU - Migliore M AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. FAU - Mekary, Rania A AU - Mekary RA AUID- ORCID: 0000-0003-1636-0759 AD - School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. rania.mekary@mcphs.edu. AD - School of Pharmacy, Computational Neuroscience and Outcomes Center, Department of Biostatistics, MCPHS University, Harvard Medical School, Harvard TH Chan School of Public Health, 179 Longwood Avenue, Boston, MA, 02115, USA. rania.mekary@mcphs.edu. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review DEP - 20260112 PL - Italy TA - Neurol Sci JT - Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology JID - 100959175 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/psychology MH - *Cognitive Dysfunction/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Randomized Controlled Trials as Topic MH - Cognitive Enhancement MH - *Cognition/drug effects OTO - NOTNLM OT - Alzheimer's disease OT - Exenatide OT - GLP-1 receptor agonists OT - Glucagon-like peptide-1 receptor agonists OT - Liraglutide OT - Mild cognitive impairment COIS- Declarations. The present study was performed solely on previously published data and was therefore carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Competing interests: The authors declare that they have no conflict of interest. Beyond the authors' primary affiliations, no additional support was provided for this research. EDAT- 2026/01/12 13:14 MHDA- 2026/01/12 13:15 CRDT- 2026/01/12 11:14 PHST- 2025/09/28 00:00 [received] PHST- 2025/12/01 00:00 [accepted] PHST- 2026/01/12 13:15 [medline] PHST- 2026/01/12 13:14 [pubmed] PHST- 2026/01/12 11:14 [entrez] AID - 10.1007/s10072-025-08602-z [pii] AID - 10.1007/s10072-025-08602-z [doi] PST - epublish SO - Neurol Sci. 2026 Jan 12;47(1):149. doi: 10.1007/s10072-025-08602-z. PMID- 41510365 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260109 LR - 20260109 IS - 2251-6581 (Print) IS - 2251-6581 (Electronic) IS - 2251-6581 (Linking) VI - 25 IP - 1 DP - 2026 Jun TI - Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study. PG - 25 LID - 10.1007/s40200-025-01838-8 [doi] LID - 25 AB - PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD. METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation. RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors. CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences. CI - (c) The Author(s), under exclusive licence to Tehran University of Medical Sciences 2026. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. FAU - Wang, Yingqi AU - Wang Y AD - Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA. ROR: https://ror.org/00za53h95. GRID: grid.21107.35. ISNI: 0000 0001 2171 9311 FAU - Alexander, G Caleb AU - Alexander GC AD - Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA. ROR: https://ror.org/00za53h95. GRID: grid.21107.35. ISNI: 0000 0001 2171 9311 AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA. ROR: https://ror.org/00za53h95. GRID: grid.21107.35. ISNI: 0000 0001 2171 9311 FAU - Mehta, Hemalkumar B AU - Mehta HB AD - Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA. ROR: https://ror.org/00za53h95. GRID: grid.21107.35. ISNI: 0000 0001 2171 9311 AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA. ROR: https://ror.org/00za53h95. GRID: grid.21107.35. ISNI: 0000 0001 2171 9311 LA - eng PT - Journal Article DEP - 20260106 PL - Switzerland TA - J Diabetes Metab Disord JT - Journal of diabetes and metabolic disorders JID - 101590741 PMC - PMC12775190 OTO - NOTNLM OT - Alzheimer's disease OT - Antidiabetic medication OT - Drug use OT - Medicare OT - Type 2 diabetes mellitus COIS- Competing interestsDr. Alexander is the past Chair of FDA's Peripheral and Central Nervous System Advisory Committee and is a co-founding Principal and equity holder in Stage Analytics. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. All other authors report no conflicts of interest. EDAT- 2026/01/09 07:06 MHDA- 2026/01/09 07:07 PMCR- 2027/01/06 CRDT- 2026/01/09 05:10 PHST- 2025/10/20 00:00 [received] PHST- 2025/12/22 00:00 [accepted] PHST- 2026/01/09 07:07 [medline] PHST- 2026/01/09 07:06 [pubmed] PHST- 2026/01/09 05:10 [entrez] PHST- 2027/01/06 00:00 [pmc-release] AID - 1838 [pii] AID - 10.1007/s40200-025-01838-8 [doi] PST - epublish SO - J Diabetes Metab Disord. 2026 Jan 6;25(1):25. doi: 10.1007/s40200-025-01838-8. eCollection 2026 Jun. PMID- 41501059 OWN - NLM STAT- MEDLINE DCOM- 20260127 LR - 20260131 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 17 IP - 1 DP - 2026 Jan 7 TI - Comprehensive evaluation of GLP-1 receptor agonists: an umbrella review of clinical outcomes across multiple diseases. PG - 972 LID - 10.1038/s41467-025-67701-9 [doi] LID - 972 AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially approved for type 2 diabetes mellitus. Recent evidence suggests their therapeutic potential in various diseases, though their efficacy and safety remain incompletely understood. Here, we conduct an umbrella review including 123 meta-analyses covering 464 outcomes from 5617 articles to comprehensively assess the effectiveness and adverse events (AEs) of GLP-1 RAs across diverse outcomes. GLP-1 RAs showed trends toward improvements in endocrine and metabolic, cardiovascular, renal, and respiratory outcomes, cognitive function, with a potential reduction in fracture risk and all-cause mortality in certain populations. However, increased risks of certain AEs, including diabetic retinopathy, ketoacidosis, gastrointestinal events, and treatment discontinuation, were also observed. AMSTAR 2 assessments indicate that the existing evidence is limited by methodological shortcomings, including incomplete reporting of excluded studies, suboptimal literature search strategies, and insufficient evaluation of how bias in primary studies may influence meta-analytic estimates. Some outcomes did not reach statistical significance in all populations, highlighting the need for further high-quality clinical research. Careful consideration of potential benefits and risks is essential for optimizing treatment outcomes and ensuring patient safety when using GLP-1 RAs in clinical practice. CI - (c) 2026. The Author(s). FAU - Kong, Fanjing AU - Kong F AUID- ORCID: 0009-0004-1453-8562 AD - School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Zhao, Yanru AU - Zhao Y AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Zhang, Weiming AU - Zhang W AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Wang, Xinyi AU - Wang X AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Wu, Tianyu AU - Wu T AUID- ORCID: 0009-0003-0206-3101 AD - School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Zhou, Ziyi AU - Zhou Z AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Xu, Ying AU - Xu Y AUID- ORCID: 0000-0003-1445-4997 AD - Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. xuying.doctor@gmail.com. FAU - Xia, Lina AU - Xia L AUID- ORCID: 0000-0001-5338-9126 AD - School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China. xialina@cdutcm.edu.cn. FAU - Sun, Tao AU - Sun T AUID- ORCID: 0000-0003-2773-9174 AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. suntao513@gmail.com. AD - State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. suntao513@gmail.com. LA - eng PT - Journal Article PT - Systematic Review DEP - 20260107 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Treatment Outcome MH - Meta-Analysis as Topic MH - Glucagon-Like Peptide-1 Receptor/metabolism PMC - PMC12847739 COIS- Competing interests: The authors declare no competing interests. EDAT- 2026/01/08 00:26 MHDA- 2026/01/28 19:20 PMCR- 2026/01/07 CRDT- 2026/01/07 23:17 PHST- 2025/01/07 00:00 [received] PHST- 2025/12/05 00:00 [accepted] PHST- 2026/01/28 19:20 [medline] PHST- 2026/01/08 00:26 [pubmed] PHST- 2026/01/07 23:17 [entrez] PHST- 2026/01/07 00:00 [pmc-release] AID - 10.1038/s41467-025-67701-9 [pii] AID - 67701 [pii] AID - 10.1038/s41467-025-67701-9 [doi] PST - epublish SO - Nat Commun. 2026 Jan 7;17(1):972. doi: 10.1038/s41467-025-67701-9. PMID- 41482564 OWN - NLM STAT- MEDLINE DCOM- 20260122 LR - 20261009 IS - 1546-170X (Electronic) IS - 1078-8956 (Linking) VI - 32 IP - 1 DP - 2026 Jan TI - The expanding landscape of GLP-1 medicines. PG - 47-57 LID - 10.1038/s41591-025-04124-5 [doi] AB - Glucagon-like peptide-1 medicines are being prescribed to growing numbers of patients worldwide, for type 2 diabetes, obesity and associated comorbidities, including cardiovascular disease, peripheral artery disease and obstructive sleep apnea, and are revolutionizing public health strategies for these conditions. These medicines improve health through reduction of blood glucose and body weight, by attenuation of inflammation and via direct activation of receptors in target tissues. New, more effective molecules with optimized pharmacokinetics produce greater weight loss and some may be more effective for various metabolic disorders, through incorporation of one or more additional peptide epitopes. Parallel efforts are exploring new indications, including neurodegenerative and substance use disorders, metabolic liver disease, arthritis, type 1 diabetes and inflammatory bowel disease. Here we highlight data informing the safety, efficacy, and potential utility of new and emerging glucagon-like peptide-1 medicines. We outline new mechanistic concepts, future therapeutic opportunities, potential for differentiation from currently available medicines and areas of uncertainty requiring additional investigation. CI - (c) 2026. Springer Nature America, Inc. FAU - Drucker, Daniel J AU - Drucker DJ AUID- ORCID: 0000-0001-6688-8127 AD - The Lunenfeld, Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. drucker@lunenfeld.ca. LA - eng GR - 154321/Gouvernement du Canada | Instituts de Recherche en Sante du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20260102 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - Obesity/drug therapy MH - *Hypoglycemic Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Animals MH - Diabetes Mellitus, Type 1/drug therapy COIS- Competing interests: D.J.D. has received financial remuneration from Alnylam, Amgen, AstraZeneca, Crinetics, Eli Lilly, Insulet, Kallyope, Metsera, Pfizer and Sanofi for consulting and from Novo Nordisk for speaking, and Mt. Sinai Hospital receives investigator-initiated grant support from Amgen, Eli Lilly, Novo Nordisk and Zealand Pharma for preclinical studies in the Drucker lab. EDAT- 2026/01/03 00:30 MHDA- 2026/01/22 07:43 CRDT- 2026/01/02 23:04 PHST- 2025/08/22 00:00 [received] PHST- 2025/11/14 00:00 [accepted] PHST- 2026/01/22 07:43 [medline] PHST- 2026/01/03 00:30 [pubmed] PHST- 2026/01/02 23:04 [entrez] AID - 10.1038/s41591-025-04124-5 [pii] AID - 10.1038/s41591-025-04124-5 [doi] PST - ppublish SO - Nat Med. 2026 Jan;32(1):47-57. doi: 10.1038/s41591-025-04124-5. Epub 2026 Jan 2. PMID- 41480353 OWN - NLM STAT- MEDLINE DCOM- 20260102 LR - 20260104 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 16 DP - 2025 TI - Recent advances in incretin-based therapy for the treatment of cognitive impairment associated to the type 2 diabetes mellitus: preclinical and clinical studies - a narrative review. PG - 1696419 LID - 10.3389/fendo.2025.1696419 [doi] LID - 1696419 AB - It is well-established that individuals with type 2 diabetes mellitus (T2DM) have an increased risk of developing cognitive impairment and dementia, suggesting a close relation between hyperglycemia, insulin resistance, and chronic inflammation. This decline is characterized by a large variety of symptoms going from mild to major form of cognitive impairment characterized of loss of memory, attention, processing speed, and executive function. Preserving the physiological level of glycemia improves cognitive performance, but untreated or inadequately diabetes therapy facilitates the risk of dementia. Some experimental studies have disclosed that drug for diabetes can have protective outcomes on cognitive impairment. In this context, incretin hormone glucagon-like peptide-1 (GLP-1) can reduce blood glucose, improve glucose transport through cell membranes, and to improve brain insulin resistance modulating neuroinflammation. In fact, GLP-1 acts as a neurotransmitter and neuromodulator activating central GLP-1 receptors located in the neurons determining its neurotropic and neuroprotective role in central nervous system. Preclinical and clinical studies suggest the potential role of dipeptidyl peptidase-4 inhibitors (DPP4-i) as therapy for the treatment and prevention of cognitive impairment and dementia. Similarly, several evidences demonstrated that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduces the risk of cognitive impairment and dementia in T2DM patients by improving learning, memory, attention and executive functions. In addition, preclinical studies suggest a possible neuroprotective effect of GLP-1/GIP dual receptor agonist in animal models. The current narrative review, including studies published from September 1987 to September 2025, summarized the recent improvements regarding to the incretin-based therapy for cognitive impairment associated to the type 2 diabetes mellitus. CI - Copyright (c) 2025 Giofre, Zaffina, Pelle and Arturi. FAU - Giofre, Federica AU - Giofre F AD - Unit of Internal Medicine, Department of Medicine, Hospital of Vibo Valentia, Vibo Valentia, Italy. FAU - Zaffina, Isabella AU - Zaffina I AD - Internal Medicine Unit, San Francesco Hospital, Paola, Cosenza, Italy. FAU - Pelle, Maria Chiara AU - Pelle MC AD - "Renato Dulbecco" University Hospital, Catanzaro, Italy. FAU - Arturi, Franco AU - Arturi F AD - Internal Medicine, Department of Science, Magna Graecia University, Catanzaro, Italy. AD - Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), "Magna Graecia" University of Catanzaro, Catanzaro, Italy. LA - eng PT - Journal Article PT - Review DEP - 20251217 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Incretins) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Incretins/therapeutic use MH - *Cognitive Dysfunction/drug therapy/etiology MH - Animals MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Glucagon-Like Peptide 1 MH - Hypoglycemic Agents/therapeutic use PMC - PMC12753325 OTO - NOTNLM OT - cognitive impairment OT - dementia OT - diabetes OT - diabetic complications OT - incretines COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2026/01/02 06:29 MHDA- 2026/01/02 06:30 PMCR- 2025/12/17 CRDT- 2026/01/02 04:46 PHST- 2025/08/31 00:00 [received] PHST- 2025/10/30 00:00 [revised] PHST- 2025/11/04 00:00 [accepted] PHST- 2026/01/02 06:30 [medline] PHST- 2026/01/02 06:29 [pubmed] PHST- 2026/01/02 04:46 [entrez] PHST- 2025/12/17 00:00 [pmc-release] AID - 10.3389/fendo.2025.1696419 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2025 Dec 17;16:1696419. doi: 10.3389/fendo.2025.1696419. eCollection 2025. PMID- 41468681 OWN - NLM STAT- MEDLINE DCOM- 20260121 LR - 20260123 IS - 1873-5126 (Electronic) IS - 1353-8020 (Linking) VI - 143 DP - 2026 Feb TI - Incretin-based therapy and Parkinson's disease risk among patients with type 2 diabetes: Retrospective cohort study and meta-analysis. PG - 108171 LID - S1353-8020(25)00920-4 [pii] LID - 10.1016/j.parkreldis.2025.108171 [doi] AB - INTRODUCTION: Despite the widespread adoption of incretin-based therapy (IBT) for type 2 diabetes (T2D) and weight management, its potential neuroprotective effects remain inadequately characterized. Given emerging evidence of IBT's effects on neurodegenerative pathways, determining its association with Parkinson's disease (PD) incidence could have major clinical implications. We investigated the association between IBT and PD incidence in patients with T2D. METHODS: This retrospective cohort study identified patients with T2D between January 2008 and December 2021 who were classified as users or non-users of IBT based on time-dependent exposure and were followed for incident PD until December 2022. Additionally, a systematic literature review and meta-analysis were conducted. RESULTS: We identified 86,105 patients with T2D, of those, 347 patients developed PD. IBT use was associated with a decreased risk of PD (Hazard Ratio [HR] = 0.76, 95 % Confidence Interval [CI]:0.59-0.98), but this effect did not remain significant after confounders control (HR = 0.87, 95 % CI:0.65-1.15). The meta-analysis, comprising 12 studies and 964,446 patients, including our current cohort, revealed that IBT use was associated with a 30 % lower risk of PD (RR = 0.70, 95 % CI:0.56-0.87). This effect was more pronounced in studies including younger subjects and those with shorter T2D duration at baseline. CONCLUSIONS: The current findings suggest a negative relationship between IBT and risk of PD among patients with T2D, particularly in younger age group with short duration of the disease. CI - Copyright (c) 2025 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Barer, Yael AU - Barer Y AD - Department of Preventive Medicine and Epidemiology, School of Public Health, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Israel. Electronic address: yaelbarer@tauex.tau.ac.il. FAU - Ast, Tal AU - Ast T AD - Department of Preventive Medicine and Epidemiology, School of Public Health, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. Electronic address: talast60@gmail.com. FAU - Chodick, Gabriel AU - Chodick G AD - Department of Preventive Medicine and Epidemiology, School of Public Health, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Israel. Electronic address: chodick@tauex.tau.ac.il. FAU - Twig, Gilad AU - Twig G AD - Department of Preventive Medicine and Epidemiology, School of Public Health, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; The Institute of Endocrinology Diabetes and Metabolism, Sheba Medical Center, Ramat Gan, Israel; Incumbent of the Hella Gertner Chair for Research in Hypertension, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; The Gertner Institute for Epidemiology & Health Policy Research, Sheba Medical Center, Ramat Gan, Israel. Electronic address: gilad.twig@gmail.com. FAU - Giladi, Nir AU - Giladi N AD - Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Faculty of Medicine and Clinical Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20251225 PL - England TA - Parkinsonism Relat Disord JT - Parkinsonism & related disorders JID - 9513583 RN - 0 (Incretins) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - *Parkinson Disease/epidemiology/prevention & control MH - Retrospective Studies MH - *Incretins/therapeutic use/pharmacology MH - Male MH - Middle Aged MH - Female MH - Aged MH - Incidence MH - *Hypoglycemic Agents/therapeutic use OTO - NOTNLM OT - Incidence OT - Incretin-based therapy OT - Parkinson's disease OT - Type 2 diabetes COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nir Giladi reports a relationship with NeuroDerm, Sanofi, and Biogen, BIAL, Vibrant, Longevity, GaitBetter that includes: consulting or advisory, equity or stocks, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2025/12/31 00:33 MHDA- 2026/01/22 01:09 CRDT- 2025/12/30 18:02 PHST- 2025/08/10 00:00 [received] PHST- 2025/12/07 00:00 [revised] PHST- 2025/12/24 00:00 [accepted] PHST- 2026/01/22 01:09 [medline] PHST- 2025/12/31 00:33 [pubmed] PHST- 2025/12/30 18:02 [entrez] AID - S1353-8020(25)00920-4 [pii] AID - 10.1016/j.parkreldis.2025.108171 [doi] PST - ppublish SO - Parkinsonism Relat Disord. 2026 Feb;143:108171. doi: 10.1016/j.parkreldis.2025.108171. Epub 2025 Dec 25. PMID- 41465832 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251230 LR - 20260102 IS - 2075-1729 (Print) IS - 2075-1729 (Electronic) IS - 2075-1729 (Linking) VI - 15 IP - 12 DP - 2025 Dec 11 TI - The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials. LID - 10.3390/life15121893 [doi] LID - 1893 AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes. FAU - Pilsniak, Joanna AU - Pilsniak J AD - Student Scientific Society, Department of Internal Medicine, Autoimmune Diseases and Diabetology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Wegrzynek-Gallina, Julia AU - Wegrzynek-Gallina J AD - Department of Neurology, Faculty of Medical Sciences in Katowice, University Clinical Centre Prof K. Gibinski, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Bednarczyk, Blazej AU - Bednarczyk B AD - Student Scientific Society, Department of Internal Medicine, Autoimmune Diseases and Diabetology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Buczek, Aleksandra AU - Buczek A AD - Student Scientific Society, Department of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Pilsniak, Aleksandra AU - Pilsniak A AD - Department of Internal Medicine, Autoimmune Diseases and Diabetology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Chmiela, Tomasz AU - Chmiela T AUID- ORCID: 0000-0001-6022-7731 AD - Department of Neurology, Faculty of Medical Sciences in Katowice, University Clinical Centre Prof K. Gibinski, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Jarosinska, Agnieszka AU - Jarosinska A AUID- ORCID: 0000-0002-2078-2375 AD - Department of Internal Medicine, Autoimmune Diseases and Diabetology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Siuda, Joanna AU - Siuda J AUID- ORCID: 0000-0002-0340-660X AD - Department of Neurology, Faculty of Medical Sciences in Katowice, University Clinical Centre Prof K. Gibinski, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. FAU - Holecki, Michal AU - Holecki M AUID- ORCID: 0000-0002-3289-1050 AD - Department of Internal Medicine, Autoimmune Diseases and Diabetology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 14 Medykow St., 40-752 Katowice, Poland. LA - eng PT - Journal Article PT - Review DEP - 20251211 PL - Switzerland TA - Life (Basel) JT - Life (Basel, Switzerland) JID - 101580444 PMC - PMC12735111 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1RA OT - Parkinson's disease OT - antidiabetic drugs OT - neurodegenerative diseases COIS- The authors declare no conflict of interest. EDAT- 2025/12/30 07:41 MHDA- 2025/12/30 07:42 PMCR- 2025/12/11 CRDT- 2025/12/30 02:13 PHST- 2025/11/11 00:00 [received] PHST- 2025/12/05 00:00 [revised] PHST- 2025/12/07 00:00 [accepted] PHST- 2025/12/30 07:42 [medline] PHST- 2025/12/30 07:41 [pubmed] PHST- 2025/12/30 02:13 [entrez] PHST- 2025/12/11 00:00 [pmc-release] AID - life15121893 [pii] AID - life-15-01893 [pii] AID - 10.3390/life15121893 [doi] PST - epublish SO - Life (Basel). 2025 Dec 11;15(12):1893. doi: 10.3390/life15121893. PMID- 41465588 OWN - NLM STAT- MEDLINE DCOM- 20251230 LR - 20260102 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 26 IP - 24 DP - 2025 Dec 18 TI - GLP-1 Signalling as a Therapeutic Avenue in Parkinson's Disease: A Comprehensive Review. LID - 10.3390/ijms262412163 [doi] LID - 12163 AB - Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K/Akt, MAPK/ERK, cAMP/PKA-CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood-brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD. FAU - Orozco, Maria Paz AU - Orozco MP AD - NeurALL Research Group, Quito 170157, Ecuador. FAU - Vintimilla Rivadeneira, Valentina AU - Vintimilla Rivadeneira V AD - Cerebro, Emocion y Conduca (CEC) Research Group, Escuela de Medicina, Universidad de las Americas (UDLA), Quito 170124, Ecuador. FAU - Leon-Rojas, Jose E AU - Leon-Rojas JE AUID- ORCID: 0000-0002-8130-6460 AD - Cerebro, Emocion y Conduca (CEC) Research Group, Escuela de Medicina, Universidad de las Americas (UDLA), Quito 170124, Ecuador. LA - eng GR - 592.A.XVII.25/Universidad de las Americas (UDLA)/ PT - Journal Article PT - Review DEP - 20251218 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 839I73S42A (Liraglutide) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) SB - IM MH - Humans MH - *Parkinson Disease/drug therapy/metabolism MH - *Glucagon-Like Peptide 1/metabolism MH - Animals MH - *Signal Transduction/drug effects MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Liraglutide/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Incretins/therapeutic use PMC - PMC12733648 OTO - NOTNLM OT - GLP-1 OT - Parkinson's disease OT - exendin-4 OT - glucagon-like peptide-1 agonists OT - lixisenatide OT - semaglutide COIS- The authors declare no conflicts of interest. EDAT- 2025/12/30 07:41 MHDA- 2025/12/30 07:42 PMCR- 2025/12/18 CRDT- 2025/12/30 02:10 PHST- 2025/10/10 00:00 [received] PHST- 2025/12/07 00:00 [revised] PHST- 2025/12/16 00:00 [accepted] PHST- 2025/12/30 07:42 [medline] PHST- 2025/12/30 07:41 [pubmed] PHST- 2025/12/30 02:10 [entrez] PHST- 2025/12/18 00:00 [pmc-release] AID - ijms262412163 [pii] AID - ijms-26-12163 [pii] AID - 10.3390/ijms262412163 [doi] PST - epublish SO - Int J Mol Sci. 2025 Dec 18;26(24):12163. doi: 10.3390/ijms262412163. PMID- 41451400 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251226 LR - 20251226 IS - 2251-6581 (Print) IS - 2251-6581 (Electronic) IS - 2251-6581 (Linking) VI - 25 IP - 1 DP - 2026 Jun TI - Bibliometric analysis of global research trends on the relationship between alzheimer's disease and type 2 diabetes mellitus. PG - 12 LID - 10.1007/s40200-025-01812-4 [doi] LID - 12 AB - BACKGROUND: Background: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are highly prevalent chronic disorders with overlapping pathophysiological features. Increasing evidence suggests a bidirectional association, supported by shared mechanisms such as insulin resistance, neuroinflammation, and amyloid pathology giving rise to the concept of "type 3 diabetes." To map the global scientific output on the T2DM, AD relationship through a comprehensive bibliometric analysis, identifying publication trends, key contributors, and thematic developments. METHODS: A search was conducted in the Web of Science database on February 16, 2025, without time or language restrictions. Studies related to the association between T2DM and AD were retrieved and analyzed using VOSviewer and the Bibliometrix package in R. Metrics included publication volume, citation count, authorship, institutional affiliations, journal impact, and keyword co-occurrence. RESULTS: A total of 2,943 articles were identified, with a marked increase in output after 2011. The most cited article, by Craft et al., proposed a mechanistic link between insulin resistance and AD. The United States and China led in publication volume. Key institutions included Huazhong University of Science and Technology and Columbia University. Prominent authors included Hoelscher C and Liu Y. Keyword analysis revealed strong focus on "insulin resistance," "oxidative stress," and "neuroinflammation." Emerging trends included interest in GLP-1 receptor agonists, metformin, and biomarker-guided strategies. CONCLUSION: Research linking T2DM and AD has expanded substantially, reflecting growing recognition of shared mechanisms. Despite progress, gaps remain in biomarker integration and precision strategies. Future studies should emphasize longitudinal designs, mechanistic targets, and collaborative translational approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-025-01812-4. CI - (c) The Author(s), under exclusive licence to Tehran University of Medical Sciences 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. FAU - da Silva, Anderson Matheus Pereira AU - da Silva AMP AD - Department of Physiology and Pharmacology, Federal University of Pernambuco, PE Recife, Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 AD - Department of Physiology and Pharmacology, Federal University of Pernambuco, Av. Professor Moraes Rego, Cidade Universitaria, PE 50670-420 Recife, Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 FAU - da Santos do Nascimento, Maria AU - da Santos do Nascimento M AD - Graduate Programme in Translational Health, Centre for Medical Sciences, Federal University of Pernambuco, Recife, PE Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 FAU - Tudella, Gabriel Caruso Novaes AU - Tudella GCN AD - Department of Medicine, Federal University of Santa Maria, Santa Maria, RS Brazil. ROR: https://ror.org/01b78mz79. GRID: grid.411239.c. ISNI: 0000 0001 2284 6531 FAU - Reis, Richard Daniel Ferreira AU - Reis RDF AD - Department of Medicine, University of Itauna, Itauna, MG Brazil. ROR: https://ror.org/05sw4bn05. GRID: grid.441787.9. ISNI: 0000 0001 0152 1834 FAU - Corin, Anderson Silva AU - Corin AS AD - Department of Medicine, Federal University of Pelotas, Pelotas, RS Brazil. ROR: https://ror.org/05msy9z54. GRID: grid.411221.5. ISNI: 0000 0001 2134 6519 FAU - de Bastos Maximiano, Mariana Leticia AU - de Bastos Maximiano ML AD - Department of Medicine, Federal Fluminense University, Niteroi, RJ Brazil. ROR: https://ror.org/02rjhbb08. GRID: grid.411173.1. ISNI: 0000 0001 2184 6919 FAU - de Souza Franco, Eryvelton AU - de Souza Franco E AD - Graduate Programme in Translational Health, Centre for Medical Sciences, Federal University of Pernambuco, Recife, PE Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 FAU - de Sousa Maia, Maria Bernadete AU - de Sousa Maia MB AD - Department of Physiology and Pharmacology, Federal University of Pernambuco, PE Recife, Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 AD - Graduate Programme in Translational Health, Centre for Medical Sciences, Federal University of Pernambuco, Recife, PE Brazil. ROR: https://ror.org/047908t24. GRID: grid.411227.3. ISNI: 0000 0001 0670 7996 LA - eng PT - Journal Article PT - Review DEP - 20251223 PL - Switzerland TA - J Diabetes Metab Disord JT - Journal of diabetes and metabolic disorders JID - 101590741 PMC - PMC12728145 OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid OT - Bibliometric analysis OT - Insulin resistance OT - Neuroinflammation OT - Type 2 diabetes mellitus COIS- Competing interestsThe authors declare no competing interests. EDAT- 2025/12/26 07:40 MHDA- 2025/12/26 07:41 PMCR- 2026/12/23 CRDT- 2025/12/26 04:47 PHST- 2025/07/20 00:00 [received] PHST- 2025/11/24 00:00 [accepted] PHST- 2025/12/26 07:41 [medline] PHST- 2025/12/26 07:40 [pubmed] PHST- 2025/12/26 04:47 [entrez] PHST- 2026/12/23 00:00 [pmc-release] AID - 1812 [pii] AID - 10.1007/s40200-025-01812-4 [doi] PST - epublish SO - J Diabetes Metab Disord. 2025 Dec 23;25(1):12. doi: 10.1007/s40200-025-01812-4. eCollection 2026 Jun. PMID- 41445693 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251225 LR - 20251227 IS - 2045-1253 (Print) IS - 2045-1261 (Electronic) IS - 2045-1253 (Linking) VI - 15 DP - 2025 TI - Effects of glucagon-like peptide-1 receptor agonists on psychiatric disorders: a systematic review. PG - 20451253251396304 LID - 10.1177/20451253251396304 [doi] LID - 20451253251396304 AB - Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer's disease, Parkinson's disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry. CI - (c) The Author(s), 2025. FAU - Lee, Serene AU - Lee S AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. FAU - Yin, Liyang AU - Yin L AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. FAU - Teopiz, Kayla M AU - Teopiz KM AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. FAU - Wong, Sabrina AU - Wong S AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. AD - Department of Pharmacology and Toxicology, University of Toronto, ON, Canada. FAU - Han Le, Gia AU - Han Le G AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. AD - Institute of Medical Science, University of Toronto, Toronto, ON, Canada. FAU - Xiao, Naomi AU - Xiao N AD - Department of Health Sciences, Queen's University, Kingston, ON, CanadaBrain and Cognition Discovery Foundation, Toronto, ON, Canada. FAU - Stahl, Stephen AU - Stahl S AD - University of California, San Diego, San Diego, CA, USA. FAU - Valentino, Kyle AU - Valentino K AD - Brain and Cognition Discovery Foundation, Toronto, ON, Canada. AD - Department of Pharmacology and Toxicology, University of Toronto, ON, Canada. FAU - Ho, Roger AU - Ho R AD - Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore. AD - Division of Life Science (LIFS), Hong Kong University of Science and Technology (HKUST), Hong Kong. AD - Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. FAU - Zhang, Melanie C AU - Zhang MC AD - Department of Psychiatry, University of Toronto, Toronto, ON, Canada. FAU - Greg Rhee, Taeho AU - Greg Rhee T AD - Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. AD - Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA. FAU - McIntyre, Roger S AU - McIntyre RS AUID- ORCID: 0000-0003-4733-2523 AD - Department of Psychiatry, University of Toronto, ON, Canada Department of Pharmacology and Toxicology, University of Toronto, 77 Bloor Street West, Suite 617, Toronto, ON M5S 1M2, Canada. LA - eng PT - Journal Article PT - Review DEP - 20251221 PL - England TA - Ther Adv Psychopharmacol JT - Therapeutic advances in psychopharmacology JID - 101555693 PMC - PMC12722685 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - anxiety OT - depression OT - liraglutide OT - lixisenatide OT - substance use disorder COIS- Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Kayla M. Teopiz has received fees from Braxia Scientific Corp. Roger Ho has received National University of Singapore iHealthtech Other Operating Expenses (A-0001415-09-00). Dr. Taeho Greg Rhee was supported in part by the National Institute on Aging (#R21AG070666; R21AG078972; R01AG088647), National Institute of Mental Health (#R01MH131528), National Institute on Drug Abuse (#R21DA057540), and Health Resources and Services Administration (#R42MC53154-01-00). Dr. Rhee serves as a review committee member for the National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute (PCORI), and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from NIH, PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). EDAT- 2025/12/25 07:40 MHDA- 2025/12/25 07:41 PMCR- 2025/12/21 CRDT- 2025/12/25 04:50 PHST- 2025/03/30 00:00 [received] PHST- 2025/10/22 00:00 [accepted] PHST- 2025/12/25 07:41 [medline] PHST- 2025/12/25 07:40 [pubmed] PHST- 2025/12/25 04:50 [entrez] PHST- 2025/12/21 00:00 [pmc-release] AID - 10.1177_20451253251396304 [pii] AID - 10.1177/20451253251396304 [doi] PST - epublish SO - Ther Adv Psychopharmacol. 2025 Dec 21;15:20451253251396304. doi: 10.1177/20451253251396304. eCollection 2025. PMID- 41444101 OWN - NLM STAT- MEDLINE DCOM- 20260708 LR - 20260920 IS - 1471-499X (Electronic) IS - 1471-4914 (Print) IS - 1471-4914 (Linking) VI - 32 IP - 7 DP - 2026 Jul TI - GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach. PG - 711-725 LID - S1471-4914(25)00288-6 [pii] LID - 10.1016/j.molmed.2025.12.001 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer's disease (AD) and Parkinson's disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration. CI - Copyright (c) 2025 Elsevier Ltd. All rights reserved. FAU - Santiago, Jose A AU - Santiago JA AD - NeuroHub Analytics, LLC, Chicago, IL, USA; Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: jose.santiago@neurohubanalytics.com. FAU - Gutierrez-Silva, Jean C AU - Gutierrez-Silva JC AD - NeuroHub Analytics, LLC, Chicago, IL, USA. FAU - Hsu, Wei-Chuan AU - Hsu WC AD - NeuroHub Analytics, LLC, Chicago, IL, USA. FAU - Sanchez, Kameron AU - Sanchez K AD - NeuroHub Analytics, LLC, Chicago, IL, USA. FAU - Almanza, Cesar AU - Almanza C AD - NeuroHub Analytics, LLC, Chicago, IL, USA. FAU - Ramos, William AU - Ramos W AD - NeuroHub Analytics, LLC, Chicago, IL, USA. FAU - Haq, Ihtsham Ul AU - Haq IU AD - Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA. FAU - Rundek, Tatjana AU - Rundek T AD - Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA. LA - eng GR - T32 AG081170/AG/NIA NIH HHS/United States GR - T32 HL166609/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20251223 PL - England TA - Trends Mol Med JT - Trends in molecular medicine JID - 100966035 RN - 0 (Biomarkers) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Biomarkers/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Neurodegenerative Diseases/drug therapy/metabolism MH - Parkinson Disease/drug therapy/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Glucagon-Like Peptide 1/metabolism MH - Alzheimer Disease/drug therapy/metabolism MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Neuroprotective Agents/therapeutic use/pharmacology PMC - PMC13005735 MID - NIHMS2149382 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - artificial intelligence OT - biomarkers OT - diabetes OT - glucagon-like peptide-1 agonist COIS- Declaration of interests J.A.S. is the founder and principal of NeuroHub Analytics LLC and a co-inventor on United States Patent US 9,970,056 B2, Methods and Kits for Diagnosing, Prognosing, and Monitoring Parkinson's Disease. Biomarkers identified by J.A.S. are included in the study protocol for the LIXIPARK trial (NCT03439943). J.C.G, W.H, K.S, C.A, W.R, I.H, and T.R declare no competing interests. EDAT- 2025/12/25 00:29 MHDA- 2026/07/09 00:40 PMCR- 2026/03/22 CRDT- 2025/12/24 22:02 PHST- 2025/10/25 00:00 [received] PHST- 2025/12/01 00:00 [revised] PHST- 2025/12/08 00:00 [accepted] PHST- 2026/07/09 00:40 [medline] PHST- 2025/12/25 00:29 [pubmed] PHST- 2025/12/24 22:02 [entrez] PHST- 2026/03/22 00:00 [pmc-release] AID - S1471-4914(25)00288-6 [pii] AID - 10.1016/j.molmed.2025.12.001 [doi] PST - ppublish SO - Trends Mol Med. 2026 Jul;32(7):711-725. doi: 10.1016/j.molmed.2025.12.001. Epub 2025 Dec 23. PMID- 41424236 OWN - NLM STAT- MEDLINE DCOM- 20260210 LR - 20260925 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 28 IP - 3 DP - 2026 Mar TI - Association between glucagon-like peptide-1 receptor agonists and risk of dementia in older adults with type 2 diabetes: A target trial emulation. PG - 1984-1996 LID - 10.1111/dom.70384 [doi] AB - AIM: Type 2 diabetes (T2D) is associated with increased dementia risk, but comparative data across newer glucose-lowering therapies remain limited. We examined whether the initiation of GLP-1 receptor agonists (GLP-1 RAs) was associated with incident dementia compared with DPP4 inhibitors (DPP4is) and SGLT2 inhibitors (SGLT2is) in older adults with T2D. MATERIALS AND METHODS: We conducted a retrospective cohort study emulating a target trial using electronic health records from the University of Pennsylvania Health System (2019-2024), with external validation in the TriNetX U.S. Collaborative Network. Adults aged >/=50 with T2D, no prior dementia, and no GLP-1 RA, DPP4i, or SGLT2i use in the previous year were eligible. New GLP-1 RA users were propensity-score matched (1:1) to DPP4i users (n = 6677 pairs) and SGLT2i users (n = 8434 pairs). The outcome was incident dementia, defined by ICD-10-CM codes. Cox proportional hazards models estimated hazard ratios (HRs), with multiple sensitivity and subgroup analyses performed. RESULTS: Over a median follow-up of 3.0 years (GLP-1 RA vs. DPP4i) and 2.4 years (GLP-1 RA vs. SGLT2i), GLP-1 RA use was associated with a lower dementia risk versus DPP4is (109 vs. 148 events; HR 0.76, 95% CI 0.59-0.97), but a higher risk versus SGLT2is (127 vs. 64 events; HR 1.53, 95% CI 1.13-2.07). Findings were consistent across sensitivity and subgroup analyses. External validation confirmed reduced dementia risk versus DPP4is but not versus SGLT2is. CONCLUSIONS: In this large real-world cohort, GLP-1 RAs were associated with lower dementia risk than DPP4is but higher risk than SGLT2is. Prospective, biomarker-informed studies are needed to clarify mechanisms and inform treatment choices in older adults with T2D. CI - (c) 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Zhou, Ting AU - Zhou T AUID- ORCID: 0000-0003-3392-2979 AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Tang, Huilin AU - Tang H AUID- ORCID: 0000-0002-5814-6657 AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Zhang, Bingyu AU - Zhang B AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Zhang, Dazheng AU - Zhang D AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Lu, Yiwen AU - Lu Y AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Li, Lu AU - Li L AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Chen, Jiajie AU - Chen J AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Chen, Yong AU - Chen Y AUID- ORCID: 0009-0006-9094-7012 AD - Pfizer, New York City, New York, USA. FAU - Asch, David A AU - Asch DA AD - Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Division of General Internal Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Chen, Yong AU - Chen Y AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Penn Medicine Center for Evidence-Based Practice (CEP), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Penn Institute for Biomedical Informatics (IBI), University of Pennsylvania, Philadelphia, Pennsylvania, USA. LA - eng GR - R01DK128237/NH/NIH HHS/United States GR - R01AG073435/NH/NIH HHS/United States GR - R01 DK128237/DK/NIDDK NIH HHS/United States GR - R21AI167418/NH/NIH HHS/United States GR - RF1 AG077820/AG/NIA NIH HHS/United States GR - R01 LM013519/LM/NLM NIH HHS/United States GR - U24 MH136069/MH/NIMH NIH HHS/United States GR - R56AG074604/NH/NIH HHS/United States GR - RF1AG077820/NH/NIH HHS/United States GR - R01LM013519/NH/NIH HHS/United States GR - R21 AI167418/AI/NIAID NIH HHS/United States GR - R21EY034179/NH/NIH HHS/United States GR - U01 TR003709/TR/NCATS NIH HHS/United States GR - U24MH136069/NH/NIH HHS/United States GR - R56 AG074604/AG/NIA NIH HHS/United States GR - R01 AG073435/AG/NIA NIH HHS/United States GR - R21 EY034179/EY/NEI NIH HHS/United States GR - U01TR003709/NH/NIH HHS/United States PT - Journal Article DEP - 20251222 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - *Dementia/epidemiology/chemically induced MH - Female MH - Aged MH - Male MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Retrospective Studies MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Middle Aged MH - Risk Factors MH - Aged, 80 and over MH - Incidence PMC - PMC12890729 OTO - NOTNLM OT - GLP-1 analogue OT - antidiabetic drug OT - cohort study OT - elderly OT - pharmaco-epidemiology OT - real-world evidence COIS- Dr. David Asch is a partner and part-owner of VAL Health and serves on the advisory boards of Thrive Global and Morpheus. Dr. Yong Chen (University of Pennsylvania) reported receiving personal fees from Merck & Co., Inc. and Pfizer Inc. outside the submitted work. Dr. Yong Chen (Pfizer, New York City, NY, USA) is a Pfizer employee and owns Pfizer stock. No potential conflicts of interest relevant to this article were reported by Ting Zhou, Huilin Tang, Bingyu Zhang, Dazheng Zhang, Yiwen Lu, Lu Li, and Jiajie Chen. EDAT- 2025/12/22 06:29 MHDA- 2026/02/11 00:40 PMCR- 2026/02/11 CRDT- 2025/12/22 04:43 PHST- 2025/12/04 00:00 [revised] PHST- 2025/09/16 00:00 [received] PHST- 2025/12/08 00:00 [accepted] PHST- 2026/02/11 00:40 [medline] PHST- 2025/12/22 06:29 [pubmed] PHST- 2025/12/22 04:43 [entrez] PHST- 2026/02/11 00:00 [pmc-release] AID - DOM70384 [pii] AID - 10.1111/dom.70384 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Mar;28(3):1984-1996. doi: 10.1111/dom.70384. Epub 2025 Dec 22. PMID- 41420258 OWN - NLM STAT- MEDLINE DCOM- 20260626 LR - 20260626 IS - 1758-9193 (Electronic) VI - 17 IP - 1 DP - 2025 Dec 20 TI - Comparative dementia risk with GLP1 receptor agonists, SGLT2 inhibitors, or DPP4 inhibitors: a population-based cohort study. PG - 269 LID - 10.1186/s13195-025-01929-x [doi] LID - 269 AB - BACKGROUND: We aim to investigate comparative dementia risk associated with glucagon-like peptide-1 receptor agonists (GLP1-RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP4i) in adults aged >/= 60 years with type 2 diabetes. METHODS: This target trial emulation cohort study used primary care electronic health records from the UK Clinical Practice Research Datalink. Initiators of GLP1-RAs, SGLT2i, or DPP4i aged >/= 60 years with type 2 diabetes and without cognitive impairment were compared pairwise in three separate analyses. After propensity scores overlap weighting, 13,965 pairs of GLP1-RA versus DPP4i initiators (cohort entry: 2006-2022; mean age: 66.9 years), 25,533 pairs of SGLT2i versus DPP4i initiators (cohort entry: 2013-2022; mean age: 69.0 years), and 14,214 pairs of GLP1-RA versus SGLT2i initiators (cohort entry: 2013-2022; mean age: 67.9 years) were analyzed. The primary outcome was incident all-cause dementia. The primary analysis was an intention-to-treat analysis. A secondary as-treated analysis for continuous use was performed. RESULTS: In the intention-to-treat analysis, dementia risk was not different between GLP1-RA and DPP4i initiators (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.87-1.04; rates: 6.29 versus 6.64 per 1000 person-years; mean follow-up: 6.54 years); however, continuous GLP1-RA versus DPP4i use was associated with a 21% lower risk (HR 0.79, 95% CI 0.64-0.97; rates: 3.64 versus 4.82; mean follow-up: 2.71 years). SGLT2i versus DPP4i initiation was associated with a 14% lower dementia risk in the intention-to-treat analysis (HR 0.86, 95% CI 0.79-0.94; rates: 4.83 versus 5.60; mean follow-up: 4.91 years), and the as-treated analysis showed greater risk reduction (HR 0.70, 95% CI 0.60-0.82; rates: 3.82 versus 5.46; mean follow-up: 2.43 years). Dementia risk was comparable between GLP1-RA versus SGLT2i in both intention-to-treat (HR 0.98, 95% CI 0.87-1.11; rates: 4.85 versus 4.95; mean follow-up: 5.09 years) and as-treated (HR 1.07, 95% CI 0.85-1.36; rates: 3.71 versus 3.56; mean follow-up: 2.40 years) analyses. CONCLUSIONS: In people with type 2 diabetes aged >/= 60 years, SGLT2i are associated with reduced dementia risk, but dementia risk reduction associated with the GLP1-RAs studied is less certain. FAU - Wu, Che-Yuan AU - Wu CY AD - Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. AD - Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. FAU - Alkabbani, Wajd AU - Alkabbani W AD - School of Pharmacy, University of Waterloo, Kitchener, ON, Canada. FAU - Shah, Baiju R AU - Shah BR AD - Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. AD - Department of Medicine, University of Toronto, Toronto, ON, Canada. AD - ICES, Toronto, ON, Canada. FAU - Kapral, Moira K AU - Kapral MK AD - ICES, Toronto, ON, Canada. AD - Division of General Internal Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada. AD - Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada. FAU - Edwards, Jodi D AU - Edwards JD AD - School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada. AD - ICES uOttawa, Ottawa, ON, Canada. FAU - Maxwell, Colleen J AU - Maxwell CJ AD - School of Pharmacy, University of Waterloo, Kitchener, ON, Canada. AD - ICES, Toronto, ON, Canada. AD - School of Public Health Sciences, University of Waterloo, Waterloo, ON, Canada. FAU - Swardfager, Walter AU - Swardfager W AD - Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. w.swardfager@utoronto.ca. AD - Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. w.swardfager@utoronto.ca. AD - KITE University Health Network Toronto Rehabilitation Institute, Toronto, ON, Canada. w.swardfager@utoronto.ca. LA - eng GR - 202111FBD-47623-75801/CAPMC/CIHR/Canada GR - GC-202209-2024050/Alzheimer's Drug Discovery Foundation/ GR - CRC-2024-00213/Canada Excellence Research Chairs, Government of Canada/ GR - ER21-16-146/Ministry of Colleges and Universities/ PT - Comparative Study PT - Journal Article DEP - 20251220 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects/therapeutic use MH - *Dementia/epidemiology/chemically induced MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Sodium-Glucose Transporter 2 Inhibitors/adverse effects/therapeutic use MH - Male MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - Aged MH - Female MH - Cohort Studies MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Middle Aged MH - United Kingdom/epidemiology PMC - PMC12751920 OTO - NOTNLM OT - 1 (GLP1) receptor agonist, Dipeptidyl peptidase OT - 2 (SGLT2) inhibitor, Glucagon OT - 4 (DPP4) inhibitors, Diabetes, Dementia OT - Glucose cotransporter OT - Like peptide OT - Sodium COIS- Declarations. Ethics approval and consent for publication: The present study was approved by the CPRD Research Data Governance (#23_002545), the Research Ethics Board of Sunnybrook Health Sciences Centre (PIN: 6013), and the Research Ethics Board of University of Toronto (#46463). Competing interests: The authors declare no competing interests. EDAT- 2025/12/20 06:31 MHDA- 2026/06/27 00:55 PMCR- 2025/12/20 CRDT- 2025/12/20 00:18 PHST- 2025/08/18 00:00 [received] PHST- 2025/12/03 00:00 [accepted] PHST- 2026/06/27 00:55 [medline] PHST- 2025/12/20 06:31 [pubmed] PHST- 2025/12/20 00:18 [entrez] PHST- 2025/12/20 00:00 [pmc-release] AID - 10.1186/s13195-025-01929-x [pii] AID - 1929 [pii] AID - 10.1186/s13195-025-01929-x [doi] PST - epublish SO - Alzheimers Res Ther. 2025 Dec 20;17(1):269. doi: 10.1186/s13195-025-01929-x. PMID- 41419667 OWN - NLM STAT- MEDLINE DCOM- 20260122 LR - 20260902 IS - 2662-8465 (Electronic) IS - 2662-8465 (Linking) VI - 6 IP - 1 DP - 2026 Jan TI - Repurposing glucagon-like peptide-1 receptor agonists for the treatment of neurodegenerative disorders. PG - 56-67 LID - 10.1038/s43587-025-01029-3 [doi] AB - With therapeutic progress in Alzheimer's disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD. CI - (c) 2025. Springer Nature America, Inc. FAU - Sabbagh, Marwan N AU - Sabbagh MN AUID- ORCID: 0000-0001-8139-3309 AD - Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA. marwan.sabbagh@barrowneuro.org. FAU - Cummings, Jeffrey L AU - Cummings JL AUID- ORCID: 0000-0001-8944-4158 AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, USA. FAU - Ballard, Clive AU - Ballard C AUID- ORCID: 0000-0003-0022-5632 AD - Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK. FAU - van der Flier, Wiesje M AU - van der Flier WM AUID- ORCID: 0000-0001-8766-6224 AD - Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, Netherlands. AD - Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands. AD - Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, Netherlands. FAU - Heneka, Michael T AU - Heneka MT AUID- ORCID: 0000-0003-4996-1630 AD - Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. FAU - Holst, Jens Juul AU - Holst JJ AD - Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Knudsen, Lotte Bjerre AU - Knudsen LB AD - Chief Scientific Advisor Office, Novo Nordisk A/S, Malov, Denmark. FAU - Salloway, Stephen AU - Salloway S AD - Warren Alpert Medical School, Brown University, Providence, RI, USA. FAU - Tansey, Malu Gamez AU - Tansey MG AUID- ORCID: 0000-0002-1719-4708 AD - Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Drucker, Daniel J AU - Drucker DJ AUID- ORCID: 0000-0001-6688-8127 AD - Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. LA - eng GR - R01 AG059008/AG/NIA NIH HHS/United States GR - R35 AG071476/AG/NIA NIH HHS/United States GR - R25 AG083721/AG/NIA NIH HHS/United States GR - P30 AG072980/AG/NIA NIH HHS/United States GR - R01 NS139383/NS/NINDS NIH HHS/United States GR - P20 GM109025/GM/NIGMS NIH HHS/United States GR - RF1 NS128800/NS/NINDS NIH HHS/United States GR - R01 AG073212/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20251219 PL - United States TA - Nat Aging JT - Nature aging JID - 101773306 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Neurodegenerative Diseases/drug therapy MH - *Alzheimer Disease/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy MH - *Drug Repositioning MH - Animals MH - Cognitive Dysfunction/drug therapy PMC - PMC13528608 MID - NIHMS2134733 COIS- Competing interests: M.N.S. discloses ownership interest (stock or stock options) in Lighthouse Pharmaceuticals; he consults for Eisai, Lilly, NeuroTherapia, Signant Health, Novo Nordisk, Anavex Life Sciences, Alzheon, Cognito Therapeutics, GSK and AbbVie. M.N.S. is supported by the National Institutes of Health grants R01AG059008, R01AG073212 and P30AG072980, as well as by the Barrow Neurological Foundation. J.L.C. has provided consultation to Acadia Pharmaceuticals, Acumen Pharmaceuticals, ALZpath, Annovis, Aprinoia Therapeutics, Artery Therapeutics, Biogen, Biohaven, BioXcel, Bristol Myers Squibb, Eisai, Fosun, GAP Foundation, Green Valley, Janssen, Karuna, Kinoxis Therapeutics, Lighthouse Pharmaceuticals, Lilly, Lundbeck, LSP/EQT Life Sciences, Mangrove Therapeutics, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, OptoCeutics, Otsuka, Oxford Brain Diagnostics, Praxis, Prothena, reMYND, Roche, Scottish Brain Sciences, Signant Health, Simcere, Sinaptica, T-Neuro, TrueBinding and Vaxxinity pharmaceutical, assessment and investment companies. J.L.C. is supported by the National Institute of General Medical Sciences (NIGMS) grant P20GM109025, National Institute on Aging (NIA) grants R35AG71476 and R25AG083721-01, National Institute of Neurological Disorders and Stroke (NINDS) grant RO1NS139383, the Alzheimer's Drug Discovery Foundation (ADDF), Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment. C.B. has received contract grant funding from Acadia Pharmaceuticals, Lundbeck, Takeda and Axovant pharmaceutical companies, as well as honoraria from Lundbeck, Lilly, Otsuka and Orion pharmaceutical companies. W.M.v.d.F. declares having research programs that have been funded by ZonMw, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland (Topsector Life Sciences & Health), Stichting Dioraphte, Gieskes-Strijbis Fonds, Stichting Equilibrio, Edwin Bouw Fonds, Pasman Stichting, Stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc., Novartis-NL, Life-MI, AVID, Roche BV, Eli Lilly-NL, Fujifilm, Eisai and Combinostics. W.M.v.d.F. holds the Pasman chair. W.M.v.d.F. is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMw (#73305095007) and Health~Holland (Topsector Life Sciences & Health) (public-private partnership allowance; #LSHM20106). W.M.v.d.F. is a recipient of TAP-dementia ( www.tap-dementia.nl ), which receives funding from ZonMw (#10510032120003). TAP-dementia receives cofinancing from Avid Radiopharmaceuticals and Amprion. All funding is paid to her institution. W.M.v.d.F. has been an invited speaker at Biogen MA Inc., Danone, Eisai, WebMD Neurology (Medscape), Novo Nordisk, Springer Healthcare and European Brain Council. All funding is paid to her institution. W.M.v.d.F. is a consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc. and Eisai. All funding is paid to her institution. W.M.v.d.F. participated in the advisory boards of Biogen MA Inc., Roche and Eli Lilly. W.M.v.d.F. is a member of the steering committee of evoke/evoke+ (Novo Nordisk). All funding is paid to her institution. W.M.v.d.F. is a member of the steering committee of PAVE and Think Brain Health. W.M.v.d.F. was an associate editor of Alzheimer's Research & Therapy in 2020/2021 and is an associate editor at Brain. M.T.H. serves on the science advisory board of the UK Dementia Research Institute at Imperial College London, Life and Health Sciences Research Institute of the University of Minho School of Medicine, the Lyon Neuroscience Research Center, Alector, Muna Therapeutics and T3D Therapeutics. He has received speaking honoraria from Novo Nordisk, Novartis, Biogen and Eli Lilly. J.J.H. consults for Novo Nordisk and is the founder of Antag Pharmaceuticals. L.B.K. is an employee and a minor employee related shareholder of Novo Nordisk A/S. L.B.K. is an inventor on several patents related to GLP-1-based medicines and various uses of them. S.S. has provided consultation to Eisai, Biogen, Lilly, Roche, Genentech, Bolden, Novo Nordisk, Prothena, Acumen Pharmaceuticals, Labcorp, Alector, Corium, Kisbee, Neurophet, Icometrix and AbbVie. S.S. receives research support for clinical trials from Janssen, Lilly, Eisai, Genentech, Roche and Biogen. S.S. is an associate editor of the Journal of Prevention of Alzheimer's Disease and Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. M.G.T. is supported by NINDS grant RF1NS128800, the Michael J. Fox Foundation for Parkinson's Research and the Parkinson's Foundation. She has provided consultation to INmune Bio, Merck, Calico, Forward Therapeutics, Jaya, SciNeuro, NysnoBio, Longevity Biotech, Sanofi, iMetabolic Pharma, Novo Nordisk and iMMvention. She serves on advisory boards for the Weston Family Foundation, the Medical and Scientific Advisory Group of the Alzheimer's Association, Longeveron and the Parkinson's Foundation. D.J.D. has been a supported speaker or consultant for AstraZeneca, Boehringer Ingelheim, Kallyope, Merck, Novo Nordisk and Pfizer, as well as receives grant support for preclinical studies from Amgen, Zealand Pharma and Eli Lilly. EDAT- 2025/12/20 00:41 MHDA- 2026/01/22 07:43 PMCR- 2026/08/31 CRDT- 2025/12/19 23:33 PHST- 2025/03/25 00:00 [received] PHST- 2025/10/31 00:00 [accepted] PHST- 2026/01/22 07:43 [medline] PHST- 2025/12/20 00:41 [pubmed] PHST- 2025/12/19 23:33 [entrez] PHST- 2026/08/31 00:00 [pmc-release] AID - 10.1038/s43587-025-01029-3 [pii] AID - 10.1038/s43587-025-01029-3 [doi] PST - ppublish SO - Nat Aging. 2026 Jan;6(1):56-67. doi: 10.1038/s43587-025-01029-3. Epub 2025 Dec 19. PMID- 41417476 OWN - NLM STAT- MEDLINE DCOM- 20260210 LR - 20260808 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 28 IP - 3 DP - 2026 Mar TI - Beyond diabetes and obesity: GLP-1 receptor agonists in disrupting the vicious cycle of metabolic dysfunction and neuroinflammation. PG - 1622-1637 LID - 10.1111/dom.70400 [doi] AB - Neurodegenerative diseases, including debilitating conditions like Alzheimer's and Parkinson's, are characterized by progressive neuronal loss, a process fundamentally driven by persistent chronic neuroinflammation and central metabolic dysfunction. In these disorders, persistent danger signals, such as the aggregation of misfolded proteins, activate resident microglial cells, leading to a functional shift toward a detrimental, pro-inflammatory phenotype. This damaging cycle is critically exacerbated by impaired Insulin/Insulin-like Growth Factor 1 signalling, which compromises neuronal mitochondrial homeostasis, decreases energy production, and severely diminishes synaptic plasticity, thereby establishing a self-perpetuating cycle of metabolic disturbance and neuroinflammation. This review examines the burgeoning therapeutic potential of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), a class of drugs traditionally used to manage type 2 diabetes mellitus and obesity, as neuroprotective agents. We discuss mechanistic insights demonstrating how GLP-1RAs operate through a crucial dual action: effectively mitigating central insulin resistance and directly suppressing the multi-faceted neuroinflammatory cascade. By activating specific neuronal and glial signalling pathways, GLP-1RAs are shown to restore mitochondrial function, increase neuronal resilience, and crucially, modulate adverse glial cell responses-inhibiting the release of major pro-inflammatory cytokines and significantly reducing cellular oxidative stress within the central nervous system. Clinical trials and comprehensive preclinical data, analysed through diverse experimental models of neurodegeneration, strongly support the translational potential relevance of these compounds. The accumulating evidence suggests that GLP-1RAs offer a promising, readily available therapeutic strategy to disrupt the core inflammatory and metabolic pathways common across many neurodegenerative conditions, warranting further investigation in large-scale human trials. CI - (c) 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Spezani, Renata AU - Spezani R AUID- ORCID: 0000-0002-6144-8525 AD - Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Institute of Biology, Biomedical Center, The University of the State of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Mandarim-de-Lacerda, Carlos A AU - Mandarim-de-Lacerda CA AUID- ORCID: 0000-0003-4134-7978 AD - Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Institute of Biology, Biomedical Center, The University of the State of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil. LA - eng GR - E-26/203.981/2024/Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro/ GR - 305993/2021-6/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ PT - Journal Article PT - Review DEP - 20251219 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Neuroinflammatory Diseases/drug therapy/metabolism MH - *Obesity/drug therapy/metabolism/complications MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism/complications MH - *Neurodegenerative Diseases/drug therapy/metabolism MH - Insulin Resistance MH - *Neuroprotective Agents/therapeutic use/pharmacology MH - *Metabolic Diseases/drug therapy MH - Signal Transduction/drug effects PMC - PMC12890747 OTO - NOTNLM OT - insulin resistance OT - metabolic dysfunction OT - microglia/glial modulation OT - neurodegenerative diseases OT - synaptic resilience COIS- The authors declare no conflicts of interest. EDAT- 2025/12/19 18:33 MHDA- 2026/02/11 00:40 PMCR- 2026/02/11 CRDT- 2025/12/19 12:13 PHST- 2025/12/10 00:00 [revised] PHST- 2025/10/27 00:00 [received] PHST- 2025/12/13 00:00 [accepted] PHST- 2026/02/11 00:40 [medline] PHST- 2025/12/19 18:33 [pubmed] PHST- 2025/12/19 12:13 [entrez] PHST- 2026/02/11 00:00 [pmc-release] AID - DOM70400 [pii] AID - 10.1111/dom.70400 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Mar;28(3):1622-1637. doi: 10.1111/dom.70400. Epub 2025 Dec 19. PMID- 41406951 OWN - NLM STAT- MEDLINE DCOM- 20251217 LR - 20260108 IS - 2666-3791 (Electronic) IS - 2666-3791 (Linking) VI - 6 IP - 12 DP - 2025 Dec 16 TI - Glucagon-like peptide-1 medicines in neurological and psychiatric disorders. PG - 102511 LID - S2666-3791(25)00584-1 [pii] LID - 10.1016/j.xcrm.2025.102511 [doi] LID - 102511 AB - Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce rates of smoking, or use of alcohol, tobacco, cannabis, or cocaine in individuals with substance use disorders. More limited clinical data suggest utility for GLP-1 medicines in patients with migraine or intracranial hypertension. The available data suggest that the use of GLP-1 medicines exhibits an acceptable safety profile in most individuals with neuropsychiatric disorders. Here, we review recent clinical evidence and ongoing trials exploring the efficacy and safety of GLP-1 medicines across a broad range of neurological conditions. CI - Copyright (c) 2025 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Fang, Susanna AU - Fang S AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. FAU - Cui, Fiona AU - Cui F AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. FAU - Drucker, Daniel J AU - Drucker DJ AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G1X5, Canada. Electronic address: drucker@lunenfeld.ca. LA - eng PT - Journal Article PT - Review PL - United States TA - Cell Rep Med JT - Cell reports. Medicine JID - 101766894 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/therapeutic use/metabolism MH - *Mental Disorders/drug therapy MH - *Nervous System Diseases/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy PMC - PMC12765848 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - addiction OT - headache OT - intracranial hypertension OT - substance use disorders COIS- Declaration of interests D.J.D. has received consulting fees from Amgen, AstraZeneca Inc., Alnylam, Crinetics Eli Lilly Inc., Insulet, Kallyope, Metsera. Pfizer Inc. and Sanofi Inc. and speaking fees from Novo Nordisk Inc. Mt. Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc., and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker lab. EDAT- 2025/12/18 01:31 MHDA- 2025/12/18 01:32 PMCR- 2025/12/16 CRDT- 2025/12/17 18:16 PHST- 2025/08/26 00:00 [received] PHST- 2025/10/17 00:00 [revised] PHST- 2025/11/17 00:00 [accepted] PHST- 2025/12/18 01:32 [medline] PHST- 2025/12/18 01:31 [pubmed] PHST- 2025/12/17 18:16 [entrez] PHST- 2025/12/16 00:00 [pmc-release] AID - S2666-3791(25)00584-1 [pii] AID - 102511 [pii] AID - 10.1016/j.xcrm.2025.102511 [doi] PST - ppublish SO - Cell Rep Med. 2025 Dec 16;6(12):102511. doi: 10.1016/j.xcrm.2025.102511. PMID- 41394161 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251215 LR - 20251217 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 16 DP - 2025 TI - Association between ranolazine therapy and cognitive decline in elderly patients with ischemic heart disease. PG - 1664988 LID - 10.3389/fphar.2025.1664988 [doi] LID - 1664988 AB - INTRODUCTION: Ischemic Heart Disease (IHD) represents one of the major causes of mortality and morbidity in the geriatric population This clinical complexity of these patients substantially impacts their quality of life and is associated with an increased risk of cognitive impairment (CoI). Ranolazine, plays a pivotal role in managing anginal symptoms and improving exercise tolerance. OBJECTIVE: To investigate the potential protective effect of Ranolazine on CoI over time in elderly patients with IHD and multiple comorbidities. METHODS: We performed a single-center, prospective, observational cohort study. The primary endpoint was a reduction in MMSE score >/=3 points during follow-up compared to baseline values. RESULTS: 519 patients with a mean age of 74.2 +/- 6.8 years were enrolled and divided into two groups based on Ranolazine use. The groups demonstrated comparable distribution by sex; however, Ranolazine group, although younger, displayed increased severity of anginal symptoms (Canadian Angina Scale 2.6 vs. 2.3; p < 0.0001), higher prevalence of previous acute coronary syndrome (p < 0.046), sarcopenia (p < 0.0001), and type 2 diabetes mellitus (p < 0.040). During a 4-year follow-up, 186 cases of CoI were observed (8.9 events/100 patient-years) in the general population. The incidence of CoI was significantly lower in the Ranolazine group compared to the control group (5.7 vs. 10.3 events/100 patient-years; p < 0.001). Multivariate analysis revealed a statistically significant association between CoI and the use of Ranolazine, GLP-1RAs, and SGLT2i. Specifically, Ranolazine use was associated with a 61% odds reduction in CoI. CONCLUSION: The use of Ranolazine is associated with a significant odds reduction in CoI in elderly patients with IHD and multiple comorbidities. The neuroprotective effect of Ranolazine may be attributed to the improvement of anginal symptoms and consequent optimization of functional status and quality of life, advocating for a comprehensive therapeutic strategy in geriatric patient management. CI - Copyright (c) 2025 Severini, Armentaro, Cassano, Condoleo, Pastura, Panza, Fuoco, Miceli, Fiorentino, Perticone, Maio, Succurro, Andreozzi, Sesti and Sciacqua. FAU - Severini, Giandomenico AU - Severini G AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. FAU - Armentaro, Giuseppe AU - Armentaro G AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. FAU - Cassano, Velia AU - Cassano V AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Condoleo, Valentino AU - Condoleo V AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. FAU - Pastura, Carlo Alberto AU - Pastura CA AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Panza, Alberto AU - Panza A AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Fuoco, Carlo AU - Fuoco C AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Miceli, Sofia AU - Miceli S AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. FAU - Fiorentino, Vanessa Teresa AU - Fiorentino VT AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Perticone, Maria AU - Perticone M AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Maio, Raffaele AU - Maio R AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. FAU - Succurro, Elena AU - Succurro E AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR-METDIS), University Magna Graecia, Catanzaro, Italy. FAU - Andreozzi, Francesco AU - Andreozzi F AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR-METDIS), University Magna Graecia, Catanzaro, Italy. FAU - Sesti, Giorgio AU - Sesti G AD - Department of Clinical and Molecular Medicine, University Rome-Sapienza, Rome, Italy. FAU - Sciacqua, Angela AU - Sciacqua A AD - Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro, Catanzaro, Italy. AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR-METDIS), University Magna Graecia, Catanzaro, Italy. LA - eng PT - Journal Article DEP - 20251128 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC12698426 OTO - NOTNLM OT - cognitive impairment OT - comprehensive geriatric assessment OT - elderly OT - ischemic heart disease OT - ranolazine COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2025/12/15 13:10 MHDA- 2025/12/15 13:11 PMCR- 2025/11/28 CRDT- 2025/12/15 06:16 PHST- 2025/07/13 00:00 [received] PHST- 2025/10/22 00:00 [revised] PHST- 2025/11/10 00:00 [accepted] PHST- 2025/12/15 13:11 [medline] PHST- 2025/12/15 13:10 [pubmed] PHST- 2025/12/15 06:16 [entrez] PHST- 2025/11/28 00:00 [pmc-release] AID - 1664988 [pii] AID - 10.3389/fphar.2025.1664988 [doi] PST - epublish SO - Front Pharmacol. 2025 Nov 28;16:1664988. doi: 10.3389/fphar.2025.1664988. eCollection 2025. PMID- 41383947 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251212 LR - 20260925 IS - 2770-730X (Electronic) IS - 2770-7296 (Print) IS - 2770-7296 (Linking) VI - 3 IP - 2 DP - 2025 Jun TI - Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease. PG - 145-164 LID - 10.1002/nep3.70008 [doi] AB - The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population. CI - (c) 2025 The Author(s). Neuroprotection published by John Wiley & Sons, Ltd on behalf of Chinese Medical Association. FAU - Schwartz, Stanley S AU - Schwartz SS AD - University of Pennsylvania Philadelphia Pennsylvania USA. FAU - Rhea, Elizabeth M AU - Rhea EM AD - Geriatric Research Education and Clinical Center Veterans Affairs Puget Sound Health Care System Seattle Washington USA. AD - Division of Gerontology and Geriatric Medicine, Department of Medicine University of Washington School of Medicine Seattle Washington USA. FAU - Banks, William A AU - Banks WA AD - Geriatric Research Education and Clinical Center Veterans Affairs Puget Sound Health Care System Seattle Washington USA. AD - Division of Gerontology and Geriatric Medicine, Department of Medicine University of Washington School of Medicine Seattle Washington USA. FAU - Herman, Mary E AU - Herman ME AUID- ORCID: 0000-0002-8146-7352 AD - Independent Health Researcher and Educator: Building Global Research Competency Antigua Guatemala. LA - eng PT - Journal Article PT - Review DEP - 20250609 PL - England TA - Neuroprotection JT - Neuroprotection (Chichester, England) JID - 9918452086806676 PMC - PMC12486931 OTO - NOTNLM OT - Alzheimer's disease OT - T2D OT - cognition OT - complication-centric prescribing OT - insulin resistance COIS- The authors declare no conflicts of interest. EDAT- 2025/12/12 07:20 MHDA- 2025/12/12 07:21 PMCR- 2025/06/09 CRDT- 2025/12/12 04:34 PHST- 2024/09/02 00:00 [received] PHST- 2025/01/10 00:00 [revised] PHST- 2025/01/14 00:00 [accepted] PHST- 2025/12/12 07:21 [medline] PHST- 2025/12/12 07:20 [pubmed] PHST- 2025/12/12 04:34 [entrez] PHST- 2025/06/09 00:00 [pmc-release] AID - NEP370008 [pii] AID - 10.1002/nep3.70008 [doi] PST - epublish SO - Neuroprotection. 2025 Jun 9;3(2):145-164. doi: 10.1002/nep3.70008. eCollection 2025 Jun. PMID- 41359407 OWN - NLM STAT- MEDLINE DCOM- 20260402 LR - 20260402 IS - 1758-1095 (Electronic) IS - 0141-0768 (Print) IS - 0141-0768 (Linking) VI - 119 IP - 2 DP - 2026 Feb TI - The concentration-dependent protective effects by new generation hypoglycemic agents on delirium, depression, dementia and coma: evidence from a network meta-analysis. PG - 46-54 LID - 10.1177/01410768251395877 [doi] AB - OBJECTIVES: Emerging evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors may exert neuroprotective effects. However, the comparative efficacy of individual agents remains unclear. This network meta-analysis (NMA) aimed to evaluate the differential impacts of these therapies on the incidence of mental status changes, specifically delirium, depression, dementia and coma. DESIGN: A frequentist NMA was conducted using data from randomised controlled trials (RCTs) investigating GLP-1 receptor agonists or SGLT2 inhibitors. The robustness of the findings was verified through a Bayesian NMA framework. SETTING: This study adopted a confirmatory framework focusing on pre-defined neuropsychiatric adverse outcomes in alignment with Cochrane recommendations. PARTICIPANTS: Included trials enrolled individuals without baseline cognitive or psychiatric disorders. MAIN OUTCOME MEASURES: The primary endpoint was the incidence of delirium, depression, dementia or coma during treatment. Secondary endpoints included changes in cognitive performance and drop-out rates. RESULTS: A total of 62 RCTs comprising 200,068 participants were included. Among all treatments, only high-dose dapagliflozin (10 mg/day) significantly reduced the occurrence of delirium and depression, particularly in patients with type 2 diabetes. Dulaglutide and liraglutide were the only agents associated with cognitive improvement. No significant benefits were observed for dementia or coma across all agents. CONCLUSIONS: This analysis highlights agent-specific neuroprotective profiles: SGLT2 inhibitors, especially high-dose dapagliflozin, may mitigate the onset of delirium and depression, while GLP-1 receptor agonists, notably dulaglutide and liraglutide, may enhance cognitive function. These findings warrant consideration in selecting antihyperglycemic therapies for individuals at elevated neuropsychiatric risk. TRIAL REGISTRATION: PROSPERO CRD42024601021.The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007). FAU - Tseng, Ping-Tao AU - Tseng PT AUID- ORCID: 0000-0001-5761-7800 AD - Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804, Taiwan. AD - Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan. AD - Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan. AD - Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan. FAU - Zeng, Bing-Yan AU - Zeng BY AD - Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan. AD - Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung 807, Taiwan. FAU - Hsu, Chih-Wei AU - Hsu CW AUID- ORCID: 0000-0002-8650-4060 AD - Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. FAU - Suen, Mein-Woei AU - Suen MW AD - Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan. AD - Gender Equality Education and Research Center, Asia University, Taichung 413, Taiwan. AD - Department of Medical Research, Asia University Hospital, Asia University, Taichung 413, Taiwan. AD - Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan. FAU - Hung, Chao-Ming AU - Hung CM AD - Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan. AD - School of Medicine, College of Medicine, I-Shou University, Kaohsiung 840, Taiwan. FAU - Carvalho, Andre F AU - Carvalho AF AD - Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia. FAU - Stubbs, Brendon AU - Stubbs B AD - Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London WC2R 2LS, UK. AD - Department of Sport, University of Vienna, Vienna 1010, Austria. FAU - Chen, Yen-Wen AU - Chen YW AD - Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan. FAU - Chen, Tien-Yu AU - Chen TY AD - Department of Psychiatry, Tri-Service General Hospital, National Defense Medical University, Taipei 114, Taiwan. AD - Department of Psychiatry, College of Medicine, National Defense Medical University, Taipei 114, Taiwan. FAU - Lei, Wei-Te AU - Lei WT AD - Division of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, Hsinchu Municipal MacKay Children's Hospital, Hsinchu 300, Taiwan. AD - Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan. FAU - Lin, Pao-Yen AU - Lin PY AD - Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. AD - Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. FAU - Chen, Jiann-Jy AU - Chen JJ AD - Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan. AD - Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan. FAU - Su, Kuan-Pin AU - Su KP AUID- ORCID: 0000-0002-4501-2502 AD - Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London WC2R 2LS, UK. AD - Office of Research and Development, Asia University, Taichung 404, Taiwan. AD - College of Medicine, China Medical University, Taichung 404, Taiwan. AD - An-Nan Hospital, China Medical University, Tainan 709, Taiwan. FAU - Wang, Hung-Yu AU - Wang HY AD - Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City 802, Taiwan. FAU - Zeng, Bing-Syuan AU - Zeng BS AD - Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan. FAU - Shiue, Yow-Ling AU - Shiue YL AD - Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804, Taiwan. AD - Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan. FAU - Liang, Chih-Sung AU - Liang CS AUID- ORCID: 0000-0003-1138-5586 AD - Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical University, Taipei 114, Taiwan. AD - Department of Psychiatry, National Defense Medical University, Taipei 114, Taiwan. LA - eng PT - Journal Article PT - Meta-Analysis DEP - 20251208 PL - England TA - J R Soc Med JT - Journal of the Royal Society of Medicine JID - 7802879 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Dementia/prevention & control MH - *Delirium/prevention & control MH - *Hypoglycemic Agents/therapeutic use/administration & dosage MH - *Coma/prevention & control MH - *Depression/prevention & control MH - Network Meta-Analysis as Topic MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/administration & dosage MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Randomized Controlled Trials as Topic MH - *Diabetes Mellitus, Type 2/drug therapy MH - Dose-Response Relationship, Drug MH - *Neuroprotective Agents/therapeutic use PMC - PMC12685696 OTO - NOTNLM OT - GLP-1 receptor agonist OT - Network meta-analysis OT - SGLT2 inhibitor OT - delirium OT - depression OT - mental status COIS- The authors report no financial interests or potential conflicts of interest. EDAT- 2025/12/08 19:23 MHDA- 2026/04/02 12:37 PMCR- 2025/12/08 CRDT- 2025/12/08 12:23 PHST- 2026/04/02 12:37 [medline] PHST- 2025/12/08 19:23 [pubmed] PHST- 2025/12/08 12:23 [entrez] PHST- 2025/12/08 00:00 [pmc-release] AID - 10.1177_01410768251395877 [pii] AID - 10.1177/01410768251395877 [doi] PST - ppublish SO - J R Soc Med. 2026 Feb;119(2):46-54. doi: 10.1177/01410768251395877. Epub 2025 Dec 8. PMID- 41356006 OWN - NLM STAT- MEDLINE DCOM- 20251208 LR - 20251210 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 16 DP - 2025 TI - GLP-1 receptor agonists in Alzheimer's and Parkinson's disease: endocrine pathways, clinical evidence, and future directions. PG - 1708565 LID - 10.3389/fendo.2025.1708565 [doi] LID - 1708565 AB - Initially developed for type 2 diabetes and obesity, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now emerging as promising candidates for modifying the course of neurodegenerative diseases. This potential stems from the presence of GLP-1 and its receptors within the central nervous system (CNS), where their signaling activity influences critical processes like synaptic plasticity, neuroinflammation, insulin signaling, and cellular energy management. In fact, preclinical models of both Alzheimer's disease (AD) and Parkinson's disease (PD) have shown that GLP-1RAs can reduce neuroinflammation, improve mitochondrial function, and enhance the clearance of toxic proteins (proteostasis), leading to benefits in cognition and the survival of dopaminergic neurons. Yet, when tested in humans, the picture has been more nuanced and less straightforward. Early clinical trials in AD have produced mixed cognitive signals, though they have shown intriguing biological effects, such as preserved cerebral glucose metabolism with liraglutide on FDG-PET scans. In contrast, the evidence in PD has been more consistent, with agents like exenatide and lixisenatide demonstrating motor benefits, although one trial with a pegylated exendin (NLY01) did not meet its primary endpoint. The definitive test will come from large, ongoing phase 3 programs, such as the EVOKE and EVOKE+ trials for semaglutide. Should these trials are successful, GLP-1RAs could become a cornerstone of earlier, mechanism-based intervention strategies for neurodegenerative diseases. CI - Copyright (c) 2025 Gandhi and Parhizgar. FAU - Gandhi, Ayush AU - Gandhi A AD - Department of Hospital Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Parhizgar, Alireza AU - Parhizgar A AD - Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States. LA - eng PT - Journal Article PT - Review DEP - 20251120 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/metabolism MH - *Parkinson Disease/drug therapy/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - Signal Transduction/drug effects PMC - PMC12675206 OTO - NOTNLM OT - Alzheimer OT - GLP - 1 OT - Parkinson OT - insulin resistance OT - neurodegenerative disease COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/12/08 13:19 MHDA- 2025/12/08 13:20 PMCR- 2025/11/20 CRDT- 2025/12/08 06:06 PHST- 2025/09/18 00:00 [received] PHST- 2025/11/04 00:00 [accepted] PHST- 2025/12/08 13:20 [medline] PHST- 2025/12/08 13:19 [pubmed] PHST- 2025/12/08 06:06 [entrez] PHST- 2025/11/20 00:00 [pmc-release] AID - 10.3389/fendo.2025.1708565 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2025 Nov 20;16:1708565. doi: 10.3389/fendo.2025.1708565. eCollection 2025. PMID- 41349262 OWN - NLM STAT- MEDLINE DCOM- 20260202 LR - 20260322 IS - 1758-535X (Electronic) IS - 1079-5006 (Linking) VI - 81 IP - 2 DP - 2026 Jan 12 TI - Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5 x FAD mice. LID - glaf265 [pii] LID - 10.1093/gerona/glaf265 [doi] AB - BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory decline. The increasing prevalence of AD has attracted considerable attention globally. The glucagon-like peptide-1 analog, liraglutide, a drug widely used in the treatment of type 2 diabetes, has shown promising neuroprotective effects in AD, including enhancing neuronal survival, reducing amyloid beta protein accumulation, improving synaptic plasticity, and reducing tau protein hyperphosphorylation. However, its potential impact on cognitive function remains unclear. METHODS: We evaluated the effects of liraglutide (25 nmol/day for 8 weeks) on the cognitive ability of 12-month-old 5 x familial AD (FAD) mice. The Morris water maze test was used to evaluate the spatial learning ability of mice. Histological evaluations were performed by Nissl staining and transmission electron microscopy. Neuroinflammation was detected by double immunofluorescence staining and enzyme-linked immunosorbent assay. Protein expression in the cortex and hippocampus was detected by immunohistochemistry and Western blotting. RESULTS: The spatial cognitive ability improved in 5 x FAD mice after liraglutide administration and was associated with an increased number of pyramidal cells in the cortex and hippocampus. Liraglutide also alleviated ultrastructural changes in the chemical synapses and reduced both local and systemic inflammation in AD mice. Furthermore, liraglutide reduced amyloid beta protein expression, which may be associated with the regulation of nuclear factor kappa B/beta-secretase 1 pathways in AD mice. CONCLUSIONS: The potential of liraglutide to improve cognitive function in AD mice offers an effective pharmacological approach for treating neurodegenerative diseases. CI - (c) The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. FAU - Qi, Liqin AU - Qi L AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. FAU - Lin, Lijing AU - Lin L AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. FAU - Zheng, Jiaping AU - Zheng J AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. FAU - Liu, Xiaoying AU - Liu X AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. FAU - Liu, Xiaohong AU - Liu X AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. FAU - Chen, Zhou AU - Chen Z AD - Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Liu, Libin AU - Liu L AUID- ORCID: 0000-0002-0352-3865 AD - Department of Endocrinology, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China. LA - eng GR - 2022XH036/Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital/ GR - 81800712/National Natural Science Foundation of China/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Gerontol A Biol Sci Med Sci JT - The journals of gerontology. Series A, Biological sciences and medical sciences JID - 9502837 RN - 839I73S42A (Liraglutide) RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) SB - IM MH - Animals MH - *Liraglutide/pharmacology/therapeutic use MH - *Amyloid beta-Peptides/metabolism MH - Mice MH - *Cognition/drug effects MH - *Alzheimer Disease/drug therapy/metabolism MH - Hippocampus/metabolism/drug effects MH - Disease Models, Animal MH - Male MH - *Neuroprotective Agents/pharmacology MH - Maze Learning/drug effects MH - Mice, Transgenic OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid beta protein OT - Cognitive function OT - Liraglutide OT - Neuroinflammation EDAT- 2025/12/06 00:32 MHDA- 2026/02/02 06:28 CRDT- 2025/12/05 18:04 PHST- 2025/04/30 00:00 [received] PHST- 2025/11/20 00:00 [accepted] PHST- 2026/02/02 06:28 [medline] PHST- 2025/12/06 00:32 [pubmed] PHST- 2025/12/05 18:04 [entrez] AID - 8371868 [pii] AID - 10.1093/gerona/glaf265 [doi] PST - ppublish SO - J Gerontol A Biol Sci Med Sci. 2026 Jan 12;81(2):glaf265. doi: 10.1093/gerona/glaf265. PMID- 41333115 OWN - NLM STAT- MEDLINE DCOM- 20251203 LR - 20260708 IS - 2090-0716 (Electronic) IS - 2090-0708 (Print) IS - 2090-0708 (Linking) VI - 2025 DP - 2025 TI - Harnessing GLP-1 Receptor Agonists for Obesity Treatment: Prospects and Obstacles on the Horizon. PG - 9919810 LID - 10.1155/jobe/9919810 [doi] LID - 9919810 AB - BACKGROUND: Obesity has emerged as a pressing global health challenge, and therapies based on glucagon-like Peptide 1 receptor agonists (GLP-1RAs) have transformed its management. Currently, liraglutide, semaglutide, and tirzepatide are FDA-approved for obesity treatment, while other agents are used off-label. These drugs not only provide unprecedented efficacy and acceptable safety in weight reduction and glycemic control for patients with obesity and Type 2 diabetes but also hold promise in broader indications, including neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular conditions. METHODS: This narrative review examined the therapeutic applications of GLP-1RAs for obesity, emphasizing their efficacy, safety profile, challenges with patient adherence, and limitations. The review also explored emerging innovations such as ultralong-acting formulations, combination therapies, and the integration of digital health and artificial intelligence in advancing antiobesity drug development. RESULTS: GLP-1RAs represent a paradigm shift in the treatment of obesity and metabolic diseases, with rapidly expanding indications and global uptake. Recent evidence highlights improvements in tolerability, global accessibility, and the potential of novel technologies to optimize patient outcomes. By 2025, GLP-1RAs are anticipated to receive FDA approval for new indications, such as chronic kidney disease, heart failure with preserved ejection fraction, and metabolic dysfunction-associated steatohepatitis. Novel agents including CagriSema and higher dose oral semaglutide are advancing through clinical trials, while pivotal trial results for orforglipron, mazdutide, retatrutide, and survodutide are anticipated to further expand the therapeutic landscape. At the same time, the arrival of generic liraglutide and evolving insurance coverage are reshaping access and affordability. CONCLUSION: The convergence of pharmacological innovation, digital health strategies, and equitable care initiatives is expected to revolutionize obesity therapeutics in the coming decade. Priorities for future research include sustaining long-term weight loss, establishing disease-modifying potential in nonmetabolic disorders, and addressing health equity concerns to ensure broader global benefit. CI - Copyright (c) 2025 Riad Mohammed Abdelrahman et al. Journal of Obesity published by John Wiley & Sons Ltd. FAU - Abdelrahman, Riad Mohammed AU - Abdelrahman RM AUID- ORCID: 0000-0002-1157-2739 AD - Faculty of Graduate Studies and Scientific Research, National Ribat University, Khartoum, Sudan. AD - Faculty of Pharmacy, National Ribat University, Khartoum, Sudan. FAU - Musa, Taha Hussein AU - Musa TH AUID- ORCID: 0000-0003-4452-1943 AD - Pharmacy Program, School of Medical & Health Sciences, Libyan International University, Benghazi, Libya. AD - School of Medicine & Biomedical Research Institute, Darfur University College, Nyala, Sudan. FAU - Arbab, Ismail Adam AU - Arbab IA AUID- ORCID: 0000-0001-5811-501X AD - Pharmacy Program, School of Medical & Health Sciences, Libyan International University, Benghazi, Libya. FAU - Suliman, Mohsen Hussein AU - Suliman MH AUID- ORCID: 0000-0002-6263-6712 AD - Pharmacy Program, School of Medical & Health Sciences, Libyan International University, Benghazi, Libya. FAU - Ahmed, Eltieb Omer AU - Ahmed EO AUID- ORCID: 0000-0002-4439-4932 AD - Department of Pharmacy Practice, Faculty of Pharmacy, International University of Africa, Khartoum, Sudan. FAU - Mohamed, Asma Noureldaim AU - Mohamed AN AUID- ORCID: 0009-0009-0710-6514 AD - Department of Pharmacy Practice, Faculty of Pharmacy, International University of Africa, Khartoum, Sudan. FAU - Musa, Hassan Hussein AU - Musa HH AUID- ORCID: 0000-0003-0227-6484 AD - Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan. FAU - Jalal, Mohammed AU - Jalal M AUID- ORCID: 0009-0001-4893-6321 AD - Faculty of Pharmacy, Karary University, Khartoum, Sudan. FAU - Gasmallah, Sahar Ibrahim AU - Gasmallah SI AUID- ORCID: 0009-0000-5183-5604 AD - College of Public and Environmental Health, University of Bahri, Khartoum, Sudan. LA - eng PT - Journal Article PT - Review DEP - 20251124 PL - United States TA - J Obes JT - Journal of obesity JID - 101526295 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Anti-Obesity Agents) RN - 839I73S42A (Liraglutide) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Obesity/drug therapy MH - *Anti-Obesity Agents/therapeutic use MH - Liraglutide/therapeutic use MH - Glucagon-Like Peptides/therapeutic use MH - Hypoglycemic Agents/therapeutic use MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC12668848 OTO - NOTNLM OT - GIP-1 OT - GLP-1RAs OT - liraglutide OT - obesity OT - semaglutide OT - tirzepatide COIS- The authors declare no conflicts of interest. EDAT- 2025/12/03 07:41 MHDA- 2025/12/03 14:11 PMCR- 2025/11/24 CRDT- 2025/12/03 05:35 PHST- 2025/05/03 00:00 [received] PHST- 2025/08/25 00:00 [revised] PHST- 2025/10/28 00:00 [accepted] PHST- 2025/12/03 14:11 [medline] PHST- 2025/12/03 07:41 [pubmed] PHST- 2025/12/03 05:35 [entrez] PHST- 2025/11/24 00:00 [pmc-release] AID - 10.1155/jobe/9919810 [doi] PST - epublish SO - J Obes. 2025 Nov 24;2025:9919810. doi: 10.1155/jobe/9919810. eCollection 2025. PMID- 41309383 OWN - NLM STAT- MEDLINE DCOM- 20260114 LR - 20260808 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 28 IP - 2 DP - 2026 Feb TI - Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists for incident dementia: A retrospective multicohort study. PG - 1443-1452 LID - 10.1111/dom.70336 [doi] AB - OBJECTIVE: This study provides real-world evidence on the comparative effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) regarding the risk of incident dementia in adults with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This cohort study utilised electronic health records from TriNetX (1 April 2013 to 31 December 2019). Adults with T2DM on metformin who initiated GLP-1 RAs or SGLT2i were analysed using Cox proportional hazards models in 1:1 propensity score-matched cohorts. The primary outcome was all-cause dementia; secondary outcomes included vascular and Alzheimer's dementia. Confounding variables were adjusted. RESULTS: Among 16 271 participants using GLP-1 RAs and 16 271 using SGLT2i over a median 6.3-year follow-up, 581 GLP-1 RA users and 572 SGLT2i users developed dementia. No significant differences were observed in all-cause dementia (hazard ratio: 1.01, 95% confidence interval: 0.90-1.13), vascular, or Alzheimer's dementia. Subgroup analyses confirmed these findings. CONCLUSIONS: SGLT2i use was not associated with increased risk of dementia compared with GLP-1RAs in patients with T2DM. Further research is warranted to explore the effects of (newer) incretin-based (co-)agonists on cognitive outcomes. CI - (c) 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Anagnostakis, Filippos AU - Anagnostakis F AD - Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Medical and Surgical Sciences, Alma Mater University of Bologna, Bologna, Italy. FAU - Kokkorakis, Michail AU - Kokkorakis M AUID- ORCID: 0000-0002-0027-5659 AD - Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. FAU - Nagarajan, Shrihari AU - Nagarajan S AD - Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas, Missouri, USA. FAU - Anastasiou, Georgia AU - Anastasiou G AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. FAU - Mantzoros, Christos S AU - Mantzoros CS AUID- ORCID: 0000-0003-3755-8158 AD - Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. AD - Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts, USA. LA - eng PT - Comparative Study PT - Journal Article DEP - 20251127 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Male MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - Female MH - *Dementia/epidemiology/prevention & control MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Retrospective Studies MH - Aged MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use MH - Incidence MH - Metformin/therapeutic use PMC - PMC12803637 OTO - NOTNLM OT - EHR OT - GLP-1 RA OT - SGLT-2i OT - dementia OT - incidence OT - real world COIS- FA, SN and GA have no competing interests. MK receives funding support from an MD-PhD grant from the University Medical Center Groningen. Over the past 3 years, CSM reports grants through his institution from Merck, Massachusetts Life Sciences Center and Boehringer Ingelheim; he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Nestle, Amgen, Corcept, Aligos, Intercept, 89 Bio, Madrigal, Novo Nordisk and Regeneron, reports travel support and fees from TMIOA, Elsevier and the Cardio Metabolic Health Conference. No consulting activity above is related to the work presented herein. EDAT- 2025/11/28 00:26 MHDA- 2026/01/15 06:07 PMCR- 2026/01/14 CRDT- 2025/11/27 21:54 PHST- 2025/11/06 00:00 [revised] PHST- 2025/08/23 00:00 [received] PHST- 2025/11/16 00:00 [accepted] PHST- 2026/01/15 06:07 [medline] PHST- 2025/11/28 00:26 [pubmed] PHST- 2025/11/27 21:54 [entrez] PHST- 2026/01/14 00:00 [pmc-release] AID - DOM70336 [pii] AID - 10.1111/dom.70336 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Feb;28(2):1443-1452. doi: 10.1111/dom.70336. Epub 2025 Nov 27. PMID- 41253199 OWN - NLM STAT- MEDLINE DCOM- 20251217 LR - 20260526 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 222 DP - 2025 Dec TI - Psychotropic effects of GLP-1R agonists. PG - 108036 LID - S1043-6618(25)00461-X [pii] LID - 10.1016/j.phrs.2025.108036 [doi] AB - The use of Glucagon-like peptide-1 receptor agonists (GLP-1RAs) is an established therapy for type 2 diabetes (T2D) and obesity, providing effective glycemic control, weight loss, and cardiovascular and renal benefits. Evidence is emerging on the potential neuropsychiatric and neuroprotective effects mediated via central GLP-1R. This review summarizes preclinical, clinical, and real-world findings on the use of GLP-1R agonists in depression, anxiety, binge eating disorder (BED), cognitive impairment, dementia, and substance use disorders involving alcohol, nicotine, cocaine, and opioids. Literature emphasizes human studies and translational models. Reported mechanisms include modulation of neuroinflammation, neurotransmitter systems, and reward pathways. Preliminary results are promising but limited by small and methodologically heterogeneous studies with short follow-up. Robust randomized trials with standardized psychotropic endpoints are needed. If confirmed, GLP-1RAs could represent an innovative treatment option bridging metabolic and mental health care. CI - Copyright (c) 2025 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Bucciarelli, Loredana AU - Bucciarelli L AD - Pio Albergo Trivulzio, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Universita di Milano, Italy. FAU - Cimino, Vincenzo AU - Cimino V AD - International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Universita di Milano, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy. FAU - Dell'Osso, Bernardo AU - Dell'Osso B AD - Department of Biomedical and Clinical Sciences, University of Milan, Italy; Department of Mental Health and Addictions, ASST Fatebenefratelli-Sacco, Milan, Italy; Department of Psychiatry and Beahvioural Sciences, Stanford University, CA, USA. FAU - Fiorina, Paolo AU - Fiorina P AD - International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Universita di Milano, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Paolo.Fiorina@childrens.harvard.edu. LA - eng PT - Journal Article PT - Review DEP - 20251116 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Psychotropic Drugs) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Psychotropic Drugs/therapeutic use/pharmacology MH - *Mental Disorders/drug therapy/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism OTO - NOTNLM OT - Alcohol use disorder OT - Binge-eating disorder OT - Depression OT - Opioid use disorder OT - Psychotropic benefits OT - Psychotropic risks COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2025/11/19 00:26 MHDA- 2025/12/18 01:31 CRDT- 2025/11/18 19:11 PHST- 2025/09/15 00:00 [received] PHST- 2025/11/10 00:00 [revised] PHST- 2025/11/15 00:00 [accepted] PHST- 2025/12/18 01:31 [medline] PHST- 2025/11/19 00:26 [pubmed] PHST- 2025/11/18 19:11 [entrez] AID - S1043-6618(25)00461-X [pii] AID - 10.1016/j.phrs.2025.108036 [doi] PST - ppublish SO - Pharmacol Res. 2025 Dec;222:108036. doi: 10.1016/j.phrs.2025.108036. Epub 2025 Nov 16. PMID- 41252314 OWN - NLM STAT- MEDLINE DCOM- 20260120 LR - 20260715 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 109 IP - 2 DP - 2026 Jan TI - Incidence of dementia in patients with type 2 diabetes using SGLT2 inhibitors versus GLP-1 receptor agonists or DPP-4 inhibitors: A systematic review and meta-analysis of cohort studies. PG - 594-603 LID - 10.1177/13872877251395086 [doi] AB - BackgroundIndividuals with type 2 diabetes mellitus (T2DM) have a higher incidence of dementia than those without the disease, possibly due to overlapping pathophysiological mechanisms. While glycemic control is essential to reduce dementia risk, recent studies suggest that newer antidiabetic agents, SGLT2i, GLP-1 RA, and DPP-4i, may offer neuroprotective effects.ObjectiveTo investigate the incidence of dementia in T2DM patients treated with SGLT2i compared to GLP-1 RA or DPP-4i.MethodsA systematic search of PubMed, Embase, and Cochrane databases was conducted for cohort studies published up to June 2025 that assessed dementia incidence in T2DM patients using SGLT2i versus DPP-4i or GLP-1 RA. Risk ratios (RRs) were calculated using the Mantel-Haenszel random-effects model, with variance estimated via restricted maximum likelihood in R version 4.3.0.ResultsTen studies met inclusion criteria. Four compared SGLT2i with GLP-1 RA, and seven with DPP-4i; one study contributed to both comparisons. The pooled RR for dementia in SGLT2i versus GLP-1 RA users was 0.91 (95% CI: 0.73-1.12; p < 0.003; I(2) = 78.7%). When comparing SGLT2i to DPP-4i, the RR was 0.39 (95% CI: 0.28-0.56; p < 0.00001; I(2) = 96.4%).ConclusionsUse of SGLT2i was associated with a lower risk of dementia compared to DPP-4i, with no significant difference observed when compared to GLP-1 RA. FAU - Milori, Pedro Henrique AU - Milori PH AUID- ORCID: 0000-0003-3307-0956 AD - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. FAU - Armelin, Larissa Maria AU - Armelin LM AUID- ORCID: 0000-0002-9389-3586 AD - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. FAU - Mutarelli, Antonio AU - Mutarelli A AUID- ORCID: 0000-0002-5595-9433 AD - Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. FAU - Caramelli, Paulo AU - Caramelli P AUID- ORCID: 0000-0002-4786-6990 AD - Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20251118 PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - Cohort Studies MH - *Dementia/epidemiology MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use MH - Incidence MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use OTO - NOTNLM OT - Alzheimer's disease OT - dementia OT - diabetes mellitus OT - dipeptidyl-peptidase IV inhibitors OT - glucagon-like peptide-1 receptor agonists OT - meta-analysis OT - sodium-glucose transporter 2 inhibitors COIS- Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Paulo Caramelli: Preparation of CME materials and speaker in symposium sponsored by Ache, Biogen, Danone, Fleury, Lilly, Lundbeck, Novo Nordisk and Pratti-Donaduzzi. Consulting activities for para Ache, Danone and Knight Therapeutics. Investigator in clinical trials sponsored by Passage Bio and Roche.Paulo Caramelli is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. EDAT- 2025/11/18 18:30 MHDA- 2026/01/20 07:43 CRDT- 2025/11/18 13:22 PHST- 2026/01/20 07:43 [medline] PHST- 2025/11/18 18:30 [pubmed] PHST- 2025/11/18 13:22 [entrez] AID - 10.1177/13872877251395086 [doi] PST - ppublish SO - J Alzheimers Dis. 2026 Jan;109(2):594-603. doi: 10.1177/13872877251395086. Epub 2025 Nov 18. PMID- 41242536 OWN - NLM STAT- MEDLINE DCOM- 20260116 LR - 20261022 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 103 DP - 2026 Jan TI - NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice. PG - 102282 LID - S2212-8778(25)00189-9 [pii] LID - 10.1016/j.molmet.2025.102282 [doi] LID - 102282 AB - The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1beta, IL-18, IL-1alpha, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease. CI - Copyright (c) 2025 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Bultinck, Jennyfer AU - Bultinck J AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA; Zomagen Biosciences Belgium BV/Ventyx Biosciences, Inc. Technologiepark 94 Unit 24, Zwijnaarde, 9052, Belgium. Electronic address: jbultinck@ventyxbio.com. FAU - Yuan, Shendong AU - Yuan S AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA. FAU - Cantuti-Castelvetri, Ludovico AU - Cantuti-Castelvetri L AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA; Zomagen Biosciences Belgium BV/Ventyx Biosciences, Inc. Technologiepark 94 Unit 24, Zwijnaarde, 9052, Belgium. FAU - Brosens, Lander AU - Brosens L AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA; Zomagen Biosciences Belgium BV/Ventyx Biosciences, Inc. Technologiepark 94 Unit 24, Zwijnaarde, 9052, Belgium. FAU - Bracke, Debby AU - Bracke D AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA; Zomagen Biosciences Belgium BV/Ventyx Biosciences, Inc. Technologiepark 94 Unit 24, Zwijnaarde, 9052, Belgium. FAU - Collins, James AU - Collins J AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA. FAU - Goethals, Jens AU - Goethals J AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA; Zomagen Biosciences Belgium BV/Ventyx Biosciences, Inc. Technologiepark 94 Unit 24, Zwijnaarde, 9052, Belgium. FAU - Christianson, Christina AU - Christianson C AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA. FAU - Nuss, John AU - Nuss J AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA. FAU - Ogilvie, Kathleen AU - Ogilvie K AD - Ventyx Biosciences, Inc. 12790 El Camino Real, Suite 200, San Diego, CA 92130, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20251114 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Inflammasomes) RN - 0 (7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid) RN - 0 (Cytokines) RN - 25167-62-8 (Docosahexaenoic Acids) SB - IM MH - Animals MH - *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism MH - Mice MH - Male MH - *Hyperglycemia/metabolism/drug therapy MH - *Inflammation/metabolism/drug therapy MH - *Obesity/metabolism/drug therapy MH - Mice, Inbred C57BL MH - Humans MH - *Fatty Liver/metabolism/drug therapy MH - Body Weight/drug effects MH - Mice, Obese MH - Hepatocytes/metabolism/drug effects MH - Insulin Resistance MH - Inflammasomes/metabolism MH - Cytokines/metabolism MH - Macrophages/metabolism MH - Docosahexaenoic Acids PMC - PMC12682222 OTO - NOTNLM OT - Drug therapy OT - Inflammation OT - Insulin resistance OT - Metabolism OT - Obesity OT - Steatosis COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennyfer Bultinck, Shendong Yuan, James Collins, and John Nuss are employed by, shareholders of, and report patents planned, issued, or pending with Ventyx Biosciences, Inc., or a wholly-owned subsidiary thereof (hereafter referred to as "Ventyx"). Ludovico Cantuti-Castelvetri, Lander Brosens, Debby Bracke, Jens Goethals, and Christina Christianson are employed by and own stock or stock options in Ventyx. Kathleen Ogilvie is employed by and has received financial support for attending meetings and/or travel from Ventyx, reports patents planned, issued, or pending with Ventyx and aTyr Pharma, and owns stock or stock options in Ventyx, aTyr Pharma, and Pfizer. Zomagen Biosciences, Ltd., a wholly-owned subsidiary of Ventyx, owns VTX3232. The authors declare that these studies received funding from Ventyx. Specifically, Ventyx funded and was involved with study designs, data collection, data analyses, data interpretations, writing, review, approval of the final manuscript, and provided financial support for this manuscript (including, but not limited to, medical writing/editing and article processing charges). EDAT- 2025/11/17 00:28 MHDA- 2026/01/17 00:37 PMCR- 2025/11/14 CRDT- 2025/11/16 19:14 PHST- 2025/08/12 00:00 [received] PHST- 2025/11/06 00:00 [revised] PHST- 2025/11/10 00:00 [accepted] PHST- 2026/01/17 00:37 [medline] PHST- 2025/11/17 00:28 [pubmed] PHST- 2025/11/16 19:14 [entrez] PHST- 2025/11/14 00:00 [pmc-release] AID - S2212-8778(25)00189-9 [pii] AID - 102282 [pii] AID - 10.1016/j.molmet.2025.102282 [doi] PST - ppublish SO - Mol Metab. 2026 Jan;103:102282. doi: 10.1016/j.molmet.2025.102282. Epub 2025 Nov 14. PMID- 41234238 OWN - NLM STAT- MEDLINE DCOM- 20251114 LR - 20251116 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 16 DP - 2025 TI - Comparative effects of SGLT2 inhibitors and incretin-based therapies on dementia risk in type 2 diabetes: a systematic review and meta-analysis. PG - 1695075 LID - 10.3389/fendo.2025.1695075 [doi] LID - 1695075 AB - BACKGROUND: Antidiabetic drugs lower blood glucose levels and may also have neuroprotective and vascular protection effects. In particular, sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin mimetics have demonstrated dementia-reducing effects. We evaluated whether SGLT2is reduce dementia risk compared with incretin mimetics in patients with type 2 diabetes (T2D). METHODS: Systematic review and meta-analysis were performed by searching the PubMed, Embase, and Cochrane Library databases through February 2025. Both randomized trials and cohort studies were identified and qualitatively assessed, but only cohort studies were included in the quantitative meta-analysis. We also compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia incidence. RESULTS: Nine studies were identified for analysis. Compared with incretin mimetics, SGLT2is significantly reduced the overall dementia risk [hazard ratio (HR) 0.82, 95% CI: 0.73-0.91], and SGLT2is had stronger effects than DPP-4i (HR 0.67, 95% CI: 0.59-0.77) and GLP-1RA (HR 0.93, 95% CI: 0.86-1.00). SGLT2i also reduced the risks of vascular dementia and Alzheimer's disease (HR 0.49, 95% CI: 0.35-0.70 vs. HR 0.68, 95% CI: 0.52-0.88, respectively). The results of subgroup analyses revealed increased benefits for patients aged older than 65 years. Empagliflozin was the most consistently protective among the SGLT2i agents. CONCLUSION: SGLT2is may provide neuroprotective benefits beyond glycemic control in patients with T2D, particularly in older populations at higher risk of cognitive decline. These findings support consideration of SGLT2is as a preferred therapeutic option for patients with T2D at increased risk of dementia, although randomized controlled trials would further strengthen this evidence base. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024567890 identifier PROSPERO (CRD420251037959). CI - Copyright (c) 2025 Song, Choi, Jeong, Shin, Ah, Lee and Choi. FAU - Song, Kirim AU - Song K AD - College of Pharmacy, Gachon University, Incheon, Republic of Korea. AD - Department of Pharmacy, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea. FAU - Choi, Jiwon AU - Choi J AD - College of Pharmacy, Gachon University, Incheon, Republic of Korea. FAU - Jeong, Dayeon AU - Jeong D AD - College of Pharmacy, Gachon University, Incheon, Republic of Korea. AD - Department of Pharmacy, Samsung Medical Center, Seoul, Republic of Korea. FAU - Shin, Dongyun AU - Shin D AD - College of Pharmacy, Gachon University, Incheon, Republic of Korea. FAU - Ah, Young-Mi AU - Ah YM AD - College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea. FAU - Lee, Ki Young AU - Lee KY AD - Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea. AD - Department of Internal Medicine, Gachon University School of Medicine, Incheon, Republic of Korea. FAU - Choi, Kyung Hee AU - Choi KH AD - College of Pharmacy, Gachon University, Incheon, Republic of Korea. AD - Department of Pharmacy, Gachon University Gil Medical Center, Incheon, Republic of Korea. LA - eng PT - Comparative Study PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20251029 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Incretins) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Incretins/therapeutic use MH - *Dementia/prevention & control/epidemiology/etiology MH - *Hypoglycemic Agents/therapeutic use MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use PMC - PMC12605505 OTO - NOTNLM OT - cognitive impairment OT - dementia OT - incretins OT - sodium-glucose transporter 2 inhibitors OT - type 2 diabetes COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/11/14 06:28 MHDA- 2025/11/14 06:29 PMCR- 2025/10/29 CRDT- 2025/11/14 04:33 PHST- 2025/09/02 00:00 [received] PHST- 2025/10/17 00:00 [accepted] PHST- 2025/11/14 06:29 [medline] PHST- 2025/11/14 06:28 [pubmed] PHST- 2025/11/14 04:33 [entrez] PHST- 2025/10/29 00:00 [pmc-release] AID - 10.3389/fendo.2025.1695075 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2025 Oct 29;16:1695075. doi: 10.3389/fendo.2025.1695075. eCollection 2025. PMID- 41232069 OWN - NLM STAT- MEDLINE DCOM- 20251219 LR - 20260919 IS - 1935-5548 (Electronic) IS - 0149-5992 (Print) IS - 0149-5992 (Linking) VI - 49 IP - 1 DP - 2026 Jan 1 TI - GLP-1s Versus DPP-4s and Risk of Dementia in Patients Requiring Hemodialysis: A Target Trial Emulation Study. PG - 128-136 LID - 10.2337/dc25-1836 [doi] AB - OBJECTIVE: Glucagon-like peptide 1 agonists (GLP-1s) compared with dipeptidyl peptidase 4 inhibitors (DPP-4s) are associated with reduced risk of dementia in the general population with diabetes, but whether this association is true for patients requiring hemodialysis is unknown. RESEARCH DESIGN AND METHODS: Using the U.S. Renal Data System and Medicare Parts A, B, and D claims data from 2011 to 2021, we used the active comparator, new-user design to evaluate incident dementia comparing GLP-1s versus DPP-4s among individuals with both diabetes and hemodialysis dependence. We used inverse probability of treatment weights (IPTW) to balance baseline characteristics and Fine-Gray models to estimate subdistribution hazard ratios (sHRs) accounting for competing risks of death and kidney transplantation. We estimated intention-to-treat and as-treated effects. RESULTS: We identified 3,619 GLP-1 users and 11,502 DPP-4 users. After IPTW, the average individual was 63 years old, 63% were White, and mean BMI was 31 kg/m2. The median (interquartile interval) follow-up was 1.5 (0.6-2.9) years, and 2,014 patients received a dementia diagnosis. In the intention-to-treat analysis, the IPTW-sHR for dementia was 0.82 (95% CI 0.67-0.98), and after 2 years of follow-up, the cumulative incidence of dementia was 10.2% on GLP-1s vs 11.2% on DPP-4s. As-treated and subgroup analyses were consistent. GLP-1s were also associated with an increased risk of ketoacidosis (sHR 1.52, 95% CI 1.14-2.02; 2-year cumulative incidence: 3.1% vs. 2.2%). CONCLUSIONS: In patients with diabetes requiring hemodialysis, GLP-1s (vs. DPP-4s) may be a promising therapy to reduce the risk of dementia. CI - (c) 2025 by the American Diabetes Association. FAU - Le, Dustin AU - Le D AUID- ORCID: 0000-0003-3231-6758 AD - Division of Nephrology, Thomas Jefferson University, Philadelphia, PA. FAU - Kilpatrick, Mark AU - Kilpatrick M AD - Department of Medicine, Thomas Jefferson University, Philadelphia, PA. FAU - Kraft, Walter K AU - Kraft WK AD - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA. FAU - Grams, Morgan E AU - Grams ME AD - Division of Precision Medicine, New York University, New York, NY. FAU - Jaar, Bernard G AU - Jaar BG AD - Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, MD. AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. AD - Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. FAU - Shin, Jung-Im AU - Shin JI AD - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. AD - Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. LA - eng GR - R01 DK115534/DK/NIDDK NIH HHS/United States GR - Young Investigator Award/National Kidney Foundation/ GR - R01DK139324/DK/NIDDK NIH HHS/United States GR - R01DK115534/DK/NIDDK NIH HHS/United States GR - R01 DK139324/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Dementia/epidemiology/etiology MH - *Renal Dialysis MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Male MH - Female MH - *Glucagon-Like Peptide 1/agonists/therapeutic use MH - Aged MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use MH - Diabetes Mellitus, Type 2/drug therapy/complications PMC - PMC12719713 COIS- Duality of Interest. No potential conflicts of interest relevant to this article were reported. EDAT- 2025/11/13 18:30 MHDA- 2025/12/19 18:32 PMCR- 2025/11/13 CRDT- 2025/11/13 16:13 PHST- 2025/07/29 00:00 [received] PHST- 2025/10/15 00:00 [accepted] PHST- 2025/12/19 18:32 [medline] PHST- 2025/11/13 18:30 [pubmed] PHST- 2025/11/13 16:13 [entrez] PHST- 2025/11/13 00:00 [pmc-release] AID - 163800 [pii] AID - 251836 [pii] AID - 10.2337/dc25-1836 [doi] PST - ppublish SO - Diabetes Care. 2026 Jan 1;49(1):128-136. doi: 10.2337/dc25-1836. PMID- 41226575 OWN - NLM STAT- MEDLINE DCOM- 20251113 LR - 20251116 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 26 IP - 21 DP - 2025 Oct 29 TI - Key Signals Produced by Gut Microbiota Associated with Metabolic Syndrome, Cancer, Cardiovascular Diseases, and Brain Functions. LID - 10.3390/ijms262110539 [doi] LID - 10539 AB - Gut microbiota have a significant impact neurotransmitters, short-chain fatty acids (SCFAs), immune signaling molecules, and gut hormones. These signaling molecules interact with receptors on the gut wall, immune cells, or the enteric nervous system (ENS), and reach the central nervous system (CNS) via the Vagus nerve (VN). SCFAs interact with G protein-coupled receptors (GPCRs), Toll-like receptors (TLRs), and proliferator-activated receptors (PPARs), influencing inflammatory reactions, gut motility, nutrient absorption, hormone secretion, neurochemical signaling, and brain functions. Olfactory receptor OR51E1 influences blood pressure, vascular reactivity, and arterial stiffness. Activation of the brainstem nucleus tractus solitarius (NTS) by glucagon-like peptide 1 (GLP-1) influences mood, cognition, and gastrointestinal motility. Prolactin-releasing peptide (PrRP) binds to its receptor (PrRPR), suppressing food intake, and regulating stress, cardiovascular reactions, and circadian rhythms. In-depth studies on how gut microbiota control cognitive behavior, mood, and neuropsychiatric disorders are lacking. G protein receptor 119 (GPR119) suppresses appetite and may find an application in the treatment of type 2 diabetes and obesity. The binding of butyrate to nuclear factor kappa B (NF-kappaB) and proliferator-activated receptor gamma (PPARgamma) regulates the production of pro-and anti-inflammatory cytokines. This suppresses protein CD36, preventing the uptake of oxidized low-density lipoprotein (ox-LDL) and cardiovascular diseases (CVDs). This review focuses on a few prominent health conditions related to CVDs, i.e., metabolic syndrome (MetS), cancer, and brain functions. Information in this review is based on animal and preclinical studies published in repositories such as PubMed, the National Institutes of Health (NIH), NIH PubChem, ScienceDirect, MDPI, Frontiers, Cell Press, and the CAS Content Collection. FAU - Dicks, Leon M T AU - Dicks LMT AUID- ORCID: 0000-0002-5157-9046 AD - Department of Microbiology, Stellenbosch University, Stellenbosch 7600, South Africa. LA - eng PT - Journal Article PT - Review DEP - 20251029 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 SB - IM MH - Humans MH - *Gastrointestinal Microbiome/physiology MH - *Metabolic Syndrome/metabolism/microbiology MH - *Cardiovascular Diseases/metabolism/microbiology MH - Animals MH - *Brain/metabolism MH - *Neoplasms/metabolism/microbiology MH - Signal Transduction PMC - PMC12607389 OTO - NOTNLM OT - brain functions OT - cancer OT - cardiovascular diseases OT - gut microbiota OT - metabolic syndrome OT - molecular signals COIS- The author declares no conflicts of interest. EDAT- 2025/11/13 06:29 MHDA- 2025/11/13 18:30 PMCR- 2025/10/29 CRDT- 2025/11/13 01:04 PHST- 2025/09/25 00:00 [received] PHST- 2025/10/23 00:00 [revised] PHST- 2025/10/28 00:00 [accepted] PHST- 2025/11/13 18:30 [medline] PHST- 2025/11/13 06:29 [pubmed] PHST- 2025/11/13 01:04 [entrez] PHST- 2025/10/29 00:00 [pmc-release] AID - ijms262110539 [pii] AID - ijms-26-10539 [pii] AID - 10.3390/ijms262110539 [doi] PST - epublish SO - Int J Mol Sci. 2025 Oct 29;26(21):10539. doi: 10.3390/ijms262110539. PMID- 41204243 OWN - NLM STAT- MEDLINE DCOM- 20251108 LR - 20260908 IS - 1475-2840 (Electronic) IS - 1475-2840 (Linking) VI - 24 IP - 1 DP - 2025 Nov 7 TI - Neurodegeneration onset with glucagon-like peptide-1 receptor agonists in people with type 2 diabetes: a real-world multinational cohort study. PG - 426 LID - 10.1186/s12933-025-02962-8 [doi] LID - 426 AB - BACKGROUND: Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for neurodegenerative disorders. Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D. METHODS: In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 inhibitors (DPP4i) (2010-2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for /= 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin. CONCLUSIONS: In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population. CI - (c) 2025. The Author(s). FAU - Schechter, Meir AU - Schechter M AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, 9112001, Jerusalem, Israel. meir.schechter@mail.huji.ac.il. AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. meir.schechter@mail.huji.ac.il. AD - The Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel. meir.schechter@mail.huji.ac.il. AD - Dina Recanati School of Medicine, Reichman University, Herzliya, Israel. meir.schechter@mail.huji.ac.il. FAU - Fishkin, Alisa AU - Fishkin A AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, 9112001, Jerusalem, Israel. AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Mosenzon, Ofri AU - Mosenzon O AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. AD - Regeneron Pharmaceuticals Inc., New York, NY, USA. FAU - Sehtman-Shachar, Dvora R AU - Sehtman-Shachar DR AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, 9112001, Jerusalem, Israel. AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Ramat Gan, Israel. AD - Department of Epidemiology and Preventive Medicine, School of Public Health, Dear Gray Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv, Israel. FAU - Leibowitz, Gil AU - Leibowitz G AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, 9112001, Jerusalem, Israel. AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Aharon-Hananel, Genya AU - Aharon-Hananel G AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, 9112001, Jerusalem, Israel. AD - Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. LA - eng PT - Journal Article PT - Multicenter Study DEP - 20251107 PL - England TA - Cardiovasc Diabetol JT - Cardiovascular diabetology JID - 101147637 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Incretins) RN - 0 (GLP1R protein, human) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - Female MH - Male MH - *Diabetes Mellitus, Type 2/drug therapy/diagnosis/epidemiology/blood MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Retrospective Studies MH - Middle Aged MH - Aged MH - *Neurodegenerative Diseases/epidemiology/diagnosis/prevention & control MH - Risk Factors MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - *Incretins/therapeutic use/adverse effects MH - Time Factors MH - Treatment Outcome MH - Risk Assessment MH - Biomarkers/blood MH - *Blood Glucose/drug effects/metabolism MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Electronic Health Records MH - Glucagon-Like Peptide-1 Receptor PMC - PMC12595915 OTO - NOTNLM OT - Alzheimer's disease OT - Dementia OT - Glucagon-like peptide-1 receptor agonists OT - Neurodegeneration OT - Neuroprotection OT - Parkinson's disease COIS- Declarations. Conflict of interest: MS reports travel support from Novo Nordisk and AstraZeneca through Hadassah Medical Center, and lecturing fees from AstraZeneca (2022). AF and DRSS report no conflict of interest. OM reports Advisory Board membership for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and BOL Pharma, research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and Speaker's Bureau participation for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim. From May 1st, 2023, OM has been an employee of Regeneron Pharmaceuticals Inc. This work was not funded by Regeneron Pharmaceuticals, Inc.; it was not part of OM's job responsibilities; and the company had no role in conception, data acquisition, analysis, interpretation, or manuscript preparation. TCY reports receiving research support from Medtronic, Regeneron, Novo Nordisk, and Merck Sharp & Dohme. Honorarium for lecture/advisory board from Medtronic, Sanofi, Novo Nordisk, Boehringer Ingelheim, AstraZeneca, and Amgen. GL reports participation in previous Advisory Boards: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Medtronic. He reports travel support from Novo Nordisk, Boehringer Ingelheim and AstraZeneca through Hadassah Medical Center. Speaker's Bureau: AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim. GAH reported previous Advisory Board: Sanofi and Eli Lilly. She is a current PI in several RCTs conducted by Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca and Bayer including the CONFIDENCE study, through Hadassah Medical Center. GAH reports travel support from Novo Nordisk and Medetronic through Hadassah Medical Center and AstraZeneca through Sheba medical center. Speaker's Bureau: AstraZeneca, Novo Nordisk, Eli Lilly and Sanofi. EDAT- 2025/11/08 00:28 MHDA- 2025/11/08 06:29 PMCR- 2025/11/07 CRDT- 2025/11/07 23:53 PHST- 2025/08/02 00:00 [received] PHST- 2025/09/26 00:00 [accepted] PHST- 2025/11/08 06:29 [medline] PHST- 2025/11/08 00:28 [pubmed] PHST- 2025/11/07 23:53 [entrez] PHST- 2025/11/07 00:00 [pmc-release] AID - 10.1186/s12933-025-02962-8 [pii] AID - 2962 [pii] AID - 10.1186/s12933-025-02962-8 [doi] PST - epublish SO - Cardiovasc Diabetol. 2025 Nov 7;24(1):426. doi: 10.1186/s12933-025-02962-8. PMID- 41196686 OWN - NLM STAT- MEDLINE DCOM- 20251121 LR - 20260223 IS - 1479-6805 (Electronic) IS - 0022-0795 (Linking) VI - 267 IP - 2 DP - 2025 Nov 1 TI - Pathomechanisms, genetic insights, and therapeutics in diabetes-associated dementia. LID - e250016 [pii] LID - 10.1530/JOE-25-0016 [doi] AB - Type 2 diabetes (T2DM) significantly increases the risk of dementia due to overlapping metabolic, molecular, and genetic factors. This review comprehensively analyzes the pathophysiological links between diabetes and cognitive decline, focusing on chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cerebrovascular complications. Key genetic and epigenetic contributors to diabetes-associated dementia (DAD), including variations in APOE, PICALM, SORL1, and GSK3B, are discussed. The roles of pathological proteins such as amyloid-beta (Abeta) and hyperphosphorylated tau in neurodegeneration are also highlighted. Preclinical and clinical evidence supports targeting insulin signaling pathways, oxidative damage, and inflammatory responses as potential therapeutic strategies. Promising therapies, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and anti-inflammatory drugs, are reviewed alongside emerging approaches such as gene therapy, stem cell therapy, and immunomodulation. Despite encouraging advances, the clinical translation of these therapies remains challenging due to the complexity of DAD pathogenesis. This review aims to advance understanding of diabetes-induced cognitive impairment and guide the development of personalized dementia therapies by integrating molecular, genetic, and clinical insights. Future research should focus on elucidating the precise molecular mechanisms of DAD progression and on developing targeted, patient-specific therapeutic interventions to overcome translational barriers. FAU - Meher, Rakesh AU - Meher R AUID- ORCID: 0000-0002-9340-7306 AD - School of Pharmacy, Centurion University of Technology and Management, Balangir, Odisha, India. FAU - Sahu, Roja AU - Sahu R AUID- ORCID: 0000-0001-8331-6614 AD - School of Pharmacy, Centurion University of Technology and Management, Balangir, Odisha, India. FAU - Ranajit, Santosh Kumar AU - Ranajit SK AUID- ORCID: 0000-0003-4472-9357 AD - School of Pharmacy, Centurion University of Technology and Management, Balangir, Odisha, India. FAU - Swain, Trupti Rekha AU - Swain TR AUID- ORCID: 0000-0002-7596-2031 AD - Pharmacology Department, SCB Medical College and Hospital, Cuttack, Odisha, India. FAU - Acharya, Biswajeet AU - Acharya B AUID- ORCID: 0000-0002-1802-5818 AD - Department of Pharmacology, GITAM School of Pharmacy, GITAM (Deemed to be University), Gandhi Nagar Campus, Rushikonda, Visakhapatnam, Andhra Pradesh, India. FAU - Feehan, Jack AU - Feehan J AD - School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia. FAU - Sahu, Prafulla Kumar AU - Sahu PK AUID- ORCID: 0000-0002-5199-3861 AD - School of Pharmacy, GIET University, Gunupur,Odisha, India. FAU - Apostolopoulos, Vasso AU - Apostolopoulos V AUID- ORCID: 0000-0001-6788-2771 AD - School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia. LA - eng PT - Journal Article PT - Review DEP - 20251121 PL - England TA - J Endocrinol JT - The Journal of endocrinology JID - 0375363 SB - IM MH - Humans MH - *Dementia/genetics/etiology/therapy/metabolism MH - *Diabetes Mellitus, Type 2/complications/genetics/metabolism MH - Animals MH - Insulin Resistance MH - *Diabetes Complications/genetics/therapy MH - Oxidative Stress OTO - NOTNLM OT - amyloid-beta OT - dementia OT - diabetes OT - mitochondrial dysfunction OT - neurodegeneration OT - protein aggregation and misfolding OT - tau EDAT- 2025/11/06 18:27 MHDA- 2025/11/21 18:26 CRDT- 2025/11/06 12:43 PHST- 2025/01/21 00:00 [received] PHST- 2025/11/05 00:00 [accepted] PHST- 2025/11/21 18:26 [medline] PHST- 2025/11/06 18:27 [pubmed] PHST- 2025/11/06 12:43 [entrez] AID - e250016 [pii] AID - 10.1530/JOE-25-0016 [doi] PST - epublish SO - J Endocrinol. 2025 Nov 21;267(2):e250016. doi: 10.1530/JOE-25-0016. Print 2025 Nov 1. PMID- 41196232 OWN - NLM STAT- MEDLINE DCOM- 20251209 LR - 20251209 IS - 1744-7658 (Electronic) IS - 1354-3784 (Linking) VI - 34 IP - 11 DP - 2025 Nov TI - Glucagon‑like peptide‑1 receptor agonists in multiple sclerosis: therapeutic promise, challenges, and future directions. PG - 929-941 LID - 10.1080/13543784.2025.2587277 [doi] AB - INTRODUCTION: This review evaluates the potential of glucagon‑like peptide‑1 receptor agonists (GLP‑1RAs) - first developed for type 2 diabetes and later approved for chronic weight management and additional indications - to be repurposed as neuroprotective and remyelinating therapies in multiple sclerosis (MS). We synthesize emerging pre‑clinical and early clinical evidence, highlight practical barriers to translation, and outline directions for future research. AREAS COVERED: In experimental autoimmune encephalomyelitis and toxin-induced demyelination mouse models, GLP-1RAs have been shown to reduce oxidative stress, preserve axonal integrity, suppress microglial and astrocytic activation, and, in some cases, promote remyelination. Early observational data in people with MS suggest GLP-1RAs are well tolerated, provide expected metabolic benefits, and do not exacerbate disease activity. Moreover, signals of reduced neurological impairment and lower dementia incidence in broader diabetic cohorts further support their translational promise. However, to date, there are no published randomized controlled trials of GLP-1RAs in MS. EXPERT OPINION: Pre‑clinical and early clinical signals support GLP‑1RAs as promising candidates for neuroprotection in MS, yet definitive evidence of disease‑modifying efficacy is lacking. Practical barriers, such as drug availability and cost, together with unresolved mechanistic questions underscore the need for biomarker‑rich mechanistic trials. Rigorous prospective studies are essential to establish whether GLP‑1RAs can meaningfully alter the trajectory of MS. FAU - Shirani, Afsaneh AU - Shirani A AD - Saint Luke's Marion Bloch Neuroscience Institute, Kansas City, MO, USA. AD - Department of Neurology, University of Missouri-Kansas City, Kansas City, MO, USA. FAU - Stuve, Olaf AU - Stuve O AD - Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA. AD - Neurology Section, VA North Texas Health Care System, Dallas, TX, USA. AD - Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. LA - eng PT - Journal Article PT - Review DEP - 20251110 PL - England TA - Expert Opin Investig Drugs JT - Expert opinion on investigational drugs JID - 9434197 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - Animals MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Multiple Sclerosis/drug therapy/physiopathology MH - *Neuroprotective Agents/pharmacology/adverse effects/therapeutic use MH - Mice MH - Disease Models, Animal MH - Encephalomyelitis, Autoimmune, Experimental/drug therapy/physiopathology MH - Diabetes Mellitus, Type 2/drug therapy MH - Drug Repositioning OTO - NOTNLM OT - Glucagon-Like Peptide-1 receptor agonists OT - medication repurposing OT - multiple sclerosis OT - neurodegenerative disorders OT - neuroprotection EDAT- 2025/11/06 12:33 MHDA- 2025/12/09 07:38 CRDT- 2025/11/06 10:22 PHST- 2025/12/09 07:38 [medline] PHST- 2025/11/06 12:33 [pubmed] PHST- 2025/11/06 10:22 [entrez] AID - 10.1080/13543784.2025.2587277 [doi] PST - ppublish SO - Expert Opin Investig Drugs. 2025 Nov;34(11):929-941. doi: 10.1080/13543784.2025.2587277. Epub 2025 Nov 10. PMID- 41178710 OWN - NLM STAT- MEDLINE DCOM- 20251103 LR - 20260620 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 135 IP - 21 DP - 2025 Nov 3 TI - Antiinflammatory actions of glucagon-like peptide-1-based therapies beyond metabolic benefits. LID - 10.1172/JCI194751 [doi] LID - e194751 AB - Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity, with ongoing clinical trials investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans, through weight loss-dependent and -independent mechanisms, actions that may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines. In this Review, we highlight current understanding of the direct and indirect antiinflammatory effects and mechanisms of GLP-1 medicines in both preclinical and clinical studies, covering emerging concepts, clinical relevance, and areas of uncertainty that require further investigation. FAU - Wong, Chi Kin AU - Wong CK AD - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. FAU - Drucker, Daniel J AU - Drucker DJ AD - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. AD - Department of Medicine, University of Toronto, Ontario, Canada. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20251103 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Animals MH - *Glucagon-Like Peptide 1/therapeutic use/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology MH - Mice MH - *Anti-Inflammatory Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Obesity/drug therapy/metabolism/pathology MH - Inflammation/drug therapy/metabolism MH - Signal Transduction/drug effects MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC12578379 COIS- Conflict of interest: DJD has received consulting fees from Anylam, Amgen, AstraZeneca Inc., Crinetics, Eli Lilly, Insulet, Kallyope, Metsara, and Pfizer Inc. and speaking fees from Novo Nordisk. Mount Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly, Novo Nordisk, Pfizer Inc., and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker laboratory. EDAT- 2025/11/03 13:42 MHDA- 2025/11/03 13:43 PMCR- 2025/11/03 CRDT- 2025/11/03 06:03 PHST- 2025/11/03 13:43 [medline] PHST- 2025/11/03 13:42 [pubmed] PHST- 2025/11/03 06:03 [entrez] PHST- 2025/11/03 00:00 [pmc-release] AID - 194751 [pii] AID - 10.1172/JCI194751 [doi] PST - epublish SO - J Clin Invest. 2025 Nov 3;135(21):e194751. doi: 10.1172/JCI194751. eCollection 2025 Nov 3. PMID- 41169480 OWN - NLM STAT- MEDLINE DCOM- 20251031 LR - 20251102 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 16 DP - 2025 TI - Mechanisms underlying cognitive impairment and management strategies in type 2 diabetes. PG - 1655768 LID - 10.3389/fendo.2025.1655768 [doi] LID - 1655768 AB - Type 2 diabetes (T2D) is increasingly recognized as a risk factor for cognitive impairment, ranging from mild cognitive impairment (MCI) to dementia. The underlying mechanisms involve a complex interplay of hyperglycemia, insulin resistance, neuroinflammation, oxidative stress, vascular dysfunction, and amyloid pathology. Effective management strategies remain an area of active investigation. This review explores the pathophysiological mechanisms linking T2D to cognitive dysfunction and evaluates current and emerging therapeutic strategies to preserve cognitive function in diabetic patients. Chronic hyperglycemia and insulin resistance impair neuronal function and synaptic plasticity, while microvascular complications contribute to cerebral hypoperfusion and white matter lesions. Additionally, metabolic disturbances exacerbate neurodegenerative processes, further compromising cognitive health. Effective management strategies for cognitive impairment in T2D include regular cognitive screening, stringent glycemic control, lifestyle modifications, comprehensive cardiovascular risk management, patient education and pharmacological interventions such as metformin, GLP-1 receptor agonists (GLP1RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which may offer neuroprotective benefits. In this review, we conclude that cognitive impairment in T2D results from complex, interrelated mechanisms requiring early intervention and personalized strategies. While current therapies focus on metabolic and vascular risk reduction, future research should prioritize biomarker discovery, mechanism-driven treatments, and long-term clinical trials to optimize outcomes. A proactive, integrated care model is essential to mitigate cognitive decline in this high-risk population. CI - Copyright (c) 2025 Chen, Huang and Xiong. FAU - Chen, Xiaolin AU - Chen X AD - Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. FAU - Huang, Yan AU - Huang Y AD - Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. FAU - Xiong, Xiaoxing AU - Xiong X AD - Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. LA - eng PT - Journal Article PT - Review DEP - 20251015 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/therapy MH - *Cognitive Dysfunction/etiology/therapy MH - Hypoglycemic Agents/therapeutic use MH - Disease Management PMC - PMC12568408 OTO - NOTNLM OT - cognitive impairment OT - glycemic control OT - insulin resistance OT - neuroinflammation OT - neuroprotection OT - type 2 diabetes COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/10/31 06:26 MHDA- 2025/10/31 06:27 PMCR- 2025/10/15 CRDT- 2025/10/31 04:45 PHST- 2025/06/28 00:00 [received] PHST- 2025/09/29 00:00 [accepted] PHST- 2025/10/31 06:27 [medline] PHST- 2025/10/31 06:26 [pubmed] PHST- 2025/10/31 04:45 [entrez] PHST- 2025/10/15 00:00 [pmc-release] AID - 10.3389/fendo.2025.1655768 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2025 Oct 15;16:1655768. doi: 10.3389/fendo.2025.1655768. eCollection 2025. PMID- 41143244 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251027 LR - 20251029 IS - 1663-4365 (Print) IS - 1663-4365 (Electronic) IS - 1663-4365 (Linking) VI - 17 DP - 2025 TI - Metabolic Parkinson's disease. PG - 1665957 LID - 10.3389/fnagi.2025.1665957 [doi] LID - 1665957 AB - Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. While most cases are sporadic, there is growing evidence of a link between PD and metabolic dysfunctions such as type 2 diabetes mellitus, obesity, and metabolic syndrome. Proposed pathogenic mechanisms underlying this overlap include insulin resistance and chronic inflammation. Similar patterns of cellular damage are observed in both metabolic disorders and PD, including mitochondrial dysfunction, impaired autophagy, oxidative stress, endoplasmic reticulum stress, and gut microbiota alterations. Given the current lack of disease-modifying therapies for PD, there is increasing interest in interventions traditionally used to treat metabolic conditions, such as lifestyle and dietary modifications. Notably, antidiabetic drugs like metformin and incretin mimetics have shown beneficial effects in PD due to their neuroprotective and anti-inflammatory properties, their ability to restore insulin sensitivity, and their role in reducing neuronal susceptibility to toxic insults, as demonstrated in both preclinical and clinical studies. Conversely, traditionally antiparkinsonian drugs such as bromocriptine have long been approved for improving glycemic control in diabetes. This cross-efficacy between drugs used for the two conditions may indirectly support the hypothesis of a shared pathogenesis. A deeper understanding of the connections between metabolic disorders and PD could pave the way for novel preventive and therapeutic strategies. CI - Copyright (c) 2025 Invernizzi, Ciocca, Contaldi, Inverso, Calandrella, Mignone, Barichella, Isaias and Pezzoli. FAU - Invernizzi, Federica AU - Invernizzi F AD - Center for Liver disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan, Italy. FAU - Ciocca, Lorenzo AU - Ciocca L AD - Center for Liver disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan, Italy. AD - Vita-Salute San Raffaele University, Milan, Italy. FAU - Contaldi, Elena AU - Contaldi E AD - Parkinson Institute of Milan, ASST G.Pini-CTO, Milan, Italy. FAU - Inverso, Donato AU - Inverso D AD - Vita-Salute San Raffaele University, Milan, Italy. AD - Division of Immunology, Transplantation, and infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. FAU - Calandrella, Daniela AU - Calandrella D AD - Parkinson Institute of Milan, ASST G.Pini-CTO, Milan, Italy. AD - Fondazione Pezzoli per la Malattia di Parkinson, Milan, Italy. FAU - Mignone, Francesco AU - Mignone F AD - Vita-Salute San Raffaele University, Milan, Italy. FAU - Barichella, Michela AU - Barichella M AD - Clinical Nutrition Unit, ASST G.Pini-CTO, Milan, Italy. FAU - Isaias, Ioannis Ugo AU - Isaias IU AD - Parkinson Institute of Milan, ASST G.Pini-CTO, Milan, Italy. AD - University Hospital of Wurzburg and Julius Maximilian University of Wurzburg, Wurzburg, Germany. FAU - Pezzoli, Gianni AU - Pezzoli G AD - Parkinson Institute of Milan, ASST G.Pini-CTO, Milan, Italy. AD - Fondazione Pezzoli per la Malattia di Parkinson, Milan, Italy. LA - eng PT - Journal Article PT - Review DEP - 20251010 PL - Switzerland TA - Front Aging Neurosci JT - Frontiers in aging neuroscience JID - 101525824 PMC - PMC12549673 OTO - NOTNLM OT - GLP-1/GIP RA OT - Obesity OT - Parkinson's disease OT - diabetes OT - metabolic sybdrome COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/10/27 15:18 MHDA- 2025/10/27 15:19 PMCR- 2025/10/10 CRDT- 2025/10/27 07:29 PHST- 2025/07/14 00:00 [received] PHST- 2025/09/25 00:00 [accepted] PHST- 2025/10/27 15:19 [medline] PHST- 2025/10/27 15:18 [pubmed] PHST- 2025/10/27 07:29 [entrez] PHST- 2025/10/10 00:00 [pmc-release] AID - 10.3389/fnagi.2025.1665957 [doi] PST - epublish SO - Front Aging Neurosci. 2025 Oct 10;17:1665957. doi: 10.3389/fnagi.2025.1665957. eCollection 2025. PMID- 41132242 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251024 LR - 20251027 IS - 1918-3003 (Print) IS - 1918-3011 (Electronic) IS - 1918-3003 (Linking) VI - 17 IP - 9 DP - 2025 Oct TI - Adenosine Monophosphate-Activated Protein Kinase Activation and Mammalian Target of Rapamycin Complex 1 Inhibition: A Mechanistic Rationale for Anti-Aging Therapy in Type 2 Diabetes. PG - 469-489 LID - 10.14740/jocmr6370 [doi] AB - Aging is a complicated biological process that induces a decline in the human organs' structure and function and elevates the risks of aging-related diseases such as Alzheimer's disease (AD) and type 2 diabetes. Type 2 diabetes accelerates all clinical manifestations of aging. Metabolic disorders in type 2 diabetes are unfavorably associated with all hallmarks of aging, such as inflammation and mitochondrial dysfunction. Adenosine monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1) are key players in cellular metabolism, and AMPK activation and mTORC1 inhibition improve all hallmarks of aging. AMPK activation and mTORC1 inhibition are favorably associated with diabetic complications. Nutritional interventions, such as caloric restriction, resveratrol, and astaxanthin, have AMPK-activating and mTORC1-inhibitory effects and improve metabolic abnormalities in type 2 diabetes. Anti-diabetic drugs, metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists have been reported to have AMPK-activating and mTORC1-inhibiting effects and show prevention of aging-related diseases such as cardiovascular disease. The therapeutic interventions that activate AMPK and inhibit mTORC1 may be optimal treatments for type 2 diabetes from the perspective of anti-aging medicine. Furthermore, senolytics may be a promising, direct anti-aging therapeutic strategy specifically for type 2 diabetes and its complications. CI - Copyright 2025 Authors. FAU - Yanai, Hidekatsu AU - Yanai H AD - Department of Diabetes, Endocrinology and Metabolism, National Kohnodai Medical Center, Japan Institute for Health Security, Chiba, Japan. FAU - Adachi, Hiroki AU - Adachi H AD - Department of Diabetes, Endocrinology and Metabolism, National Kohnodai Medical Center, Japan Institute for Health Security, Chiba, Japan. FAU - Hakoshima, Mariko AU - Hakoshima M AD - Department of Diabetes, Endocrinology and Metabolism, National Kohnodai Medical Center, Japan Institute for Health Security, Chiba, Japan. FAU - Katsuyama, Hisayuki AU - Katsuyama H AD - Department of Diabetes, Endocrinology and Metabolism, National Kohnodai Medical Center, Japan Institute for Health Security, Chiba, Japan. LA - eng PT - Journal Article PT - Review DEP - 20251015 PL - Canada TA - J Clin Med Res JT - Journal of clinical medicine research JID - 101538301 PMC - PMC12542718 OTO - NOTNLM OT - AMP-activated protein kinase OT - Aging OT - Mammalian target of rapamycin complex 1 OT - Metformin OT - Type 2 diabetes COIS- The authors declare that they have no conflict of interest concerning this article. EDAT- 2025/10/24 06:26 MHDA- 2025/10/24 06:27 PMCR- 2025/10/15 CRDT- 2025/10/24 04:44 PHST- 2025/08/28 00:00 [received] PHST- 2025/10/04 00:00 [accepted] PHST- 2025/10/24 06:27 [medline] PHST- 2025/10/24 06:26 [pubmed] PHST- 2025/10/24 04:44 [entrez] PHST- 2025/10/15 00:00 [pmc-release] AID - 10.14740/jocmr6370 [doi] PST - epublish SO - J Clin Med Res. 2025 Oct 15;17(9):469-489. doi: 10.14740/jocmr6370. eCollection 2025 Oct. PMID- 41126557 OWN - NLM STAT- MEDLINE DCOM- 20251203 LR - 20260623 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 28 IP - 1 DP - 2026 Jan TI - Antidiabetic agents and dementia risk in type 2 diabetes: A systematic review and network meta-analysis. PG - 256-264 LID - 10.1111/dom.70182 [doi] AB - AIMS: Certain antidiabetic agents may prevent dementia in patients with type 2 diabetes mellitus (T2DM). The purpose of this study is to elucidate the relative effect of antidiabetic agents on reducing dementia risk in patients with T2DM. MATERIALS AND METHODS: PubMed, Cochrane Library and Igaku Chuo Zasshi-Web from inception to 31 December 2023 were searched. Trials reported in English or Japanese language that assessed the effects of glucose-lowering drugs on dementia were selected. RESULTS: Overall, 67 trials (4 088 683 individuals) assessing nine antidiabetic agent classes were included. Studies comprised monotherapies versus control (no use of antidiabetic agents or placebo) (three trials), monotherapies versus add-on therapies (one trial) and real-world database studies (63 trials). The analysis showed that the risk of dementia decreased with sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP4i) compared with the reference (placebo, no use of antidiabetic agents or other antidiabetic agents). Conversely, insulin was associated with an increased risk of dementia, whereas no significant association was found with the use of metformin, sulfonylureas, glinides and alpha-glucosidase inhibitors. Analyses of treatment rankings further revealed the relative effect on reducing dementia risk in the following order: SGLT2i > GLP1-RA > TZD > DPP4i; insulin ranked the lowest. CONCLUSIONS: The most effective antidiabetic agent in reducing dementia risk in T2DM is SGLT2i, followed by GLP1-RA, TZD and DPP4i, whereas insulin is associated with an elevated risk of dementia. CI - (c) 2025 John Wiley & Sons Ltd. FAU - Kato, Sayaka AU - Kato S AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. AD - Department of Metabolism and Endocrinology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan. FAU - Ozu, Naoki AU - Ozu N AUID- ORCID: 0009-0004-8790-587X AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Institute for Clinical and Translational Science, Nara Medical University Hospital, Nara, Japan. FAU - Yamakage, Hajime AU - Yamakage H AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Department of Metabolic Research, Geroscience Research Center, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan. FAU - Kato, Hisashi AU - Kato H AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Department of Metabolic Research, Geroscience Research Center, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan. FAU - Iuchi, Takujiro AU - Iuchi T AD - Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan. AD - Department of Diabetes, Samukawa Hospital, Kanagawa, Japan. FAU - Suzuki, Ryo AU - Suzuki R AD - Department of Diabetes, Metabolism and Endocrinology, Tokyo Medical University, Tokyo, Japan. FAU - Noto, Hiroshi AU - Noto H AD - Division of Endocrinology and Metabolism, St. Luke's International Hospital, Tokyo, Japan. FAU - Tanaka, Masashi AU - Tanaka M AUID- ORCID: 0000-0003-0719-8972 AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Department of Metabolic Research, Geroscience Research Center, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan. AD - Department of Rehabilitation, Health Science University, Yamanashi, Japan. FAU - Fukui, Michiaki AU - Fukui M AD - Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. FAU - Noda, Mitsuhiko AU - Noda M AD - Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan. AD - Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Chiba, Japan. FAU - Satoh-Asahara, Noriko AU - Satoh-Asahara N AUID- ORCID: 0000-0002-8645-3144 AD - Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, NHO Kyoto Medical Center, Kyoto, Japan. AD - Department of Metabolic Research, Geroscience Research Center, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan. AD - Department of Diabetes and Endocrinology, Hospital, National Center for Geriatrics and Gerontology, Aichi, Japan. AD - Department of Clinical Laboratory, Hospital, National Center for Geriatrics and Gerontology, Aichi, Japan. LA - eng SI - UMIN-CTR/UMIN000042499 GR - JP17dk0207038/Japan Agency for Medical Research and Development/ PT - Journal Article PT - Network Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20251022 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Hypoglycemic Agents/therapeutic use MH - *Dementia/prevention & control/epidemiology/etiology MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Risk Factors OTO - NOTNLM OT - antidiabetic agents OT - dementia OT - network meta-analysis OT - type 2 diabetes EDAT- 2025/10/23 06:27 MHDA- 2025/12/03 14:11 CRDT- 2025/10/23 02:12 PHST- 2025/09/14 00:00 [revised] PHST- 2025/06/25 00:00 [received] PHST- 2025/09/26 00:00 [accepted] PHST- 2025/12/03 14:11 [medline] PHST- 2025/10/23 06:27 [pubmed] PHST- 2025/10/23 02:12 [entrez] AID - 10.1111/dom.70182 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Jan;28(1):256-264. doi: 10.1111/dom.70182. Epub 2025 Oct 22. PMID- 41123870 OWN - NLM STAT- MEDLINE DCOM- 20260319 LR - 20261009 IS - 1179-1942 (Electronic) IS - 0114-5916 (Linking) VI - 49 IP - 4 DP - 2026 Apr TI - Incretin-Based Drugs and the Risk of Dementia Among Patients with Type 2 Diabetes. PG - 419-434 LID - 10.1007/s40264-025-01623-9 [doi] AB - BACKGROUND: Incretin-based drugs, namely glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, may have neuroprotective effects. Thus, we assessed whether these drugs are associated with a decreased risk of dementia among patients with type 2 diabetes. METHODS: Using the Clinical Practice Research Datalink from the UK, we formed two new user cohorts of patients at least 50 years of age with type 2 diabetes starting incretin-based drugs or sulfonylureas between 2007 and 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia were estimated separately for GLP-1 RAs and DPP-4 inhibitors using Cox proportional hazards models with propensity score fine-stratification weighting and inverse probability of censoring weights. RESULTS: Among 275,144 initiators of DPP-4 inhibitors or sulfonylureas, followed for 750,846 person-years, DPP-4 inhibitors were associated with a reduced dementia risk compared with sulfonylureas (4.4 vs. 5.7 events per 1000 person-years; HR 0.77, 95% CI 0.71-0.85). HRs decreased with increasing cumulative duration of use and dose. Similar associations were observed across dementia subtypes and individual DPP-4 inhibitors molecules. Among 181,215 initiators of GLP-1 RAs or sulfonylureas, followed for 530,415 person-years, GLP-1 RAs were associated with a similar reduction in dementia risk compared with sulfonylureas, although with high uncertainty (2.3 vs. 3.1 events per 1000 person-years; HR 0.74, 95% CI 0.46-1.18). The magnitude of the association increased with cumulative duration of use and dose but with high uncertainty. CONCLUSIONS: In this population-based study, DPP-4 inhibitors, and possibly GLP-1 RAs, were associated with a reduced dementia risk compared with sulfonylureas. CI - (c) 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Wang, Yun-Han AU - Wang YH AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. FAU - Johnson, Kyle AU - Johnson K AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. FAU - Beradid, Sarah AU - Beradid S AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. FAU - Yin, Hui AU - Yin H AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. FAU - Yu, Oriana H Y AU - Yu OHY AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. AD - Division of Endocrinology, Jewish General Hospital, Montreal, Canada. FAU - Suissa, Samy AU - Suissa S AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. AD - Department of Medicine, McGill University, Montreal, Canada. FAU - Azoulay, Laurent AU - Azoulay L AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. AD - Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada. FAU - Renoux, Christel AU - Renoux C AUID- ORCID: 0000-0002-4691-9579 AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. christel.renoux@mcgill.ca. AD - Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine H 416.1, Montreal, QC, H3T 1E2, Canada. christel.renoux@mcgill.ca. AD - Department of Medicine, McGill University, Montreal, Canada. christel.renoux@mcgill.ca. AD - Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. christel.renoux@mcgill.ca. LA - eng GR - PJT-180357/CAPMC/CIHR/Canada GR - PJT-180357/CAPMC/CIHR/Canada PT - Journal Article DEP - 20251022 PL - New Zealand TA - Drug Saf JT - Drug safety JID - 9002928 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Incretins) RN - 0 (Sulfonylurea Compounds) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - *Dementia/epidemiology/prevention & control MH - Male MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/administration & dosage MH - *Incretins/therapeutic use/administration & dosage MH - Female MH - Aged MH - Middle Aged MH - Sulfonylurea Compounds/therapeutic use/administration & dosage MH - *Hypoglycemic Agents/therapeutic use/administration & dosage MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Cohort Studies MH - United Kingdom/epidemiology COIS- Declarations. Conflict of Interest: SS attended scientific advisory committee meetings for Atara, Bristol-Myers-Squibb, Merck, Novartis, Pfizer and Seqirus, and received speaking fees from Boehringer-Ingelheim and Novartis. LA served as a consultant for Roche and Pfizer for work unrelated to this study. LA is an Editorial Board member of Drug Safety. LA was not involved in the selection of peer reviewers for the manuscript nor in any of the subsequent editorial decisions. The other authors have no conflicts of interest to declare. Data Availability: This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the UK National Health Service as part of their care and support. The interpretation and conclusions contained in this study are those of the authors alone. Because electronic health records are classified as "sensitive data" by the UK Data Protection Act, information governance restrictions (to protect patient confidentiality) prevent data sharing via public deposition. Data are available with approval through the individual constituent entities controlling access to the data. Specifically, the primary-care data can be requested via application to the Clinical Practice Research Datalink ( https://www.cprd.com ). Ethics Approval: The study protocol was approved by the CPRD Research Data Governance (No. 22_001853) and the Research Ethics Board of the Jewish General Hospital, Montreal, Canada. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Code Availability: Codes may be made privately available upon reasonable request to the corresponding author. Author Contributions: YHW, LA, and CR conceived and designed the study and were involved in the analysis and interpretation of the results. All authors contributed to the study design, analysis, and interpretation of the results. Analyses were performed by YHW and SB. The first draft of the manuscript was written by YHW, with editing by KJ and CR. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. CR and LA obtained funding and CR supervised the study. EDAT- 2025/10/22 12:30 MHDA- 2026/03/19 21:44 CRDT- 2025/10/22 11:25 PHST- 2025/05/26 00:00 [received] PHST- 2025/09/24 00:00 [accepted] PHST- 2026/03/19 21:44 [medline] PHST- 2025/10/22 12:30 [pubmed] PHST- 2025/10/22 11:25 [entrez] AID - 10.1007/s40264-025-01623-9 [pii] AID - 10.1007/s40264-025-01623-9 [doi] PST - ppublish SO - Drug Saf. 2026 Apr;49(4):419-434. doi: 10.1007/s40264-025-01623-9. Epub 2025 Oct 22. PMID- 41122341 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251022 LR - 20251024 IS - 2542-4823 (Electronic) IS - 2542-4823 (Linking) VI - 9 DP - 2025 Jan-Dec TI - Exploring the neuroprotective role of GLP-1 agonists against Alzheimer's disease: Real-world evidence from a propensity-matched cohort. PG - 25424823251388650 LID - 10.1177/25424823251388650 [doi] LID - 25424823251388650 AB - BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia with societal and economic burdens. While recent therapies offer disease-modifying potential, concerns remain about efficacy and safety. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in type 2 diabetes, show neuroprotective effects via reduced neuroinflammation and amyloid burden. OBJECTIVE: To evaluate whether GLP-1RA use is associated with a reduced risk of incident dementia in adults aged >/=50 years using real-world data. METHODS: We conducted a retrospective cohort study using the TriNetX platform, analyzing records from 142 healthcare organizations. Adults aged >/=50 were included, comparing GLP-1RA users (liraglutide, semaglutide, dulaglutide, exenatide, albiglutide) to non-users. Propensity-score matching balanced demographics and comorbidities. Incident dementia, defined by ICD-10 codes, was analyzed with Cox proportional-hazards models. RESULTS: Matched cohorts (n = 147,505 each) had similar baseline characteristics. Dementia incidence was lower in GLP-1RA users (0.20% versus 0.44%), with a hazard ratio of 0.30 (95% CI 0.28-0.33; p < 0.001). CONCLUSIONS: GLP-1RA use was associated with a 70% reduced dementia risk, warranting further clinical evaluation. CI - (c) The Author(s) 2025. FAU - AbuAlrob, Majd A AU - AbuAlrob MA AUID- ORCID: 0000-0002-9707-9266 AD - Neurosciences Department, Hamad Medical Corporation, Doha, Qatar. RINGGOLD: 36977 FAU - Itbaisha, Adham AU - Itbaisha A AD - Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine. RINGGOLD: 61147 FAU - Abujwaid, Yahya Kayed AU - Abujwaid YK AD - Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine. RINGGOLD: 61147 FAU - Abulehia, Ayah AU - Abulehia A AD - Faculty of Medicine, Al-Quds University, East Jerusalem, Palestine. RINGGOLD: 61147 FAU - Hussein, Abdallah AU - Hussein A AD - Department of Internal Medicine, Virtua Health, Camden, NJ, USA. RINGGOLD: 5948 FAU - Mesraoua, Boulenouar AU - Mesraoua B AD - Neurosciences Department, Hamad Medical Corporation, Doha, Qatar. RINGGOLD: 36977 AD - Weill Cornell Medicine-Qatar, Doha, Qatar. LA - eng PT - Journal Article DEP - 20251016 PL - United States TA - J Alzheimers Dis Rep JT - Journal of Alzheimer's disease reports JID - 101705500 PMC - PMC12536097 OTO - NOTNLM OT - Alzheimer's disease OT - diabetes OT - glucagon-like peptide-1 receptor agonists COIS- The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2025/10/22 06:32 MHDA- 2025/10/22 06:33 PMCR- 2025/10/16 CRDT- 2025/10/22 04:17 PHST- 2025/08/11 00:00 [received] PHST- 2025/09/23 00:00 [accepted] PHST- 2025/10/22 06:33 [medline] PHST- 2025/10/22 06:32 [pubmed] PHST- 2025/10/22 04:17 [entrez] PHST- 2025/10/16 00:00 [pmc-release] AID - 10.1177_25424823251388650 [pii] AID - 10.1177/25424823251388650 [doi] PST - epublish SO - J Alzheimers Dis Rep. 2025 Oct 16;9:25424823251388650. doi: 10.1177/25424823251388650. eCollection 2025 Jan-Dec. PMID- 41104525 OWN - NLM STAT- MEDLINE DCOM- 20260317 LR - 20260819 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 28 IP - 4 DP - 2026 Apr TI - Effects of GLP-1 receptor agonists on cognitive function in patients with type 2 diabetes: A systematic review and meta-analysis based on randomized controlled trials. PG - 3396-3407 LID - 10.1111/dom.70201 [doi] AB - AIMS: Patients with type 2 diabetes mellitus (T2DM) have a significantly increased risk of cognitive impairment, and the protective effects of traditional hypoglycaemic drugs on cognitive function remain unclear. This study systematically evaluated the neuroprotective effects of GLP-1 receptor agonists (GLP-1RAs) based on randomized controlled trial (RCT) evidence, aiming to provide key evidence-based insights for optimizing diabetes management strategies. MATERIALS AND METHODS: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, and ClinicalTrials.gov databases to identify studies investigating the impact of GLP-1RAs on cognitive function in T2DM patients, with the search timeframe extending up to July 2025. The analysis focused on RCTs comparing the effects of GLP-1RAs versus placebo (or conventional therapy) on neurocognitive function in T2DM patients. RESULTS: Based on the inclusion criteria, 18 RCTs involving 11 114 participants were included in the primary meta-analysis. Pooled results demonstrated that, compared to the placebo group, GLP-1RA treatment significantly increased Mini-Mental State Examination (MMSE) scores by a weighted mean difference (WMD) of 1.33 (95% CI: 0.67-1.99; I(2) = 82%) and Montreal Cognitive Assessment (MoCA) scores by a WMD of 1.70 (95% CI: 0.83-2.56; I(2) = 96%). The effect size on MMSE was significantly greater with long-term GLP-1RA use (>/=24 weeks) compared to short-term use (<24 weeks) (mean difference = 3.74; t = 6.52, df = 269, p < 0.0001; Cohen's d = 0.79). Sensitivity analyses yielded results closely aligned with the primary analysis, indicating robust stability. Jadad scale assessment confirmed that all included studies achieved a score >/=3. CONCLUSIONS: Current evidence indicates that GLP-1 RA-based therapy may improve cognitive function in patients with type 2 diabetes mellitus compared with placebo. Furthermore, long-term administration or early initiation of GLP-1 RA treatment may offer greater cognitive benefits. CI - (c) 2025 John Wiley & Sons Ltd. FAU - Wan, Suxin AU - Wan S AD - Department of Pharmacy, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China. FAU - Yan, He AU - Yan H AD - Department of Endocrinology and Metabolism, Three Gorges Hospital, Chongqing University, Chongqing, China. FAU - Sun, Qiu-Yan AU - Sun QY AD - Department of Pharmacy, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China. FAU - Zhu, Jia-Quan AU - Zhu JQ AD - Fengdu General Hospital & Department of Pharmacy, Chongqing, China. FAU - Wang, Hui-Hong AU - Wang HH AD - Department of Pharmacy, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China. FAU - Qu, Ke-Yi AU - Qu KY AUID- ORCID: 0009-0003-0402-1570 AD - Fengdu General Hospital & Department of Stomatology, Chongqing, China. FAU - Yi, Xiang AU - Yi X AD - Department of Liver Disease, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China. LA - eng GR - YXQN202401/Chongqing Medical Young Elite Talent Program/ PT - Journal Article PT - Meta-Analysis PT - Retracted Publication PT - Systematic Review DEP - 20251017 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM RIN - Diabetes Obes Metab. 2026 Apr;28(4):3451. doi: 10.1111/dom.70552. PMID: 41667890 MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/psychology/complications MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Randomized Controlled Trials as Topic MH - *Cognition/drug effects MH - *Hypoglycemic Agents/therapeutic use MH - *Cognitive Dysfunction/prevention & control/etiology OTO - NOTNLM OT - GLP-1 receptor agonists OT - cognitive impairment OT - meta-analysis OT - systematic review OT - type 2 diabetes mellitus EDAT- 2025/10/17 06:26 MHDA- 2026/03/17 06:47 CRDT- 2025/10/17 05:42 PHST- 2025/10/03 00:00 [revised] PHST- 2025/07/31 00:00 [received] PHST- 2025/10/04 00:00 [accepted] PHST- 2026/03/17 06:47 [medline] PHST- 2025/10/17 06:26 [pubmed] PHST- 2025/10/17 05:42 [entrez] AID - 10.1111/dom.70201 [doi] PST - ppublish SO - Diabetes Obes Metab. 2026 Apr;28(4):3396-3407. doi: 10.1111/dom.70201. Epub 2025 Oct 17. PMID- 41098220 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251016 LR - 20251018 IS - 1650-3414 (Electronic) IS - 1650-3414 (Linking) VI - 36 IP - 3 DP - 2025 Oct TI - Inflammation: The Mother of All Diseases Meets the Mother of All Therapies. PG - 236-243 AB - INTRODUCTION: Incretins are small peptides secreted by the gastrointestinal tract. These peptides exert their action by binding to G-protein-coupled receptors that are widely distributed in the pancreas, throughout the gastrointestinal tract, and the brain. The physiological role of incretins (such as GLP-1) is to regulate glucose levels by increasing insulin secretion, delaying gastric emptying, and decreasing appetite, leading to weight loss. METHOD: In this review, we aimed to report the effects of inflammation on human health and how GLP-1 and GLP-1 receptor agonists, which are now being used as first-line agents to control obesity, can have a broader effect on human diseases. RESULTS: The literature shows the benefits of these drugs in diseases other than obesity, including in diseases of many organs such as heart, kidneys, liver, blood vessels, and in neurodegenerative and psychiatric conditions. These diverse beneficial effects are attributed to the anti-inflammatory activities of these new drugs. CONCLUSIONS: The physiological actions of incretins have recently been better understood. The surprisingly diverse therapeutic activities of this class of new drugs suggest that they will likely play central roles not only in the management of type-2 diabetes but for the treatment of obesity and a wide spectrum of diseases for which inflammation is a major factor. CI - Copyright (c) 2025 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved. FAU - Chatanaka, Miyo K AU - Chatanaka MK AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. FAU - Diamandis, Eleftherios P AU - Diamandis EP AD - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. LA - eng PT - Journal Article PT - Review DEP - 20251001 PL - Italy TA - EJIFCC JT - EJIFCC JID - 101092742 PMC - PMC12519629 OTO - NOTNLM OT - GLP-1 OT - GLP-1 side effects OT - Incretins OT - Type-2 diabetes OT - inflammation OT - obesity OT - peptide therapeutics OT - weight loss EDAT- 2025/10/16 06:30 MHDA- 2025/10/16 06:31 PMCR- 2025/10/01 CRDT- 2025/10/16 04:36 PHST- 2025/10/16 06:31 [medline] PHST- 2025/10/16 06:30 [pubmed] PHST- 2025/10/16 04:36 [entrez] PHST- 2025/10/01 00:00 [pmc-release] AID - ejifcc-36-03-236 [pii] PST - epublish SO - EJIFCC. 2025 Oct 1;36(3):236-243. eCollection 2025 Oct. PMID- 41095837 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251016 LR - 20251019 IS - 2077-0383 (Print) IS - 2077-0383 (Electronic) IS - 2077-0383 (Linking) VI - 14 IP - 19 DP - 2025 Sep 24 TI - GLP-1 Agonists in Cardiovascular Diseases: Mechanisms, Clinical Evidence, and Emerging Therapies. LID - 10.3390/jcm14196758 [doi] LID - 6758 AB - Glucagon-like peptide-1 (GLP-1) receptor agonists now serve as therapeutic agents for cardiovascular diseases (CVDs) beyond their original use for treating type 2 diabetes mellitus (T2DM). This review combines molecular mechanisms with clinical evidence to demonstrate how GLP-1 agonists help lower cardiovascular risk for conditions, including atherosclerosis, heart failure, stroke, and vascular dementia. These agents produce multiple beneficial effects, which include anti-inflammatory action along with anti-atherogenic effects, endothelial-protective benefits, and cardioprotective actions to minimize major adverse cardiovascular events (MACEs). GLP-1 agonists achieved substantial reductions in myocardial infarction, stroke, cardiovascular mortality, and heart failure events according to major cardiovascular outcome trials (CVOTs). Recent research, notably the pivotal SELECT trial, has confirmed their suitability for non-diabetic subjects with obesity and established CVD. New drug delivery methods and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists demonstrate potent efficacy, with tirzepatide showing significant MACE reduction in its own CVOT. However, significant challenges related to high cost, long-term safety uncertainties, and implementation barriers remain, requiring a balanced perspective. The review presents both mechanistic data and clinical evidence to demonstrate how GLP-1 agonists function as vital cardiovascular medications and outlines future research directions to address critical evidence gaps and maximize their therapeutic effectiveness. FAU - Yang, Han-Mo AU - Yang HM AUID- ORCID: 0000-0002-1548-2351 AD - Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea. LA - eng GR - RS-2025-02263992/Ministry of Health & Welfare, Republic of Korea./ PT - Journal Article PT - Review DEP - 20250924 PL - Switzerland TA - J Clin Med JT - Journal of clinical medicine JID - 101606588 PMC - PMC12525426 OTO - NOTNLM OT - GLP-1 receptor agonists OT - atherosclerosis, heart failure OT - cardiovascular diseases OT - dual GLP-1/GIP agonists, cardiovascular outcome trials, inflammation OT - stroke, vascular dementia OT - type 2 diabetes COIS- The author declares no conflicts of interest. EDAT- 2025/10/16 06:30 MHDA- 2025/10/16 06:31 PMCR- 2025/09/24 CRDT- 2025/10/16 01:08 PHST- 2025/07/23 00:00 [received] PHST- 2025/08/10 00:00 [revised] PHST- 2025/08/16 00:00 [accepted] PHST- 2025/10/16 06:31 [medline] PHST- 2025/10/16 06:30 [pubmed] PHST- 2025/10/16 01:08 [entrez] PHST- 2025/09/24 00:00 [pmc-release] AID - jcm14196758 [pii] AID - jcm-14-06758 [pii] AID - 10.3390/jcm14196758 [doi] PST - epublish SO - J Clin Med. 2025 Sep 24;14(19):6758. doi: 10.3390/jcm14196758. PMID- 41091899 OWN - NLM STAT- MEDLINE DCOM- 20260515 LR - 20260515 IS - 1497-0015 (Electronic) IS - 0706-7437 (Print) IS - 0706-7437 (Linking) VI - 71 IP - 6 DP - 2026 Jun TI - GLP-1 Receptor Agonists as a Novel Solution for Antipsychotic-Induced Weight Gain in Severe and Persistent Mental Illness. PG - 413-419 LID - 10.1177/07067437251386626 [doi] AB - Patients with severe and persistent mental illness (SPMI) experience significant metabolic side effects from antipsychotic medications, including antipsychotic-induced weight gain (AIWG). This contributes to a high prevalence of obesity, insulin resistance, and type 2 diabetes in this population, ultimately reducing life expectancy. Traditional weight management strategies, such as behavioural interventions, are often less feasible in this group. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes, have shown promise in addressing AIWG by reducing weight, improving metabolic parameters, and offering potential neuroprotective and psychiatric benefits. Evidence supports the efficacy of GLP-1RAs in managing AIWG, with studies demonstrating substantial reductions in weight and body mass index without exacerbating psychiatric symptoms. However, access to these medications remains limited due to high costs and restrictive healthcare policies. Expanding access to GLP-1RAs could bridge a critical gap in care for patients with SPMI, improving both physical and mental health outcomes. Future research should focus on evaluating long-term efficacy and cost-effectiveness, particularly in the Canadian healthcare context, to inform policy changes and optimize treatment strategies.Plain Language Summary TitleCan diabetes medications help treat weight gain caused by antipsychotics? FAU - Jacobson, Samantha AU - Jacobson S AUID- ORCID: 0009-0005-9665-8361 AD - Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada. RINGGOLD: 12370 FAU - Margolese, Noah AU - Margolese N AD - Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada. RINGGOLD: 12370 FAU - Margolese, Howard C AU - Margolese HC AD - Department of Psychiatry, McGill University Health Centre, Montreal, Canada. RINGGOLD: 54473 LA - eng PT - Journal Article PT - Review DEP - 20251015 PL - United States TA - Can J Psychiatry JT - Canadian journal of psychiatry. Revue canadienne de psychiatrie JID - 7904187 RN - 0 (Antipsychotic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Antipsychotic Agents/adverse effects MH - *Weight Gain/drug effects MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Mental Disorders/drug therapy MH - *Obesity/chemically induced/drug therapy PMC - PMC12528064 OAB - People with serious mental illnesses, like schizophrenia, often take antipsychotic medications. While these drugs are important for managing symptoms, many cause rapid weight gain. This side effect can lead to physical health problems, worsen mental health, and make people stop taking their medication. Unfortunately, current weight-loss strategies are often unrealistic for people with severe mental illness. This study explores whether a group of medications called GLP-1 receptor agonists, originally developed to treat diabetes, could help reduce this medication-related weight gain. GLP-1RAs led to meaningful weight loss, even in patients who hadn't responded to other medications like metformin. These drugs also helped lower blood sugar and improve other health markers. Some studies even showed that GLP-1RAs might reduce psychiatric symptoms and risks of conditions like substance use, suicide, and dementia. However, side effects such as nausea and vomiting were common, especially at the beginning of treatment. Access remains limited due to high costs and lack of public insurance coverage in many regions. This highlights a new way to support people who struggle with weight gain from antipsychotics. If made more accessible, GLP-1RAs could help patients stay on their medications, improve both mental and physical health, and reduce long-term healthcare costs. More studies are needed, especially in psychiatric populations, but this treatment option shows promise for improving quality of life in a group that often faces major health inequalities. OABL- eng OTO - NOTNLM OT - adherence OT - antipsychotics OT - healthcare policy OT - schizophrenia COIS- Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Howard Margolese disclosures: 1. Membership on advisory board or speakers' bureaus or consultant: Abbvie, Bausch Health, BI, HLS, Janssen, Newron, Otsuka, Lundbeck, Teva. 2. Funded grants, research, or clinical trials: AIFred, MGH Foundation, Newron, SyneuRx. 3. Volunteer/Advocacy: President, EPI Canada 2025-2027, Early Psychosis Intervention Canada. The remaining authors have no conflicts of interest to declare. EDAT- 2025/10/15 18:28 MHDA- 2026/05/15 17:36 PMCR- 2026/10/15 CRDT- 2025/10/15 14:03 PHST- 2026/05/15 17:36 [medline] PHST- 2025/10/15 18:28 [pubmed] PHST- 2025/10/15 14:03 [entrez] PHST- 2026/10/15 00:00 [pmc-release] AID - 10.1177_07067437251386626 [pii] AID - 10.1177/07067437251386626 [doi] PST - ppublish SO - Can J Psychiatry. 2026 Jun;71(6):413-419. doi: 10.1177/07067437251386626. Epub 2025 Oct 15. PMID- 41088211 OWN - NLM STAT- MEDLINE DCOM- 20251015 LR - 20260903 IS - 1475-2840 (Electronic) IS - 1475-2840 (Linking) VI - 24 IP - 1 DP - 2025 Oct 14 TI - Genetic variation in the glucagon-like peptide-1 receptor protein encoding region is associated with higher heart rate variability, but not with neurodegeneration of the brain, retina, and peripheral nerves: The Maastricht study. PG - 397 LID - 10.1186/s12933-025-02888-1 [doi] LID - 397 AB - BACKGROUND: Degeneration of organ-specific nervous systems precede major clinical conditions such as heart failure, dementia, diabetic retinopathy, and diabetic neuropathy. Glucagon-like peptide-1 receptor (GLP1R) agonists may have neuroprotective effects, independent of their glucose-lowering effects, and as such may be tools for early prevention of neurodegeneration. We investigated whether genetic variation in the GLP1R protein encoding region, assessed using a genetic score, was associated with neurodegeneration measured in the heart, brain, retina, and peripheral nerves. METHODS: Data from up to 7446 individuals from The Maastricht Study were used (mean [standard deviation (SD)] age 59.5 ([8.7] years, 49.4% men, and 20.0% with type 2 diabetes [by design]). A GLP1R score (0-8 points) was calculated using four genetic variants located in the GLP1R protein encoding region, with putative functional consequences on GLP1R activity (rs1042044, rs1004280, rs10305423, rs880067). Multivariable regression analysis was used to examine the associations between GLP1R genetic score and neural measures of the heart (time- and frequency-domain heart rate variability [HRV]), brain (magnetic resonance imaging-assessed local and global structural connectivity indices, brain volume, and global cognitive performance), retina (retinal nerve fiber layer thickness and retinal sensitivity) and peripheral nerves (conduction velocity). Associations were adjusted for age, sex, and HbA1c. Interaction with sex, age, and glucose metabolism status was examined. RESULTS: In fully adjusted analyses, higher GLP1R genetic score (corresponding to higher predicted GLP1R protein expression) was significantly associated with higher time-domain HRV (per SD higher GLP1R score, 0.031 (0.006, 0.056) SD) and similarly, but not statistically significantly, with higher frequency-domain HRV (0.024 (- 0.001, 0.048) SD). The GLP1R genetic score was not significantly associated with brain, retinal, or peripheral nerves measures. Associations did not consistently differ as a function of age, sex, or glucose metabolism status. CONCLUSIONS: Higher putative GLP1R protein expression, assessed from genetic variation in the GLP1R protein encoding region, was significantly associated with lower levels of neurodegeneration in the heart, but not in the brain, retina, and peripheral nerves. Future clinical trials should test whether use of GLP1R agonists can contribute to prevention of cardiac autonomic nerve degeneration and associated clinical disease. CI - (c) 2025. The Author(s). FAU - van der Heide, Frank C T AU - van der Heide FCT AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. frank.vander.heide@mumc.nl. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. frank.vander.heide@mumc.nl. AD - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Universite Paris Cite, Paris, France. frank.vander.heide@mumc.nl. AD - Rothschild BRAIN Lab, Adolphe de Rothschild Foundation Hospital, Paris, France. frank.vander.heide@mumc.nl. FAU - Steens, Indra L M AU - Steens ILM AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. FAU - Singh-Manoux, Archana AU - Singh-Manoux A AD - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Universite Paris Cite, Paris, France. FAU - Sabia, Severine AU - Sabia S AD - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases, Universite Paris Cite, Paris, France. FAU - Zhou, Tan Lai AU - Zhou TL AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. FAU - Kohler, Sebastian AU - Kohler S AD - Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands. AD - Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands. FAU - Schram, Miranda T AU - Schram MT AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. AD - Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands. AD - Heart and Vascular Center, MUMC+, Maastricht, The Netherlands. AD - Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. FAU - van der Kallen, Carla J H AU - van der Kallen CJH AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. FAU - Berendschot, Tos T J M AU - Berendschot TTJM AD - University Eye Clinic Maastricht, MUMC+, Maastricht, The Netherlands. FAU - Webers, Carroll A B AU - Webers CAB AD - University Eye Clinic Maastricht, MUMC+, Maastricht, The Netherlands. FAU - van Greevenbroek, Marleen M J AU - van Greevenbroek MMJ AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. FAU - Wesselius, Anke AU - Wesselius A AD - NUTRIM School for Nutrition and Translational Research in Metabolism, UM, Maastricht, The Netherlands. FAU - Arts, Ilja C W AU - Arts ICW AD - Maastricht Centre for Systems Biology, Maastricht University, Maastricht, The Netherlands. FAU - Jansen, Jacobus F A AU - Jansen JFA AD - Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands. AD - Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands. AD - Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. FAU - Backes, Walter H AU - Backes WH AD - Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands. AD - Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands. FAU - van Sloten, Thomas T AU - van Sloten TT AD - Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. FAU - Blokland, Gabriella A M AU - Blokland GAM AD - Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands. AD - Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands. FAU - Stehouwer, Coen D A AU - Stehouwer CDA AD - CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), P. Debyelaan 25, P.O. Box 5800, 6202AZ, Maastricht, The Netherlands. AD - Department of Chronic Diseases and Metabolism, KU Leuven, Belgium. LA - eng GR - 2021.81.004/Dutch Diabetes Foundation/ GR - 101043884/European Union/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20251014 PL - England TA - Cardiovasc Diabetol JT - Cardiovascular diabetology JID - 101147637 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (GLP1R protein, human) SB - IM MH - Humans MH - Male MH - Female MH - Middle Aged MH - *Glucagon-Like Peptide-1 Receptor/genetics MH - Aged MH - *Heart Rate/genetics MH - *Brain/pathology/physiopathology/diagnostic imaging MH - *Diabetes Mellitus, Type 2/genetics/physiopathology/diagnosis MH - *Retina/pathology/physiopathology/metabolism MH - *Peripheral Nerves/physiopathology/pathology/metabolism MH - *Genetic Variation MH - Phenotype MH - *Polymorphism, Single Nucleotide MH - Genetic Predisposition to Disease MH - Risk Factors PMC - PMC12519852 OTO - NOTNLM OT - Dementia OT - Diabetic retinopathy OT - GLP1R OT - Glucagon-like peptide-1 receptor OT - Heart failure OT - Neurodegeneration OT - Neuropathy COIS- Declarations. Ethics approval and consent to participate: The study was approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG). All participants gave written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. EDAT- 2025/10/15 06:30 MHDA- 2025/10/15 06:31 PMCR- 2025/10/14 CRDT- 2025/10/15 00:09 PHST- 2025/04/25 00:00 [received] PHST- 2025/07/28 00:00 [accepted] PHST- 2025/10/15 06:31 [medline] PHST- 2025/10/15 06:30 [pubmed] PHST- 2025/10/15 00:09 [entrez] PHST- 2025/10/14 00:00 [pmc-release] AID - 10.1186/s12933-025-02888-1 [pii] AID - 2888 [pii] AID - 10.1186/s12933-025-02888-1 [doi] PST - epublish SO - Cardiovasc Diabetol. 2025 Oct 14;24(1):397. doi: 10.1186/s12933-025-02888-1. PMID- 41086442 OWN - NLM STAT- MEDLINE DCOM- 20251201 LR - 20251201 IS - 1205-7541 (Electronic) IS - 0008-4212 (Linking) VI - 103 IP - 12 DP - 2025 Dec 1 TI - Anti-inflammatory properties of GLP-1 receptor agonists and other ancillary benefits from a pharmacological perspective. PG - 369-377 LID - 10.1139/cjpp-2025-0148 [doi] AB - Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chronic low-grade inflammation is a common pathological mechanism underlying metabolic, cardiovascular, hepatic, and neurodegenerative diseases. GLP-1RAs reduce systemic and tissue-specific inflammation through both direct and indirect mechanisms, including inhibition of nuclear factor kappa B signaling, reduction of proinflammatory cytokines, and modulation of immune cell activity, such as that of macrophages and microglia. In type 2 diabetes and obesity, GLP-1RAs improve insulin sensitivity and endothelial function by attenuating inflammation. In metabolic dysfunction-associated steatotic liver disease, GLP-1RAs reduce hepatic steatosis and fibrosis by modulating inflammation in hepatocytes and Kupffer cells. In cardiovascular disease, they mitigate atherosclerosis progression and improve vascular health. GLP-1RAs also exert direct nephroprotective effects by reducing renal inflammation, oxidative stress, and glomerular hyperfiltration in both diabetic and nondiabetic models. GLP-RAs have been also associated with the preservation of cognitive and motor function. Preclinical studies suggest that these neuroprotective effects may involve the attenuation of neuroinflammation and reduced aggregation of pathological proteins. Overall, these pleiotropic actions position incretin-based therapies as promising tools for the management of complex chronic diseases with an inflammatory component. FAU - Ros-Madrid, Inmaculada AU - Ros-Madrid I AUID- ORCID: 0000-0001-6862-1012 AD - Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain. RINGGOLD: 16518 AD - Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain. FAU - Cano-Marmol, Rosario Paloma AU - Cano-Marmol R AD - Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain. RINGGOLD: 16518 AD - Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain. FAU - Ferrer-Gomez, Mercedes AU - Ferrer-Gomez M AD - Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain. RINGGOLD: 16518 AD - Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain. FAU - Ramos-Molina, Bruno AU - Ramos-Molina B AD - Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain. LA - eng PT - Journal Article PT - Review DEP - 20251118 PL - Canada TA - Can J Physiol Pharmacol JT - Canadian journal of physiology and pharmacology JID - 0372712 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Anti-Inflammatory Agents/therapeutic use/pharmacology MH - *Inflammation/drug therapy/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Incretins/therapeutic use OTO - NOTNLM OT - GLP-1 receptor agonists OT - chronic inflammation OT - metabolic diseases OT - neuroprotection COIS- The authors declare there are no competing interests. EDAT- 2025/10/14 18:29 MHDA- 2025/12/01 12:28 CRDT- 2025/10/14 17:43 PHST- 2025/12/01 12:28 [medline] PHST- 2025/10/14 18:29 [pubmed] PHST- 2025/10/14 17:43 [entrez] AID - 10.1139/cjpp-2025-0148 [doi] PST - ppublish SO - Can J Physiol Pharmacol. 2025 Dec 1;103(12):369-377. doi: 10.1139/cjpp-2025-0148. Epub 2025 Nov 18. PMID- 41075815 OWN - NLM STAT- MEDLINE DCOM- 20251212 LR - 20260704 IS - 1538-9375 (Electronic) IS - 1525-8610 (Linking) VI - 26 IP - 12 DP - 2025 Dec TI - Glucagon-Like Peptide-1 Receptor Agonists and Dementia Risk Reduction in Older Adults With Type 2 Diabetes: A Retrospective Cohort Study. PG - 105901 LID - S1525-8610(25)00418-9 [pii] LID - 10.1016/j.jamda.2025.105901 [doi] AB - OBJECTIVE: To evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on dementia risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) among older adults with type 2 diabetes (T2D). DESIGN: Retrospective cohort study using an active-comparator, new-user design with propensity score matching. SETTING AND PARTICIPANTS: Data were obtained from the TriNetX Global Collaborative Network, which includes electronic health records from 134 health care organizations worldwide. Participants were adults aged >/=65 years with T2D who initiated GLP-1RA or DPP-4i therapy between January 2017 and November 2024. METHODS: Eligible participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident dementia. Secondary outcomes included prescriptions for dementia-related drugs, Alzheimer's disease, and vascular dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were performed. RESULTS: After PSM, 82,689 patients were included in each treatment group. GLP-1RA use was associated with a lower risk of dementia compared with DPP-4i (HR, 0.58; 95% CI, 0.55-0.61; P < .0001). Stratified analyses revealed consistent risk reductions across age, sex, and GLP-1RA type. In addition, GLP-1RA was also associated with lower risks of dementia-related drug prescriptions (HR, 0.76; 95% CI, 0.70-0.81), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.70), and vascular dementia (HR, 0.62; 95% CI, 0.55-0.70). Sensitivity analyses supported the robustness of these findings. CONCLUSIONS AND IMPLICATIONS: GLP-1RA use in older adults with T2D is associated with a significantly lower risk of dementia compared with DPP-4i. These findings suggest the potential neuroprotective benefits of GLP-1RAs and highlight their importance in managing T2D with a view toward reducing dementia risk. Further studies are warranted to explore the underlying mechanisms and validate these observations in randomized controlled trials. CI - Copyright (c) 2025 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved. FAU - Wu, Jheng-Yan AU - Wu JY AD - Department of Nutrition, Chi Mei Medical Center, Tainan, Taiwan; Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Lin, Yu-Min AU - Lin YM AD - Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan. FAU - Hsu, Wan-Hsuan AU - Hsu WH AD - Department of Internal Medicine, Chi Mei Medical Center, Tainan Taiwan. FAU - Liu, Ting-Hui AU - Liu TH AD - Department of Psychiatry, Chi Mei Medical Center, Tainan, Taiwan. FAU - Tsai, Ya-Wen AU - Tsai YW AD - Division of Preventive Medicine, Chi Mei Medical Center, Tainan, Taiwan. FAU - Huang, Po-Yu AU - Huang PY AD - Department of Internal Medicine, Chi Mei Medical Center, Tainan Taiwan. FAU - Chuang, Min-Hsiang AU - Chuang MH AD - Department of Internal Medicine, Chi Mei Medical Center, Tainan Taiwan. FAU - Yu, Tsung AU - Yu T AD - Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Lai, Chih-Cheng AU - Lai CC AD - Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address: dtmed141@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20251029 PL - United States TA - J Am Med Dir Assoc JT - Journal of the American Medical Directors Association JID - 100893243 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Aged MH - Retrospective Studies MH - Male MH - Female MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Dementia/prevention & control/epidemiology MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Aged, 80 and over MH - *Hypoglycemic Agents/therapeutic use MH - Propensity Score MH - *Risk Reduction Behavior OTO - NOTNLM OT - Dementia OT - dipeptidyl peptidase-4 inhibitors OT - glucagon-like peptide-1 receptor agonists OT - neuroprotection OT - older adults OT - type 2 diabetes COIS- Disclosure The authors declare no conflicts of interest. EDAT- 2025/10/12 00:34 MHDA- 2025/12/13 00:32 CRDT- 2025/10/11 19:21 PHST- 2025/06/12 00:00 [received] PHST- 2025/08/12 00:00 [revised] PHST- 2025/08/12 00:00 [accepted] PHST- 2025/12/13 00:32 [medline] PHST- 2025/10/12 00:34 [pubmed] PHST- 2025/10/11 19:21 [entrez] AID - S1525-8610(25)00418-9 [pii] AID - 10.1016/j.jamda.2025.105901 [doi] PST - ppublish SO - J Am Med Dir Assoc. 2025 Dec;26(12):105901. doi: 10.1016/j.jamda.2025.105901. Epub 2025 Oct 29. PMID- 41074575 OWN - NLM STAT- MEDLINE DCOM- 20251229 LR - 20260807 IS - 1532-6535 (Electronic) IS - 0009-9236 (Linking) VI - 119 IP - 1 DP - 2026 Jan TI - Ocular Complications of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors in T2DM Treatments: A Retrospective Real-World Cohort Study. PG - 255-266 LID - 10.1002/cpt.70087 [doi] AB - Glaucoma is a leading cause of irreversible vision loss worldwide, and type 2 diabetes mellitus (T2DM) is increasingly recognized as a risk factor for glaucoma. This study compared the effects of 3 classes of antidiabetic drugs-sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is)-on ocular and systemic complications in adults with T2DM. Using the TriNetX database from 2015 to 2025, adults aged >/= 40 years initiating SGLT-2is, GLP-1 RAs, or DPP-4is were identified and matched through propensity score methods to create three cohorts. The primary outcomes included open-angle glaucoma and ocular hypertension, with secondary outcomes of cataract, diabetic retinopathy, macular edema, and various systemic events. The matched cohorts included 68,283 patients (SGLT-2is vs. GLP-1 RAs), 69,765 patients (SGLT-2is vs. DPP-4is), and 55,760 patients (GLP-1 RAs vs. DPP-4is). Compared with GLP-1 RAs and DPP-4is, SGLT-2i use was associated with significantly lower risks of open-angle glaucoma (HR: 0.88 and 0.90), ocular hypertension (HR: 0.78 and 0.90), cataract (HR: 0.84 and 0.87), diabetic retinopathy (HR: 0.84 and 0.87), and macular edema (HR: 0.77 and 0.71). Conversely, GLP-1 RAs demonstrated stronger protective effects against systemic complications, such as diabetic nephropathy or chronic kidney disease, liver cirrhosis, dementia, cerebral infarction, and ischemic heart disease. These findings suggest that SGLT-2is may be prioritized in T2DM patients at higher risk for ocular complications, while GLP-1 RAs may be preferred when systemic risk reduction is the primary therapeutic goal. CI - (c) 2025 The Author(s). Clinical Pharmacology & Therapeutics (c) 2025 American Society for Clinical Pharmacology and Therapeutics. FAU - Lin, Lee-Yuan AU - Lin LY AUID- ORCID: 0009-0007-7212-3535 AD - School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Wu, Jie-Syuan AU - Wu JS AUID- ORCID: 0009-0001-8164-3299 AD - School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Jeng, Wei-Jung AU - Jeng WJ AUID- ORCID: 0009-0006-2400-9626 AD - School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Tsai, Chen-Hsin AU - Tsai CH AD - Department of Ophthalmology, Taipei Medical University Hospital, Taipei, Taiwan. FAU - Sun, Jia-Wei AU - Sun JW AUID- ORCID: 0009-0004-8018-8847 AD - School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Kuo, Cheng-Hao AU - Kuo CH AUID- ORCID: 0009-0006-0399-3329 AD - School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. AD - Ph.D. Program of Interdisciplinary Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. FAU - Yuliani, Fara Silvia AU - Yuliani FS AD - Department of Pharmacology and Therapy, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. FAU - Lin, Shyh-Hsiang AU - Lin SH AUID- ORCID: 0000-0002-3723-560X AD - School of Food Safety, College of Nutrition, Taipei Medical University, Taipei, Taiwan. AD - School of Nutrition, College of Nutrition, Taipei Medical University, Taipei, Taiwan. LA - eng PT - Comparative Study PT - Journal Article DEP - 20251011 PL - United States TA - Clin Pharmacol Ther JT - Clinical pharmacology and therapeutics JID - 0372741 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/diagnosis/complications MH - Male MH - Female MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/adverse effects/therapeutic use MH - Middle Aged MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Retrospective Studies MH - Aged MH - *Hypoglycemic Agents/adverse effects/therapeutic use MH - Diabetic Retinopathy/epidemiology MH - Glaucoma, Open-Angle/epidemiology/chemically induced MH - Adult MH - Databases, Factual MH - Ocular Hypertension/epidemiology/chemically induced MH - Risk Factors EDAT- 2025/10/11 06:31 MHDA- 2025/12/29 13:02 CRDT- 2025/10/11 03:44 PHST- 2025/07/17 00:00 [received] PHST- 2025/09/19 00:00 [accepted] PHST- 2025/12/29 13:02 [medline] PHST- 2025/10/11 06:31 [pubmed] PHST- 2025/10/11 03:44 [entrez] AID - 10.1002/cpt.70087 [doi] PST - ppublish SO - Clin Pharmacol Ther. 2026 Jan;119(1):255-266. doi: 10.1002/cpt.70087. Epub 2025 Oct 11. PMID- 41069980 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20251010 LR - 20260917 IS - 1687-8337 (Print) IS - 1687-8345 (Electronic) IS - 1687-8337 (Linking) VI - 2025 DP - 2025 TI - Unveiling Tirzepatide's Therapeutic Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health. PG - 2876156 LID - 10.1155/ije/2876156 [doi] LID - 2876156 AB - Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a groundbreaking treatment for Type 2 diabetes mellitus (T2DM) and obesity. Initially developed for glycemic control, recent clinical and preclinical data reveal its broader therapeutic potential across a range of metabolic and systemic conditions. This review explores tirzepatide's mechanisms of action, clinical efficacy, and safety profile, with particular attention to its impact on T2DM, obesity, cardiovascular health, metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD), and neurological disorders such as Alzheimer's and Parkinson's diseases. By addressing multiple pathophysiological pathways, including insulin resistance, inflammation, and oxidative stress, Tirzepatide presents a unique opportunity to redefine treatment paradigms beyond glycemic management. Our review also synthesizes recent evidence on the efficacy and safety of tirzepatide for obesity management specifically in Asian populations; a group frequently underrepresented in global trials. This demographic focus introduces a valuable dimension to the existing body of knowledge. As ongoing trials continue to evaluate its long-term effects, tirzepatide stands at the forefront of a new era in integrated cardiometabolic and neuroprotective therapeutics. CI - Copyright (c) 2025 Joya Ghaleb et al. International Journal of Endocrinology published by John Wiley & Sons Ltd. FAU - Ghaleb, Joya AU - Ghaleb J AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Khouzami, Katy Kaleen AU - Khouzami KK AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Nassif, Nicolas AU - Nassif N AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Attieh, Philippe AU - Attieh P AUID- ORCID: 0009-0006-8491-0790 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Ajlani, Mohammad Feras Al AU - Ajlani MFA AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Sleiman, Jana Bou AU - Sleiman JB AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Khalouf, Ali AU - Khalouf A AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Harb, Frederic AU - Harb F AUID- ORCID: 0000-0001-5882-1619 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Azar, Sami AU - Azar S AUID- ORCID: 0000-0001-6212-7080 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Kannan, Amjad AU - Kannan A AUID- ORCID: 0000-0003-2111-7294 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. FAU - Ghadieh, Hilda E AU - Ghadieh HE AUID- ORCID: 0000-0002-7983-2090 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, P.O. Box 100, Al-Koura, Tripoli, Lebanon. LA - eng PT - Journal Article PT - Review DEP - 20251001 PL - United States TA - Int J Endocrinol JT - International journal of endocrinology JID - 101516376 PMC - PMC12507501 OTO - NOTNLM OT - Type 2 diabetes OT - glucagon-like peptide-1 OT - neuroprotection OT - nonalcoholic fatty liver disease OT - nonalcoholic steatohepatitis OT - obesity OT - tirzepatide COIS- The authors declare no conflicts of interest. EDAT- 2025/10/10 06:29 MHDA- 2025/10/10 06:30 PMCR- 2025/10/01 CRDT- 2025/10/10 04:52 PHST- 2025/05/14 00:00 [received] PHST- 2025/07/21 00:00 [revised] PHST- 2025/09/05 00:00 [accepted] PHST- 2025/10/10 06:30 [medline] PHST- 2025/10/10 06:29 [pubmed] PHST- 2025/10/10 04:52 [entrez] PHST- 2025/10/01 00:00 [pmc-release] AID - 10.1155/ije/2876156 [doi] PST - epublish SO - Int J Endocrinol. 2025 Oct 1;2025:2876156. doi: 10.1155/ije/2876156. eCollection 2025. PMID- 41025359 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250930 LR - 20260124 IS - 2799-8010 (Electronic) IS - 2799-8010 (Linking) VI - 42 DP - 2025 TI - Glucagon-like peptide-1 receptor agonists and mental health: a narrative review of emerging benefits and risks. PG - 61 LID - 10.12701/jyms.2025.42.61 [doi] LID - 61 AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus and obesity, are increasingly recognized for their significant impact on the central nervous system, leading to reports of both beneficial and adverse mental health effects. This review summarizes the current evidence on the effects of GLP-1 RAs on various psychiatric and neurocognitive conditions to evaluate their clinical benefits and potential risks. The literature has revealed a complex and multifaceted psychiatric profile. For depression and anxiety, the evidence is conflicting, with large observational studies showing contradictory results that are largely attributable to confounding by indication or methodological differences in the study design. In contrast, consistent and positive evidence suggests therapeutic potential for substance use disorders, particularly alcohol use disorders. Furthermore, emerging data indicate a significant neuroprotective role, with several cohort studies indicating a reduced risk of dementia. The major public and regulatory attention regarding suicidality appears to be driven by the methodological limitations of the initial reports, as well-controlled active comparator studies have not found an increased risk. However, the safety of GLP-1 RAs in high-risk psychiatric populations has not been established. In conclusion, while GLP-1 RAs show considerable therapeutic potential, their unresolved safety profile in patients with preexisting psychiatric conditions necessitates a cautious clinical approach. Future large-scale randomized controlled trials that include psychiatric populations are crucial for clarifying the direct neuromodulatory effects of these agents and establishing guidelines for their safe use. FAU - Kim, JinWoo AU - Kim J AD - Department of Psychiatry, Yeungnam University Hospital, Daegu, Korea. LA - eng PT - Journal Article DEP - 20250929 PL - Korea (South) TA - J Yeungnam Med Sci JT - Journal of Yeungnam medical science JID - 9918333886606676 PMC - PMC12824553 OTO - NOTNLM OT - Depressive disorder OT - Glucagon-like peptide-1 receptor agonists OT - Mental health OT - Suicidal ideation COIS- Conflicts of interest No potential conflict of interest relevant to this article was reported. EDAT- 2025/09/30 06:38 MHDA- 2025/09/30 06:39 PMCR- 2025/09/29 CRDT- 2025/09/30 06:01 PHST- 2025/08/31 00:00 [received] PHST- 2025/09/24 00:00 [accepted] PHST- 2025/09/30 06:39 [medline] PHST- 2025/09/30 06:38 [pubmed] PHST- 2025/09/30 06:01 [entrez] PHST- 2025/09/29 00:00 [pmc-release] AID - jyms.2025.42.61 [pii] AID - jyms-2025-42-61 [pii] AID - 10.12701/jyms.2025.42.61 [doi] PST - ppublish SO - J Yeungnam Med Sci. 2025;42:61. doi: 10.12701/jyms.2025.42.61. Epub 2025 Sep 29. PMID- 41019986 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250929 LR - 20260925 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 16 DP - 2025 TI - GLP-1 receptor agonists: exploration of transformation from metabolic regulation to multi-organ therapy. PG - 1675552 LID - 10.3389/fphar.2025.1675552 [doi] LID - 1675552 AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes and obesity, have evolved into multi-organ potential therapeutics due to their pleiotropic effects beyond glycemic control. Mechanistically, GLP-1 signaling modulates immune and inflammatory pathways, regulates autophagy and pyroptosis, alleviates endoplasmic reticulum stress, and interacts with the gut microbiome. These pleiotropic effects provide a rationale for exploring their role in multiple organ systems. Clinical trials have demonstrated cardiovascular and renal protection, leading to additional approvals in high-risk populations. Early data also suggest potential benefits in liver disease, obstructive sleep apnea, chronic respiratory disorders, neurodegenerative and psychiatric conditions, reproductive dysfunction, obesity-associated cancers, and sepsis, although these remain investigational. Therefore, this review aims to synthesize the evidence on the mechanistic expansion of GLP-1RAs from metabolic regulators to systemic modulators of inflammation, autophagy, and organ protection, and explores their therapeutic repurposing across diseases. CI - Copyright (c) 2025 Gong, Li, Shi, Wang, Dai, Chen and Su. FAU - Gong, Bing AU - Gong B AD - Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. AD - Medical School, Kunming University of Science and Technology, Kunming, China. AD - Department of Emergency Medicine, The First People's Hospital of Yunnan Province, Kunming, China. FAU - Li, Couwen AU - Li C AD - Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. AD - Medical School, Kunming University of Science and Technology, Kunming, China. FAU - Shi, Zhuang'e AU - Shi Z AD - Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. AD - Medical School, Kunming University of Science and Technology, Kunming, China. FAU - Wang, FuPing AU - Wang F AD - Department of Emergency Medicine, The First People's Hospital of Yunnan Province, Kunming, China. AD - The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China. FAU - Dai, Ruanxian AU - Dai R AD - Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. AD - Medical School, Kunming University of Science and Technology, Kunming, China. FAU - Chen, Guobing AU - Chen G AD - Department of Emergency Medicine, The First People's Hospital of Yunnan Province, Kunming, China. AD - The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China. FAU - Su, Heng AU - Su H AD - Department of Emergency Medicine, The First People's Hospital of Yunnan Province, Kunming, China. AD - The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China. LA - eng PT - Journal Article PT - Review DEP - 20250911 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC12461214 OTO - NOTNLM OT - GLP-1 receptor agonist OT - gut microbiota OT - molecular mechanisms OT - multi-organ protection OT - therapeutic repurposing COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/09/29 13:17 MHDA- 2025/09/29 13:18 PMCR- 2025/09/11 CRDT- 2025/09/29 07:05 PHST- 2025/07/29 00:00 [received] PHST- 2025/08/28 00:00 [accepted] PHST- 2025/09/29 13:18 [medline] PHST- 2025/09/29 13:17 [pubmed] PHST- 2025/09/29 07:05 [entrez] PHST- 2025/09/11 00:00 [pmc-release] AID - 1675552 [pii] AID - 10.3389/fphar.2025.1675552 [doi] PST - epublish SO - Front Pharmacol. 2025 Sep 11;16:1675552. doi: 10.3389/fphar.2025.1675552. eCollection 2025. PMID- 41010364 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250927 LR - 20250930 IS - 2075-1729 (Print) IS - 2075-1729 (Electronic) IS - 2075-1729 (Linking) VI - 15 IP - 9 DP - 2025 Sep 10 TI - GLP-1 Receptor Agonists in Mood Disorders: A Psychiatric Perspective. LID - 10.3390/life15091422 [doi] LID - 1422 AB - Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the leading causes of disability worldwide and are frequently associated with treatment resistance, functional impairment, and high comorbidity with metabolic dysfunction. Increasing evidence implicates insulin resistance (IR) as a key pathophysiological factor linking metabolic and psychiatric illness. IR is associated with chronic low-grade inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, impaired neuroplasticity, mitochondrial dysfunction, and altered reward processing mechanisms that may contribute to core depressive features such as anhedonia, cognitive slowing, and emotional dysregulation. These processes are further exacerbated by the metabolic side effects of many psychotropic medications, creating a self-perpetuating cycle that worsens both psychiatric and physical health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes and obesity, have emerged as promising candidates to address this metabolic-psychiatric interface. Beyond improving glycemic control and promoting weight loss, GLP-1 RAs exert central actions relevant to mood disorders, including modulation of dopaminergic reward pathways, enhancement of hippocampal neurogenesis, attenuation of neuroinflammation, and regulation of appetite and energy balance. Preclinical studies demonstrate that GLP-1 RAs reduce microglial activation, promote hippocampal neurogenesis, and normalize stress-induced behavioral changes. Early clinical trials in patients with metabolic disorders suggest improvements in depressive symptoms, quality of life, and cognitive function, with some effects independent of weight loss or glycemic outcomes. Observational evidence also indicates reduced antidepressant use and psychological distress in diabetic and obese populations receiving GLP-1 RAs. While these findings are promising, large randomized controlled trials in primary psychiatric populations are lacking. Key challenges include clarifying dose-response relationships, disentangling central from peripheral effects, and addressing safety and adherence concerns in individuals with comorbid psychiatric conditions. Future research should focus on biomarker-informed stratification, comparative trials with standard treatments, and integration of GLP-1 RAs into multimodal care frameworks. Overall, GLP-1 RAs represent a biologically plausible and clinically relevant approach to bridging metabolic and psychiatric care, with the potential to improve outcomes in patients with mood disorders who carry a high metabolic burden. FAU - Carmellini, Pietro AU - Carmellini P AUID- ORCID: 0000-0001-8130-4388 AD - Department of Molecular and Developmental Medicine, Division of Psychiatry, School of Medicine, University of Siena, 53100 Siena, Italy. FAU - Cuomo, Alessandro AU - Cuomo A AD - Department of Molecular and Developmental Medicine, Division of Psychiatry, School of Medicine, University of Siena, 53100 Siena, Italy. FAU - Rescalli, Maria Beatrice AU - Rescalli MB AD - Department of Molecular and Developmental Medicine, Division of Psychiatry, School of Medicine, University of Siena, 53100 Siena, Italy. FAU - Fagiolini, Andrea AU - Fagiolini A AUID- ORCID: 0000-0001-5827-0853 AD - Department of Molecular and Developmental Medicine, Division of Psychiatry, School of Medicine, University of Siena, 53100 Siena, Italy. LA - eng PT - Journal Article PT - Review DEP - 20250910 PL - Switzerland TA - Life (Basel) JT - Life (Basel, Switzerland) JID - 101580444 PMC - PMC12471315 OTO - NOTNLM OT - GLP-1 receptor agonists OT - insulin resistance OT - mood disorders OT - personalized psychiatry COIS- The authors declare no conflicts of interest. EDAT- 2025/09/27 06:33 MHDA- 2025/09/27 06:34 PMCR- 2025/09/10 CRDT- 2025/09/27 01:17 PHST- 2025/08/10 00:00 [received] PHST- 2025/09/07 00:00 [revised] PHST- 2025/09/09 00:00 [accepted] PHST- 2025/09/27 06:34 [medline] PHST- 2025/09/27 06:33 [pubmed] PHST- 2025/09/27 01:17 [entrez] PHST- 2025/09/10 00:00 [pmc-release] AID - life15091422 [pii] AID - life-15-01422 [pii] AID - 10.3390/life15091422 [doi] PST - epublish SO - Life (Basel). 2025 Sep 10;15(9):1422. doi: 10.3390/life15091422. PMID- 41003796 OWN - NLM STAT- MEDLINE DCOM- 20250926 LR - 20260916 IS - 1573-7365 (Electronic) IS - 0885-7490 (Print) IS - 0885-7490 (Linking) VI - 40 IP - 7 DP - 2025 Sep 26 TI - From metabolic dysregulation to neurodegenerative pathology: the role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer's disease. PG - 276 LID - 10.1007/s11011-025-01700-z [doi] LID - 276 AB - Type 2 Diabetes (T2D) and Alzheimer's Disease (AD) share common risk factors that can be seen through T2D nearly doubling an individual's likelihood of developing AD. Some AD patients show signs of metabolic dysfunction as well. This review focuses on the potential mechanisms associated with these two diseases, like insulin resistance, inflammation, oxidative damage, mitochondrial injury, and cell death. One of the notable elements in this connection is the "brain insulin resistance," most frequently named as "type 3 diabetes," which impairs glucose metabolism and facilitates amyloid beta (Abeta) plaque synthesis while reducing the action of insulin-degrading enzyme (IDE). Moreover, the overactivity of glycogen synthase kinase-3 beta (GSK-3beta) also triggers taurine protein pathology. Raised concentrations of glucose in blood can produce advanced glycation end products (AGEs), which further exacerbate neuroinflammation in tandem with the mitigation of neurotoxic Abeta oligomers. Inflammation and subsequent damage to mitochondria lead to the dissolution of synapses. Current vascular insults include the breakdown of the blood-brain barrier (BBB) and decreased brain perfusion, along with other contributory factors to conditions conducive to neurotoxicity. Recently, novel therapies are emerging, including GLP-1 agonists, intranasal insulin, and mitochondrial antioxidants, that show surprising results for treating both conditions, but on the contrary, bioavailability and the timing of interventions remain a big challenge in the management of these diseases. Eventually, further research should center on understanding the mechanisms of integration along with the development of molecular biology, neuroimaging, and outcome-driven treatment strategies. Comprehensive strategies that exist between T2D-AD for integration and preservation of brain and metabolic health are addressed in this review. CI - (c) 2025. The Author(s). FAU - Raza, Ahmad AU - Raza A AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Saleem, Shafaq AU - Saleem S AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Imran, Samar AU - Imran S AD - Department of Neurology, Fauji Foundation Hospital, Rawalpindi, Pakistan. FAU - Rahman, Sarah AU - Rahman S AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Haroon, Muhammad AU - Haroon M AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Razzaq, Azeen AU - Razzaq A AD - Department of Medicine, Rawalpindi Medical University, Rawalpindi, Pakistan. FAU - Hussain, Ahmad AU - Hussain A AD - Punjab Medical College, Faisalabad, Pakistan. FAU - Iqbal, Javed AU - Iqbal J AUID- ORCID: 0000-0003-2627-685X AD - Hamad Medical Corporation, P.O Box 3050, Doha, Qatar. jiqbal3@hamad.qa. FAU - Sathian, Brijesh AU - Sathian B AD - Hamad Medical Corporation, P.O Box 3050, Doha, Qatar. LA - eng PT - Journal Article PT - Review DEP - 20250926 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 SB - IM MH - Humans MH - *Alzheimer Disease/metabolism/pathology MH - *Oxidative Stress/physiology MH - *Blood-Brain Barrier/metabolism/pathology MH - *Diabetes Mellitus, Type 2/metabolism/pathology/complications MH - Animals MH - *Hyperglycemia/metabolism/pathology MH - Insulin Resistance/physiology MH - Brain/metabolism/pathology PMC - PMC12474712 OTO - NOTNLM OT - Advanced glycation end products (AGEs) OT - Alzheimer's disease (AD) OT - Amyloid-beta (Abeta) accumulation OT - Insulin resistance OT - Mitochondrial dysfunction OT - Neuroinflammation OT - Type 2 diabetes mellitus (T2D) COIS- Declarations. Competing interests: The authors declare no competing interests. EDAT- 2025/09/26 12:32 MHDA- 2025/09/26 12:33 PMCR- 2025/09/26 CRDT- 2025/09/26 11:16 PHST- 2025/05/10 00:00 [received] PHST- 2025/08/11 00:00 [accepted] PHST- 2025/09/26 12:33 [medline] PHST- 2025/09/26 12:32 [pubmed] PHST- 2025/09/26 11:16 [entrez] PHST- 2025/09/26 00:00 [pmc-release] AID - 10.1007/s11011-025-01700-z [pii] AID - 1700 [pii] AID - 10.1007/s11011-025-01700-z [doi] PST - epublish SO - Metab Brain Dis. 2025 Sep 26;40(7):276. doi: 10.1007/s11011-025-01700-z. PMID- 40991062 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250924 LR - 20260916 IS - 1319-0164 (Print) IS - 2213-7475 (Electronic) IS - 1319-0164 (Linking) VI - 33 IP - 5 DP - 2025 Sep 24 TI - GLP-1 receptor agonism: a transformative approach for managing type-2 diabetes and obesity. PG - 34 LID - 10.1007/s44446-025-00038-y [doi] LID - 34 AB - GLP-1 receptor agonists represent a breakthrough for managing type-2 diabetes and obesity, offering metabolic benefits across multiple organ systems. These medications provide effective glycaemic control, significant weight reduction, and cardiovascular protection through complex signalling pathways affecting pancreatic, gastrointestinal, neural, and cardiovascular tissues. Their therapeutic potential extends beyond metabolic disorders. Clinical studies demonstrate substantial decreases in HbA1c, body weight (15-20%), and cardiovascular events compared to traditional treatments. Emerging applications include non-alcoholic fatty liver disease and neurodegenerative conditions. Significant barriers still exist despite established safety profiles, such as high costs that restrict access worldwide, a lack of predictive biomarkers for treatment response, a lack of knowledge about the mechanistics of gut microbiota interactions, and an incomplete understanding of long-term safety, particularly with regard to thyroid and pancreatic effects. Research gaps include appropriate patient classification, cost-effectiveness across healthcare systems, and established methodologies for developing applications. Potential future developments include novel delivery mechanisms, multi-receptor agonists, and a broader range of therapeutic uses for the treatment of metabolic disorders and their consequences. From their identification as incretin hormones to development of long-acting analogue, GLP-1 agonists have revolutionized metabolic disease management. Their pleiotropic benefits arise from intricate signalling cascades that regulate appetite, insulin secretion, and energy homeostasis across multiple tissues. CI - (c) 2025. The Author(s). FAU - Alharbi, Abdulrahman G AU - Alharbi AG AUID- ORCID: 0009-0004-9446-2034 AD - Department of Pharmacology and Toxicology College of Pharmacy, Taibah University, P.O. Box 30001, Medina, 41477, Kingdom of Saudi Arabia. aqharbi@taibahu.edu.sa. LA - eng PT - Journal Article PT - Review DEP - 20250924 PL - Netherlands TA - Saudi Pharm J JT - Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society JID - 9705695 PMC - PMC12460220 OTO - NOTNLM OT - Cardiovascular protection OT - Drug development OT - GLP-1 receptor agonists OT - Metabolic disorders OT - Obesity OT - Type-2 diabetes COIS- Declarations. Ethics: Not applicable. Competing interests: The authors declare that they have no competing interests. EDAT- 2025/09/24 13:00 MHDA- 2025/09/24 13:01 PMCR- 2025/09/24 CRDT- 2025/09/24 11:16 PHST- 2025/03/06 00:00 [received] PHST- 2025/07/30 00:00 [accepted] PHST- 2025/09/24 13:01 [medline] PHST- 2025/09/24 13:00 [pubmed] PHST- 2025/09/24 11:16 [entrez] PHST- 2025/09/24 00:00 [pmc-release] AID - 10.1007/s44446-025-00038-y [pii] AID - 38 [pii] AID - 10.1007/s44446-025-00038-y [doi] PST - epublish SO - Saudi Pharm J. 2025 Sep 24;33(5):34. doi: 10.1007/s44446-025-00038-y. PMID- 40979705 OWN - NLM STAT- MEDLINE DCOM- 20250922 LR - 20250924 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 16 DP - 2025 TI - Crosstalk of kidney and brain in diabetes-related cognitive impairment and therapeutic strategies. PG - 1562518 LID - 10.3389/fendo.2025.1562518 [doi] LID - 1562518 AB - Type 2 diabetes mellitus (T2DM) and its associated complications pose a global health threat. Notably, the rise in diabetes-induced cognitive dysfunction has garnered widespread attention. T2DM patients frequently face an elevated risk of both cognitive impairment and diabetic kidney disease (DKD) comorbidity. There is evidence to suggest that kidney and brain dysfunction share common pathogenic factors, such as vascular endothelial injury, oxidative stress, and inflammation activation. Whereas, the underlying mechanisms of kidney-brain interaction and effective treatments for DKD-related cognitive decline remain incompletely understood. Our review preliminarily summarized the relationship between renal dysfunction and cognitive decline based on the existing clinical trial evidence. The mechanisms underlying DKD-related cognitive decline which mainly included the accumulation of harmful metabolites, inflammation activation and endothelial dysfunction were also clarified. And the brain renin-angiotensin-aldosterone system (RAAS) may serve as a bridge connecting renal dysfunction in DKD with cognitive impairment. In addition, we further concluded that potential lifestyle interventions and pharmacological approaches, including antioxidants, RAS inhibitors, finerenone and hypoglycemic agents, such as sodium-glucose cotransporter-2 inhibitors, liraglutide and pioglitazone may exert the preservation of cognitive function. The review could offer valuable insights for therapeutic strategies of cognitive impairment associated with diabetes and DKD in future. CI - Copyright (c) 2025 Xu, Miao, Chen and Liao. FAU - Xu, Chunmei AU - Xu C AD - Research Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, China. AD - Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, China. AD - Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. AD - Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China. FAU - Miao, Huikai AU - Miao H AD - Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. FAU - Chen, Yongjun AU - Chen Y AD - Research Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, China. AD - South China Research Center for Acupuncture and Moxibustion, Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Liao, Lin AU - Liao L AD - Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China. AD - Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China. LA - eng PT - Journal Article PT - Review DEP - 20250904 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Cognitive Dysfunction/etiology/therapy/metabolism MH - *Diabetes Mellitus, Type 2/complications/metabolism MH - *Brain/metabolism/physiopathology MH - *Diabetic Nephropathies/metabolism/therapy/etiology MH - *Kidney/metabolism/physiopathology MH - Renin-Angiotensin System MH - Animals MH - Hypoglycemic Agents/therapeutic use PMC - PMC12443575 OTO - NOTNLM OT - cognitive impairment OT - crosstalk OT - diabetes mellitus OT - diabetic kidney disease OT - pharmacological therapy COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/09/22 12:47 MHDA- 2025/09/22 12:48 PMCR- 2025/09/04 CRDT- 2025/09/22 08:12 PHST- 2025/01/17 00:00 [received] PHST- 2025/08/12 00:00 [accepted] PHST- 2025/09/22 12:48 [medline] PHST- 2025/09/22 12:47 [pubmed] PHST- 2025/09/22 08:12 [entrez] PHST- 2025/09/04 00:00 [pmc-release] AID - 10.3389/fendo.2025.1562518 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2025 Sep 4;16:1562518. doi: 10.3389/fendo.2025.1562518. eCollection 2025. PMID- 40954925 OWN - NLM STAT- MEDLINE DCOM- 20251105 LR - 20260907 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 27 IP - 12 DP - 2025 Dec TI - Dapagliflozin restores odour-induced functional integration of primary olfactory cortex circuit but not olfactory-related regional brain activation in patients with type 2 diabetes: A 16-week randomised comparative study. PG - 7309-7322 LID - 10.1111/dom.70132 [doi] AB - AIMS: Although some hypoglycaemic agents have been suggested to possess neuroprotective effects, their mechanisms and efficacy remain controversial. We aimed to investigate the effects of dapagliflozin, liraglutide or acarbose treatment on the directed functional connectivity (FC) of the primary olfactory cortex (POC) circuit and regional activation under odour stimulation in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: The 16-week randomised, prospective, parallel-group, and open-label trial included 36 patients with T2D inadequately controlled with metformin, who were randomised (1:1:1) to receive dapagliflozin, liraglutide or acarbose. Meanwhile, 36 healthy controls were recruited. All participants underwent olfactory task functional magnetic resonance imaging, along with a battery of olfactory and cognitive tests, both at baseline and postintervention. RESULTS: After 16 weeks, dapagliflozin restored odour-induced functional integration of the POC-sensorimotor cortex-middle temporal cortex circuit (Gaussian random field correction applied), whereas liraglutide and acarbose did not. Dapagliflozin also tended to improve attention (p = 0.071). In contrast, liraglutide enhanced odour-induced activation in the left hippocampus, which was not observed with dapagliflozin and acarbose. The decreased odour-induced directed FC was associated with changes in lipid levels, olfactory threshold, executive function and memory performance (all p < 0.05). CONCLUSIONS: These results suggest that dapagliflozin and liraglutide exhibit distinct neuroprotective effects. While liraglutide enhances activation in local olfactory-related regions, dapagliflozin facilitates functional integration within neural circuits. This highlights the importance of targeting both metabolic and neural pathways to manage diabetes-related cognitive decline. CI - (c) 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Li, Xin AU - Li X AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. FAU - Zhang, Yi AU - Zhang Y AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Lu, Jiaming AU - Lu J AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Ji, Cheng AU - Ji C AD - Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Zhang, Xin AU - Zhang X AUID- ORCID: 0000-0001-7592-1195 AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. FAU - Li, Qian AU - Li Q AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Wang, Shuang AU - Wang S AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Chen, Jiu AU - Chen J AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. FAU - Zhu, Zhengyang AU - Zhu Z AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Zhang, Wen AU - Zhang W AUID- ORCID: 0000-0002-5864-4656 AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. FAU - Zhang, Bing AU - Zhang B AUID- ORCID: 0000-0002-3953-0290 AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China. LA - eng GR - (2022-LCYJ-PY-15/Affiliated Drum Tower Hospital, Medical School of Nanjing University/ GR - 2022-LCYJ-MS-03/Affiliated Drum Tower Hospital, Medical School of Nanjing University/ GR - 82271965/National Natural Science Foundation of China/ GR - 82302172/National Natural Science Foundation of China/ GR - 82330059/National Natural Science Foundation of China/ GR - Medical Imaging Artificial Intelligence Special Research Fund Project, Nanjing Medical Association Radiology Branch/ PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial DEP - 20250915 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Benzhydryl Compounds) RN - 0 (Glucosides) RN - 1ULL0QJ8UC (dapagliflozin) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - T58MSI464G (Acarbose) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/physiopathology/complications MH - Male MH - Female MH - *Benzhydryl Compounds/therapeutic use/pharmacology MH - Middle Aged MH - *Glucosides/therapeutic use/pharmacology MH - *Olfactory Cortex/drug effects/diagnostic imaging/physiopathology MH - Magnetic Resonance Imaging MH - *Hypoglycemic Agents/therapeutic use MH - Odorants MH - Liraglutide/therapeutic use/pharmacology MH - Acarbose/therapeutic use MH - Aged MH - Prospective Studies MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Adult PMC - PMC12587237 OTO - NOTNLM OT - acarbose OT - cognitive function OT - dapagliflozin OT - generalised psychophysiological interaction OT - hypoglycaemic agents OT - liraglutide OT - olfactory task fMRI OT - type 2 diabetes COIS- The authors declare no competing interests. EDAT- 2025/09/16 06:36 MHDA- 2025/11/05 06:29 PMCR- 2025/11/05 CRDT- 2025/09/16 01:08 PHST- 2025/08/26 00:00 [revised] PHST- 2025/06/09 00:00 [received] PHST- 2025/09/04 00:00 [accepted] PHST- 2025/11/05 06:29 [medline] PHST- 2025/09/16 06:36 [pubmed] PHST- 2025/09/16 01:08 [entrez] PHST- 2025/11/05 00:00 [pmc-release] AID - DOM70132 [pii] AID - 10.1111/dom.70132 [doi] PST - ppublish SO - Diabetes Obes Metab. 2025 Dec;27(12):7309-7322. doi: 10.1111/dom.70132. Epub 2025 Sep 15. PMID- 40952016 OWN - NLM STAT- MEDLINE DCOM- 20250916 LR - 20260925 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 21 IP - 9 DP - 2025 Sep TI - GLP-1RA comparative effectiveness against dementia onset relative to other antidiabetic medications in a large, multi-site cohort of patients with type 2 diabetes. PG - e70621 LID - 10.1002/alz.70621 [doi] LID - e70621 AB - INTRODUCTION: To address gaps in current research, this study aims to compare the impact of exposure to glucagon-like peptide-1 receptor agonists (GLP-1RA) versus sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), and sulfonylureas (SU) on reducing the risk of dementia, using a rigorous targeted learning causal inference approach. METHODS: Using clinical and claims data from four diverse US health-care systems, we emulated three two-arm trials contrasting sustained treatment with GLP-1RA versus SGLT2i, DPP4i, and SU on dementia diagnosis. We included diabetes patients aged >/= 60 years who initiated medication between 2014 and 2022. We estimated cumulative risk differences at 2.5 years. RESULTS: In Cohort 1, there was no evidence of differential dementia risk between sustained exposure to GLP1-RA versus SGLT2i (adjusted risk difference [aRD] -0.001, 95% confidence interval [CI] -0.004, 0.001). In Cohorts 2 and 3, GLP-1RA was associated with reduced risk of dementia diagnosis compared to DPP4i and SU, respectively (aRD -0.013, 95% CI -0.017, -0.009; aRD -0.016, 95% CI -0.018, -0.015). DISCUSSION: Rigorous causal inference analysis suggests that sustained exposure to GLP-1RA may modestly reduce risk of dementia, compared to DPP4i or SU exposure-but not compared to SGLT2i. HIGHLIGHTS: We researched the comparative effects of diabetes medications on dementia. We studied a large, diverse observational cohort of patients with diabetes in the United States. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may modestly reduce risk of dementia compared to dipeptidyl peptidase 4 inhibitor or sulfonylurea exposure. GLP-1RAs do not show evidence of dementia risk reduction compared to sodium-glucose cotransporter 2 inhibitors. Physicians may consider this when making prescription decisions with patients. CI - (c) 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Nance, Nerissa AU - Nance N AUID- ORCID: 0000-0002-8407-2364 AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. AD - University of California, Berkeley School of Public Health, Berkeley, California, USA. AD - Novo Nordisk A/S, Bagsvaerd, Denmark. FAU - Gilsanz, Paola AU - Gilsanz P AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - Karter, Andrew J AU - Karter AJ AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - Finertie, Holly AU - Finertie H AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - Schmittdiel, Julie A AU - Schmittdiel JA AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. AD - Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California, USA. FAU - An, JaeJin AU - An J AD - Kaiser Permanente Southern California Research and Evaluation, Pasadena, California, USA. FAU - Adams, Alyce S AU - Adams AS AD - Stanford University, Stanford, California, USA. FAU - Oshiro, Caryn AU - Oshiro C AD - Kaiser Permanente Hawaii, Honolulu, Hawai'i, USA. FAU - Cassidy-Bushrow, Andrea E AU - Cassidy-Bushrow AE AD - Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA. AD - Henry Ford Health + Michigan State University Health Sciences, Detroit, Michigan, USA. AD - Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA. FAU - Krahe-Dombrowski, Sarah AU - Krahe-Dombrowski S AD - Geisinger Research, Danville, Pennsylvania, USA. FAU - Yassin, Maher AU - Yassin M AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - Lin, Sharon AU - Lin S AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - Izadian, Keanu AU - Izadian K AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. FAU - O'Connor, Patrick J AU - O'Connor PJ AD - HealthPartners Institute, Bloomington, Minnesota, USA. FAU - Neugebauer, Romain AU - Neugebauer R AD - Kaiser Permanente Northern California Division of Research, Pleasanton, California, USA. AD - Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California, USA. LA - eng GR - P30 DK092924/DK/NIDDK NIH HHS/United States GR - R01 AG067199/AG/NIA NIH HHS/United States GR - DB-2020C2-20318/Patient-Centered Outcomes Research Institute (PCORI)/ PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Observational Study PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Sulfonylurea Compounds) SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - Cohort Studies MH - *Dementia/prevention & control/epidemiology MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Sulfonylurea Compounds/therapeutic use MH - United States MH - Retrospective Studies PMC - PMC12434700 OTO - NOTNLM OT - causal inference OT - diabetes OT - diabetes medications OT - glucagon-like peptide-1 receptor agonist OT - longitudinal data OT - targeted learning COIS- Nerissa Nance conducted this research while employed as a graduate student researcher at University of California Berkeley through a financial gift to University of California Berkeley from Novo Nordisk. After completing this research as part of their graduate studies, Nerissa Nance accepted a position at Novo Nordisk. No other authors state disclosures. EDAT- 2025/09/15 12:32 MHDA- 2025/09/16 20:01 PMCR- 2025/09/15 CRDT- 2025/09/15 08:13 PHST- 2025/07/11 00:00 [revised] PHST- 2025/03/17 00:00 [received] PHST- 2025/07/24 00:00 [accepted] PHST- 2025/09/16 20:01 [medline] PHST- 2025/09/15 12:32 [pubmed] PHST- 2025/09/15 08:13 [entrez] PHST- 2025/09/15 00:00 [pmc-release] AID - ALZ70621 [pii] AID - 10.1002/alz.70621 [doi] PST - ppublish SO - Alzheimers Dement. 2025 Sep;21(9):e70621. doi: 10.1002/alz.70621. PMID- 40928600 OWN - NLM STAT- MEDLINE DCOM- 20250930 LR - 20261010 IS - 1179-1969 (Electronic) IS - 1170-229X (Linking) VI - 42 IP - 10 DP - 2025 Oct TI - Hypoglycaemia in Older Adults with Diabetes: Pathophysiology, Prevention, and Personalized Care in an Aging Population. PG - 921-932 LID - 10.1007/s40266-025-01236-y [doi] AB - Managing diabetes in older adults requires balancing long-term glycaemic control with the prevention of hypoglycaemia, to which this population is particularly vulnerable owing to frailty, multimorbidity and cognitive decline. Guidelines recommend individualized glucose targets for older adults, particularly those with multimorbidity or increased hypoglycaemia risk. For individuals with frailty or cognitive impairment, relaxed HbA1c targets are often appropriate to reduce the risk of adverse events. While HbA1c is widely used, it has important limitations in this population due to its inability to reflect daily glucose fluctuations. Continuous glucose monitoring (CGM) or self-monitoring of blood glucose provide more granular data to guide therapy. This review explores the pathophysiology, complications, and management of hypoglycaemia in older adults, emphasizing individualized care, safer pharmacotherapies (e.g. DPP-4 inhibitors, GLP-1 receptor agonists, ultra-long-acting insulins), and emerging technologies (continuous glucose monitoring, artificial Intelligence-guided insulin delivery and telehealth). CI - (c) 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Boccardi, Virginia AU - Boccardi V AD - Division of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy. FAU - Sinclair, Alan J AU - Sinclair AJ AD - Foundation for Diabetes Research in Older People (fDROP) and King's College London, London, UK. alan.sinclair@kcl.ac.uk. LA - eng PT - Journal Article PT - Review DEP - 20250910 PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 0 (Hypoglycemic Agents) RN - 0 (Blood Glucose) SB - IM MH - Humans MH - *Hypoglycemia/prevention & control/physiopathology/chemically induced/drug therapy MH - Aged MH - Precision Medicine MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Blood Glucose/analysis/drug effects MH - *Aging MH - *Diabetes Mellitus/drug therapy/physiopathology MH - *Diabetes Mellitus, Type 2/drug therapy MH - Blood Glucose Self-Monitoring COIS- Declarations. Funding: No specific funding was received for the preparation of this manuscript. No financial support was provided for open access publication at the time of submission. Conflicts of Interest: The authors declare that they have no conflicts of interest relevant to the content of this manuscript. Data Availability: Not applicable. This is a narrative review based on published literature and publicly available data. Ethics Approval: Not applicable. This study did not involve original research with human participants or the use of patient data or biological materials. Author Contributions: Virginia Boccardi (VB) and Alan J. Sinclair (AJS) contributed equally to the conception, literature review, drafting and critical revision of the manuscript. Both authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. EDAT- 2025/09/10 12:33 MHDA- 2025/09/30 06:37 CRDT- 2025/09/10 11:07 PHST- 2025/07/13 00:00 [accepted] PHST- 2025/09/30 06:37 [medline] PHST- 2025/09/10 12:33 [pubmed] PHST- 2025/09/10 11:07 [entrez] AID - 10.1007/s40266-025-01236-y [pii] AID - 10.1007/s40266-025-01236-y [doi] PST - ppublish SO - Drugs Aging. 2025 Oct;42(10):921-932. doi: 10.1007/s40266-025-01236-y. Epub 2025 Sep 10. PMID- 40916127 OWN - NLM STAT- In-Process LR - 20250911 IS - 2287-1012 (Print) IS - 2287-1292 (Electronic) IS - 2287-1012 (Linking) VI - 30 IP - 4 DP - 2025 Aug TI - Mechanisms of glucagon-like-peptide 1 in the brain beyond metabolic effects. PG - 165-174 LID - 10.6065/apem.2448320.160 [doi] AB - Ever since its discovery, glucagon-like-peptide 1 (GLP-1) and drugs with similar function (collectively GLP-1s) have been used for type 2 diabetes mellitus and have been effective for obesity. Their profound effect on weight loss has resulted in widespread use of these medicines for treating obesity. Extensive studies have shown that GLP-1s decrease body weight, lean mass, and other metabolic phenotypes. These studies were supported by the mechanism of signaling pathways of GLP-1s in cells and their metabolic effects. Recently, studies have focused on the effect of GLP-1s on the brain, showing that they affect food cognition, depression, drug addiction, and even neurodegenerative diseases. Although recent studies have investigated the impact of GLP-1s on the brain, our understanding of these effects is limited. This review describes how GLP-1s have become the most effective drugs in obesity, such as their known signaling pathway in cells and their pharmaceutical processing over the years. This review covers recent discoveries of the GLP-1 mechanisms in the brain, including their prominent effects on obesity, and discusses discoveries that imply their potential usage in brain disorders. FAU - Kim, Kyu Sik AU - Kim KS AD - Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. FAU - Park, Joon Seok AU - Park JS AD - Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. FAU - Choi, Hyung Jin AU - Choi HJ AD - Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. AD - Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea. AD - Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. AD - Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea. AD - Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea. LA - eng GR - RS-2024-00406774/National Research Foundation of Korea/ GR - RS-2024-00404132/Korea Health Industry Development Institute/Republic of Korea GR - RS-2024-00440099/Korea Health Industry Development Institute/Republic of Korea GR - Ministry of Health and Welfare/ PT - Journal Article DEP - 20250831 PL - Korea (South) TA - Ann Pediatr Endocrinol Metab JT - Annals of pediatric endocrinology & metabolism JID - 101588279 PMC - PMC12415283 OTO - NOTNLM OT - Brain disorder OT - Glucagon-like peptide-1 OT - Glucagon-like peptide-1 receptor OT - Hindbrain OT - Hypothalamus OT - Metabolism OT - Obesity COIS- Conflicts of interest No potential conflict of interest relevant to this article was reported. EDAT- 2025/09/08 06:32 MHDA- 2025/09/08 06:32 PMCR- 2025/08/01 CRDT- 2025/09/08 00:20 PHST- 2024/12/26 00:00 [received] PHST- 2025/01/21 00:00 [accepted] PHST- 2025/09/08 06:32 [medline] PHST- 2025/09/08 06:32 [pubmed] PHST- 2025/09/08 00:20 [entrez] PHST- 2025/08/01 00:00 [pmc-release] AID - apem.2448320.160 [pii] AID - apem-2448320-160 [pii] AID - 10.6065/apem.2448320.160 [doi] PST - ppublish SO - Ann Pediatr Endocrinol Metab. 2025 Aug;30(4):165-174. doi: 10.6065/apem.2448320.160. Epub 2025 Aug 31. PMID- 40904035 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250915 LR - 20250915 IS - 2056-5623 (Print) IS - 2056-5623 (Electronic) IS - 2056-5623 (Linking) VI - 11 IP - 1 DP - 2025 Dec TI - The multifaceted effects of semaglutide: exploring its broad therapeutic applications. PG - 2483607 LID - 10.1080/20565623.2025.2483607 [doi] LID - 2483607 AB - Semaglutide, a GLP-1 receptor agonist, is FDA-approved for managing type 2 diabetes (T2D) and reducing cardiovascular risk. Its off-label use in weight management and other conditions has grown, prompting a review of its benefits and risks. This review evaluates evidence on semaglutide's effects, highlighting its therapeutic potential beyond approved indications. Studies from 2021-2024 were reviewed via PubMed, ScienceDirect, and Google Scholar. Semaglutide showed promise in managing PCOS-related obesity, insulin resistance, and demonstrated renoprotective effects in diabetics and chronic kidney disease (CKD). Additionally, it improves liver enzyme levels, steatosis, and stiffness, aiding in managing Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in non-fibrotic patients. The FDA has approved it for reducing major adverse cardiovascular events, heart failure symptoms, and physical limitations in diabetic and non-diabetics. Preclinical studies suggest benefits in cognitive disorders associated with insulin resistance, including Alzheimer's disease, Parkinson's disease, and vascular dementia in animals. Although rare cases of thyroid cancer have been reported, no causal relationship has been established, emphasizing the need of caution in high-risk populations. GLP-1 therapy has also exerted protective effects against the risk of various types of cancer. However, ongoing human studies are essential to validate these findings and clarify semaglutide's association with cancer. FAU - Alkhatib, Mesk AU - Alkhatib M AD - University of Jordan, Amman, Jordan. FAU - Almasri, Noor AU - Almasri N AUID- ORCID: 0009-0004-1152-9337 AD - University of Jordan, Amman, Jordan. FAU - Alshwayyat, Sakhr AU - Alshwayyat S AUID- ORCID: 0000-0002-2295-1945 AD - King Hussein Cancer Center, Amman, Jordan. AD - Princess Basma Teaching Hospital, Irbid, Jordan. AD - Applied Science Research Center, Applied Science Private University, Amman, Jordan. FAU - Almahariq, Hebah AU - Almahariq H AD - University of Jordan, Amman, Jordan. FAU - Hammadeh, Bara M AU - Hammadeh BM AD - Faculty of Medicine, Al-Balqa' Applied University, Salt, Jordan. FAU - Taimeh, Zaid AU - Taimeh Z AD - Jordanian Royal Medical Services, Amman, Jordan. FAU - Alkhatib, Lean AU - Alkhatib L AD - Nephrology Department, University of Arkansas for Medical Sciences, Little Rock, AR, USA. FAU - Alshwayat, Anas AU - Alshwayat A AD - Nephrology Department, University of Arkansas for Medical Sciences, Little Rock, AR, USA. FAU - A Saadeh, Nesreen AU - A Saadeh N AD - Internal Medicine Department, Jordan University of Science and Technology, Irbid, Jordan. FAU - Al-Kurdi, Mohammed Al-Mahdi AU - Al-Kurdi MA AD - Faculty of Medicine, University of Aleppo, Aleppo, Syrian Arab Republic. LA - eng PT - Journal Article PT - Review DEP - 20250903 PL - England TA - Future Sci OA JT - Future science OA JID - 101665030 PMC - PMC12413075 OAB - Semaglutide is a medicine that helps people with type 2 diabetes and can also lower the risk of heart problems. It might also help people with PCOS by making insulin work better and helping them lose weight. It may also protect the kidneys and make the liver healthier.Doctors use semaglutide to help people with heart problems even if they do not have diabetes. In some studies with animals, it has also helped with memory and thinking problems like in Alzheimer's disease.There is no proof that semaglutide causes thyroid cancer, but doctors are careful with people at high risk. It might even lower cancer risk in people with diabetes but more research is needed. Scientists are still studying its safety and long-term effects. OABL- eng OTO - NOTNLM OT - Cardiovascular diseases OT - cognitive dysfunction OT - glucagon-like peptide-1 receptor agonists OT - neoplasms OT - polycystic ovary syndrome OT - semaglutide COIS- The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. EDAT- 2025/09/04 06:37 MHDA- 2025/09/04 06:38 PMCR- 2025/09/03 CRDT- 2025/09/04 02:43 PHST- 2025/09/04 06:38 [medline] PHST- 2025/09/04 06:37 [pubmed] PHST- 2025/09/04 02:43 [entrez] PHST- 2025/09/03 00:00 [pmc-release] AID - 2483607 [pii] AID - 10.1080/20565623.2025.2483607 [doi] PST - ppublish SO - Future Sci OA. 2025 Dec;11(1):2483607. doi: 10.1080/20565623.2025.2483607. Epub 2025 Sep 3. PMID- 40892247 OWN - NLM STAT- MEDLINE DCOM- 20251223 LR - 20251226 IS - 1432-5233 (Electronic) IS - 0940-5429 (Print) IS - 0940-5429 (Linking) VI - 62 IP - 12 DP - 2025 Dec TI - The impact of type 2 diabetes on aging: multidimensional approaches to preserve cognitive health. PG - 2223-2234 LID - 10.1007/s00592-025-02583-3 [doi] AB - The growing prevalence of type 2 diabetes (T2D) among older adults represents a major public health concern, given its association with accelerated cognitive decline and increased risk of neurodegenerative diseases. Several diabetes-related mechanisms, including chronic hyperglycaemia, oxidative stress, vascular dysfunction, and insulin resistance in the brain, negatively impact key cognitive domains, including memory and executive functions. These neuropathophysiological alterations are also linked to structural brain changes, contributing to vulnerability to dementia. This narrative review examines both established and emerging strategies aimed at counteracting the cognitive impact of T2D in aging populations. Traditional interventions, especially structured physical activity programs, have consistently demonstrated benefits for global cognitive functioning. In parallel, new pharmacological treatments, such as GLP-1 receptor agonists (e.g., semaglutide), not only improve glycemic control but may also exert neuroprotective effects. Multidomain approaches integrating metabolic management, nutritional optimization, physical exercise, and social engagement, such as those tested in the J-MIND-Diabetes study, have yielded promising outcomes in preserving cognitive functions. We argue that combining pharmacological and behavioral strategies holds significant potential for supporting cognitive health in elderly individuals with T2D. Such multimodal interventions may enhance resilience to cognitive decline, improve quality of life, and promote healthy brain aging in this at-risk population. CI - (c) 2025. The Author(s). FAU - Lucia, Stefania AU - Lucia S AUID- ORCID: 0000-0002-5033-2121 AD - Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. slucia@sissa.it. FAU - Fornaro, Silvia AU - Fornaro S AD - Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. FAU - Federici, Massimo AU - Federici M AD - Department of Systems Medicine, University of Roma Tor Vergata, 00133, Rome, Italy. FAU - Rumiati, Raffaella Ida AU - Rumiati RI AD - Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. AD - Department of Systems Medicine, University of Roma Tor Vergata, 00133, Rome, Italy. LA - eng PT - Journal Article PT - Review DEP - 20250902 PL - Germany TA - Acta Diabetol JT - Acta diabetologica JID - 9200299 SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/therapy/psychology MH - *Aging/physiology/psychology MH - *Cognition/physiology MH - *Cognitive Dysfunction/prevention & control MH - Exercise MH - Aged MH - Brain PMC - PMC12727764 OTO - NOTNLM OT - Aging OT - Cognition OT - Physical activity OT - Semaglutide OT - Type 2 diabetes COIS- Declarations. Conflict of interest: The authors declare no conflicts of interest. EDAT- 2025/09/02 22:20 MHDA- 2025/12/23 12:48 PMCR- 2025/09/02 CRDT- 2025/09/02 11:14 PHST- 2025/07/11 00:00 [received] PHST- 2025/08/13 00:00 [accepted] PHST- 2025/12/23 12:48 [medline] PHST- 2025/09/02 22:20 [pubmed] PHST- 2025/09/02 11:14 [entrez] PHST- 2025/09/02 00:00 [pmc-release] AID - 10.1007/s00592-025-02583-3 [pii] AID - 2583 [pii] AID - 10.1007/s00592-025-02583-3 [doi] PST - ppublish SO - Acta Diabetol. 2025 Dec;62(12):2223-2234. doi: 10.1007/s00592-025-02583-3. Epub 2025 Sep 2. PMID- 40849485 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20250914 LR - 20250914 IS - 1758-5996 (Print) IS - 1758-5996 (Electronic) IS - 1758-5996 (Linking) VI - 17 IP - 1 DP - 2025 Aug 23 TI - GLP-1 receptor agonists in Parkinson's disease: an updated comprehensive systematic review with meta-analysis. PG - 352 LID - 10.1186/s13098-025-01888-1 [doi] LID - 352 AB - Previous studies have demonstrated an increased risk of developing Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM), as well as more severe and rapid motor and non-motor deterioration in diabetic PD patients compared to their non-diabetic counterparts. Additional research has suggested that diabetic subjects treated with glucagon-like peptide-1 (GLP-1) receptor agonists exhibit a reduced incidence of PD compared to those receiving other anti-diabetic medications. GLP-1 receptor agonists are FDA-approved therapies for T2DM, and recent studies have explored their potential as repurposed treatments for neurodegenerative diseases, including PD, AD, and ALS, as well as cerebrovascular disorders. This systematic review aims to assess the available literature on the efficacy and safety profiles of GLP-1 receptor agonists in PD management. A comprehensive search of PubMed, Scopus, CENTRAL, Web of Science, Embase, and ClinicalTrials.gov was conducted to identify relevant studies. The primary outcomes of this review include motor impairment in PD, as assessed by MDS-UPDRS Part III, as well as motor complications (Part IV) and motor experiences of daily living (Part II), and the incidence of gastrointestinal and systemic side effects. Meta-analysis showed that GLP-1 receptor agonists significantly improved motor function, as reflected by MDS-UPDRS Part III scores in the ON state (mean difference = - 2.88; p = 0.01; I(2) = 30%), although they were associated with a higher incidence of adverse events across all safety outcomes. Findings and conclusions of this review will contribute to a clearer understanding of the therapeutic potential of GLP-1 receptor agonists in PD, guiding future clinical research and treatment strategies. CI - (c) 2025. The Author(s). FAU - Helal, Mohamed Mohsen AU - Helal MM AUID- ORCID: 0009-0002-6387-623X AD - Faculty of Medicine, Zagazig University, Zagazig, Egypt. helal.rsch@gmail.com. FAU - AbouShawareb, Hala AU - AbouShawareb H AD - Faculty of Medicine, Mansoura University, Mansoura, Egypt. FAU - Abbas, Omarfayez Hussein AU - Abbas OH AD - Faculty of Medicine, Al-Azhar University, Cairo, Egypt. FAU - Haddad, Roaa AU - Haddad R AD - Faculty of Medicine, October 6 University, Giza, Egypt. FAU - Zain, Youmna AU - Zain Y AD - Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Osman, Ahmed S A AU - Osman ASA AD - Faculty of Medicine, Minia University, Minia, Egypt. FAU - Hassan, Amr K AU - Hassan AK AD - Department of Ophthalmology, School of Medicine, University of California, Irvine, CA, USA. AD - Medical Research Group of Egypt, Negida Academy, Arlington, MA, USA. LA - eng PT - Journal Article PT - Review DEP - 20250823 PL - England TA - Diabetol Metab Syndr JT - Diabetology & metabolic syndrome JID - 101488958 PMC - PMC12374370 OTO - NOTNLM OT - Glucagon-like peptide-1 receptor agonists OT - Humans OT - Motor disorders OT - Parkinson disease OT - Randomized controlled trials COIS- Declarations. Ethics approval and consent to participate: Ethical approval and informed consent were not required for this study, as it did not involve human participants or material. Competing interests: The authors declare no competing interests. EDAT- 2025/08/26 04:47 MHDA- 2025/08/26 04:48 PMCR- 2025/08/23 CRDT- 2025/08/23 23:28 PHST- 2025/06/14 00:00 [received] PHST- 2025/07/27 00:00 [accepted] PHST- 2025/08/26 04:48 [medline] PHST- 2025/08/26 04:47 [pubmed] PHST- 2025/08/23 23:28 [entrez] PHST- 2025/08/23 00:00 [pmc-release] AID - 10.1186/s13098-025-01888-1 [pii] AID - 1888 [pii] AID - 10.1186/s13098-025-01888-1 [doi] PST - epublish SO - Diabetol Metab Syndr. 2025 Aug 23;17(1):352. doi: 10.1186/s13098-025-01888-1. PMID- 40840993 OWN - NLM STAT- MEDLINE DCOM- 20250821 LR - 20260109 IS - 2044-6055 (Electronic) IS - 2044-6055 (Linking) VI - 15 IP - 8 DP - 2025 Aug 21 TI - Evaluating the effects of liraglutide, empagliflozin and linagliptin on mild cognitive impairment remission in patients with type 2 diabetes (LIGHT-MCI): study protocol for a multicentre, randomised controlled trial with an extension phase. PG - e095382 LID - 10.1136/bmjopen-2024-095382 [doi] LID - e095382 AB - INTRODUCTION: Diabetes is a significant modifiable risk factor for cognitive dysfunction. There are currently no effective treatments that delay or reverse the progression of cognitive dysfunction. Accumulating evidence demonstrates that specific antidiabetes medications hold promise in improving cognitive function. However, the comparative effects of various antidiabetic drug classes on cognitive protection remain to be fully elucidated. This study aims to investigate and compare the cognitive benefits of liraglutide, empagliflozin and linagliptin on achieving mild cognitive impairment (MCI) remission in individuals with type 2 diabetes (T2D). METHODS AND ANALYSIS: The LIGHT-MCI trial is an investigator-initiated, multicentre, open-label, parallel-group, randomised, superiority trial involving T2D patients with MCI, consisting of a 48-week core study followed by an extension phase through to 76 weeks. A total of 396 participants will be randomly allocated 1:1:1 to receive liraglutide, empagliflozin or linagliptin treatment. The primary outcome measure is the efficacy difference of liraglutide, empagliflozin and linagliptin in achieving MCI remission in individuals with T2D. The key secondary outcome measures include changes in scores of general cognition and various cognitive subdomains (including processing speed, executive function, immediate memory, visuospatial construction ability, language, attention and delayed memory), basic and instrumental daily living ability, MRI-derived normalised measures of total brain volume, cerebral microstructures, cortical and nuclear volume, white matter hyperintensity, volume, white matter microstructural integrity, odour-induced brain activation and resting-state functional connectivity, olfactory function and metabolic parameters. ETHICS AND DISSEMINATION: The LIGHT-MCI trial has received approval from the Ethics Committees of the Drum Tower Hospital Affiliated to Nanjing University Medical School (2022-092-02) and other participating centres in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation for Good Clinical Practice (ICH GCP E6). Informed consent is required for participation. Findings from this trial are disseminated through peer-reviewed publications, conference presentations, newsletters and social media. TRIAL REGISTRATION NUMBER: NCT05313529. CI - (c) Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. FAU - Yu, Congcong AU - Yu C AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Yang, Huijie AU - Yang H AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhang, Bing AU - Zhang B AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. FAU - Chen, Shihua AU - Chen S AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Yang, Sijue AU - Yang S AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Li, Fangyi AU - Li F AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhu, Wenhui AU - Zhu W AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhai, Beibei AU - Zhai B AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Wu, Tianyu AU - Wu T AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhao, Shengyi AU - Zhao S AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhang, Wen AU - Zhang W AD - Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. FAU - Tong, Xuewei AU - Tong X AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Duan, Yanjie AU - Duan Y AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Zhang, Lu AU - Zhang L AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Chao, Yining AU - Chao Y AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Wu, Jindan AU - Wu J AD - Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. FAU - Zhu, Xiaowei AU - Zhu X AD - Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China. FAU - Wang, Kun AU - Wang K AD - Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. FAU - Ye, Xinhua AU - Ye X AD - Department of Endocrinology, The Affiliated Changzhou No 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China. FAU - Zhang, Xiaoya AU - Zhang X AD - Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. FAU - Xu, Xiang AU - Xu X AD - Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China. FAU - Cheng, Haiyan AU - Cheng H AD - Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China. FAU - Liu, Jie AU - Liu J AD - Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. FAU - Zhang, Jie AU - Zhang J AD - Department of Endocrinology, The Affiliated Changzhou No 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China. FAU - Wang, Ying AU - Wang Y AD - Department of Endocrinology, The Affiliated Changzhou No 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. FAU - Yan, Weili AU - Yan W AUID- ORCID: 0000-0002-7633-7449 AD - Department of Clinical Epidemiology, Children's Hospital of Fudan University National Children's Medical Center, Shanghai, Shanghai, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China biyan@nju.edu.cn. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China. LA - eng SI - ClinicalTrials.gov/NCT05313529 PT - Clinical Trial Protocol PT - Journal Article DEP - 20250821 PL - England TA - BMJ Open JT - BMJ open JID - 101552874 RN - 839I73S42A (Liraglutide) RN - 0 (Glucosides) RN - 3X29ZEJ4R2 (Linagliptin) RN - 0 (Benzhydryl Compounds) RN - HDC1R2M35U (empagliflozin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Liraglutide/therapeutic use MH - *Glucosides/therapeutic use MH - *Linagliptin/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Benzhydryl Compounds/therapeutic use MH - *Cognitive Dysfunction/drug therapy/etiology MH - *Hypoglycemic Agents/therapeutic use MH - Multicenter Studies as Topic MH - Randomized Controlled Trials as Topic MH - Male MH - Female MH - Aged MH - Middle Aged MH - Cognition/drug effects MH - Remission Induction MH - Equivalence Trials as Topic PMC - PMC12374654 OTO - NOTNLM OT - Cognition OT - Dementia OT - Diabetes Mellitus, Type 2 COIS- Competing interests: None declared. EDAT- 2025/08/26 04:45 MHDA- 2025/08/26 04:46 PMCR- 2025/08/21 CRDT- 2025/08/21 20:53 PHST- 2025/08/26 04:46 [medline] PHST- 2025/08/26 04:45 [pubmed] PHST- 2025/08/21 20:53 [entrez] PHST- 2025/08/21 00:00 [pmc-release] AID - bmjopen-2024-095382 [pii] AID - 10.1136/bmjopen-2024-095382 [doi] PST - epublish SO - BMJ Open. 2025 Aug 21;15(8):e095382. doi: 10.1136/bmjopen-2024-095382. PMID- 40813122 OWN - NLM STAT- MEDLINE DCOM- 20250826 LR - 20260703 IS - 1756-1833 (Electronic) IS - 0959-8138 (Linking) VI - 390 DP - 2025 Aug 14 TI - Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis. PG - e083039 LID - 10.1136/bmj-2024-083039 [doi] AB - OBJECTIVE: To provide up-to-date evidence on key benefits, harms, and uncertainties regarding medications for adults with type 2 diabetes. DESIGN: Living systematic review and network meta-analysis (NMA), using frequentist random effects and GRADE (grading of recommendations, assessment, development and evaluation) approaches. Updates are planned at least two times a year. DATA SOURCES: Medline and Embase, searched up to 31 July 2024 for the current iteration. STUDY SELECTION: Randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other. RESULTS: The systematic review and NMA includes 493 168 participants from 869 trials (adding 53 trials since October 2022) reporting data for 13 drug classes (63 drugs) and 26 outcomes of interest. Regarding benefits, moderate to high certainty evidence confirms the well established cardiovascular and kidney benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone (the last for patients with established chronic kidney disease). The most effective drugs in reducing body weight were tirzepatide (mean difference (MD) -8.63 kg (95% confidence interval -9.34 to -7.93); moderate certainty) and orforglipron (MD -7.87 kg (-10.24 to -5.50); low certainty), followed by eight other GLP-1RAs (high to moderate certainty). Absolute benefits of medications vary substantially depending on the baseline risk of cardiovascular and kidney outcomes; risk-stratified absolute effects of medications are summarised using an interactive multiple comparisons tool (https://matchit.magicevidence.org/250709dist-diabetes/#!/). Regarding medication-specific harms, SGLT-2 inhibitors increase genital infections (odds ratio (OR) 3.29 (95% CI 2.88 to 3.77); high certainty) and ketoacidosis due to diabetes (OR 2.08 (1.45 to 2.99); high certainty), and probably increase amputations (OR 1.27 (1.01 to 1.61); moderate certainty); tirzepatide and GLP-1RAs probably increase severe gastrointestinal events (most increased risk with tirzepatide (OR 4.21 (1.87 to 9.49); moderate certainty)); finerenone increases severe hyperkalaemia (OR 5.92 (3.02 to 11.62); high certainty); and thiazolidinediones increase major osteoporotic fractures and probably increase hospitalisation for heart failure. Sulfonylureas, insulin, and dipeptidyl peptidase-4 inhibitors probably increase the risk of severe hypoglycaemia. There is low to very low certainty evidence for effects on other diabetes-related complications, including neuropathy and visual impairment. Despite interest in the issue, there is uncertainty about whether GLP-1RAs may reduce dementia (OR 0.92 (0.83 to 1.02); low certainty). CONCLUSIONS: This living systematic review provides a comprehensive summary of the cardiovascular, kidney, and weight loss benefits, as well as medication-specific harms of medications for adults with type 2 diabetes, including effects of SGLT-2 inhibitors, GLP-1RAs, finerenone and tirzepatide. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number: CRD42022325948. A more detailed protocol is available at https://data.aliveevidence.org/records/q02rv-km486. READERS' NOTES: This article is the first version of a living systematic review. It is linked to a living BMJ Rapid Recommendation and other living clinical practice guidelines, presenting risk stratified recommendations for patients with type 2 diabetes at lower, moderate, and higher risk of cardiovascular and kidney complications. The latest evidence will be made available via the BMJ Rapid Recommendation and via an interactive GRADE evidence summary (MATCH-IT: https://matchit.magicevidence.org/250709dist-diabetes/#!/). Major updates will be published in The BMJ. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. FAU - Nong, Kailei AU - Nong K AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - co-first authors who contribute equally to this study. FAU - Jeppesen, Britta Tendal AU - Jeppesen BT AD - Future Evidence Foundation, Melbourne, Australia. AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. AD - co-first authors who contribute equally to this study. FAU - Shi, Qingyang AU - Shi Q AD - Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands. AD - co-first authors who contribute equally to this study. FAU - Agoritsas, Thomas AU - Agoritsas T AD - Department of Health Research Methods, Evidence and Impact, McMaster University, ON, Canada. AD - Division of General Internal Medicine, Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland. AD - MAGIC Evidence Ecosystem Foundation, Oslo, Norway. FAU - Guyatt, Gordon H AU - Guyatt GH AD - Department of Health Research Methods, Evidence and Impact, McMaster University, ON, Canada. AD - MAGIC Evidence Ecosystem Foundation, Oslo, Norway. FAU - White, Heath AU - White H AD - Australian Living Evidence Collaboration (ALEC), Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Gao, Yiyuan AU - Gao Y AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Agarwal, Arnav AU - Agarwal A AD - Department of Health Research Methods, Evidence and Impact, McMaster University, ON, Canada. AD - MAGIC Evidence Ecosystem Foundation, Oslo, Norway. AD - Division of General Internal Medicine, University of Alberta, Edmonton, Alberta, Canada. FAU - Macdonald, Helen AU - Macdonald H AD - BMJ Editorial Tavistock Square, London, UK. FAU - Zou, Xinyu AU - Zou X AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Millard, Tanya AU - Millard T AD - Australian Living Evidence Collaboration (ALEC), Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. AD - Australian Diabetes Society, Sydney, Australia. FAU - Schnell, Oliver AU - Schnell O AD - Forschergruppe Diabetes eV at the Helmholtz Centre, Munich-Neuherberg, Germany. FAU - Marx, Nikolaus AU - Marx N AD - Clinic for Cardiology, Angiology, and Intensive Care Medicine, RWTH Aachen University, University Hospital Aachen, Aachen, Germany. FAU - Brosius, Frank C 3rd AU - Brosius FC 3rd AD - Division of Nephrology, University of Arizona College of Medicine Tucson, Tucson, AZ, USA. FAU - McDonald, Steve AU - McDonald S AD - Australian Living Evidence Collaboration (ALEC), Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Quigley, Matthew AU - Quigley M AD - Australian Living Evidence Collaboration (ALEC), Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Tian, Xin AU - Tian X AD - Healthcare Innovation Research Laboratory, Nursing Key Laboratory of Sichuan Province, National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China. FAU - Fan, Qinlin AU - Fan Q AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - White, Barbara AU - White B AD - Australian Diabetes Society, Sydney, Australia. FAU - Mao, Yunhe AU - Mao Y AD - Department of Orthopaedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, China. FAU - Pan, Xiaohui AU - Pan X AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Liu, Changhai AU - Liu C AD - Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China. AD - Division of Infectious Diseases, State Key Laboratory of Biotherapy and Centre of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China. FAU - Zhai, Chunjuan AU - Zhai C AD - Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China. FAU - Yuan, Chi AU - Yuan C AD - Department of Paediatric Surgery, West China Hospital, Sichuan University, Chengdu, China. FAU - Li, Qiang AU - Li Q AD - Department of Hypertension and Endocrinology, Daping Hospital, Centre for Hypertension and Metabolic Diseases, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing, China lisheyu@gmail.com. FAU - An, Jing AU - An J AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Gan, Yu AU - Gan Y AD - Department of Anaesthesiology, Laboratory of Anaesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anaesthesiology, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Wang, Yanyan AU - Wang Y AD - Healthcare Innovation Research Laboratory, Nursing Key Laboratory of Sichuan Province, National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China. FAU - Jin, Yinghui AU - Jin Y AD - Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Sun, Feng AU - Sun F AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China. FAU - Zhu, Zhiming AU - Zhu Z AD - Department of Hypertension and Endocrinology, Daping Hospital, Centre for Hypertension and Metabolic Diseases, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing, China. FAU - Ryden, Lars AU - Ryden L AD - Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. FAU - Standl, Eberhard AU - Standl E AD - Forschergruppe Diabetes eV at the Helmholtz Centre, Munich-Neuherberg, Germany. FAU - Turner, Tari AU - Turner T AD - Australian Living Evidence Collaboration (ALEC), Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Vandvik, Per Olav AU - Vandvik PO AD - MAGIC Evidence Ecosystem Foundation, Oslo, Norway. AD - Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway. AD - co-senior authors of this study. FAU - Li, Sheyu AU - Li S AUID- ORCID: 0000-0003-0060-0287 AD - Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, 610041, China lisheyu@gmail.com. AD - MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. AD - MAGIC Evidence Ecosystem Foundation, Oslo, Norway. AD - co-senior authors of this study. LA - eng PT - Journal Article PT - Network Meta-Analysis PT - Systematic Review DEP - 20250814 PL - England TA - BMJ JT - BMJ (Clinical research ed.) JID - 8900488 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Randomized Controlled Trials as Topic MH - Adult MH - Glucagon-Like Peptide-1 Receptor Agonists COIS- Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the West China Hospital, Sichuan University for the submitted work; KNong, BTJeppesen, QShi, TAgoritsas, GGuyatt, HWhite, YGao, AAgarwal, HMacdonald, XZou, TMillard, SMcdonald, MQuigley, XTian, QFan, BWhite, YMao, XPan, CLiu, CZhai, CYuan, QLi, JAn, YGan, YWang, YJin, FSun, ZZhu, TTurner, and POVandvik: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. EStandl reported personal fees from Oxford Diabetes Trials Unit, Bayer, Berlin Chemie, Boehringer Ingelheim, Menarini, Merck Serono, EXCEMED, Novartis, Novo Nordisk, and Sanofi. LRyden reported grants or contracts from Swedish Heart Lung Foundation, Stockholm County Council, Erling Perssons Foundation and Boehringer-Ingelheim, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer AG, Boehringer Ingelheim, Novo Nordisk. FBrosiusIII reported grants or contracts from National Institutes of Health, and consulting fees from Gilead Sciences. OSchnell reported payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott Diagnostics, Lilly Deutschland, Boehringer Ingelheim, Bayer, Mannkind, and Lifescan and is a founder and CEO of Sciarc GmbH. NMarx reported grants or contracts from Boehringer Ingelheim, Merck, Novo Nordisk, Deutsche Forschungsgesellschaft (German Research Foundation; TRR 219), and consulting fees from Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, AstraZeneca. SLi received the funds from West China Hospital of Sichuan University, National Natural Science Foundation of China, and Sichuan Science and Technology Program. EDAT- 2025/08/14 22:50 MHDA- 2025/08/31 20:08 CRDT- 2025/08/14 21:52 PHST- 2025/08/31 20:08 [medline] PHST- 2025/08/14 22:50 [pubmed] PHST- 2025/08/14 21:52 [entrez] AID - 10.1136/bmj-2024-083039 [doi] PST - epublish SO - BMJ. 2025 Aug 14;390:e083039. doi: 10.1136/bmj-2024-083039. PMID- 40810170 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260813 IS - 2575-9108 (Electronic) IS - 2575-9108 (Linking) VI - 8 IP - 8 DP - 2025 Aug 8 TI - Cognitive Dysfunction and Dementia in Type 2 Diabetes Mellitus: Insights into Mechanisms, Models, and Therapeutics. PG - 2337-2352 LID - 10.1021/acsptsci.5c00086 [doi] AB - Diabetic-related cognitive dysfunction, especially mild cognitive impairment (MCI), is a serious complication of type 2 diabetes mellitus (T2DM). It severely impacts personal health and places a substantial burden on the healthcare system, characterized by deficits in cognitive function and delayed executive abilities, and accelerates dementia progression. Accurate prediction and diagnosis of MCI in T2DM patients are critical for the effective prevention and treatment of dementia. However, this task is challenging due to the diverse subtypes of MCI (amnestic and nonamnestic) and the complex underlying mechanisms. This review highlights the critical gaps in current knowledge, focusing on the unique interaction between metabolic dysregulation and neurodegenerative processes in T2DM. Emerging technologies, such as brain and vascular organoid models, have opened new avenues for unraveling these complexities, although significant challenges remain in translating these tools into clinical practice. Furthermore, we explore the neuroprotective effects of antidiabetic treatments, including sulfonylureas, biguanides, insulin, GLP-1 receptor agonists, and SGLT2 inhibitors, emphasizing their potential role in addressing the distinct mechanisms underlying different MCI subtypes. This review aims to pave the way for approaches to mitigate the burden of diabetic-related cognitive dysfunction and slow dementia progression. CI - (c) 2025 American Chemical Society. FAU - Zeng, Junhong AU - Zeng J AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 FAU - Hu, Keer AU - Hu K AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 FAU - Wang, Zitian AU - Wang Z AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 FAU - Huang, Yi-Chun AU - Huang YC AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 FAU - Zhang, Yu AU - Zhang Y AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 FAU - Peng, Haiying AU - Peng H AD - General Hospital of the Southern Theater Command of the Chinese People's Liberation Amy, Guangzhou 510280, China. FAU - Ma, Shaohua AU - Ma S AUID- ORCID: 0000-0002-4995-2032 AD - Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China. RINGGOLD: 12442 LA - eng PT - Journal Article PT - Review DEP - 20250707 PL - United States TA - ACS Pharmacol Transl Sci JT - ACS pharmacology & translational science JID - 101721411 PMC - PMC12340629 EDAT- 2025/08/14 06:27 MHDA- 2025/08/14 06:28 PMCR- 2026/07/07 CRDT- 2025/08/14 05:34 PHST- 2025/02/02 00:00 [received] PHST- 2025/05/20 00:00 [revised] PHST- 2025/05/27 00:00 [accepted] PHST- 2025/08/14 06:28 [medline] PHST- 2025/08/14 06:27 [pubmed] PHST- 2025/08/14 05:34 [entrez] PHST- 2026/07/07 00:00 [pmc-release] AID - 10.1021/acsptsci.5c00086 [doi] PST - epublish SO - ACS Pharmacol Transl Sci. 2025 Jul 7;8(8):2337-2352. doi: 10.1021/acsptsci.5c00086. eCollection 2025 Aug 8. PMID- 40806100 OWN - NLM STAT- MEDLINE DCOM- 20250826 LR - 20250826 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 17 IP - 15 DP - 2025 Jul 31 TI - Effect of Akkermansia muciniphila on GLP-1 and Insulin Secretion. LID - 10.3390/nu17152516 [doi] LID - 2516 AB - Background/Objectives: Gut microbiota research has gained momentum in recent years broadening knowledge of microbial components and their potential effects on health and well-being. Strong association between explicit microbes and metabolic diseases associated with obesity and type 2 diabetes mellitus, gastrointestinal disorders, neurodegenerative diseases, and even cancers have been established. Akkermansia muciniphila is a budding next-generation probiotic that plays an important role in systemic metabolism, intestinal health, and immune regulation, establishing strong implications for its use as a potent therapeutic intervention in diverse diseases. This project aimed at evaluating whether bacterial cell extracts of VH Akkermansia muciniphila (Vidya Strain; VS) can stimulate insulin secretion in INS-1 pancreatic beta cells and GLP-1 secretion in NCI-H716 human L-cells, both established in vitro models for studying metabolic regulation. Methods: Cultured VH Akkermansia muciniphila extracts were administered in a dose-dependent manner on INS-1 cells, and glucose-stimulated insulin secretion (GSIS) was measured via ELISA. Treated Human L-cell lines (NCI-H716) were analyzed for GLP-1 secretion. Results: Our study demonstrated that VH Akkermansia muciniphila extracts modestly increase insulin secretion from INS-1 beta cells and, more notably, induce a robust, dose-dependent rise in GLP-1 secretion from NCI-H716 L-cells, with the highest dose achieving over a 2000% increase comparable to glutamine. Conclusions: These findings suggest that VH A. muciniphila extracts may offer metabolic benefits by enhancing GLP-1 release, highlighting their potential for managing type 2 diabetes and obesity. FAU - Arukha, Ananta Prasad AU - Arukha AP AD - Department of Infectious Disease and Immunology, University of Florida, Gainesville, FL 32608, USA. FAU - Nayak, Subhendu AU - Nayak S AD - Vidya USA Corporation, 7 Otis Stone Hunter Road, Bunnell, FL 32100, USA. FAU - Swain, Durga Madhab AU - Swain DM AUID- ORCID: 0000-0003-4904-1404 AD - Vidya USA Corporation, 7 Otis Stone Hunter Road, Bunnell, FL 32100, USA. LA - eng PT - Journal Article DEP - 20250731 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Insulin) RN - Akkermansia muciniphila SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/metabolism MH - *Insulin Secretion/drug effects MH - *Insulin-Secreting Cells/metabolism/drug effects MH - *Insulin/metabolism MH - *Probiotics/pharmacology MH - Akkermansia MH - Cell Line MH - *Verrucomicrobia MH - Gastrointestinal Microbiome PMC - PMC12348610 OTO - NOTNLM OT - Akkermansia muciniphila OT - GLP-1 secretion OT - diabetes OT - insulin secretion OT - probiotics COIS- Authors declare no competing interests. EDAT- 2025/08/14 06:28 MHDA- 2025/08/31 20:07 PMCR- 2025/07/31 CRDT- 2025/08/14 01:11 PHST- 2025/06/03 00:00 [received] PHST- 2025/07/17 00:00 [revised] PHST- 2025/07/24 00:00 [accepted] PHST- 2025/08/31 20:07 [medline] PHST- 2025/08/14 06:28 [pubmed] PHST- 2025/08/14 01:11 [entrez] PHST- 2025/07/31 00:00 [pmc-release] AID - nu17152516 [pii] AID - nutrients-17-02516 [pii] AID - 10.3390/nu17152516 [doi] PST - epublish SO - Nutrients. 2025 Jul 31;17(15):2516. doi: 10.3390/nu17152516. PMID- 40771859 OWN - NLM STAT- MEDLINE DCOM- 20250807 LR - 20250809 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 19 DP - 2025 TI - Comparative Analysis of Pioglitazone and Tirzepatide on Body Weight, Glucose Levels, Neuroinflammation, and Oxidative Stress in Diabetic Rats. PG - 6605-6618 LID - 10.2147/DDDT.S525690 [doi] AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a widespread metabolic illness that compromises cognitive function by inducing inflammation and oxidative damage. Diabetes mellitus is treated with many types of medications, including tirzepatide (TZP) and pioglitazone (PIO), which have also been shown to enhance cognitive deficits associated with the condition. This study intends to investigate the neuroprotective effects of TZP and PIO on type 2 diabetic mellitus (T2DM) via mitigating neuroinflammation and oxidative stress, along with enhancing cognitive impairment in rats as models with T2DM. METHODS: A total of six distinct groups of sixty albino rat males (n = 10) were allocated at random: Saline, TZP, PIO, T2DM, T2DM+TZP, and T2DM+PIO. Intramuscular doses of streptozotocin (50 mg/kg) and nicotinamide (120 mg/kg) precipitated T2DM. The TZP and PIO therapies persisted for a duration of 15 days. The survival percentage, body weight, behavioral assessments (Y-maze, novel object recognition (NOR)), glucose concentrations, inflammatory mediators tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and interleukin-1 beta (IL-1beta), as well as oxidative stress biomarkers superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and lipid peroxidation were evaluated following the conclusion of the treatments. RESULTS: The results demonstrate that diabetes decreased survival rates, body weight, cognitive function, increased glucose levels, neuroinflammation, and oxidative stress. The TZP and PIO increased survival rates and cognitive function as well as decreased glucose levels, neuroinflammation, and oxidative stress in diabetic rats, with PIO demonstrating a more pronounced effect on neuroinflammation and oxidative stress, contrasted with TZP. DISCUSSION: This study concluded that TZP and PIO enhanced cognitive impairment in diabetic rats, with PIO demonstrating superior efficacy in contrast to TZP. CI - (c) 2025 Alhowail et al. FAU - Alhowail, Ahmad AU - Alhowail A AUID- ORCID: 0000-0003-1427-032X AD - Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Saudi Arabia. FAU - Aldawsari, Mohammed F AU - Aldawsari MF AD - Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj, 11942, Saudi Arabia. FAU - Aldubayan, Maha AU - Aldubayan M AD - Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Saudi Arabia. LA - eng PT - Comparative Study PT - Journal Article DEP - 20250731 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - X4OV71U42S (Pioglitazone) RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 5W494URQ81 (Streptozocin) RN - 0 (Neuroprotective Agents) RN - OYN3CCI6QE (Tirzepatide) SB - IM MH - Animals MH - *Oxidative Stress/drug effects MH - Male MH - Rats MH - *Diabetes Mellitus, Experimental/drug therapy/metabolism/chemically induced MH - *Body Weight/drug effects MH - *Pioglitazone/pharmacology/administration & dosage MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Blood Glucose/drug effects/analysis MH - *Hypoglycemic Agents/pharmacology/administration & dosage MH - Streptozocin MH - *Neuroinflammatory Diseases/drug therapy/metabolism MH - Rats, Wistar MH - Neuroprotective Agents/pharmacology MH - Inflammation/drug therapy MH - Dose-Response Relationship, Drug MH - Tirzepatide PMC - PMC12325112 OTO - NOTNLM OT - cognitive impairment OT - diabetes OT - inflammation OT - insulin OT - oxidative stress OT - pioglitazone OT - tirzepatide COIS- The authors report that no conflict of interest exists. EDAT- 2025/08/07 11:42 MHDA- 2025/08/07 11:43 PMCR- 2025/07/31 CRDT- 2025/08/07 05:11 PHST- 2025/03/20 00:00 [received] PHST- 2025/07/27 00:00 [accepted] PHST- 2025/08/07 11:43 [medline] PHST- 2025/08/07 11:42 [pubmed] PHST- 2025/08/07 05:11 [entrez] PHST- 2025/07/31 00:00 [pmc-release] AID - 525690 [pii] AID - 10.2147/DDDT.S525690 [doi] PST - epublish SO - Drug Des Devel Ther. 2025 Jul 31;19:6605-6618. doi: 10.2147/DDDT.S525690. eCollection 2025. PMID- 40762930 OWN - NLM STAT- MEDLINE DCOM- 20250830 LR - 20260925 IS - 1568-5608 (Electronic) IS - 0925-4692 (Print) IS - 0925-4692 (Linking) VI - 33 IP - 8 DP - 2025 Aug TI - Antidiabetic drugs in Parkinson's disease: a comprehensive meta-analysis on efficacy and safety with trial sequential analysis and GRADE evaluation. PG - 4577-4593 LID - 10.1007/s10787-025-01873-0 [doi] AB - Recent studies highlighted the relation between type 2 diabetes and Parkinson's disease, suggesting a relation between insulin resistance and alpha-synuclein aggregation. Antidiabetic medications, including GLP-1 receptor agonists and PPAR-gamma agonists, have shown potential neuroprotective effects. We conducted a comprehensive literature search retrieving randomized controlled trials (RCTs) comparing antidiabetic drugs and placebo. Key outcomes included motor and non-motor symptoms, along with the safety profile. Data were analyzed using RevMan, and trial sequential analysis as well as sensitivity analysis were conducted to ensure the robustness of our results. In addition, to ensure the reliability of our evidence, we conducted the GRADE evaluation approach. Seven RCTs, with 973 patients, were eligible for our inclusion criteria. Antidiabetic drugs have shown no significant difference from placebo concerning change in MDS-UPDRS scores while on medication in Parts I, II, III, IV (MD = -0.04, 95% CI [-0.74 to 0.66], p = 0.90), (MD = -0.88, 95% CI [-2.11 to 0.34], p = 0.16), (MD = -1.10, 95% CI [-2.61 to 0.42], p = 0.16), (MD = -0.09, 95% CI [-0.45 to 0.27], p = 0.64), respectively. However, for MATTIS-DRS and MADRS scores, results showed a significant difference favoring GLP-1 agonists (MD = 2.42, 95% CI [0.01 to 4.83], p = 0.05), (MD = -2.08, 95% CI [-3.93 to -0.23], p = 0.03) respectively. As for safety profile, results revealed significant differences favoring the placebo group. This meta-analysis concludes that antidiabetic drugs in early-to mid-stage Parkinson's disease show no significant benefit considering non-motor symptoms detected by MDS-UPDRS I, with TSA confirming this finding as a conclusive result. Similarly, no notable effects on motor symptoms were observed, although future trials are needed. GLP-1 agonists revealed potential antidepressant effects as well as improving cognitive functions detected by MADRS and MATTIS-DRS, respectively. However, antidiabetic drugs were associated with higher risks of gastrointestinal adverse effects such as nausea, vomiting, and weight loss. CI - (c) 2025. The Author(s). FAU - Abou Elezz, Amr M AU - Abou Elezz AM AD - Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Khalefa, Kareem AU - Khalefa K AD - Faculty of Medicine, Tanta University, Tanta, Egypt. FAU - Gadelmawla, Ahmed Farid AU - Gadelmawla AF AUID- ORCID: 0000-0002-5802-2291 AD - Faculty of Medicine, Menoufia University, Menoufia, Egypt. FAU - Khattab, Youssef A AU - Khattab YA AUID- ORCID: 0009-0002-7066-4374 AD - Faculty of Medicine, Mansoura University, Mansoura, Egypt. FAU - Abo Zeid, Mohamed AU - Abo Zeid M AUID- ORCID: 0009-0007-8165-9470 AD - Faculty of Medicine, Tanta University, Tanta, Egypt. Mohamed_31059599@med.tanta.edu.eg. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20250805 PL - Switzerland TA - Inflammopharmacology JT - Inflammopharmacology JID - 9112626 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Hypoglycemic Agents/therapeutic use/adverse effects/pharmacology MH - *Parkinson Disease/drug therapy MH - Randomized Controlled Trials as Topic/methods MH - Treatment Outcome PMC - PMC12397177 OTO - NOTNLM OT - Antidiabetic agent OT - Exenatide OT - Glucagon-like peptide OT - Lixisenatide OT - Meta-analysis OT - Parkinson's disease OT - Thiazolidinedione COIS- Declarations. Conflict of interests: The authors declare that they have no competing interests. All the authors declare no conflicts of interest associated with the conduct of this work. Ethics approval and consent to participate: This article does not contain any studies with human participants or animals performed by any of the authors. Consent for publication: Not applicable. EDAT- 2025/08/05 12:35 MHDA- 2025/09/01 16:44 PMCR- 2025/08/05 CRDT- 2025/08/05 11:35 PHST- 2025/06/13 00:00 [received] PHST- 2025/07/16 00:00 [accepted] PHST- 2025/09/01 16:44 [medline] PHST- 2025/08/05 12:35 [pubmed] PHST- 2025/08/05 11:35 [entrez] PHST- 2025/08/05 00:00 [pmc-release] AID - 10.1007/s10787-025-01873-0 [pii] AID - 1873 [pii] AID - 10.1007/s10787-025-01873-0 [doi] PST - ppublish SO - Inflammopharmacology. 2025 Aug;33(8):4577-4593. doi: 10.1007/s10787-025-01873-0. Epub 2025 Aug 5. PMID- 40736492 OWN - NLM STAT- MEDLINE DCOM- 20250730 LR - 20260429 IS - 1532-0650 (Electronic) IS - 0002-838X (Linking) VI - 112 IP - 1 DP - 2025 Jul TI - Top 20 Research Studies of 2024 for Primary Care Physicians. PG - 34-41 AB - This article summarizes the top 20 research studies of 2024 identified as POEMs (patient-oriented evidence that matters). Based on a network meta-analysis, the oral antibiotics most likely to be effective for community-acquired pneumonia are telithromycin (not available in the United States), azithromycin, amoxicillin-clavulanate, and the quinolones levofloxacin and nemonoxacin (not available in the United States). The oral antivirals molnupiravir and nirmatrelvir-ritonavir reduce hospitalizations in immunocompromised patients with COVID-19. In average-risk infants, a single dose of nirsevimab reduces hospitalizations due to respiratory syncytial virus. Amoxicillin with or without clavulanate is more effective than placebo for children with symptoms of acute sinusitis. Benzyl benzoate 25% is highly effective for scabies in adolescents and adults. Lactobacillus-containing probiotics reduce the incidence of recurrent urinary tract infections (UTIs) in premenopausal women with frequent UTIs. Low-dose amitriptyline is effective as second-line therapy for irritable bowel syndrome. For patients with uncomplicated gallstones, conservative management is a reasonable option. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are better than older drugs at improving patient-oriented outcomes for type 2 diabetes. Continuous or intermittent glucose monitoring is minimally effective for control of type 2 diabetes and can be harmful. Phentermine-topiramate and GLP-1 receptor agonists are the most effective drugs for promoting weight loss. Semaglutide is effective for secondary prevention of cardiovascular disease in people with obesity and no diabetes. SGLT-2 inhibitors and GLP-1 receptor agonists decrease cardiovascular death in older adults with type 2 diabetes and heart failure. Beta blockers do not prevent subsequent events after myocardial infarction in patients with preserved ejection fraction. For patients who do not quit smoking after a trial of varenicline or combined nicotine replacement therapy, a higher dose of either drug can increase quit rates. e-Cigarettes increase abstinence from smoking, but long-term vaping is a consequence for some. Oral naltrexone and acamprosate are safe and effective treatments for alcohol use disorder. Cognitive behavior therapy can reduce fatigue attributed to long COVID. New monoclonal antibodies for Alzheimer disease are harmful, expensive, and minimally effective. Clinicians may choose to deliver bad news in person or by telephone, using their judgment or patient preference to decide which is best for the patient. FAU - Grad, Roland AU - Grad R AD - McGill University, Montreal, Canada. FAU - Ebell, Mark H AU - Ebell MH AD - Michigan State University, East Lansing. LA - eng PT - Journal Article PT - Review PL - United States TA - Am Fam Physician JT - American family physician JID - 1272646 RN - 0 (Anti-Bacterial Agents) SB - IM MH - Humans MH - Anti-Bacterial Agents/therapeutic use MH - *Physicians, Primary Care MH - COVID-19 MH - *Primary Health Care MH - SARS-CoV-2 EDAT- 2025/07/30 12:31 MHDA- 2025/07/30 12:32 CRDT- 2025/07/30 11:03 PHST- 2025/07/30 12:32 [medline] PHST- 2025/07/30 12:31 [pubmed] PHST- 2025/07/30 11:03 [entrez] AID - 2cf3c8fa-5088-45c3-8a82-1684edccb0f2 [pii] PST - ppublish SO - Am Fam Physician. 2025 Jul;112(1):34-41. PMID- 40727007 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250731 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 86 DP - 2025 Aug TI - The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions. PG - 103363 LID - 10.1016/j.eclinm.2025.103363 [doi] LID - 103363 AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed obesity management, offering substantial weight loss and metabolic benefits. This review examines their expanding role, evaluating efficacy compared to alternative treatments, emerging indications, ongoing challenges, and future directions. Beyond obesity and type 2 diabetes, the therapeutic potential of GLP-1 RAs extends to a range of conditions such as cardiovascular disease, liver disease, neurodegenerative disease, and substance abuse disorders. While early concerns regarding pancreatic and thyroid cancer have been largely attenuated by recent evidence, issues such as gallbladder and biliary disorders, psychiatric safety, and perioperative aspiration risk require ongoing investigation. Additionally, observations of weight regain after treatment discontinuation and reductions in lean mass highlight the need for long-term, individualized strategies to sustain clinical benefits. The high cost and limited access to these medications raise critical policy and equity challenges. Future research must address these gaps, focusing on long-term safety, optimizing combination approaches, and evaluating the broader clinical and economic implications of widespread GLP-1 RA use. FUNDING: K.B.F. is supported by a William Dawson Scholar award from McGill University. T.M.P. is a Fond de Recherche du Quebec-Sante (FRQS) research scholar. M.J.E. holds a James McGill Professor award from McGill University. The funding sources had no involvement in the conduct of this study, interpretation of results, or the preparation of this manuscript for publication. CI - (c) 2025 The Author(s). FAU - Moiz, Areesha AU - Moiz A AD - Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. FAU - Filion, Kristian B AU - Filion KB AD - Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Department of Medicine, McGill University, Montreal, Canada. FAU - Tsoukas, Michael A AU - Tsoukas MA AD - Department of Medicine, McGill University, Montreal, Canada. AD - Division of Endocrinology and Metabolism, McGill University, Montreal, Canada. FAU - Yu, Oriana H Y AU - Yu OHY AD - Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Department of Medicine, McGill University, Montreal, Canada. AD - Division of Endocrinology and Metabolism, McGill University, Montreal, Canada. FAU - Peters, Tricia M AU - Peters TM AD - Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Department of Medicine, McGill University, Montreal, Canada. AD - Division of Endocrinology and Metabolism, McGill University, Montreal, Canada. FAU - Eisenberg, Mark J AU - Eisenberg MJ AD - Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. AD - Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada. AD - Department of Medicine, McGill University, Montreal, Canada. AD - Division of Cardiology, Jewish General Hospital/McGill University, Canada. LA - eng PT - Journal Article PT - Review DEP - 20250717 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC12303005 OTO - NOTNLM OT - Cardiometabolic outcomes OT - Combination therapy OT - Glucagon-like peptide-1 receptor agonist OT - Health policy OT - Safety COIS- Dr. Tsoukas has received speaker honoraria from Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, and Sanofi. The other authors have no conflicts of interest to disclose. EDAT- 2025/07/29 06:30 MHDA- 2025/07/29 06:31 PMCR- 2025/07/17 CRDT- 2025/07/29 05:52 PHST- 2025/03/05 00:00 [received] PHST- 2025/06/11 00:00 [revised] PHST- 2025/07/01 00:00 [accepted] PHST- 2025/07/29 06:31 [medline] PHST- 2025/07/29 06:30 [pubmed] PHST- 2025/07/29 05:52 [entrez] PHST- 2025/07/17 00:00 [pmc-release] AID - S2589-5370(25)00295-0 [pii] AID - 103363 [pii] AID - 10.1016/j.eclinm.2025.103363 [doi] PST - epublish SO - EClinicalMedicine. 2025 Jul 17;86:103363. doi: 10.1016/j.eclinm.2025.103363. eCollection 2025 Aug. PMID- 40699685 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250731 IS - 1467-3045 (Electronic) IS - 1467-3037 (Print) IS - 1467-3037 (Linking) VI - 47 IP - 4 DP - 2025 Apr 17 TI - The Expanding Role of GLP-1 Receptor Agonists: Advancing Clinical Outcomes in Metabolic and Mental Health. LID - 10.3390/cimb47040285 [doi] LID - 285 AB - Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising therapeutic option beyond their established role in managing type 2 diabetes mellitus (T2DM) and obesity. Recent research has highlighted their beneficial effects on liver, kidney, and cardiovascular health, mediated by both direct and indirect mechanisms. In the liver, GLP-1 RAs contribute to the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing hepatic fat accumulation, inflammation, and oxidative stress. Additionally, they enhance insulin sensitivity and lipid metabolism. Similarly, in diabetic kidney disease (DKD), GLP-1 RAs exhibit renoprotective properties by mitigating inflammation, oxidative stress, and glomerular hypertension. Furthermore, they promote natriuresis and stabilize renal function. Moreover, GLP-1 RAs present significant cardiovascular benefits, including improved myocardial function, reduced atherosclerosis progression, enhanced endothelial health, and decreased major adverse cardiovascular events (MACEs). Additionally, emerging evidence suggests GLP-1 RAs may exert substantial neuropsychiatric benefits, including reductions in depressive symptoms, anxiety, substance use behaviors, and lowering the risk of Alzheimer's disease, Parkinson's disease, and other dementias likely mediated by the modulation of neurotransmitter systems and neuroinflammation. Genetic polymorphisms in the GLP1R gene also impact the therapeutic response, highlighting the importance of personalized medicine in optimizing GLP-1 RA efficacy. This review synthesizes preclinical and clinical evidence supporting the multifaceted effects of GLP-1 RAs across multiple organ systems, highlighting their therapeutic potential beyond glycemic control. As research advances, further exploration of their mechanisms of action and long-term clinical outcomes, safety and effectiveness across diverse patient populations will be essential in optimizing their use in treating metabolic and neuropsychiatric conditions. FAU - Al Qassab, Mohamad AU - Al Qassab M AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Mneimneh, Mohammad AU - Mneimneh M AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Jradi, Ahmad AU - Jradi A AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Derbas, Bassem AU - Derbas B AUID- ORCID: 0009-0007-1391-0467 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Dabboussi, Dana AU - Dabboussi D AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Khoury Baini, Justine AU - Khoury Baini J AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Katrib, Nadia AU - Katrib N AUID- ORCID: 0009-0003-7304-168X AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Chaarani, Nadim AU - Chaarani N AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Attieh, Philippe AU - Attieh P AUID- ORCID: 0009-0006-8491-0790 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Kanaan, Amjad AU - Kanaan A AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Harb, Frederic AU - Harb F AUID- ORCID: 0000-0001-5882-1619 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Azar, Sami AU - Azar S AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. FAU - Ghadieh, Hilda E AU - Ghadieh HE AUID- ORCID: 0000-0002-7983-2090 AD - Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura, Tripoli P.O. Box 100, Lebanon. LA - eng PT - Journal Article PT - Review DEP - 20250417 PL - Switzerland TA - Curr Issues Mol Biol JT - Current issues in molecular biology JID - 100931761 PMC - PMC12025658 OTO - NOTNLM OT - Alzheimer's disease OT - Glucagon-like peptide 1 receptor agonists OT - Parkinson's disease OT - cardiovascular diseases OT - dementia OT - diabetic nephropathy OT - fatty liver disease OT - genetic polymorphisms OT - metabolic health OT - neuropsychiatric disorders OT - type 2 diabetes mellitus COIS- The authors declare no conflicts of interest. EDAT- 2025/07/23 12:32 MHDA- 2025/07/23 12:33 PMCR- 2025/04/17 CRDT- 2025/07/23 11:40 PHST- 2025/03/25 00:00 [received] PHST- 2025/04/13 00:00 [revised] PHST- 2025/04/14 00:00 [accepted] PHST- 2025/07/23 12:33 [medline] PHST- 2025/07/23 12:32 [pubmed] PHST- 2025/07/23 11:40 [entrez] PHST- 2025/04/17 00:00 [pmc-release] AID - cimb47040285 [pii] AID - cimb-47-00285 [pii] AID - 10.3390/cimb47040285 [doi] PST - epublish SO - Curr Issues Mol Biol. 2025 Apr 17;47(4):285. doi: 10.3390/cimb47040285. PMID- 40695613 OWN - NLM STAT- MEDLINE DCOM- 20250722 LR - 20250731 IS - 2052-4897 (Electronic) IS - 2052-4897 (Linking) VI - 13 IP - 4 DP - 2025 Jul 22 TI - Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes. LID - 10.1136/bmjdrc-2025-004902 [doi] LID - e004902 AB - INTRODUCTION: No direct comparisons have evaluated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus metformin as first-line antidiabetic therapy for preventing dementia in patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the comparative effectiveness of GLP-1 RAs and metformin in reducing dementia risk. RESEARCH DESIGN AND METHODS: This retrospective cohort study used data from a global health research network between 2004 and 2024. Patients with T2DM initiating GLP-1 RAs or metformin as first-line monotherapy were included. Propensity score matching was employed to balance baseline characteristics. Dementia incidence was analyzed using Cox proportional hazards models, with sensitivity analyses to confirm robustness. RESULTS: Among 87,229 matched patients per cohort, GLP-1 RA use was associated with a significantly lower risk of overall dementia (adjusted HR (AHR) 0.90; 95% CI 0.85 to 0.95), Alzheimer's disease (AD) (AHR 0.88; 95% CI 0.83 to 0.94), and non-vascular dementias (non-VaDs) (AHR 0.75; 95% CI 0.70 to 0.81) compared with metformin. No significant difference was observed for VaD. Subgroup analyses showed consistent benefit across age and sex, with the strongest effect among older adults and females. CONCLUSIONS: GLP-1 RAs were more effective than metformin in reducing the risk of dementia-especially AD and non-vascular types-highlighting their potential as a preferred first-line treatment in T2DM. Further randomized trials are warranted to validate these findings. CI - (c) Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. FAU - Sun, Mingyang AU - Sun M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China zhangjiq@zzu.edu.cn szuyuanwu5399@gmail.com mingyangsun1986@163.com. AD - Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China. FAU - Wang, Xiaoling AU - Wang X AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China. AD - Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Lu, Zhongyuan AU - Lu Z AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China. AD - Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Yang, Yitian AU - Yang Y AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Lv, Shuang AU - Lv S AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Miao, Mengrong AU - Miao M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Chen, Wan-Ming AU - Chen WM AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan. AD - Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan. AD - Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan. FAU - Wu, Szu Yuan AU - Wu SY AUID- ORCID: 0000-0001-5637-558X AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan zhangjiq@zzu.edu.cn szuyuanwu5399@gmail.com mingyangsun1986@163.com. AD - Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan. AD - Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan. AD - Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan. AD - Division of Radiation Oncology, Lo-Hsu Medical Foundation,Lotung Poh-Ai Hospital, Yilan, Taiwan. AD - Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan. FAU - Zhang, Jiaqiang AU - Zhang J AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University Zhengzhou University，Henan Provincial People's Hospital, Zhengzhou, Henan, China zhangjiq@zzu.edu.cn szuyuanwu5399@gmail.com mingyangsun1986@163.com. AD - Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China. LA - eng PT - Comparative Study PT - Journal Article DEP - 20250722 PL - England TA - BMJ Open Diabetes Res Care JT - BMJ open diabetes research & care JID - 101641391 RN - 9100L32L2N (Metformin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Metformin/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Male MH - Female MH - *Dementia/prevention & control/epidemiology/etiology MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use MH - Retrospective Studies MH - Aged MH - Middle Aged MH - Risk Factors MH - Follow-Up Studies MH - Incidence MH - Aged, 80 and over PMC - PMC12306345 OTO - NOTNLM OT - Dementia OT - Diabetes Mellitus, Type 2 OT - Glucagon-Like Peptide 1 OT - Metformin COIS- Competing interests: None declared. EDAT- 2025/07/23 11:24 MHDA- 2025/07/23 11:25 PMCR- 2025/07/22 CRDT- 2025/07/22 21:42 PHST- 2025/01/13 00:00 [received] PHST- 2025/05/17 00:00 [accepted] PHST- 2025/07/23 11:25 [medline] PHST- 2025/07/23 11:24 [pubmed] PHST- 2025/07/22 21:42 [entrez] PHST- 2025/07/22 00:00 [pmc-release] AID - 13/4/e004902 [pii] AID - bmjdrc-2025-004902 [pii] AID - 10.1136/bmjdrc-2025-004902 [doi] PST - epublish SO - BMJ Open Diabetes Res Care. 2025 Jul 22;13(4):e004902. doi: 10.1136/bmjdrc-2025-004902. PMID- 40690769 OWN - NLM STAT- MEDLINE DCOM- 20250916 LR - 20260703 IS - 1539-3704 (Electronic) IS - 0003-4819 (Linking) VI - 178 IP - 9 DP - 2025 Sep TI - Glucagon-Like Peptide-1 Receptor Agonists and Incidence of Dementia Among Older Adults With Type 2 Diabetes : A Target Trial Emulation. PG - 1258-1267 LID - 10.7326/ANNALS-24-02648 [doi] AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to decrease blood glucose levels, promote weight loss, and prevent cardiovascular events. However, evidence is limited regarding their effect on dementia, although emerging observational studies, some with serious methodological limitations, have suggested large reductions in dementia associated with GLP-1RAs that may not be entirely causally related. OBJECTIVE: To compare the effect of GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP4is) as second-line therapy for type 2 diabetes on risk for dementia among older adults. DESIGN: Target trial emulation. SETTING: United States from January 2016 to December 2020. PARTICIPANTS: Medicare fee-for-service beneficiaries aged 66 years or older with diabetes who used metformin and did not have dementia at baseline and initiated GLP-1RAs or DPP4is between January 2017 and December 2018. MEASUREMENTS: Onset of dementia was defined as 1 year before the date of a new dementia diagnosis. Risks were calculated at 30 months in GLP-1RA and DPP4i groups matched in a 1:2 ratio on an estimated propensity score and compared via ratios and differences. RESULTS: Among 2418 patients initiating GLP-1RAs and 4836 matched patients initiating DPP4is, the mean age was 71 years, and 55% were female. Over a median follow-up of 1.9 years, the outcome occurred in 96 patients in the GLP-1RA group and 217 in the DPP4i group. The estimated risk difference at 30 months was -0.93 (95% CI, -2.33 to 0.23) percentage points, and the estimated risk ratio was 0.83 (95% CI, 0.61 to 1.05). The estimated risk ratios were 0.64 (95% CI, 0.46 to 0.93) and 1.22 (95% CI, 0.74 to 1.66) among those younger than 75 years and aged 75 years or older, respectively. LIMITATIONS: Potential residual confounding (no data on body mass index, glycemic control, or duration of diabetes), outcome misclassification, and short follow-up. CONCLUSION: Among older adults with diabetes, no clear evidence was found that the incidence of dementia differed overall between patients using GLP-1RAs versus DPP4is. Under conventional statistical criteria, an effect of GLP-1RAs between a 39% decrease and a 5% increase in risk for dementia was highly compatible with the data, although estimates differed by age. Randomized trials are needed to quantify the effect of GLP-1RAs on dementia. PRIMARY FUNDING SOURCE: Gregory Annenberg Weingarten, GRoW @ Annenberg. FAU - Inoue, Kosuke AU - Inoue K AUID- ORCID: 0000-0001-9614-8103 AD - Department of Social Epidemiology, Graduate School of Medicine, Kyoto University, and Hakubi Center, Kyoto University, Kyoto, Japan (K.I.). FAU - Saliba, Debra AU - Saliba D AD - U.S. Department of Veterans Affairs Greater Los Angeles Healthcare System (VAGLAS) Geriatrics Research, Education and Clinical Centers, Los Angeles, California; Borun Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and RAND Corporation, Santa Monica, California (D.S.). FAU - Gotanda, Hiroshi AU - Gotanda H AD - Division of General Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California (H.G.). FAU - Moin, Tannaz AU - Moin T AUID- ORCID: 0000-0002-5035-6641 AD - Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California (T.M.). FAU - Mangione, Carol M AU - Mangione CM AUID- ORCID: 0000-0002-9475-2275 AD - Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, and Department of Health Policy and Management, UCLA Fielding School of Public Health, Los Angeles, California (C.M.M.). FAU - Klomhaus, Alexandra M AU - Klomhaus AM AUID- ORCID: 0000-0002-7676-3595 AD - UCLA Department of Medicine Statistics Core, Los Angeles, California (A.M.K.). FAU - Tsugawa, Yusuke AU - Tsugawa Y AUID- ORCID: 0000-0002-1937-4833 AD - Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA; Department of Health Policy and Management, UCLA Fielding School of Public Health; and UCLA Department of Medicine Statistics Core, Los Angeles, California (Y.T.). LA - eng PT - Journal Article DEP - 20250722 PL - United States TA - Ann Intern Med JT - Annals of internal medicine JID - 0372351 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - Aged MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Dementia/epidemiology/prevention & control MH - Female MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Male MH - *Hypoglycemic Agents/therapeutic use MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Incidence MH - United States/epidemiology MH - Aged, 80 and over MH - Medicare MH - Metformin/therapeutic use COIS- Disclosures: Disclosure forms are available with the article online. EDAT- 2025/07/21 18:31 MHDA- 2025/09/17 00:30 CRDT- 2025/07/21 17:03 PHST- 2025/09/17 00:30 [medline] PHST- 2025/07/21 18:31 [pubmed] PHST- 2025/07/21 17:03 [entrez] AID - 10.7326/ANNALS-24-02648 [doi] PST - ppublish SO - Ann Intern Med. 2025 Sep;178(9):1258-1267. doi: 10.7326/ANNALS-24-02648. Epub 2025 Jul 22. PMID- 40663350 OWN - NLM STAT- MEDLINE DCOM- 20250715 LR - 20260127 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 8 IP - 7 DP - 2025 Jul 1 TI - Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity. PG - e2521016 LID - 10.1001/jamanetworkopen.2025.21016 [doi] AB - IMPORTANCE: Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide and tirzepatide, provide cardiometabolic benefits to patients with type 2 diabetes and obesity, but their potential benefits in mitigating neurodegenerative and cerebrovascular diseases remain unclear. OBJECTIVE: To evaluate the association of semaglutide and tirzepatide with the incidence of dementia, Parkinson disease, ischemic stroke, intracerebral hemorrhage, and all-cause mortality compared with other antidiabetic drugs in adults with type 2 diabetes and obesity. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed electronic health record-based data from the TriNetX US network (December 1, 2017, to June 30, 2024) in adults aged 40 years or older with type 2 diabetes and obesity initiating semaglutide, tirzepatide, or other antidiabetic drugs, excluding those with prior neurodegenerative or cerebrovascular diseases. Propensity score matching was used to balance the baseline characteristics. EXPOSURES: Patients treated with antidiabetic drugs were categorized as GLP-1RA (semaglutide or tirzepatide) or other antidiabetic drug (biguanides, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, and alpha-glucosidase inhibitors) users. MAIN OUTCOMES AND MEASURES: The primary outcomes were the incidence of neurodegenerative diseases (dementia, Parkinson disease, and mild cognitive impairment) and cerebrovascular (stroke and intracerebral hemorrhage) diseases, while the secondary outcome was all-cause mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs. RESULTS: A total of 60 860 adults with type 2 diabetes and obesity were included, with 30 430 each in the GLP-1RA group (mean [SD] age, 57.9 [9.9] years; 50.2% female) and the other antidiabetic drug group (mean [SD] age, 58.0 [10.8] years; 51.4% female) after propensity score matching. During a 7-year follow-up, GLP-1RA users had a lower risk of dementia (HR, 0.63; 95% CI, 0.50-0.81), stroke (HR, 0.81; 95% CI, 0.70-0.93), and all-cause mortality (HR, 0.70; 95% CI, 0.63-0.78), with no significant differences in the risk of Parkinson disease or intracerebral hemorrhage. Subgroup analyses revealed greater benefits in patients aged 60 years or older, women, and patients with a body mass index of 30 to 40. CONCLUSIONS AND RELEVANCE: In this cohort study, the use of GLP-1RAs semaglutide and tirzepatide was associated with a lower risk of dementia, stroke, and all-cause mortality in adults with type 2 diabetes and obesity. These findings suggest potential neuroprotective and cerebrovascular benefits of GLP-1RAs beyond glycemic control, warranting further trials to confirm these outcomes. FAU - Lin, Huan-Tang AU - Lin HT AD - Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. FAU - Tsai, Yung-Fong AU - Tsai YF AD - Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Liao, Pei-Lun AU - Liao PL AD - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. AD - Center for Health Data Science, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. FAU - Wei, James Cheng-Chung AU - Wei JC AD - Department of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan. AD - Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. AD - Institute of Medicine, Department of Nursing, Chung Shan Medical University, Taichung, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20250701 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - OYN3CCI6QE (Tirzepatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - Female MH - Male MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Retrospective Studies MH - Middle Aged MH - *Glucagon-Like Peptides/therapeutic use/adverse effects MH - Aged MH - *Obesity/drug therapy/complications MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Stroke/epidemiology/chemically induced MH - *Neurodegenerative Diseases/epidemiology/chemically induced MH - Incidence MH - Parkinson Disease/epidemiology MH - Dementia/epidemiology MH - Tirzepatide MH - Glucagon-Like Peptide 1 MH - Semaglutide EDAT- 2025/07/15 12:29 MHDA- 2025/07/15 12:30 CRDT- 2025/07/15 11:32 PHST- 2025/07/15 12:30 [medline] PHST- 2025/07/15 12:29 [pubmed] PHST- 2025/07/15 11:32 [entrez] AID - 2836412 [pii] AID - 10.1001/jamanetworkopen.2025.21016 [doi] PST - epublish SO - JAMA Netw Open. 2025 Jul 1;8(7):e2521016. doi: 10.1001/jamanetworkopen.2025.21016. PMID- 40659290 OWN - NLM STAT- MEDLINE DCOM- 20251012 LR - 20251012 IS - 1872-9649 (Electronic) IS - 1568-1637 (Linking) VI - 112 DP - 2025 Dec TI - Effects of antidiabetic medications on the relationship between type 2 diabetes mellitus and cognitive impairment. PG - 102834 LID - S1568-1637(25)00180-1 [pii] LID - 10.1016/j.arr.2025.102834 [doi] AB - Type 2 diabetes mellitus (T2DM)-related cognitive impairment (CI) has garnered increasing attention in recent research and is emerging as a highly relevant area of study. T2DM is a chronic and globally prevalent condition characterized by insulin resistance, hyperglycemia, oxidative stress, neuroinflammation, and cerebrovascular dysfunction, factors that collectively contribute to cognitive decline. Notably, T2DM is strongly associated with neurodegenerative conditions, ranging from mild cognitive impairment (MCI) to dementia. This review explores the potential neuroprotective effects of various antidiabetic drugs, including insulin-sensitizing agents (metformin and pioglitazone), sodium-glucose co-transporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is). These medications exert their effects through multiple mechanisms, such as reducing neuroinflammation and oxidative stress, decreasing Abeta accumulation and apoptosis, enhancing cerebral glucose metabolism, and promoting neuroplasticity, processes directly implicated in the interplay between T2DM and cognitive decline. The review highlights the therapeutic potential of these agents in mitigating CI and supporting brain health in individuals with T2DM. However, given the conflicting nature of current clinical evidence, further research is needed to clarify their cognitive benefits, elucidate underlying mechanisms of action, and assess their long-term effects on cognitive outcomes in this population. CI - Copyright (c) 2025 Elsevier B.V. All rights reserved. FAU - Cozza, Annalisa AU - Cozza A AD - Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: a.cozza@inrca.it. FAU - Chinigo, Chiara AU - Chinigo C AD - Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: c.chinigo@inrca.it. FAU - Filicetti, Elvira AU - Filicetti E AD - Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: e.filicetti@inrca.it. FAU - Greco, Giada Ida AU - Greco GI AD - Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: g.greco@inrca.it. FAU - Lappano, Rosamaria AU - Lappano R AD - Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende 87036, Italy. Electronic address: rosamaria.lappano@unical.it. FAU - Marinaro, Cinzia AU - Marinaro C AD - Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: c.marinaro@inrca.it. FAU - Muglia, Lucia AU - Muglia L AD - Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: l.muglia@inrca.it. FAU - Soraci, Luca AU - Soraci L AD - Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: l.soraci@inrca.it. FAU - Corsonello, Andrea AU - Corsonello A AD - Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy; Department of Pharmacy, Health and Nutritional Sciences, School of Medicine and Digital Technologies, University of Calabria, Arcavacata di Rende 87036, Italy. Electronic address: andrea.corsonello@unical.it. FAU - Lattanzio, Fabrizia AU - Lattanzio F AD - Scientific Direction, Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy. Electronic address: f.lattanzio@inrca.it. FAU - Volpentesta, Mara AU - Volpentesta M AD - Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Italy. Electronic address: m.volpentesta@inrca.it. LA - eng PT - Journal Article PT - Review DEP - 20250712 PL - England TA - Ageing Res Rev JT - Ageing research reviews JID - 101128963 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Cognitive Dysfunction/etiology/drug therapy/prevention & control MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - Animals OTO - NOTNLM OT - Diabetes mellitus OT - antidiabetic drugs OT - cognitive impairment OT - neurodegenerative diseases COIS- Declaration of Competing Interest The authors have no conflict of interest to disclose. EDAT- 2025/07/15 00:30 MHDA- 2025/10/13 00:27 CRDT- 2025/07/14 19:36 PHST- 2025/03/05 00:00 [received] PHST- 2025/06/17 00:00 [revised] PHST- 2025/07/10 00:00 [accepted] PHST- 2025/10/13 00:27 [medline] PHST- 2025/07/15 00:30 [pubmed] PHST- 2025/07/14 19:36 [entrez] AID - S1568-1637(25)00180-1 [pii] AID - 10.1016/j.arr.2025.102834 [doi] PST - ppublish SO - Ageing Res Rev. 2025 Dec;112:102834. doi: 10.1016/j.arr.2025.102834. Epub 2025 Jul 12. PMID- 40646278 OWN - NLM STAT- MEDLINE DCOM- 20251028 LR - 20260604 IS - 1435-1463 (Electronic) IS - 0300-9564 (Print) IS - 0300-9564 (Linking) VI - 132 IP - 10 DP - 2025 Oct TI - Approaching therapy of Alzheimer's disease via the antidiabetic drug liraglutide-a study with streptozotocin intracerebroventricularly treated Wistar rats. PG - 1587-1608 LID - 10.1007/s00702-025-02979-z [doi] AB - Risk factors for developing dementia include type 2 diabetes and obesity. Streptozotocin (STZ) intracerebroventricularly (icv) treated rats are a well-accepted animal model for the sporadic Alzheimer;s disease (sAD). STZ-icv treatment results in an insulin-resistant brain state, cognitive deficits, and reduced hippocampal adult neurogenesis (AN). As the antidiabetic drug liraglutide (LIR) has been shown to improve AN, and spatial learning in an AD mouse model, we have investigated the effects of LIR treatment on spatial and fear-motivated learning, AN, and gene expression profiles in STZ-icv treated rats. Male Wistar rats were injected icv with STZ (f.c. 3 mg/kg) or vehicle. Two months later, four weeks of subcutaneous treatment with LIR (0.3 mg/kg) began. Cognitive abilities were assessed with the Morris water maze (MWM) and passive avoidance (PA) test. We performed quantitative immunohistochemistry to evaluate AN, and quantitative real-time PCR to determine the expression levels of genes involved in insulin signaling, glucose uptake, and neuroinflammation. STZ-icv rats showed significantly impaired spatial learning performance in the MWM and fear-motivated memory deficits in the PA test accompanied by reduced AN, downregulated insulin system- and glucose metabolism-related genes in the hippocampus and prefrontal cortex. LIR treatment did not reverse these cognitive deficits of STZ-icv rats in the MWM, and did even worsen PA performance. However, LIR partially restored dysregulated gene expression, however, additionally stimulated neuroinflammation. Refined experimental designs, e.g., refined dosing, should help to further clarify the therapeutic potential of LIR in the future. CI - (c) 2025. The Author(s). FAU - Knezovic, Ana AU - Knezovic A AD - Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia. FAU - Hosch, Michael AU - Hosch M AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. FAU - Hamann, Catharina Sophia AU - Hamann CS AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. FAU - Popp, Sandy AU - Popp S AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. FAU - Ortega, Gabriela AU - Ortega G AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. FAU - Osmanovic-Barilar, Jelena AU - Osmanovic-Barilar J AD - Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia. FAU - Grunblatt, Edna AU - Grunblatt E AD - Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Monoranu, Camelia AU - Monoranu C AD - Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wurzburg, Germany. FAU - Riederer, Peter AU - Riederer P AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. FAU - Salkovic-Petrisic, Melita AU - Salkovic-Petrisic M AD - Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia. FAU - Schmitt-Bohrer, Angelika AU - Schmitt-Bohrer A AUID- ORCID: 0000-0002-2341-376X AD - Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wurzburg, Wurzburg, Germany. Schmitt_A3@ukw.de. LA - eng GR - A/00/200017/German Academic Exchange Service/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20250712 PL - Austria TA - J Neural Transm (Vienna) JT - Journal of neural transmission (Vienna, Austria : 1996) JID - 9702341 RN - 839I73S42A (Liraglutide) RN - 5W494URQ81 (Streptozocin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Animals MH - *Liraglutide/pharmacology/administration & dosage MH - *Alzheimer Disease/drug therapy/chemically induced/metabolism MH - *Streptozocin/administration & dosage MH - Rats, Wistar MH - Male MH - *Hypoglycemic Agents/pharmacology/administration & dosage MH - Rats MH - Disease Models, Animal MH - Hippocampus/drug effects/metabolism MH - Maze Learning/drug effects MH - Avoidance Learning/drug effects MH - Injections, Intraventricular MH - Neurogenesis/drug effects PMC - PMC12568868 OTO - NOTNLM OT - Alzheimer's disorder OT - Animal model OT - GLP1-analogon OT - Liraglutide OT - Rat OT - Streptozotocin intracerebroventricular treatment EDAT- 2025/07/12 16:44 MHDA- 2025/10/28 18:27 PMCR- 2025/07/12 CRDT- 2025/07/11 23:34 PHST- 2025/02/28 00:00 [received] PHST- 2025/06/26 00:00 [accepted] PHST- 2025/10/28 18:27 [medline] PHST- 2025/07/12 16:44 [pubmed] PHST- 2025/07/11 23:34 [entrez] PHST- 2025/07/12 00:00 [pmc-release] AID - 10.1007/s00702-025-02979-z [pii] AID - 2979 [pii] AID - 10.1007/s00702-025-02979-z [doi] PST - ppublish SO - J Neural Transm (Vienna). 2025 Oct;132(10):1587-1608. doi: 10.1007/s00702-025-02979-z. Epub 2025 Jul 12. PMID- 40642529 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250712 IS - 2296-889X (Print) IS - 2296-889X (Electronic) IS - 2296-889X (Linking) VI - 12 DP - 2025 TI - Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens. PG - 1622186 LID - 10.3389/fmolb.2025.1622186 [doi] LID - 1622186 AB - Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid beta (Abeta) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced beta-amyloid (Abeta) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy. CI - Copyright (c) 2025 Lizcano, Sanabria and Aviles. FAU - Lizcano, Fernando AU - Lizcano F AD - Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chia, Colombia. AD - School of Medicine, Universidad de La Sabana, Chia, Colombia. AD - Fundacion Cardioinfantil-Instituto de Cardiologia, Bogota, Colombia. AD - School of Medicine, Universidad del Rosario, Bogota, Colombia. FAU - Sanabria, Daniela AU - Sanabria D AD - Fundacion Cardioinfantil-Instituto de Cardiologia, Bogota, Colombia. AD - School of Medicine, Universidad del Rosario, Bogota, Colombia. FAU - Aviles, Eliana AU - Aviles E AD - Fundacion Cardioinfantil-Instituto de Cardiologia, Bogota, Colombia. AD - School of Medicine, Universidad del Rosario, Bogota, Colombia. LA - eng PT - Journal Article PT - Review DEP - 20250626 PL - Switzerland TA - Front Mol Biosci JT - Frontiers in molecular biosciences JID - 101653173 PMC - PMC12240769 OTO - NOTNLM OT - Alzheimerr's disease OT - GLP-1 agonists OT - estrogens OT - metabolism OT - prevention COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/07/11 06:27 MHDA- 2025/07/11 06:28 PMCR- 2025/06/26 CRDT- 2025/07/11 05:19 PHST- 2025/05/02 00:00 [received] PHST- 2025/06/02 00:00 [accepted] PHST- 2025/07/11 06:28 [medline] PHST- 2025/07/11 06:27 [pubmed] PHST- 2025/07/11 05:19 [entrez] PHST- 2025/06/26 00:00 [pmc-release] AID - 1622186 [pii] AID - 10.3389/fmolb.2025.1622186 [doi] PST - epublish SO - Front Mol Biosci. 2025 Jun 26;12:1622186. doi: 10.3389/fmolb.2025.1622186. eCollection 2025. PMID- 40630129 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250710 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 16 DP - 2025 TI - Research on the effects of GLP-1 receptor agonists in treating cognitive dysfunction and gait disorders in elderly patients with diabetes. PG - 1607443 LID - 10.3389/fphar.2025.1607443 [doi] LID - 1607443 AB - Elderly patients with Type 2 Diabetes Mellitus (T2DM) often experience cognitive dysfunction and gait disorders, which significantly affect their quality of life and daily function. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), known as "wonder drugs for weight loss," have shown potential not only for glycemic control but also for improving cognitive function and gait disturbances. GLP-1RAs may exert their effects through various mechanisms, including promoting neurogenesis and synaptic plasticity in the brain, as well as reducing neuroinflammation, thereby improving cognitive and gait impairments either directly or indirectly. This review aims to explore the role of GLP-1RAs in the treatment of diabetes-related cognitive dysfunction and gait disturbances, as well as their potential mechanisms, providing a theoretical basis for clinical treatment. CI - Copyright (c) 2025 Yang, Chen, Zhang, Fu, Liu and Jiang. FAU - Yang, Yang AU - Yang Y AD - Department of Neurology, The 2nd Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Chen, Lifeng AU - Chen L AD - Department of Neurosurgery, The 1st Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Zhang, Yanjun AU - Zhang Y AD - Department of Rehabilitation Medicine, The 2nd Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Fu, Wenqian AU - Fu W AD - Department of Rehabilitation Medicine, The 2nd Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Liu, Dandan AU - Liu D AD - Department of Rehabilitation Medicine, The 2nd Medical Center of Chinese PLA General Hospital, Beijing, China. FAU - Jiang, Tianyu AU - Jiang T AD - Department of Rehabilitation Medicine, The 2nd Medical Center of Chinese PLA General Hospital, Beijing, China. LA - eng PT - Journal Article PT - Review DEP - 20250624 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC12234456 OTO - NOTNLM OT - GLP-1R agonist OT - Parkinson's disease OT - cognitive functions OT - diabites mellitus OT - gait disorder COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2025/07/09 06:27 MHDA- 2025/07/09 06:28 PMCR- 2025/06/24 CRDT- 2025/07/09 04:55 PHST- 2025/04/07 00:00 [received] PHST- 2025/05/27 00:00 [accepted] PHST- 2025/07/09 06:28 [medline] PHST- 2025/07/09 06:27 [pubmed] PHST- 2025/07/09 04:55 [entrez] PHST- 2025/06/24 00:00 [pmc-release] AID - 1607443 [pii] AID - 10.3389/fphar.2025.1607443 [doi] PST - epublish SO - Front Pharmacol. 2025 Jun 24;16:1607443. doi: 10.3389/fphar.2025.1607443. eCollection 2025. PMID- 40620322 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260813 IS - 2251-6581 (Print) IS - 2251-6581 (Electronic) IS - 2251-6581 (Linking) VI - 24 IP - 2 DP - 2025 Dec TI - The expanding role of semaglutide: beyond glycemic control. PG - 160 LID - 10.1007/s40200-025-01663-z [doi] LID - 160 AB - Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has transformed the treatment landscape for type 2 diabetes and obesity due to its robust efficacy and wide-ranging therapeutic benefits. This review outlines semaglutide's diverse mechanisms of action, including its roles in glucose homeostasis, weight reduction, and cardiovascular protection. Data from the SUSTAIN and PIONEER clinical trials demonstrate significant reductions in HbA1c, body weight, and major adverse cardiovascular events (MACE), firmly establishing semaglutide as a key agent in diabetes management. The STEP trials further highlight its exceptional effectiveness in weight control, with participants achieving up to 20% weight loss alongside improvements in obesity-related comorbidities. Moreover, ongoing studies such as the FOCUS trial are investigating its impact on microvascular complications. Beyond glycemic control, semaglutide exhibits renoprotective, anti-inflammatory, and potential hepatoprotective effects. Emerging evidence also supports its expanding role in the management of non-alcoholic fatty liver disease (NAFLD), heart failure, polycystic ovary syndrome (PCOS), obstructive sleep apnea (OSA), alcohol use disorder (AUD), and Alzheimer's disease. While gastrointestinal side effects are the most commonly reported adverse events, long-term studies affirm its overall safety and tolerability. The availability of both subcutaneous and oral formulations further enhances treatment adherence and accessibility. As a result, semaglutide has emerged as a cornerstone therapy for a broad spectrum of metabolic, cardiovascular, and neuroendocrine disorders. Future research should continue to explore its therapeutic potential in under-studied populations, including individuals with non-diabetic cardiovascular disease and hepatic fibrosis. CI - (c) The Author(s), under exclusive licence to Tehran University of Medical Sciences 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. FAU - Zarei, Malek AU - Zarei M AD - Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Evin, Daneshjou Blvd, Koudakyar Ave, Tehran, Iran. ROR: https://ror.org/034m2b326. GRID: grid.411600.2 FAU - Sabetkasaei, Masoumeh AU - Sabetkasaei M AD - Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Evin, Daneshjou Blvd, Koudakyar Ave, Tehran, Iran. ROR: https://ror.org/034m2b326. GRID: grid.411600.2 FAU - Mozafari, Masoud AU - Mozafari M AD - Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran. ROR: https://ror.org/01n3s4692. GRID: grid.412571.4. ISNI: 0000 0000 8819 4698 FAU - Zaeri, Sasan AU - Zaeri S AD - Department of Pharmacology, Bushehr University of Medical Sciences, Bushehr, Iran. ROR: https://ror.org/02y18ts25. GRID: grid.411832.d. ISNI: 0000 0004 0417 4788 LA - eng PT - Journal Article PT - Review DEP - 20250704 PL - Switzerland TA - J Diabetes Metab Disord JT - Journal of diabetes and metabolic disorders JID - 101590741 PMC - PMC12227398 OTO - NOTNLM OT - Cardiovascular outcomes OT - GLP-1 receptor agonist OT - Semaglutide OT - Type 2 diabetes OT - Weight management COIS- Competing interestsThe authors declare no competing interests. EDAT- 2025/07/07 06:26 MHDA- 2025/07/07 06:27 PMCR- 2026/07/04 CRDT- 2025/07/07 05:05 PHST- 2025/04/22 00:00 [received] PHST- 2025/06/06 00:00 [accepted] PHST- 2025/07/07 06:27 [medline] PHST- 2025/07/07 06:26 [pubmed] PHST- 2025/07/07 05:05 [entrez] PHST- 2026/07/04 00:00 [pmc-release] AID - 1663 [pii] AID - 10.1007/s40200-025-01663-z [doi] PST - epublish SO - J Diabetes Metab Disord. 2025 Jul 4;24(2):160. doi: 10.1007/s40200-025-01663-z. eCollection 2025 Dec. PMID- 40608828 OWN - NLM STAT- MEDLINE DCOM- 20250703 LR - 20260127 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 20 IP - 7 DP - 2025 TI - Semaglutide ameliorates diabetes-associated cognitive dysfunction in mouse model of type 2 diabetes. PG - e0326897 LID - 10.1371/journal.pone.0326897 [doi] LID - e0326897 AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction, which significantly impacts the quality of life. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown potential neuroprotective effects. This study investigates the efficacy of semaglutide in ameliorating cognitive dysfunction in a mouse model of T2DM. METHODS: Male C57BL/6J mice were fed a high-fat diet for four weeks and received a single intraperitoneal injection of streptozotocin (150 mg/kg) to induce T2DM. All mice were divided into four groups: control, diabetes control (T2DM), semaglutide treatment (semaglutide, 0.1 mg/kg) and dapagliflozin treatment (dapagliflozin 1 mg/kg). Cognitive function was assessed using the Morris water maze (MWM) test. Histomorphological analysis of hippocampal tissues was performed using H&E and Nissl staining. Immunofluorescence was used to assess LRP1 expression and apoptosis. Biochemical analyses measured oxidative stress markers (SOD, MDA) and inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, CRP). RESULTS: Semaglutide treatment significantly reduced blood glucose levels in diabetic mice. In the MWM test, semaglutide-treated mice showed reduced escape latencies, indicating improved spatial learning and memory. Histomorphological analysis revealed preserved neuronal structure in the hippocampus with reduced neuronal damage and apoptosis in the semaglutide-treated group. Immunofluorescence showed increased LRP1 expression and decreased apoptosis. Biochemical analyses indicated that semaglutide reduced oxidative stress and inflammatory markers, further supporting its neuroprotective effects. CONCLUSIONS: Semaglutide effectively ameliorates cognitive dysfunction in T2DM mice, likely through mechanisms involving the reduction of oxidative stress, inflammation, and neuronal apoptosis. These findings suggest that semaglutide has potential as a therapeutic agent for managing diabetes-associated cognitive decline. Further research, including long-term studies and clinical trials, is necessary to validate these findings and explore the broader applicability of semaglutide in treating cognitive impairments in diabetic patients. CI - Copyright: (c) 2025 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. FAU - Zhu, Yan AU - Zhu Y AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - He, Yi AU - He Y AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - Yang, Hongyan AU - Yang H AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - Gao, Yanbo AU - Gao Y AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - Wang, Yan AU - Wang Y AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - Liu, Peiqing AU - Liu P AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. FAU - Zhang, Mengjuan AU - Zhang M AUID- ORCID: 0009-0007-7370-8113 AD - Department of Endocrinology, Baotou Central Hospital, Baotou, China. LA - eng PT - Journal Article DEP - 20250703 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Benzhydryl Compounds) RN - 0 (Neuroprotective Agents) RN - 0 (Blood Glucose) RN - 0 (Glucosides) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) RN - 1ULL0QJ8UC (dapagliflozin) SB - IM MH - Animals MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - Male MH - Mice MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Cognitive Dysfunction/drug therapy/etiology MH - Mice, Inbred C57BL MH - *Diabetes Mellitus, Experimental/complications/drug therapy MH - Oxidative Stress/drug effects MH - Disease Models, Animal MH - Hippocampus/drug effects/metabolism/pathology MH - Apoptosis/drug effects MH - Diet, High-Fat/adverse effects MH - Benzhydryl Compounds/pharmacology MH - Neuroprotective Agents/pharmacology MH - Blood Glucose MH - Glucosides/pharmacology MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC12225814 COIS- The authors have declared that no competing interests exist. EDAT- 2025/07/03 18:26 MHDA- 2025/07/03 18:27 PMCR- 2025/07/03 CRDT- 2025/07/03 13:53 PHST- 2024/11/03 00:00 [received] PHST- 2025/06/05 00:00 [accepted] PHST- 2025/07/03 18:27 [medline] PHST- 2025/07/03 18:26 [pubmed] PHST- 2025/07/03 13:53 [entrez] PHST- 2025/07/03 00:00 [pmc-release] AID - PONE-D-24-42194 [pii] AID - 10.1371/journal.pone.0326897 [doi] PST - epublish SO - PLoS One. 2025 Jul 3;20(7):e0326897. doi: 10.1371/journal.pone.0326897. eCollection 2025. PMID- 40552638 OWN - NLM STAT- MEDLINE DCOM- 20250913 LR - 20260829 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 106 IP - 4 DP - 2025 Aug TI - Associations of semaglutide with Alzheimer's disease-related dementias in patients with type 2 diabetes: A real-world target trial emulation study. PG - 1509-1522 LID - 10.1177/13872877251351329 [doi] AB - BACKGROUND: Almost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia. OBJECTIVE: We aim to investigate if semaglutide is associated with a decreased risk of dementia. METHODS: We conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer's disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan-Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching. RESULTS: We show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49-0.59) compared with insulin, 0.67 (0.61-0.74) compared with metformin, to 0.80 (0.72-0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias. CONCLUSIONS: These findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms. FAU - Wang, William AU - Wang W AD - Center for Science, Health, and Society, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Davis, Pamela B AU - Davis PB AD - Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Qi, Xin AU - Qi X AD - Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Gurney, Mark AU - Gurney M AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Perry, George AU - Perry G AUID- ORCID: 0000-0002-6547-0172 AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. AD - Department of Neuroscience, Development and Regenerative Biology, College of Sciences, The University of Texas at San Antonio, San Antonio, TX, USA. FAU - Volkow, Nora D AU - Volkow ND AD - National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, North Bethesda, MD, USA. FAU - Kaelber, David C AU - Kaelber DC AD - Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland, OH, USA. FAU - Xu, Rong AU - Xu R AUID- ORCID: 0000-0003-3127-4795 AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. LA - eng GR - R01 AG057557/AG/NIA NIH HHS/United States GR - R01 AG076649/AG/NIA NIH HHS/United States GR - R01 AG076051/AG/NIA NIH HHS/United States GR - R56 AG062272/AG/NIA NIH HHS/United States GR - R01 AG074346/AG/NIA NIH HHS/United States GR - R01 AG061388/AG/NIA NIH HHS/United States GR - R01 AG065240/AG/NIA NIH HHS/United States GR - RF1 AG076649/AG/NIA NIH HHS/United States GR - UM1 TR004528/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20250624 PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology/complications MH - *Glucagon-Like Peptides/therapeutic use MH - Female MH - *Alzheimer Disease/epidemiology/prevention & control MH - Aged MH - Male MH - *Hypoglycemic Agents/therapeutic use MH - Middle Aged MH - Aged, 80 and over MH - *Dementia/epidemiology MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC12262134 MID - NIHMS2093772 OTO - NOTNLM OT - Alzheimer's disease related dementias OT - Alzheimer's disease OT - Lewy body dementia OT - dementia OT - frontotemporal dementia OT - semaglutide OT - target trial emulation OT - type 2 diabetes OT - vascular dementia COIS- Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: George Perry is an Editor-in-Chief of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2025/06/24 13:08 MHDA- 2025/09/13 12:30 PMCR- 2025/07/15 CRDT- 2025/06/24 07:13 PHST- 2025/09/13 12:30 [medline] PHST- 2025/06/24 13:08 [pubmed] PHST- 2025/06/24 07:13 [entrez] PHST- 2025/07/15 00:00 [pmc-release] AID - 10.1177/13872877251351329 [doi] PST - ppublish SO - J Alzheimers Dis. 2025 Aug;106(4):1509-1522. doi: 10.1177/13872877251351329. Epub 2025 Jun 24. PMID- 40550419 OWN - NLM STAT- MEDLINE DCOM- 20250904 LR - 20260813 IS - 1938-3207 (Electronic) IS - 0002-9165 (Print) IS - 0002-9165 (Linking) VI - 122 IP - 3 DP - 2025 Sep TI - Novel strategies for medical management of obesity: mechanisms, clinical implications, and societal impacts-a report from the 25th Annual Harvard Nutrition Obesity Symposium. PG - 866-885 LID - S0002-9165(25)00337-5 [pii] LID - 10.1016/j.ajcnut.2025.06.015 [doi] AB - Obesity is a chronic, relapsing disease with a multifactorial etiology. Over the past 5 y, obesity medicine has entered a new era with the advent of novel, game-changing pharmacotherapies that achieve weight loss exceeding 15%-20%. Beyond weight loss, these powerful therapies offer additional benefits, such as cardiovascular improvements. These novel agents, such as glucagon-like peptide-1 receptor agonists, work by reducing appetite, slowing gastric emptying, and increasing feelings of fullness. Recent work also points out the potential role of these medications for other medical conditions, including addictive and neurodegenerative disorders. In June 2024, the National Institutes of Health-funded Nutrition Obesity Research Center at Harvard and the Harvard Medical School Division of Nutrition hosted their 25th annual Harvard Nutrition Obesity Symposium, titled "Novel Strategies for Medical Management of Obesity: Mechanisms, Clinical Implications, and Societal Impacts." This paper synthesizes the symposium's discussions, emphasizing the importance of innovative pharmacotherapeutic strategies in addressing the burden of obesity and the associated economic and social inequities, including disparities in access to care in adults and children. CI - Copyright (c) 2025 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Srivastava, Gitanjali AU - Srivastava G AD - Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Vanderbilt University School of Medicine, Nashville, TN, United States. Electronic address: gitanjali.srivastava@vumc.org. FAU - Campbell, Sophia L AU - Campbell SL AD - Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. FAU - Hill, Conner R AU - Hill CR AD - Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. FAU - Stanley, Takara L AU - Stanley TL AD - Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. FAU - Lawson, Elizabeth A AU - Lawson EA AD - Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. FAU - Apovian, Caroline M AU - Apovian CM AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, United States. FAU - Almandoz, Jaime P AU - Almandoz JP AD - Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas, United States. FAU - Leggio, Lorenzo AU - Leggio L AD - Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, United States. FAU - Lakdawalla, Darius N AU - Lakdawalla DN AD - Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA, United States. FAU - Dar, Mohammad AU - Dar M AD - Community Care Cooperative, Boston, MA, United States; Veterans Affairs Boston Healthcare System, West Roxbury, MA, United States. FAU - Socolovsky, Carmela AU - Socolovsky C AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. FAU - Stanford, Fatima Cody AU - Stanford FC AD - Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Department of Pediatrics, Division of Endocrinology, Massachusetts General Hospital, MGH Weight Center, Boston, MA, United States. FAU - Armstrong, Sarah AU - Armstrong S AD - Division of General Pediatrics and Adolescent Health, Duke Center for Childhood Obesity Research, Department of Pediatrics, Duke University, Chapel Hill, NC, United States. FAU - Grinspoon, Steven K AU - Grinspoon SK AD - Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. LA - eng GR - P30 DK040561/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20250621 PL - United States TA - Am J Clin Nutr JT - The American journal of clinical nutrition JID - 0376027 RN - 0 (Anti-Obesity Agents) SB - IM MH - Humans MH - *Obesity/drug therapy/therapy MH - Congresses as Topic MH - *Anti-Obesity Agents/therapeutic use PMC - PMC12489366 OTO - NOTNLM OT - addiction OT - glucagon-like peptide-1 OT - glucagon-like reptide-1 receptor agonist OT - medicare OT - nutrition OT - obesity OT - type 2 diabetes OT - weight loss COIS- Conflict of interest GS reports advisory fees from Novo Nordisk, Eli Lilly, and Rhythm; Speaker's Bureau for Rhythm and Novo Nordisk and research grant support from Eli Lilly. TLS received grant funding to her institution from Pfizer, Inc. for serving as site-PI of an industry-sponsored study. EAL received financial support and study drug from Tonix Pharmaceuticals for investigator-initiated research studies; and received royalties from UpToDate. In addition, she is an inventor on United States. provisional patent application no. 63/467,980: Oxytocin-Based Therapeutics to Improve Cognitive Control in Individuals with Attention Deficit Hyperactivity Disorder. EAL and/or immediate family member holds stock in Thermo Fisher Scientific, Zoetis, Danaher Corporation, Intuitive Surgical, Merck and West Pharmaceutical Services. CMA reports participating on advisory boards for Altimmune, Inc., BioAge, Bioinq,CinFina Pharma, Inc., Cowen and Company, LLC, EPG Communication Holdings Ltd., Form Health, Inc., Fractyl Health, Inc., Gelesis, Srl., Lilly USA, LLC, L-Nutra, Inc., NeuroBo Pharmaceuticals, Inc., Nutrisystem, OptumRx, Inc., Pain Script Corporation, Palatin Technologies, Inc., Pursuit By You, Redesign Health Inc., ReShape Lifesciences Inc., Riverview School, Roman Health, Vida Ventures Inc., Veru Inc., Wave Life Sciences and Xeno Biosciences. CMA also reports receiving research funding from the NIH, PCORI and GI Dynamics, Inc. JPA reports serving on advisory boards and consulting with Novo Nordisk, Boehringer Ingelheim, and Eli Lilly and Company. LL is a United States federal employee at the NIH and is supported by the NIH Intramural Research Program (IRP; NIDA/NIAAA). Outside LL's federal employment, he reports honoraria from the UK Medical Council on Alcohol (Editor-in-Chief for Alcohol and Alcoholism) and book royalties from Routledge. DNL reports over the last 3 y speaker fees, travel assistance, or consulting income from the following sources: Amgen, Genentech, Gilead, GRAIL, Mylan, Novartis, Otsuka, Perrigo, Pfizer, and Sorrento Therapeutics. DNL also owns equity in Precision Medicine Group, for which he previously served as a consultant. DNL is also Co-Founder and Chief Scientific Officer of EntityRisk, Inc., which develops software and analytic tools for use by healthcare firms. MD and CS have no disclosures to report. FCS reports financial support provided by the NIH and funding grants provided by Amazon. FCS reports a relationship that includes consulting and advisory for the following: Eli Lilly and Company, Novo Nordisk, Amgen, Boehringer Ingelheim, Rhythm Pharmaceuticals, Gelesis, Doximity, GoodRx, and Currax Pharmaceuticals. SA reports serving as the chair for the American Academy of Pediatrics and leads a section on obesity. SA also reports serving as a consultant for the American Academy of Pediatrics' Institute for a Healthy Childhood Weight. SKG reports grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and service on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work. EDAT- 2025/06/24 11:08 MHDA- 2025/09/05 00:35 PMCR- 2026/06/21 CRDT- 2025/06/23 19:13 PHST- 2025/01/23 00:00 [received] PHST- 2025/06/05 00:00 [revised] PHST- 2025/06/16 00:00 [accepted] PHST- 2025/09/05 00:35 [medline] PHST- 2025/06/24 11:08 [pubmed] PHST- 2025/06/23 19:13 [entrez] PHST- 2026/06/21 00:00 [pmc-release] AID - S0002-9165(25)00337-5 [pii] AID - 10.1016/j.ajcnut.2025.06.015 [doi] PST - ppublish SO - Am J Clin Nutr. 2025 Sep;122(3):866-885. doi: 10.1016/j.ajcnut.2025.06.015. Epub 2025 Jun 21. PMID- 40536952 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260212 LR - 20260813 IS - 1673-5374 (Print) IS - 1876-7958 (Electronic) IS - 1673-5374 (Linking) VI - 21 IP - 6 DP - 2026 Jun 1 TI - Metabolic breakdown: Linking insulin resistance and mitochondrial dysfunction to neurodegeneration in Alzheimer's disease. PG - 2227-2237 LID - 10.4103/NRR.NRR-D-25-00144 [doi] AB - The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer's disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer's disease and accelerated aging. Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer's disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagon-like peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative distress and neuroinflammation. This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative distress regulation, as these are pivotal in both Alzheimer's disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders. CI - Copyright (c) 2025 Neural Regeneration Research. FAU - Lanzillotta, Simona AU - Lanzillotta S AD - Department of Biochemical Sciences "A. Rossi-Fanelli", Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy. FAU - Rolfi, Lucrezia Romana AU - Rolfi LR FAU - Zulli, Barbara AU - Zulli B FAU - Barone, Eugenio AU - Barone E AUID- ORCID: 0000-0002-7028-4251 LA - eng PT - Journal Article DEP - 20250619 PL - India TA - Neural Regen Res JT - Neural regeneration research JID - 101316351 PMC - PMC13211837 OTO - NOTNLM OT - Alzheimer's disease OT - Down syndrome OT - aging OT - brain insulin resistance OT - energy metabolism OT - glucagon-like peptide 1 OT - incretins OT - insulin OT - mitochondria OT - neurodegeneration COIS- Conflicts of interest: The authors declare no conflicts of interest. EDAT- 2025/06/19 22:03 MHDA- 2025/06/19 22:04 PMCR- 2025/06/19 CRDT- 2025/06/19 14:03 PHST- 2025/01/30 00:00 [received] PHST- 2025/05/09 00:00 [accepted] PHST- 2025/06/19 22:04 [medline] PHST- 2025/06/19 22:03 [pubmed] PHST- 2025/06/19 14:03 [entrez] PHST- 2025/06/19 00:00 [pmc-release] AID - 01300535-202606000-00014 [pii] AID - NRR-21-2227 [pii] AID - 10.4103/NRR.NRR-D-25-00144 [doi] PST - ppublish SO - Neural Regen Res. 2026 Jun 1;21(6):2227-2237. doi: 10.4103/NRR.NRR-D-25-00144. Epub 2025 Jun 19. PMID- 40498212 OWN - NLM STAT- MEDLINE DCOM- 20250611 LR - 20260812 IS - 1573-7365 (Electronic) IS - 0885-7490 (Print) IS - 0885-7490 (Linking) VI - 40 IP - 5 DP - 2025 Jun 11 TI - Tirzepatide: a novel therapeutic approach for Alzheimer's disease. PG - 221 LID - 10.1007/s11011-025-01649-z [doi] LID - 221 AB - Tirzepatide (TRZ) is a dual agonist of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors that were recently approved for the treatment of type 2 diabetes (T2D) and obesity. Of note is that T2D and obesity, by inducing peripheral low-grade inflammation and oxidative stress, provoke the development of central neuroinflammation and oxidative stress. Together, T2D and obesity are regarded as potential risk factors implicated in the development and progression of Alzheimer's disease (AD), which is the most common neurodegenerative disease and represents the most typical cause of dementia. Hence, targeting low-grade inflammation and oxidative stress in T2D and obesity by TRZ may reduce AD neuropathology. In addition, TRZ can inhibit the production of amyloid beta (Abeta) and associated neuroinflammation, oxidative stress, and neuronal apoptosis. However, the underlying neuroprotective mechanism of TRZ against AD is not entirely explained. Consequently, this mini-review aims to discuss the possible molecular mechanism of TRZ in AD. CI - (c) 2025. The Author(s). FAU - Alshehri, Ghadah H AU - Alshehri GH AD - Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. FAU - Al-Kuraishy, Hayder M AU - Al-Kuraishy HM AD - Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. FAU - Waheed, Huda Jaber AU - Waheed HJ AD - Department Of Pharmacology and Toxicology, College of Pharmacy Mustansiriyah University, Baghdad, Iraq. FAU - Al-Gareeb, Ali I AU - Al-Gareeb AI AD - Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. FAU - Faheem, Safaa A AU - Faheem SA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo-Suez Road, Badr City, Cairo, 11829, Egypt. safaa-faheem@eru.edu.eg. FAU - Alexiou, Athanasios AU - Alexiou A AUID- ORCID: 0000-0002-2206-7236 AD - Department of Research & Development, Funogen, Athens, 11741, Attiki, Greece. AD - University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India. FAU - Papadakis, Marios AU - Papadakis M AD - University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany. drmariospapadakis@gmail.com. FAU - El-Saber Batiha, Gaber AU - El-Saber Batiha G AD - Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, 22511, Egypt. gaberbatiha@gmail.com. LA - eng PT - Journal Article PT - Review DEP - 20250611 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Neuroprotective Agents) RN - 0 (Amyloid beta-Peptides) RN - OYN3CCI6QE (Tirzepatide) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - Humans MH - Oxidative Stress/drug effects MH - Animals MH - Glucagon-Like Peptide 1/agonists/metabolism MH - *Neuroprotective Agents/therapeutic use/pharmacology MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Amyloid beta-Peptides/metabolism MH - Obesity/drug therapy/metabolism MH - Tirzepatide PMC - PMC12159100 OTO - NOTNLM OT - Alzheimer's disease OT - Brain insulin signaling OT - Glucagon-like peptide one and gastric inhibitory polypeptide OT - Tirzepatide COIS- Declarations. The authors have no relevant financial or non-financial interests to disclose. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Clinical trial: Not applicable. EDAT- 2025/06/11 12:32 MHDA- 2025/06/11 12:33 PMCR- 2025/06/11 CRDT- 2025/06/11 11:06 PHST- 2025/01/02 00:00 [received] PHST- 2025/05/29 00:00 [accepted] PHST- 2025/06/11 12:33 [medline] PHST- 2025/06/11 12:32 [pubmed] PHST- 2025/06/11 11:06 [entrez] PHST- 2025/06/11 00:00 [pmc-release] AID - 10.1007/s11011-025-01649-z [pii] AID - 1649 [pii] AID - 10.1007/s11011-025-01649-z [doi] PST - epublish SO - Metab Brain Dis. 2025 Jun 11;40(5):221. doi: 10.1007/s11011-025-01649-z. PMID- 40482670 OWN - NLM STAT- MEDLINE DCOM- 20250624 LR - 20260924 IS - 2213-8595 (Electronic) IS - 2213-8587 (Linking) VI - 13 IP - 7 DP - 2025 Jul TI - Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial. PG - 556-567 LID - S2213-8587(25)00052-X [pii] LID - 10.1016/S2213-8587(25)00052-X [doi] AB - BACKGROUND: IcoSema is a once-weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP-1 analogue) developed for the treatment of type 2 diabetes. We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin. METHODS: COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries. Individuals aged 18 years or older with type 2 diabetes (HbA(1c) 7.0-10.0% [53.0-85.8 mmol/mol]) receiving daily basal insulin (20-80 U per day) were randomly assigned (1:1) to receive once-weekly IcoSema injection using a pen device or BBT (once-daily insulin glargine U100 with two to four daily insulin aspart injections) using an automated, interactive central web-response system. The primary endpoint was change in HbA(1c) from baseline to week 52, tested for non-inferiority (0.3 percentage-point margin). Confirmatory secondary endpoints were change in bodyweight from baseline to week 52; weekly total insulin dose during weeks 50-52; and combined clinically significant hypoglycaemic episodes (<3.0 mmol/L [<54 mg/dL], confirmed by blood glucose meter) or severe hypoglycaemic episodes (associated with severe cognitive impairment requiring external assistance for recovery) from baseline to week 57. The primary and confirmatory secondary endpoints were evaluated using the full analysis set (all randomly assigned participants). Descriptive statistics for safety endpoints were based on the safety analysis set (participants exposed to a trial product), with statistical analyses based on the full analysis set. This trial is registered with ClinicalTrials.gov (NCT05013229) and is complete. FINDINGS: Between Nov 30, 2021, and Sept 28, 2022, 844 participants were screened; 679 (mean age 59.6 years [SD 10.4]; 399 [59%] males and 280 [41%] females) were randomly assigned to IcoSema (n=340) or BBT (n=339). At week 52, estimated mean change in HbA(1c) was -1.47 percentage points (SE 0.05; -16.0 mmol/mol [0.6]) with IcoSema and -1.40 percentage points (0.06; -15.3 mmol/mol [0.7]) with BBT, confirming non-inferiority of IcoSema versus BBT (estimated treatment difference [ETD] -0.06 percentage points [95% CI -0.22 to 0.09; -0.70 mmol/mol [-2.39 to 0.99]; p<0.0001). Superiority was confirmed for IcoSema versus BBT for change in bodyweight from baseline to week 52 (ETD -6.72 kg [95% CI -7.58 to -5.86]; p<0.0001), weekly total insulin dose during weeks 50-52 (ETD -270 U [-303 to -236]; p<0.0001), and overall rate of clinically significant or severe hypoglycaemia from baseline to week 57 (0.21 vs 2.23 episodes per person-year of exposure; estimated rate ratio 0.12 [0.08 to 0.17]; p<0.0001). The most frequently reported adverse events during the trial were gastrointestinal disorders with IcoSema (148 [44%] of 340 participants had 443 events) and infections and infestations with BBT (116 [35%] of 328 participants had 193 events). INTERPRETATION: Once-weekly IcoSema achieved non-inferior HbA(1c) reduction and superiority in change in bodyweight, weekly total insulin dose, and hypoglycaemia rates versus daily BBT, suggesting that there is a potentially beneficial treatment intensification option for adults with type 2 diabetes. FUNDING: Novo Nordisk. CI - Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. FAU - Billings, Liana K AU - Billings LK AD - Department of Medicine, Endeavor Health/NorthShore Hospitals, and University of Chicago Pritzker School of Medicine, Skokie, IL, USA. Electronic address: lbillings@northshore.org. FAU - Andreozzi, Francesco AU - Andreozzi F AD - Department of Medical and Surgical Sciences and Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Frederiksen, Marie AU - Frederiksen M AD - Novo Nordisk, Soborg, Denmark. FAU - Gourdy, Pierre AU - Gourdy P AD - Department of Diabetology, Toulouse University Hospital, Toulouse, France; Institute of Metabolic and Cardiovascular Diseases, UMR1297 INSERM/UT3, Toulouse University, Toulouse, France. FAU - Gowda, Amoolya AU - Gowda A AD - Novo Nordisk, Soborg, Denmark. FAU - Ji, Linong AU - Ji L AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. FAU - Pletsch-Borba, Laura AU - Pletsch-Borba L AD - Novo Nordisk, Soborg, Denmark. FAU - Suzuki, Ryo AU - Suzuki R AD - Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, Japan. FAU - Unnikrishnan, A G AU - Unnikrishnan AG AD - Chellaram Diabetes Institute, Pune, Maharashtra, India. FAU - Vianna, Andre G D AU - Vianna AGD AD - Curitiba Diabetes Center, Department of Endocrine Diseases, Hospital Nossa Senhora das Gracas, Curitiba, Brazil. LA - eng SI - ClinicalTrials.gov/NCT05013229 PT - Clinical Trial, Phase III PT - Equivalence Trial PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20250604 PL - England TA - Lancet Diabetes Endocrinol JT - The lancet. Diabetes & endocrinology JID - 101618821 RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) RN - 0 (Insulin) RN - 2ZM8CX04RZ (Insulin Glargine) RN - 0 (Blood Glucose) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/blood MH - Female MH - Male MH - Middle Aged MH - *Hypoglycemic Agents/administration & dosage/therapeutic use MH - Aged MH - Glycated Hemoglobin/analysis MH - *Insulin/administration & dosage MH - *Insulin Glargine/administration & dosage MH - Blood Glucose/analysis MH - Drug Administration Schedule MH - Adult MH - *Glucagon-Like Peptides/administration & dosage MH - Treatment Outcome MH - Glucagon-Like Peptide 1 MH - Semaglutide COIS- Declaration of interests LKB has received research support or consultant fees, or has served on advisory panels for Bayer, Dexcom, Endogenex, Eli Lilly, Novo Nordisk, Sanofi, Pfizer, and Xeris. FA has received consultant fees for Novo Nordisk. MF, AG, and LP-B are employees of Novo Nordisk and hold stock options. PG has received research support or consultant fees, or has served on advisory panels for Abbott, AbbVie, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Organon, Pfizer, and Sanofi. LJ has received research support or consultant fees, or has served on advisory panels for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Gan & Lee Pharmaceuticals, Haisco Pharmaceutical, Innovent Biologics, Merck, MSD, Novo Nordisk, Sanofi-Aventis, Sibionics, and Sinocare. RS has received research support or consultant fees, or has served on advisory panels for Astellas, Eli Lilly, Kowa, Mitsubishi Tanabe, MSD, Novo Nordisk, Sanofi, Sumitomo, and Teijin. AGU has received research support and served on advisory panels for Novo Nordisk and has received consulting fees for Abbott, Boehringer Ingelheim, and Novo Nordisk. AGDV has received research support or consultant fees or has served on advisory panels for Abbott Diabetes Care, AstraZeneca, Bayer, Eli Lilly, Eurofarma, Medtronic, Novo Nordisk, Roche Diabetes Care, and Servier. EDAT- 2025/06/08 03:37 MHDA- 2025/06/24 13:08 CRDT- 2025/06/07 18:52 PHST- 2024/10/11 00:00 [received] PHST- 2025/01/31 00:00 [revised] PHST- 2025/02/13 00:00 [accepted] PHST- 2025/06/24 13:08 [medline] PHST- 2025/06/08 03:37 [pubmed] PHST- 2025/06/07 18:52 [entrez] AID - S2213-8587(25)00052-X [pii] AID - 10.1016/S2213-8587(25)00052-X [doi] PST - ppublish SO - Lancet Diabetes Endocrinol. 2025 Jul;13(7):556-567. doi: 10.1016/S2213-8587(25)00052-X. Epub 2025 Jun 4. PMID- 40481813 OWN - NLM STAT- MEDLINE DCOM- 20250607 LR - 20260622 IS - 1520-7560 (Electronic) IS - 1520-7552 (Print) IS - 1520-7552 (Linking) VI - 41 IP - 5 DP - 2025 Jul TI - Impact of Glucagon-Like Peptide-1 Receptor Agonists on the Dementia Incidence in Patients With Type 2 Diabetes Mellitus: A Population-Based Longitudinal Cohort Study. PG - e70058 LID - 10.1002/dmrr.70058 [doi] LID - e70058 AB - AIMS: Type 2 diabetes mellitus (T2DM) is recognized for increasing the risk of dementia; however, conclusive evidence supporting interventions to mitigate this risk remains elusive. This study endeavours to ascertain whether the glucagon-like peptide-1 receptor agonists (GLP-1RAs) correlate with reduced incidence of dementia. MATERIALS AND METHODS: The cohort comprised individuals initiating treatment with either GLP-1RAs or non-GLP-1RAs medications between 2013 and 2021. This study examined the association between GLP-1RAs and the risk of all-cause dementia. Propensity score-matched and Cox proportional hazard models were employed to calculate the adjusted hazard ratio (aHR) and confidence interval (CI) for the incidence of dementia. RESULTS: Among a cohort comprising 109,778 individuals, the use of GLP-1RA demonstrated a reduced risk of dementia compared with its non-use (aHR, 0.90; 95% CI, 0.83-0.97). Subgroup analyses stratified by different diabetic complications revealed significantly lower dementia incidence rates among GLP-1RAs users than among non-GLP-1RAs users. Individuals aged /= 50 years) with type 2 diabetes (T2D) and newly prescribed a GLP-1RA, SGLT2i, or other second-line glucose-lowering drugs (GLDs). A doubly robust learning approach was deployed to estimate the risk difference (RD) of ADRD and identify key subgroups. RESULTS: Both GLP-1RAs (RD, -1.5%) and SGLT2is (-1.7%) were associated with a reduced ADRD risk compared to other GLDs. Key subgroups were determined based on cardiovascular disease (CVD), cerebrovascular disease (CeVD), chronic kidney disease, and Hispanic ethnicity. Patients with CVD and CeVD had the greatest benefits from GLP-1RAs (-4.8%) and SGLT2is (-4.6%). No overall difference was observed between GLP-1RAs and SGLT2i. DISCUSSION: These findings suggest the importance of personalized treatment in diabetes management regarding ADRD risk. HIGHLIGHTS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were associated with a decreased risk of Alzheimer's disease and related dementias (ADRD), while the protective association varied across subgroups defined by cardiovascular disease (CVD), cerebrovascular disease (CeVD), and chronic kidney disease (CKD). Similarly, sodium-glucose cotransporter-2 inhibitors (SGLT2is) were associated with a decreased risk of ADRD, with the protective association varying among subgroups defined by CVD, CeVD, and Hispanic ethnicity. There was no difference between GLP-1RAs and SGLT2is in the risk of ADRD. CI - (c) 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Tang, Huilin AU - Tang H AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Donahoo, William T AU - Donahoo WT AD - Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. FAU - DeKosky, Steven T AU - DeKosky ST AD - 1Florida Alzheimer's Disease Research Center (ADRC), University of Florida, Gainesville, Florida, USA. AD - Department of Neurology and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Lee, Yao An AU - Lee YA AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Kotecha, Pareeta AU - Kotecha P AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Svensson, Mikael AU - Svensson M AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Bian, Jiang AU - Bian J AD - Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Guo, Jingchuan AU - Guo J AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. LA - eng GR - R01AG076234/National Institutes of Health (NIH)/National Institute on Aging (NIA)/ GR - R01 DK133465/DK/NIDDK NIH HHS/United States GR - R01 AG076234/AG/NIA NIH HHS/United States GR - R01DK133465/NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ GR - R01 AG089445/AG/NIA NIH HHS/United States GR - R01AG089445/National Institutes of Health (NIH)/National Institute on Aging (NIA)/ GR - 2023PDVH1064032/The Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Predoctoral Fellowship/ PT - Journal Article PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Alzheimer Disease/epidemiology/prevention & control MH - Male MH - Female MH - Aged MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use MH - *Dementia/epidemiology/prevention & control MH - Risk Factors MH - Treatment Effect Heterogeneity PMC - PMC12125485 OTO - NOTNLM OT - Alzheimer's disease and related dementias OT - GLP-1RAs OT - SGLT2is OT - type 2 diabetes COIS- The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information. EDAT- 2025/05/31 22:27 MHDA- 2025/05/31 22:28 PMCR- 2025/05/30 CRDT- 2025/05/31 02:53 PHST- 2025/04/28 00:00 [revised] PHST- 2024/12/09 00:00 [received] PHST- 2025/04/29 00:00 [accepted] PHST- 2025/05/31 22:28 [medline] PHST- 2025/05/31 22:27 [pubmed] PHST- 2025/05/31 02:53 [entrez] PHST- 2025/05/30 00:00 [pmc-release] AID - ALZ70313 [pii] AID - 10.1002/alz.70313 [doi] PST - ppublish SO - Alzheimers Dement. 2025 Jun;21(6):e70313. doi: 10.1002/alz.70313. PMID- 40426650 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250601 IS - 2076-3425 (Print) IS - 2076-3425 (Electronic) IS - 2076-3425 (Linking) VI - 15 IP - 5 DP - 2025 May 1 TI - Semaglutide and High-Intensity Interval Exercise Attenuate Cognitive Impairment in Type 2 Diabetic Mice via BDNF Modulation. LID - 10.3390/brainsci15050480 [doi] LID - 480 AB - Background/Objectives: Diabetes frequently leads to cognitive impairment, encompassing issues with memory and executive function, as well as depression and anxiety. This study examines the impact of high-intensity interval exercise (HIIE) alongside glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide on cognitive dysfunction associated with diabetes. Methods: Db/db mice were divided into a control group, semaglutide group, HIIE group, and semaglutide combined with HIIE group to study metabolic and neurobehavioral effects. Cognitive and behavioral tests, hippocampal morphology, and molecular analyses (APP, BDNF, Abeta, p-Tau, PKA, AMPK) were performed. HT22 cells under high glucose were treated with semaglutide, L-lactate, PKA inhibitor H89, and AMPK inhibitor Compound C to validate mechanisms. Results: Over 8 weeks, both HIIE and semaglutide improved neuronal morphology and cognitive performance while reducing depression in db/db mice. However, the current study observed no synergistic effects. Both therapies decreased Abeta and p-Tau protein levels and increased BDNF levels in the hippocampus, likely through the AMPK and PKA signaling pathways, respectively. In vitro, HT22 cells under high glucose conditions exhibited elevated APP and p-Tau expression and reduced BDNF levels, which could be altered by L-lactate and semaglutide. The AMPK inhibitor Compound C and the PKA inhibitor H89 attenuated the increase in BDNF levels induced by L-lactate and semaglutide, but their combination mitigated this inhibitory effect. This study suggests that while HIIE and semaglutide improve cognitive function and reduce depression via BDNF, their combined use did not show the anticipated synergistic benefits due to potential antagonism between the AMPK and PKA pathways. Conclusions: This has important implications for designing exercise prescriptions for cognitive impairment in diabetics. FAU - Lai, Sijie AU - Lai S AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Kang, Zhenghong AU - Kang Z AUID- ORCID: 0009-0008-3067-220X AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Sun, Jianting AU - Sun J AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Wang, Ziyu AU - Wang Z AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Xu, Yanzi AU - Xu Y AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Xing, Sisi AU - Xing S AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Feng, Mengying AU - Feng M AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Wang, Yiyi AU - Wang Y AD - College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China. FAU - Liu, Hua AU - Liu H AD - Laboratory of Physical Fitness Monitoring & Chronic Disease Intervention, Wuhan Sports University, Wuhan 430079, China. AD - Hubei Key Laboratory of Exercise Training and Monitoring, Wuhan Sports University, Wuhan 430079, China. LA - eng PT - Journal Article DEP - 20250501 PL - Switzerland TA - Brain Sci JT - Brain sciences JID - 101598646 PMC - PMC12109977 OTO - NOTNLM OT - HIIE OT - cognition OT - diabetes OT - lactates OT - semaglutide COIS- The authors declare no conflicts of interest. EDAT- 2025/05/28 06:28 MHDA- 2025/05/28 06:29 PMCR- 2025/05/01 CRDT- 2025/05/28 01:04 PHST- 2025/03/19 00:00 [received] PHST- 2025/04/24 00:00 [revised] PHST- 2025/04/28 00:00 [accepted] PHST- 2025/05/28 06:29 [medline] PHST- 2025/05/28 06:28 [pubmed] PHST- 2025/05/28 01:04 [entrez] PHST- 2025/05/01 00:00 [pmc-release] AID - brainsci15050480 [pii] AID - brainsci-15-00480 [pii] AID - 10.3390/brainsci15050480 [doi] PST - epublish SO - Brain Sci. 2025 May 1;15(5):480. doi: 10.3390/brainsci15050480. PMID- 40029954 STAT- Publisher ISBN- 978-0-309-73505-6 ISBN- 0-309-73505-X PB - National Academies Press (US) CTI - The National Academies Collection: Reports funded by National Institutes of Health DP - 2025 May 26 BTI - Examining Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists for Central Nervous System Disorders: Proceedings of a Workshop AB - Glucagon-like peptide-1 receptor (GLP-1R) agonists, originally developed for type 2 diabetes patients and popularized by their ability to rapidly reduce body weight in patients with obesity, have recently received a lot of national attention. Repurposing GLP-1R agonists to treat some central nervous disorders is promising, but comparatively understudied. At a September 2024 workshop, the National Academies Forum on Neuroscience and Nervous System Disorders reviewed the current knowledge and research gaps about the mechanisms of action of GLP-1R agonists in the brain, and the evidence of their clinical efficacy for eating disorders, neurodegenerative diseases, substance use disorders, and pain. CI - Copyright 2025 by the National Academy of Sciences. All rights reserved. FED - Norris, Sheena M Posey ED - Norris SMP FED - Childers, Eva ED - Childers E FED - Pool, Robert ED - Pool R CN - National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Forum on Neuroscience and Nervous System Disorders LA - eng PT - Review PT - Book PL - Washington (DC) RF - 135 EDAT- 2025/05/26 00:00 CRDT- 2025/05/26 00:00 AID - NBK612411 [bookaccession] AID - 10.17226/29061 [doi] PMID- 40394225 OWN - NLM STAT- MEDLINE DCOM- 20250618 LR - 20250618 IS - 2662-8465 (Electronic) IS - 2662-8465 (Linking) VI - 5 IP - 6 DP - 2025 Jun TI - Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice. PG - 1097-1113 LID - 10.1038/s43587-025-00869-3 [doi] AB - Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Abeta) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Abeta generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Abeta phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD. CI - (c) 2025. The Author(s), under exclusive licence to Springer Nature America, Inc. FAU - Zhang, Yun AU - Zhang Y AUID- ORCID: 0009-0004-5878-6939 AD - Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. zhangyun_202104@163.com. AD - National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. zhangyun_202104@163.com. FAU - Chen, Huaqiu AU - Chen H AD - National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. FAU - Feng, Yijia AU - Feng Y AUID- ORCID: 0000-0002-7668-7350 AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Liu, Mingjing AU - Liu M AD - Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. FAU - Lu, Zhi AU - Lu Z AD - Department of Nuclear Medicine, The First Affiliated Hospital, Dalian Medical University, Dalian, China. FAU - Hu, Bolang AU - Hu B AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Chen, Lifen AU - Chen L AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Zhang, Yang AU - Zhang Y AD - National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China. FAU - Liu, Jiawen AU - Liu J AD - National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. FAU - Cai, Fang AU - Cai F AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Zhao, Yifan AU - Zhao Y AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Pan, Wenhao AU - Pan W AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Liao, Xinxin AU - Liao X AD - Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China. FAU - Pan, Sipei AU - Pan S AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Bestard-Lorigados, Isabel AU - Bestard-Lorigados I AD - Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada. FAU - Wu, Yili AU - Wu Y AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. FAU - Song, Weihong AU - Song W AUID- ORCID: 0000-0001-9928-889X AD - The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. weihong@wmu.edu.cn. AD - Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. weihong@wmu.edu.cn. AD - Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada. weihong@wmu.edu.cn. LA - eng GR - 82293642/National Natural Science Foundation of China (National Science Foundation of China)/ GR - 82230043/National Natural Science Foundation of China (National Science Foundation of China)/ GR - 82201576/National Natural Science Foundation of China (National Science Foundation of China)/ PT - Journal Article DEP - 20250520 PL - United States TA - Nat Aging JT - Nature aging JID - 101773306 RN - 0 (Amyloid beta-Peptides) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - 0 (Amyloid beta-Protein Precursor) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.23.- (Aspartic Acid Endopeptidases) RN - EC 2.7.11.17 (Camkk2 protein, mouse) RN - EC 3.4.23.46 (Bace1 protein, mouse) SB - IM MH - Animals MH - *Alzheimer Disease/drug therapy/metabolism/pathology MH - Mice, Transgenic MH - Amyloid beta-Peptides/metabolism MH - *AMP-Activated Protein Kinases/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Mice MH - Glucagon-Like Peptide 1/blood/metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism MH - Disease Models, Animal MH - Humans MH - Signal Transduction/drug effects MH - Amyloid beta-Protein Precursor/metabolism MH - Phenotype MH - Microglia/metabolism/drug effects MH - Male MH - Amyloid Precursor Protein Secretases/metabolism MH - Aspartic Acid Endopeptidases/metabolism MH - Diabetes Mellitus, Type 2/drug therapy MH - Female COIS- Competing interests: The authors declare no competing interests. EDAT- 2025/05/21 00:30 MHDA- 2025/06/19 00:25 CRDT- 2025/05/20 23:28 PHST- 2024/10/12 00:00 [received] PHST- 2025/04/07 00:00 [accepted] PHST- 2025/06/19 00:25 [medline] PHST- 2025/05/21 00:30 [pubmed] PHST- 2025/05/20 23:28 [entrez] AID - 10.1038/s43587-025-00869-3 [pii] AID - 10.1038/s43587-025-00869-3 [doi] PST - ppublish SO - Nat Aging. 2025 Jun;5(6):1097-1113. doi: 10.1038/s43587-025-00869-3. Epub 2025 May 20. PMID- 40388190 OWN - NLM STAT- MEDLINE DCOM- 20250707 LR - 20260918 IS - 2168-6114 (Electronic) IS - 2168-6106 (Print) IS - 2168-6106 (Linking) VI - 185 IP - 7 DP - 2025 Jul 1 TI - Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial. PG - 778-787 LID - 10.1001/jamainternmed.2025.1189 [doi] AB - IMPORTANCE: Type 2 diabetes (T2D) is a risk factor for cognitive impairment. Whether the choice of the second-line glucose-lowering treatment added to metformin or glycemic control affects cognitive performance in T2D of relatively short duration (<10 years) is not known. OBJECTIVE: To compare the relative effect of 4 classes of glucose-lowering medications that were randomly added to metformin on cognitive performance and to examine the association of longitudinal glycemic levels with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data. GRADE was implemented 2013 to 2021, and data for this study were analyzed from February 2024 to February 2025. INTERVENTIONS: For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin). The secondary objective assessed time-weighted hemoglobin A1c levels over the follow-up period. MAIN OUTCOMES AND MEASURES: The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores. RESULTS: At baseline, the mean (SD) duration of T2D was 4.3 (2.7) years, and the mean (SD) age was 57.1 (9.8) years. Most participants were male (2320 [62.3%]; 1401 female individuals [37.7%]) and non-Hispanic (3015 [81.6%]; 681 Hispanic individuals [18.4%]); 712 (19.1%) were Black and 2452 (65.9%) were White; 777 (20.9%) were recruited from Veterans Affairs medical centers. There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up. However, a 1-unit increase in time-weighted hemoglobin A1c levels was associated with modestly lower Digit Symbol Substitution Test scores (-0.94 points; 95% CI, -1.30 to -0.57), Spanish English Verbal Learning Test scores (immediate recall, -0.27 points; 95% CI, -0.49 to -0.06), and category fluency test scores (animal fluency, -0.28 points; 95% CI, -0.47 to -0.09) over the mean (SD) of 4.1 (0.1) years of follow-up. Severe hypoglycemia requiring assistance was uncommon in all 4 groups (34 participants [0.9%]). CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial suggest that choice of second-line glucose-lowering medication class added to metformin is not associated with change in cognitive performance in persons with early T2D. Worse glycemic control is associated with modestly worse cognitive performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01794143. FAU - Luchsinger, Jose A AU - Luchsinger JA AD - Department of Medicine, Columbia University Irving Medical Center, New York, New York. AD - Department of Epidemiology, Columbia University Irving Medical Center, New York, New York. FAU - Rosin, Samuel P AU - Rosin SP AD - Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, Maryland. FAU - Kazemi, Erin J AU - Kazemi EJ AD - Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, Maryland. FAU - Younes, Naji AU - Younes N AD - Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, Maryland. FAU - Suratt, Colleen E AU - Suratt CE AD - Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, Maryland. FAU - Fattaleh, Basma N AU - Fattaleh BN AD - Veterans Affairs Puget Sound Health Care System, Seattle Institute for Biomedical and Clinical Research, Seattle, Washington. FAU - Florez, Hermes J AU - Florez HJ AD - Department of Medicine, University of Miami, Miami, Florida. AD - Department of Public Health Sciences, Medical University of South Carolina, Charleston. AD - Geriatric Research Education and Clinical Center, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida. FAU - Gonzalez, Jeffrey S AU - Gonzalez JS AD - Ferkauf Graduate School of Psychology, Yeshiva University, New York, New York. AD - Department of Medicine (Endocrinology), Albert Einstein College of Medicine, New York, New York. AD - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York. FAU - Hollander, Priscilla AU - Hollander P AD - Department of Medicine, Baylor Scott and White Health, Dallas, Texas. FAU - Hox, Sophia H AU - Hox SH AD - Department of Veterans Affairs, Pacific Islands Health Care System, Honolulu, Hawaii. FAU - Kuo, Shihchen AU - Kuo S AD - Department of Internal Medicine, University of Michigan, Ann Arbor. FAU - Lee, Melissa S AU - Lee MS AD - Division of Endocrinology, Department of Medicine, State University of New York Down-State Medical Center, NYC Health and Hospitals/Kings County, New York. FAU - Martens, Thomas AU - Martens T AD - International Diabetes Center, HealthPartners Institute, Minneapolis, Minnesota. FAU - Pop-Busui, Rodica AU - Pop-Busui R AD - Department of Internal Medicine, University of Michigan, Ann Arbor. FAU - Seaquist, Elizabeth R AU - Seaquist ER AD - Department of Medicine, University of Minnesota, Minneapolis. FAU - Waltje, Andrea H AU - Waltje AH AD - Department of Internal Medicine, University of Michigan, Ann Arbor. FAU - Barzilay, Joshua I AU - Barzilay JI AD - Division of Endocrinology, Kaiser Permanente of Georgia, Atlanta. AD - Division of Endocrinology, Emory University School of Medicine, Atlanta, Georgia. CN - GRADE Research Group LA - eng SI - ClinicalTrials.gov/NCT01794143 GR - U01 DK098246/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PL - United States TA - JAMA Intern Med JT - JAMA internal medicine JID - 101589534 RN - 0 (Blood Glucose) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Sulfonylurea Compounds) SB - IM CIN - JAMA Intern Med. 2025 Jul 1;185(7):787. doi: 10.1001/jamainternmed.2025.1199. PMID: 40388133 MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Blood Glucose/drug effects MH - *Cognition/drug effects MH - *Cognitive Dysfunction/etiology MH - *Diabetes Mellitus, Type 2/drug therapy/blood MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Drug Therapy, Combination MH - Glycated Hemoglobin MH - *Hypoglycemic Agents/therapeutic use MH - Metformin/therapeutic use MH - Sulfonylurea Compounds/therapeutic use PMC - PMC12090067 COIS- Conflict of Interest Disclosures: Dr Luchsinger reported consulting fees from Merck and Novo Nordisk during the conduct of the study as well as a stipend from Wolters Kluwer and royalties from Springer outside the submitted work. Dr Younes reported grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) during the conduct of the study. Dr Florez reported grants from the Medical University of South Carolina during the conduct of the study. Dr Martens reported grants from Abbott, Dexcom, Insulet, Lilly, Medtronic, Novo Nordisk, Sanofi, and Tandem during the conduct of the study as well as grants from Medscape, a patent for an ambulatory glucose profile CGM visualization format pending, and a salary from the HealthPartners Institute outside the submitted work. Dr Pop-Busui reported grants and personal fees from Novo Nordisk and Lexicon Pharma, grants from Bayer, and personal fees from Roche, Nevro, and Averitas outside the submitted work. Dr Seaquist reported personal fees from Lilly and nonfinancial support from Zucara outside the submitted work. Dr Barzilay reported grants from the National Institutes of Health (NIH)/NIDDK outside the submitted work. No other disclosures were reported. EDAT- 2025/05/19 12:30 MHDA- 2025/07/07 12:28 PMCR- 2026/05/19 CRDT- 2025/05/19 11:36 PHST- 2025/07/07 12:28 [medline] PHST- 2025/05/19 12:30 [pubmed] PHST- 2025/05/19 11:36 [entrez] PHST- 2026/05/19 00:00 [pmc-release] AID - 2833831 [pii] AID - ioi250022 [pii] AID - 10.1001/jamainternmed.2025.1189 [doi] PST - ppublish SO - JAMA Intern Med. 2025 Jul 1;185(7):778-787. doi: 10.1001/jamainternmed.2025.1189. PMID- 40380806 OWN - NLM STAT- MEDLINE DCOM- 20250701 LR - 20250701 IS - 1746-045X (Electronic) IS - 1746-0441 (Linking) VI - 20 IP - 7 DP - 2025 Jul TI - Animal models for development of anti-obesity drugs in the age of GLP-1 agents. PG - 913-925 LID - 10.1080/17460441.2025.2507766 [doi] AB - INTRODUCTION: Obesity is a major health crisis globally, with prevalence escalating significantly in recent decades. Obesity is not merely excessive weight but is associated with myriad health complications. Ensuring the translational effectiveness of pre-clinical obesity models is paramount, and the success of GLP-1 therapies has highlighted important benchmarks for guiding drug development. AREAS COVERED: The authors discuss the status of various animal models used for the development of anti-obesity drugs, with particular emphasis on rodent models and their validity of preclinical-to-clinical translation. They also highlight innovative animal model integration opportunities between obesity and other associated pathology. The article is based on literature searches using PubMed for content (up until February 2025). EXPERT OPINION: The effectiveness of GLP-1 therapies in treating type 2 diabetes and obesity presents an opportunity to evaluate the translational relevance of animal models of obesity. Due to their compelling safety profiles, GLP-1(s) are being tested in a wide range of obesity-associated diseases. Optimization of the mechanistic qualities in this drug class requires the incorporation of new endpoints beyond body weight, including lean mass preservation, cardiovascular health, and anti-inflammatory activities. Finally, we are compelled by the intersection of non-obesity disease models into an obesogenic framework to understand the combinatorial effects of obesity on these other disease indications, including heart failure, neurodegenerative diseases, and cancer. FAU - Culver, Alexander AU - Culver A AD - Pelagos Pharmaceuticals, Inc, Houston, TX, USA. AD - Monument Biosciences, Indianapolis, IN, USA. FAU - Stayrook, Keith AU - Stayrook K AD - Pelagos Pharmaceuticals, Inc, Houston, TX, USA. FAU - Comerota, Michele AU - Comerota M AD - Pelagos Pharmaceuticals, Inc, Houston, TX, USA. FAU - Oblak, Adrian AU - Oblak A AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Burris, Thomas AU - Burris T AD - College of Pharmacy, University of Florida, Gainesville, FL, USA. LA - eng PT - Journal Article PT - Review DEP - 20250521 PL - England TA - Expert Opin Drug Discov JT - Expert opinion on drug discovery JID - 101295755 RN - 0 (Anti-Obesity Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - *Obesity/drug therapy/physiopathology MH - Humans MH - *Anti-Obesity Agents/pharmacology/adverse effects MH - Disease Models, Animal MH - *Glucagon-Like Peptide 1/metabolism MH - Drug Development/methods MH - Diabetes Mellitus, Type 2/drug therapy OTO - NOTNLM OT - GLP-1 OT - Obesity OT - diabetes OT - drug discovery OT - mounjaro OT - ozempic OT - semaglutide OT - tirzepitide EDAT- 2025/05/17 17:01 MHDA- 2025/07/01 21:13 CRDT- 2025/05/17 04:12 PHST- 2025/07/01 21:13 [medline] PHST- 2025/05/17 17:01 [pubmed] PHST- 2025/05/17 04:12 [entrez] AID - 10.1080/17460441.2025.2507766 [doi] PST - ppublish SO - Expert Opin Drug Discov. 2025 Jul;20(7):913-925. doi: 10.1080/17460441.2025.2507766. Epub 2025 May 21. PMID- 40370762 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250516 IS - 2542-4823 (Electronic) IS - 2542-4823 (Linking) VI - 9 DP - 2025 Jan-Dec TI - Exploring the link between GLP-1 receptor agonists and dementia: A comprehensive review. PG - 25424823251342182 LID - 10.1177/25424823251342182 [doi] LID - 25424823251342182 AB - Type 2 diabetes mellitus (T2DM) and insulin resistance are associated with an increased risk of cognitive decline and dementia, including Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for glycemic control, are emerging as neuroprotective agents. This review evaluates the evidence regarding the effects of GLP-1RAs in populations with T2DM-both with and without cognitive impairment, as well as in individuals diagnosed with AD. We conducted a comprehensive literature search and identified ten studies for inclusion: six randomized controlled trials, one prospective open-label study, and three observational studies. GLP-1RAs consistently demonstrated cognitive benefits in patients with T2DM, even in the absence of metabolic improvements. In cases of early dementia or AD, GLP-1RA treatment preserved brain metabolism and connectivity but did not significantly alter amyloid or tau biomarkers. Notably, cognitive improvements were most evident in individuals with higher body mass index (BMI) or obesity. While some studies reported neural functional changes via imaging, direct modifications in established AD biomarkers were not consistently observed. In conclusion, GLP-1RAs may improve cognitive outcomes and brain function, particularly in the early stages of neurodegeneration and among high-risk T2DM populations. Further well-designed clinical trials are needed to evaluate the impacts of GLP-1RAs on both the clinical progression and underlying pathology of dementia. CI - (c) The Author(s) 2025. FAU - Chuansangeam, Mallika AU - Chuansangeam M AUID- ORCID: 0000-0001-6341-1198 AD - Division of Geriatric Medicine, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand. FAU - Phadungsaksawasdi, Pawit AU - Phadungsaksawasdi P AD - Division of Dermatology, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand. FAU - Park, Hyo Jin AU - Park HJ AUID- ORCID: 0000-0001-5420-930X AD - Department of Family Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea. FAU - Yang, Yuan-Han AU - Yang YH AUID- ORCID: 0000-0002-1918-9021 AD - Department of Neurology, Kaohsiung Medical University Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. AD - Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. AD - School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. LA - eng PT - Journal Article PT - Review DEP - 20250512 PL - United States TA - J Alzheimers Dis Rep JT - Journal of Alzheimer's disease reports JID - 101705500 PMC - PMC12075970 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1RA OT - cognition OT - dementia COIS- The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2025/05/15 06:34 MHDA- 2025/05/15 06:35 PMCR- 2025/05/12 CRDT- 2025/05/15 04:50 PHST- 2024/11/26 00:00 [received] PHST- 2025/04/21 00:00 [accepted] PHST- 2025/05/15 06:35 [medline] PHST- 2025/05/15 06:34 [pubmed] PHST- 2025/05/15 04:50 [entrez] PHST- 2025/05/12 00:00 [pmc-release] AID - 10.1177_25424823251342182 [pii] AID - 10.1177/25424823251342182 [doi] PST - epublish SO - J Alzheimers Dis Rep. 2025 May 12;9:25424823251342182. doi: 10.1177/25424823251342182. eCollection 2025 Jan-Dec. PMID- 40367985 OWN - NLM STAT- MEDLINE DCOM- 20250515 LR - 20250521 IS - 2233-6087 (Electronic) IS - 2233-6079 (Print) IS - 2233-6079 (Linking) VI - 49 IP - 3 DP - 2025 May TI - Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies. PG - 333-347 LID - 10.4093/dmj.2025.0106 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment. FAU - Park, Joon Seok AU - Park JS AD - Department of Medicine, Seoul National University College of Medicine, Seoul, Korea. FAU - Kim, Kyu Sik AU - Kim KS AD - Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. FAU - Choi, Hyung Jin AU - Choi HJ AD - Department of Medicine, Seoul National University College of Medicine, Seoul, Korea. AD - Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. AD - Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea. AD - Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. AD - Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea. AD - Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea. LA - eng PT - Journal Article PT - Review DEP - 20250501 PL - Korea (South) TA - Diabetes Metab J JT - Diabetes & metabolism journal JID - 101556588 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/metabolism/physiology MH - Animals MH - *Satiation/drug effects/physiology MH - *Hypothalamus/physiology/drug effects/metabolism MH - *Cognition/drug effects/physiology MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-1 Receptor/metabolism PMC - PMC12086555 OTO - NOTNLM OT - Central nervous system OT - Diabetes mellitus, type 2 OT - Glucagon-like peptide 1 OT - Glucagon-like peptide-1 receptor OT - Glucagon-like peptide-1 receptor agonists OT - Hypothalamus OT - Incretins COIS- CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. EDAT- 2025/05/15 00:36 MHDA- 2025/05/15 06:34 PMCR- 2025/05/01 CRDT- 2025/05/14 19:29 PHST- 2025/02/09 00:00 [received] PHST- 2025/04/16 00:00 [accepted] PHST- 2025/05/15 06:34 [medline] PHST- 2025/05/15 00:36 [pubmed] PHST- 2025/05/14 19:29 [entrez] PHST- 2025/05/01 00:00 [pmc-release] AID - dmj.2025.0106 [pii] AID - dmj-2025-0106 [pii] AID - 10.4093/dmj.2025.0106 [doi] PST - ppublish SO - Diabetes Metab J. 2025 May;49(3):333-347. doi: 10.4093/dmj.2025.0106. Epub 2025 May 1. PMID- 40367521 OWN - NLM STAT- MEDLINE DCOM- 20250901 LR - 20250901 IS - 1205-7541 (Electronic) IS - 0008-4212 (Linking) VI - 103 IP - 9 DP - 2025 Sep 1 TI - Repurposing incretin therapies: a narrative review of emerging indications across cardiometabolic, liver, kidney, neurological, psychiatric, and other systems. PG - 298-311 LID - 10.1139/cjpp-2025-0038 [doi] AB - Incretin therapies have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests that these agents modulate key pathways involved in cardiovascular, renal, hepatic, neuropsychiatric, and reproductive health. In this narrative review, we examine the role of incretin-based therapies in chronic kidney disease, heart failure with preserved ejection fraction, metabolic dysfunction-associated steatotic liver disease, neurodegenerative and cognitive disorders, substance use disorder, obstructive sleep apnea, knee osteoarthritis, and polycystic ovary syndrome. The mechanisms underlying these benefits appear to extend beyond glucose and weight regulation, including anti-inflammatory, neuroprotective, and cardiorenal effects. We summarize key clinical trial data, highlight knowledge gaps, and discuss future directions for integrating incretin-based therapies into broader clinical practice. FAU - Alhomoud, Ibrahim S AU - Alhomoud IS AUID- ORCID: 0009-0000-3346-1223 AD - Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia. RINGGOLD: 89660 FAU - Wheeler, Sarah E AU - Wheeler S AUID- ORCID: 0000-0002-6547-8860 AD - Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA. RINGGOLD: 6889 FAU - Dixon, Dave L AU - Dixon D AUID- ORCID: 0000-0001-7560-9521 AD - Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA. RINGGOLD: 6889 LA - eng PT - Journal Article PT - Review DEP - 20250514 PL - Canada TA - Can J Physiol Pharmacol JT - Canadian journal of physiology and pharmacology JID - 0372712 RN - 0 (Incretins) SB - IM MH - Humans MH - *Incretins/therapeutic use MH - *Drug Repositioning MH - Animals MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Mental Disorders/drug therapy MH - Liver/drug effects/metabolism MH - Kidney/drug effects/metabolism OTO - NOTNLM OT - cardiometabolic disease OT - incretin therapies OT - metabolic dysfunction-associated steatotic liver disease (MASLD) OT - neurodegenerative disorders OT - obstructive sleep apnea OT - substance use disorder COIS- The authors declare no conflict of interest. EDAT- 2025/05/14 19:21 MHDA- 2025/09/01 16:45 CRDT- 2025/05/14 17:43 PHST- 2025/09/01 16:45 [medline] PHST- 2025/05/14 19:21 [pubmed] PHST- 2025/05/14 17:43 [entrez] AID - 10.1139/cjpp-2025-0038 [doi] PST - ppublish SO - Can J Physiol Pharmacol. 2025 Sep 1;103(9):298-311. doi: 10.1139/cjpp-2025-0038. Epub 2025 May 14. PMID- 40366681 OWN - NLM STAT- MEDLINE DCOM- 20250702 LR - 20260515 IS - 2168-6238 (Electronic) IS - 2168-622X (Print) IS - 2168-622X (Linking) VI - 82 IP - 7 DP - 2025 Jul 1 TI - Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis. PG - 643-653 LID - 10.1001/jamapsychiatry.2025.0679 [doi] AB - IMPORTANCE: People with obesity and diabetes have poorer psychiatric and cognitive outcomes and lower quality of life (QOL) compared with those without. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) are treatments for diabetes and obesity that may also influence psychiatric outcomes. OBJECTIVE: To conduct a meta-analysis of randomized placebo-controlled trials to evaluate psychiatric, cognitive, and QOL outcomes with GLP1-RA treatment. DATA SOURCES: MEDLINE, Embase, PsycINFO, and CENTRAL databases were searched from inception through June 24, 2024. STUDY SELECTION: Double-blind placebo-controlled trials comparing GLP1-RA to placebo in adults with overweight/obesity and/or diabetes, reporting on psychiatric, cognition, or QOL outcomes, were included. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed in parallel by 2 reviewers. Random-effects meta-analysis was performed. Effect size measures were log risk ratios (log[RR]) and standardized mean differences (Hedges g). The quality of studies was appraised using the Cochrane risk-of-bias tool (RoB2). Certainty of evidence was assessed via GRADEpro. MAIN OUTCOMES AND MEASURES: Main outcomes were risk of psychiatric adverse events (serious and nonserious) and change in mental health symptom severity, health-related quality of life, and cognition. RESULTS: Eighty randomized clinical trials involving 107 860 patients were included in the meta-analysis. The mean (SD) age of participants across studies in the meta-analysis was 60.1 (7.1) years; 43 251 were female (40.1%) and 64 608 male (59.9%). GLP1-RA treatment was not associated with a significant difference in risk of serious psychiatric adverse events (log[RR] = -0.02; 95% CI, -0.20 to 0.17; P = .87) and nonserious psychiatric adverse events (log[RR] = -0.03; 95% CI, -0.21 to 0.16], P = .76), or depressive symptom change (g = 0.02; 95% CI, -0.51 to 0.55; P = .94), compared with placebo. GLP1-RA treatment was associated with improvements in restrained eating (g = 0.35; 95% CI, 0.13 to 0.57; P = .002) and emotional eating behavior (g = 0.32; 95% CI, 0.11 to 0.54; P = .003) and in mental health-related QOL (g = 0.15; 95% CI, 0.07 to 0.22; P < .001), physical health-related QOL (g = 0.20; 95% CI, 0.14 to 0.26; P < .001), diabetes-related QOL (g = 0.23; 95% CI, 0.15 to 0.32; P < .001), and weight-related QOL (g = 0.27; 95% CI, 0.18 to 0.35; P < .001) compared with placebo. CONCLUSIONS AND RELEVANCE: In patients with overweight/obesity and/or diabetes , GLP1-RA treatment is not associated with increased risk of psychiatric adverse events or worsening depressive symptoms relative to placebo and is associated with improvements in QOL, restrained eating, and emotional eating behavior. These findings provide reassurance regarding the psychiatric safety profile of GLP1-RAs and suggest that GLP1-RA treatment contributes to both physical and emotional well-being. FAU - Pierret, Aureliane C S AU - Pierret ACS AD - Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom. FAU - Mizuno, Yuya AU - Mizuno Y AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - South London and Maudsley NHS Foundation Trust, London, United Kingdom. AD - Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan. FAU - Saunders, Pippa AU - Saunders P AD - Imperial College School of Medicine, London, United Kingdom. FAU - Lim, Eshaya AU - Lim E AD - Imperial College School of Medicine, London, United Kingdom. FAU - De Giorgi, Riccardo AU - De Giorgi R AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. AD - Oxford Health NHS Foundation Trust, Oxford, United Kingdom. FAU - Howes, Oliver D AU - Howes OD AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom. FAU - McCutcheon, Robert A AU - McCutcheon RA AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. AD - Oxford Health NHS Foundation Trust, Oxford, United Kingdom. FAU - McGowan, Barbara AU - McGowan B AD - Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. AD - Diabetes, Endocrinology and Obesity Clinical Academic Group, King's Health Partners, London, United Kingdom. FAU - Sen Gupta, Piya AU - Sen Gupta P AD - Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. AD - Diabetes, Endocrinology and Obesity Clinical Academic Group, King's Health Partners, London, United Kingdom. FAU - Smith, Daniel AU - Smith D AD - Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. AD - Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. FAU - Ismail, Khalida AU - Ismail K AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - Diabetes, Endocrinology and Obesity Clinical Academic Group, King's Health Partners, London, United Kingdom. FAU - Pillinger, Toby AU - Pillinger T AD - Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. AD - Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom. AD - Diabetes, Endocrinology and Obesity Clinical Academic Group, King's Health Partners, London, United Kingdom. AD - South London and Maudsley NHS Foundation Trust, London, United Kingdom. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - United States TA - JAMA Psychiatry JT - JAMA psychiatry JID - 101589550 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Quality of Life MH - *Obesity/drug therapy/psychology MH - Randomized Controlled Trials as Topic MH - *Hypoglycemic Agents/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/psychology PMC - PMC12079569 COIS- Conflict of Interest Disclosures: Dr Mizuno reported fellowship grants from Canon Foundation in Europe, consultant fees from WCG Clinical and Signant Health, and manuscript fees from Sumitomo Dainippon Pharma outside the submitted work. Dr Howes reported investigator-initiated research funding from and/or participated in advisory or speaker meetings organized by AbbVie, Alkermes, Angelini, Autifony, Biogen, Boehringer Ingelheim, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck (where he was previously a part-time employee), Merck, Neumora, Neurocrine, Ontrack/Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, ROVI Biotech, Viatris, and Mylan. Dr McCutcheon reported speaker/consultancy fees from Boehringer Ingelheim, Janssen, Karuna, Lundbeck, Newron, Otsuka, and Viatris and co-directing a company that designs digital resources to support treatment of mental ill health. Dr McGowan reported being a shareholder of Reset Health, receiving research grants from Novo Nordisk, and having received consultant fees for educational/advisory meetings from Novo Nordisk, Lilly, AstraZeneca, Janssen outside the submitted work. Dr Sen Gupta reported speaker fees/educational meeting support from Novo Nordisk outside the submitted work. Dr Ismail reported book royalties from Oxford University Press and her salary being funded in part by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). Dr Pillinger reported receiving speaker/consultancy fees from Boehringer Ingelheim, Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma, and Lecturing Minds Stockholm AB; receiving book royalties from Wiley Blackwell; and co-directing a company that designs digital resources to support treatment of mental illness outside the submitted work. No other disclosures were reported. EDAT- 2025/05/14 12:40 MHDA- 2025/07/02 12:31 PMCR- 2026/05/14 CRDT- 2025/05/14 11:33 PHST- 2025/07/02 12:31 [medline] PHST- 2025/05/14 12:40 [pubmed] PHST- 2025/05/14 11:33 [entrez] PHST- 2026/05/14 00:00 [pmc-release] AID - 2833558 [pii] AID - yoi250018 [pii] AID - 10.1001/jamapsychiatry.2025.0679 [doi] PST - ppublish SO - JAMA Psychiatry. 2025 Jul 1;82(7):643-653. doi: 10.1001/jamapsychiatry.2025.0679. PMID- 40356047 OWN - NLM STAT- In-Process LR - 20250515 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 21 IP - 5 DP - 2025 May TI - Comment on "Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US". PG - e70035 LID - 10.1002/alz.70035 [doi] LID - e70035 FAU - Salehi-Abargouei, Amin AU - Salehi-Abargouei A AUID- ORCID: 0000-0002-7580-6717 AD - Research Center for Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Alem Square, Yazd, Iran. AD - Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Alem Square, Yazd, Iran. AD - Yazd Cardiovascular Research Center, Institute of Non-communicable Diseases, Shahid Sadoughi University of Medical Sciences, Jomhouri Eslami Blvd, Yazd, Iran. FAU - Muka, Taulant AU - Muka T AUID- ORCID: 0000-0003-3235-3073 AD - Epistudia, Schanzenstrasse, Bern, Switzerland. FAU - Collet, Tinh-Hai AU - Collet TH AUID- ORCID: 0000-0002-3243-1222 AD - Service of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Geneva University Hospitals, Geneva, Switzerland. AD - Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Kepp, Kasper P AU - Kepp KP AUID- ORCID: 0000-0002-6754-7348 AD - Epistudia, Schanzenstrasse, Bern, Switzerland. FAU - Chatelan, Angeline AU - Chatelan A AUID- ORCID: 0000-0003-4326-4789 AD - Department of Nutrition and Dietetics, Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Carouge, Switzerland. LA - eng PT - Journal Article PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 SB - IM CIN - 10.1002/alz.14581 PMC - PMC12069008 OTO - NOTNLM OT - Alzheimer's disease OT - glucose-lowering medications OT - methodological bias OT - prevention OT - semaglutide (Ozempic) OT - type 2 diabetes mellitus COIS- The authors have no conflicting interests to declare. Author disclosures are available in the Supporting Information. EDAT- 2025/05/13 06:32 MHDA- 2025/05/13 06:32 PMCR- 2025/05/12 CRDT- 2025/05/13 00:22 PHST- 2024/12/06 00:00 [received] PHST- 2024/12/06 00:00 [accepted] PHST- 2025/05/13 06:32 [medline] PHST- 2025/05/13 06:32 [pubmed] PHST- 2025/05/13 00:22 [entrez] PHST- 2025/05/12 00:00 [pmc-release] AID - ALZ70035 [pii] AID - 10.1002/alz.70035 [doi] PST - ppublish SO - Alzheimers Dement. 2025 May;21(5):e70035. doi: 10.1002/alz.70035. PMID- 40345929 OWN - NLM STAT- MEDLINE DCOM- 20250829 LR - 20260318 IS - 2426-0266 (Electronic) IS - 2274-5807 (Print) IS - 2274-5807 (Linking) VI - 12 IP - 8 DP - 2025 Sep TI - New-generation antidiabetic medications and dementia risk in older adults with type 2 diabetes: A retrospective cohort study. PG - 100199 LID - S2274-5807(25)00144-X [pii] LID - 10.1016/j.tjpad.2025.100199 [doi] LID - 100199 AB - BACKGROUND: New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited. OBJECTIVES: To examine the association between new-generation antidiabetic medication use and dementia risk. DESIGN: Retrospective cohort study using electronic health records of a large non-profit health maintenance organization. PARTICIPANTS: 84,798 dementia-free individuals aged >/=65y with type 2 diabetes. MEASUREMENTS: Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting. RESULTS: Among 84,798 individuals with a mean diabetes onset age of 66.4 +/- 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4-12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66-0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63-0.71]; SGLT-2i, 0.63 [95% CI 0.56-0.70], GLP-1a, 0.61 [95% CI 0.54-0.69]. CONCLUSIONS: The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D. CI - Copyright (c) 2025. Published by Elsevier Masson SAS. FAU - Cohen, Avi AU - Cohen A AD - School of Public Health, University of Haifa, Haifa 3498838, Israel. Electronic address: acohe276@campus.haifa.ac.il. FAU - Levine, Stephen Z AU - Levine SZ AD - School of Public Health, University of Haifa, Haifa 3498838, Israel. FAU - Vainstein, Gabriel AU - Vainstein G AD - Kahn-Sagol-Maccabi Research and Innovation Institute, Tel-Aviv 6800001, Israel. FAU - Beeri, Michal Schnaider AU - Beeri MS AD - The Kreiger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers Health, New Brunswick 08901, NJ, USA. FAU - Weinstein, Galit AU - Weinstein G AD - School of Public Health, University of Haifa, Haifa 3498838, Israel. LA - eng GR - R01 AG061093/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20250508 PL - United States TA - J Prev Alzheimers Dis JT - The journal of prevention of Alzheimer's disease JID - 101638820 RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - Retrospective Studies MH - *Dementia/epidemiology MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Aged MH - Female MH - Male MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Aged, 80 and over MH - Risk Factors PMC - PMC12413712 OTO - NOTNLM OT - Dementia OT - Diabetes OT - Dipeptidyl peptidase-4 inhibitors (DPP-4i) OT - Glucagon-like peptide-1 analogues (GLP-1a) OT - Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Avi Cohen reports financial support was provided by Alzheimer's Association. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2025/05/10 00:48 MHDA- 2025/08/31 19:57 PMCR- 2025/05/08 CRDT- 2025/05/09 21:58 PHST- 2025/01/28 00:00 [received] PHST- 2025/04/24 00:00 [revised] PHST- 2025/04/30 00:00 [accepted] PHST- 2025/08/31 19:57 [medline] PHST- 2025/05/10 00:48 [pubmed] PHST- 2025/05/09 21:58 [entrez] PHST- 2025/05/08 00:00 [pmc-release] AID - S2274-5807(25)00144-X [pii] AID - 100199 [pii] AID - 10.1016/j.tjpad.2025.100199 [doi] PST - ppublish SO - J Prev Alzheimers Dis. 2025 Sep;12(8):100199. doi: 10.1016/j.tjpad.2025.100199. Epub 2025 May 8. PMID- 40344943 OWN - NLM STAT- MEDLINE DCOM- 20250604 LR - 20260530 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 216 DP - 2025 Jun TI - Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges. PG - 107770 LID - S1043-6618(25)00195-1 [pii] LID - 10.1016/j.phrs.2025.107770 [doi] AB - Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects. CI - Copyright (c) 2025 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Zhou, Zhi Dong AU - Zhou ZD AD - National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Electronic address: zhidong.zhou@duke-nus.edu.sg. FAU - Yi, Lingxiao AU - Yi L AD - National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore. Electronic address: ylxiao9435@hotmail.com. FAU - Poplawska-Domaszewicz, Karolina AU - Poplawska-Domaszewicz K AD - Department of Neurology, Poznan University of Medical Sciences, Poznan 60-355, Poland; Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London SE5 9RS, UK. Electronic address: karolina.poplawska@usk.poznan.pl. FAU - Chaudhuri, Kallol Ray AU - Chaudhuri KR AD - Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King's College London, Cutcombe Road, London SE5 9RT, UK. Electronic address: ray.chaudhuri@kcl.ac.uk. FAU - Jankovic, Joseph AU - Jankovic J AD - Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Electronic address: josephj@bcm.edu. FAU - Tan, Eng King AU - Tan EK AD - National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Electronic address: Tan.eng.king@singhealth.com.sg. LA - eng PT - Journal Article PT - Review DEP - 20250508 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - *Neurodegenerative Diseases/drug therapy/metabolism MH - *Neuroprotective Agents/therapeutic use MH - *Hypoglycemic Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Glucagon-like peptide-1 OT - Neurodegenerative diseases OT - Parkinsons' disease OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The authors declare that they have no competing interests. EDAT- 2025/05/10 00:47 MHDA- 2025/06/05 00:28 CRDT- 2025/05/09 18:08 PHST- 2025/02/27 00:00 [received] PHST- 2025/04/10 00:00 [revised] PHST- 2025/05/07 00:00 [accepted] PHST- 2025/06/05 00:28 [medline] PHST- 2025/05/10 00:47 [pubmed] PHST- 2025/05/09 18:08 [entrez] AID - S1043-6618(25)00195-1 [pii] AID - 10.1016/j.phrs.2025.107770 [doi] PST - ppublish SO - Pharmacol Res. 2025 Jun;216:107770. doi: 10.1016/j.phrs.2025.107770. Epub 2025 May 8. PMID- 40337158 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260924 IS - 2352-8737 (Electronic) IS - 2352-8737 (Linking) VI - 11 IP - 2 DP - 2025 Apr-Jun TI - Safety considerations of semaglutide in the potential treatment of Alzheimer's disease: A pooled analysis of semaglutide in adults aged >/= 65 years. PG - e70076 LID - 10.1002/trc2.70076 [doi] LID - e70076 AB - INTRODUCTION: The evoke/evoke+ trials are investigating semaglutide in a population with early Alzheimer's disease (AD). Specific analyses of semaglutide safety data in older adults are limited; therefore, in the current analysis, we aimed to evaluate safety considerations with semaglutide in adults >/= 65 years. METHODS: Adverse event (AE) data from three semaglutide phase 3a programs in participants >/= 65 years with type 2 diabetes and/or overweight/obesity were pooled. Change in body weight was also assessed in a smaller subset of participants >/= 65 years. RESULTS: The analysis included 3529 participants >/= 65 years. Baseline mean age and body mass index in participants >/= 65 years were 69.3 to 70.2 years and 29.7 to 35.4 kg/m(2), respectively, compared to 47.8 to 58.5 years and 31.3 to 36.7 kg/m(2) in the overall population. AEs with semaglutide occurred in 73.6% to 92.4% of participants >/= 65 years versus 73.2% to 90.8% of the overall population. AEs with semaglutide leading to permanent discontinuation appeared to be more frequent in participants >/= 65 years (9.3%-12.4%) versus the overall population (5.7%-8.7%). Gastrointestinal disorders were the most frequently reported AEs with semaglutide in participants >/= 65 years (44.6%-73.8%) and in the overall population (39.1%-73.4%). Participants aged >/= 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo. DISCUSSION: Age >/= 65 years did not appear to affect the safety considerations of semaglutide. The ongoing evoke/evoke+ trials will elucidate the balance of efficacy and safety in the treatment of early AD with semaglutide. HIGHLIGHTS: This was a post hoc analysis evaluating adverse event (AE) data of semaglutide in people >/= 65 years.The most common AE with semaglutide was gastrointestinal (GI).GI event rates were similar in people >/= 65 years and the overall study populations. CI - (c) 2025 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Sabbagh, Marwan AU - Sabbagh M AUID- ORCID: 0000-0001-8139-3309 AD - Department of Neurology Barrow Neurological Institute Phoenix Arizona USA. FAU - Boschini, Cristina AU - Boschini C AD - Novo Nordisk A/S Bagsvaerd Denmark. FAU - Cohen, Sharon AU - Cohen S AD - Toronto Memory Program Toronto Ontario Canada. FAU - Fugger, Magnus AU - Fugger M AD - Novo Nordisk A/S Bagsvaerd Denmark. FAU - Jessen, Frank AU - Jessen F AD - Department of Psychiatry University Hospital of Cologne Cologne Germany. FAU - Dandanell, Sune AU - Dandanell S AD - Novo Nordisk A/S Bagsvaerd Denmark. FAU - Pedersen, Sue D AU - Pedersen SD AD - C-endo Diabetes and Endocrinology Clinic Calgary Canada. FAU - Tarazona, Luis Rafael Solis AU - Tarazona LRS AD - Novo Nordisk A/S Bagsvaerd Denmark. FAU - Aroda, Vanita R AU - Aroda VR AD - Brigham and Women's Hospital, Harvard Medical School Boston Massachusetts USA. LA - eng PT - Journal Article DEP - 20250506 PL - United States TA - Alzheimers Dement (N Y) JT - Alzheimer's & dementia (New York, N. Y.) JID - 101650118 PMC - PMC12056300 OTO - NOTNLM OT - Alzheimer's disease OT - adverse event OT - early OT - glucagon-like peptide-1 analogue OT - pooled analysis OT - safety OT - semaglutide COIS- Marwan Sabbagh reports consulting for Corium, Eisai, Eli Lilly, KeifeRx, NeuroTherapia, Novo Nordisk, Prothena, Roche-Genentech, Signant Health, Synaptogenix, and T3D. Cristina Boschini, Magnus Fugger, Sune Dandanell, and Luis Rafael Solis Tarazona are employees and/or shareholders of Novo Nordisk A/S. Sharon Cohen is an employee of the Toronto Memory Program and has no financial conflicts of interest. Frank Jessen reports fees for advice and presentations for AC Immune, Biogen, Danone/Nutricia, Eisai, Grifols, Eli Lilly, Janssen, Novo Nordisk, and Roche; funding from BMBF, BZGA, DFG, DZNE, Era-net Neuron, Horizon 2020, IMI, Innovationsfonds (GBA), and JPND; memberships for the German Association of Psychiatry (DGPPN, member of the board), German Association of Biological Psychiatry (DGBP), German Psychogeriatric Association (DGGPP), German Memory Clinic Network (DNG, Chair), and European Alzheimer's Disease Consortium (EADC, Chair); and served on the scientific advisory boards for German Alzheimer Association, Alzheimer Europe, and Hirnliga. Sue D. Pedersen reports consulting fees or speaking honoraria from Abbott, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi; and research studies for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Medpace, and Novo Nordisk. Vanita R. Aroda reports grants and other from Applied Therapeutics, grants and other from Corcept, grants and other from Fractyl, other from Mediflix, grants and other from Novo Nordisk, other from Pfizer, grants and other from Sanofi, grants from Eli Lilly, and other from Janssen (spouse) outside the submitted work. Author disclosures are available in the supporting information. EDAT- 2025/05/08 11:14 MHDA- 2025/05/08 11:15 PMCR- 2025/05/06 CRDT- 2025/05/08 05:13 PHST- 2025/01/09 00:00 [received] PHST- 2025/02/25 00:00 [revised] PHST- 2025/03/03 00:00 [accepted] PHST- 2025/05/08 11:15 [medline] PHST- 2025/05/08 11:14 [pubmed] PHST- 2025/05/08 05:13 [entrez] PHST- 2025/05/06 00:00 [pmc-release] AID - TRC270076 [pii] AID - 10.1002/trc2.70076 [doi] PST - epublish SO - Alzheimers Dement (N Y). 2025 May 6;11(2):e70076. doi: 10.1002/trc2.70076. eCollection 2025 Apr-Jun. PMID- 40318928 OWN - NLM STAT- MEDLINE DCOM- 20250603 LR - 20250604 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) VI - 36 IP - 6 DP - 2025 Jun TI - Dietary and pharmacological energy restriction and exercise for healthspan extension. PG - 521-545 LID - S1043-2760(25)00076-1 [pii] LID - 10.1016/j.tem.2025.04.001 [doi] AB - Extending healthspan - the years lived in optimal health - holds transformative potential to reduce chronic diseases and healthcare costs. Dietary restriction (DR), particularly when combined with nutrient-rich diets and exercise, is among the most effective, evidence-based strategies for enhancing metabolic health and longevity. By targeting fundamental pathways, it mitigates the onset and progression of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), neurodegeneration, and cancer. This review synthesizes human data on the impact of DR and exercise on metabolic and age-related diseases, while emphasizing key biological mechanisms such as nutrient sensing, insulin sensitivity, inflammation, mitochondrial function, and gut microbiota. We also examine the emerging role of pharmacologically induced DR, focusing on glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) that partially mimic DR and present opportunities for chronic disease prevention. CI - Copyright (c) 2025 Elsevier Ltd. All rights reserved. FAU - Cagigas, Maria Lastra AU - Cagigas ML AD - Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. FAU - De Ciutiis, Isabella AU - De Ciutiis I AD - Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. FAU - Masedunskas, Andrius AU - Masedunskas A AD - Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. FAU - Fontana, Luigi AU - Fontana L AD - Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. Electronic address: luigi.fontana@sydney.edu.au. LA - eng PT - Journal Article PT - Review DEP - 20250502 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 SB - IM MH - Humans MH - *Exercise/physiology MH - *Caloric Restriction/methods MH - *Longevity/physiology MH - Diabetes Mellitus, Type 2/metabolism MH - Obesity/metabolism MH - Gastrointestinal Microbiome MH - Animals OTO - NOTNLM OT - GLP-1 receptor agonists OT - clinical trials OT - dietary restriction OT - endurance and resistance training OT - healthspan OT - metabolic health OT - preventive healthcare COIS- Declaration of interests The authors declare no competing interests. EDAT- 2025/05/04 00:46 MHDA- 2025/06/04 00:29 CRDT- 2025/05/03 21:57 PHST- 2025/02/23 00:00 [received] PHST- 2025/03/30 00:00 [revised] PHST- 2025/04/02 00:00 [accepted] PHST- 2025/06/04 00:29 [medline] PHST- 2025/05/04 00:46 [pubmed] PHST- 2025/05/03 21:57 [entrez] AID - S1043-2760(25)00076-1 [pii] AID - 10.1016/j.tem.2025.04.001 [doi] PST - ppublish SO - Trends Endocrinol Metab. 2025 Jun;36(6):521-545. doi: 10.1016/j.tem.2025.04.001. Epub 2025 May 2. PMID- 40287898 OWN - NLM STAT- MEDLINE DCOM- 20250609 LR - 20260521 IS - 1179-1969 (Electronic) IS - 1170-229X (Print) IS - 1170-229X (Linking) VI - 42 IP - 6 DP - 2025 Jun TI - Testosterone Therapy in Older Men: Present and Future Considerations. PG - 501-512 LID - 10.1007/s40266-025-01209-1 [doi] AB - Testosterone is the classical male anabolic hormone, involved in sexual development, virilisation and regulation of body composition in adult men. Organic disease involving the hypothalamus, pituitary or testes may interfere with endogenous testosterone production. In such men, testosterone treatment effectively ameliorates symptoms and signs of androgen deficiency. However, non-gonadal factors including age, body mass index and medical comorbidities influence circulating testosterone, and older men have on average lower testosterone concentrations compared with younger men. In these men, testosterone treatment would be a pharmacological intervention requiring stringent justification via high-quality evidence from randomised controlled trials (RCTs). Recent RCTs show benefits of testosterone treatment to improve sexual function, anaemia and bone mineral density in older men, and to prevent or revert type 2 diabetes mellitus in men at high risk. Results from a large cardiovascular safety trial in men with or at risk of cardiovascular disease provide important reassurance as to cardiovascular and prostate safety of testosterone treatment. Key questions remain as to whether testosterone's anabolic and other effects can be used safely to counter reductions in lean mass associated with incretin-based weight loss medications in men with obesity, and whether it might prevent disabilities including frailty, osteoporotic fractures and dementia in older men generally. This last question could be answered by a new testosterone RCT, targeting men in the 65-80 years age bracket, which would necessarily be large and of extended duration. A composite endpoint could be used which integrates potential benefits and risks, such as disability-free survival. CI - (c) 2025. The Author(s). FAU - Yeap, Bu B AU - Yeap BB AUID- ORCID: 0000-0002-7612-5892 AD - Medical School, University of Western Australia, Perth, Australia. bu.yeap@uwa.edu.au. AD - Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia. bu.yeap@uwa.edu.au. FAU - Tran, Cammie AU - Tran C AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Douglass, Catherine M AU - Douglass CM AD - Ellen Health, Perth, Australia. FAU - McNeil, John J AU - McNeil JJ AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20250427 PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 3XMK78S47O (Testosterone) SB - IM MH - Humans MH - Male MH - *Testosterone/therapeutic use/adverse effects MH - Aged MH - Aged, 80 and over MH - Diabetes Mellitus, Type 2/prevention & control PMC - PMC12148964 COIS- Declarations. Funding: Open Access funding enabled and organized by CAUL and its Member Institutions. Conflicts of Interest: B.B.Y. has received speaker honoraria and conference support from Bayer, Lilly and Besins Healthcare; research support from Lawley Pharmaceuticals, Lilly and Bayer; and participated in advisory roles for Lilly, Besins Healthcare, Ferring and Lawley Pharmaceuticals. J.J.M. is an NHMRC Leadership Fellow (IG 1173690). C.T. and C.M.D. have no relevant disclosures. Availability of Data and Material: Not applicable. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: B.B.Y. drafted the manuscript; C.T., C.M.D. and J.J.M. contributed important intellectual content; and all authors revised the manuscript in response to peer-review, and all authors approved the final version. EDAT- 2025/04/27 13:08 MHDA- 2025/06/09 12:31 PMCR- 2025/04/27 CRDT- 2025/04/27 11:04 PHST- 2025/04/03 00:00 [accepted] PHST- 2025/06/09 12:31 [medline] PHST- 2025/04/27 13:08 [pubmed] PHST- 2025/04/27 11:04 [entrez] PHST- 2025/04/27 00:00 [pmc-release] AID - 10.1007/s40266-025-01209-1 [pii] AID - 1209 [pii] AID - 10.1007/s40266-025-01209-1 [doi] PST - ppublish SO - Drugs Aging. 2025 Jun;42(6):501-512. doi: 10.1007/s40266-025-01209-1. Epub 2025 Apr 27. PMID- 40281304 OWN - NLM STAT- MEDLINE DCOM- 20250801 LR - 20260311 IS - 1474-1784 (Electronic) IS - 1474-1776 (Linking) VI - 24 IP - 8 DP - 2025 Aug TI - GLP-1-based therapies for diabetes, obesity and beyond. PG - 631-650 LID - 10.1038/s41573-025-01183-8 [doi] AB - Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics. CI - (c) 2025. Springer Nature Limited. FAU - Drucker, Daniel J AU - Drucker DJ AUID- ORCID: 0000-0001-6688-8127 AD - Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. drucker@lunenfeld.ca. LA - eng PT - Journal Article PT - Review DEP - 20250425 PL - England TA - Nat Rev Drug Discov JT - Nature reviews. Drug discovery JID - 101124171 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Anti-Obesity Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM EIN - Nat Rev Drug Discov. 2025 Jul;24(7):570. doi: 10.1038/s41573-025-01231-3. PMID: 40437221 MH - Humans MH - *Obesity/drug therapy/metabolism MH - *Glucagon-Like Peptide 1/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Hypoglycemic Agents/therapeutic use/pharmacology/adverse effects MH - Animals MH - Weight Loss/drug effects MH - *Anti-Obesity Agents/therapeutic use/adverse effects MH - Semaglutide COIS- Competing interests: D.J.D. has received consulting fees from Amgen, AstraZeneca Inc., Insulet, Kallyope and Pfizer Inc. and speaking fees from Boehringer Ingelheim and Novo Nordisk Inc. Mount Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc., Novo Nordisk, Pfizer and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker laboratory. EDAT- 2025/04/26 16:17 MHDA- 2025/08/02 10:43 CRDT- 2025/04/25 23:33 PHST- 2025/03/13 00:00 [accepted] PHST- 2025/08/02 10:43 [medline] PHST- 2025/04/26 16:17 [pubmed] PHST- 2025/04/25 23:33 [entrez] AID - 10.1038/s41573-025-01183-8 [pii] AID - 10.1038/s41573-025-01183-8 [doi] PST - ppublish SO - Nat Rev Drug Discov. 2025 Aug;24(8):631-650. doi: 10.1038/s41573-025-01183-8. Epub 2025 Apr 25. PMID- 40277068 OWN - NLM STAT- Publisher LR - 20250425 IS - 1875-533X (Electronic) IS - 0929-8673 (Linking) DP - 2025 Apr 23 TI - Neuroprotective Role of the Novel GLP-1R Agonist Semaglutide. LID - 10.2174/0109298673359635250401051339 [doi] AB - Disturbances in insulin signaling and glucose metabolism within the brain are associated with the onset of neuronal degeneration and a reduction in synaptic activity. Research increasingly supports the therapeutic potential of GLP-1R agonists for diabetes- related neurodegenerative diseases. The incretin hormone recognized as GLP-1 is of major significance in ensuring the control of blood glucose levels and the facilitation of appropriate insulin signaling, which are also known to have neuroprotective properties against Alzheimer's disease, including the prevention of neuronal death, inhibition of Abeta accumulation, and mitigation of tau hyperphosphorylation. In contrast to other types of GLP-1R agonists, limited studies have focused on the novel GLP-1R agonist Semaglutide. The principal aim of this review is to determine the molecular mechanisms that link Alzheimer's disease and type 2 diabetes mellitus, as well as to understand the neuroprotective role of semaglutide. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Kenzheshova, Akniyet AU - Kenzheshova A AD - Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan. FAU - Moldasheva, Aiman AU - Moldasheva A AD - Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan. FAU - Aljofan, Mohamad AU - Aljofan M AD - Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan. AD - Drug Discovery and Development Laboratory, National Laboratory Astana, 010000, Kazakhstan. LA - eng PT - Journal Article DEP - 20250423 PL - United Arab Emirates TA - Curr Med Chem JT - Current medicinal chemistry JID - 9440157 SB - IM OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1R agonist OT - amyloid beta peptide OT - islet amyloid polypeptide OT - semaglutide OT - tau hyperphosphorylation. OT - type 2 diabetes mellitus EDAT- 2025/04/25 13:46 MHDA- 2025/04/25 13:46 CRDT- 2025/04/25 07:03 PHST- 2024/10/30 00:00 [received] PHST- 2025/01/13 00:00 [revised] PHST- 2025/01/17 00:00 [accepted] PHST- 2025/04/25 13:46 [medline] PHST- 2025/04/25 13:46 [pubmed] PHST- 2025/04/25 07:03 [entrez] AID - CMC-EPUB-147887 [pii] AID - 10.2174/0109298673359635250401051339 [doi] PST - aheadofprint SO - Curr Med Chem. 2025 Apr 23. doi: 10.2174/0109298673359635250401051339. PMID- 40274715 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250427 IS - 2199-1170 (Print) IS - 2198-9761 (Electronic) IS - 2198-9761 (Linking) VI - 11 IP - 1 DP - 2025 Apr 24 TI - The Impact of Exercise Training on the Brain and Cognition in Type 2 Diabetes, and its Physiological Mediators: A Systematic Review. PG - 42 LID - 10.1186/s40798-025-00836-7 [doi] LID - 42 AB - BACKGROUND: Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and brain structure and function, at least in healthy people, but the impact of exercise training on these aspects remains to be fully elucidated in patients with T2DM. OBJECTIVE: To determine the impact of exercise training on cognition and brain structure and function in T2DM, and identify the involved physiological mediators. METHODS: This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the 14th of January 2025 were searched by means of the electronic databases PubMed, Embase, and Web of Science. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (e.g. dietary changes, cognitive training, etc.). Study quality was assessed by means of the TESTEX tool for human studies, and the CAMARADES tool for animal studies. RESULTS: For the systematic part of the review, 22 papers were found to be eligible. 18 out of 22 papers (81.8%) showed a significant positive effect of exercise training on cognition in T2DM, of which two studies only showed significant improvements in the minority of the cognitive tests. Four papers (18.2%) could not find a significant effect of exercise on cognition in T2DM. Resistance and endurance exercise were found to be equally effective for achieving cognitive improvement. Machine-based power training is seemingly more effective than resistance training with body weight and elastic bands to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3beta, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on brain structure and function in T2DM. Via these mediators, exercise training induces multiple beneficial brain changes, such as increased neuroplasticity, increased insulin sensitivity, and decreased inflammation. CONCLUSION: Overall, exercise training beneficially affects cognition and brain structure and function in T2DM, with resistance and endurance exercise having similar effects. However, there is a need for additional studies, and more methodological consistency between different studies in order to define an exercise program optimal for improving cognition in T2DM. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process. CI - (c) 2025. The Author(s). FAU - Vandersmissen, Jitske AU - Vandersmissen J AUID- ORCID: 0000-0003-1861-5401 AD - Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium. Jitske.vandersmissen@uhasselt.be. FAU - Dewachter, Ilse AU - Dewachter I AUID- ORCID: 0000-0001-7202-515X AD - Biomedical Research Institute, BIOMED, Hasselt University, 3590, Diepenbeek, Belgium. FAU - Cuypers, Koen AU - Cuypers K AUID- ORCID: 0000-0002-7867-7439 AD - Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium. AD - Movement Control and Neuroplasticity Research Group, Department of Movement Sciences, Group Biomedical Sciences, KU Leuven, 3000, Leuven, Belgium. FAU - Hansen, Dominique AU - Hansen D AUID- ORCID: 0000-0003-3074-2737 AD - Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium. AD - Heart Centre Hasselt, Jessa Hospital, 3500, Hasselt, Belgium. LA - eng GR - 23OWB01BOF/Universiteit Hasselt/ PT - Journal Article PT - Systematic Review DEP - 20250424 PL - Switzerland TA - Sports Med Open JT - Sports medicine - open JID - 101662568 PMC - PMC12022206 COIS- Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors confirm that there were no conflicts of interest. The authors have no relevant financial or non-financial interests to disclose. EDAT- 2025/04/25 01:20 MHDA- 2025/04/25 01:21 PMCR- 2025/04/24 CRDT- 2025/04/24 23:16 PHST- 2024/09/30 00:00 [received] PHST- 2025/03/16 00:00 [accepted] PHST- 2025/04/25 01:21 [medline] PHST- 2025/04/25 01:20 [pubmed] PHST- 2025/04/24 23:16 [entrez] PHST- 2025/04/24 00:00 [pmc-release] AID - 10.1186/s40798-025-00836-7 [pii] AID - 836 [pii] AID - 10.1186/s40798-025-00836-7 [doi] PST - epublish SO - Sports Med Open. 2025 Apr 24;11(1):42. doi: 10.1186/s40798-025-00836-7. PMID- 40231506 OWN - NLM STAT- MEDLINE DCOM- 20251129 LR - 20260616 IS - 1996-3181 (Electronic) IS - 1871-5273 (Linking) VI - 24 IP - 10 DP - 2025 TI - Neuroprotective Effect of Sitagliptin beyond the Incretin Effect: A Narrative Review. PG - 743-749 LID - 10.2174/0118715273367858250321124131 [doi] AB - Sitagliptin is a dipeptidyl peptidase-IV inhibitor approved for treating type 2 diabetes mellitus. It increases the active form of incretin Glucagon-like Peptide-1 (GLP-1). The GLP-1 peptide prevents damage to neurons due to its anti-inflammatory and anti-apoptotic activities. This article summarizes the studies assessing the neuroprotective properties of sitagliptin, especially through the GLP-1 pathway. The outcomes of experimental research indicate that sitagliptin has a decreasing effect on inflammation response. Sitagliptin decreases proinflammatory factors, such as Glial Fibrillary Acidic Protein (GFAP), Nuclear factor kappa B (NF-kappaB), Tumor Necrosis Factor-alpha (TNF- alpha), and Interleukin-6 (IL-6). It also decreases glutamate levels, the primary excitatory neurotransmitter. Furthermore, sitagliptin shows antioxidative and antiapoptotic effects. Lastly, sitagliptin may provide a novel agent for the management of neurological disease. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Pourbagher-Shahri, Ali Mohammad AU - Pourbagher-Shahri AM AD - Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. AD - Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. FAU - Forouzanfar, Fatemeh AU - Forouzanfar F AD - Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. AD - Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - CNS Neurol Disord Drug Targets JT - CNS & neurological disorders drug targets JID - 101269155 RN - TS63EW8X6F (Sitagliptin Phosphate) RN - 0 (Neuroprotective Agents) RN - 0 (Incretins) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Sitagliptin Phosphate/pharmacology/therapeutic use MH - Humans MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - Animals MH - *Incretins/metabolism MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - Glucagon-Like Peptide 1/metabolism MH - Diabetes Mellitus, Type 2/drug therapy OTO - NOTNLM OT - Alzheimer's disease OT - Sitagliptin OT - glucagon-like peptide-1. OT - inflammation OT - neuroprotection OT - oxidative stress EDAT- 2025/04/15 12:29 MHDA- 2025/11/29 06:27 CRDT- 2025/04/15 06:23 PHST- 2024/10/30 00:00 [received] PHST- 2025/01/31 00:00 [revised] PHST- 2025/02/04 00:00 [accepted] PHST- 2025/11/29 06:27 [medline] PHST- 2025/04/15 12:29 [pubmed] PHST- 2025/04/15 06:23 [entrez] AID - CNSNDDT-EPUB-147648 [pii] AID - 10.2174/0118715273367858250321124131 [doi] PST - ppublish SO - CNS Neurol Disord Drug Targets. 2025;24(10):743-749. doi: 10.2174/0118715273367858250321124131. PMID- 40210453 OWN - NLM STAT- MEDLINE DCOM- 20250825 LR - 20260925 IS - 1468-330X (Electronic) IS - 0022-3050 (Print) IS - 0022-3050 (Linking) VI - 96 IP - 9 DP - 2025 Aug 14 TI - Glucagon-like peptide-1 receptor agonists for major neurocognitive disorders. PG - 870-883 LID - 10.1136/jnnp-2024-335593 [doi] LID - e335593 AB - Disease-modifying treatments for major neurocognitive disorders, including Alzheimer's disease, Parkinson's disease and other cognitive deficits, are among the main unmet needs in modern medicine. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently licensed for the treatment of type 2 diabetes mellitus and obesity, offer a novel, multilayered mechanism for intervention in neurodegeneration through intermediate, aetiology-agnostic pathways, likely involving metabolic, inflammatory and several other relevant neurobiological processes. In vitro and animal studies have revealed promising signals of neuroprotection, with preliminary supportive evidence emerging from recent pharmacoepidemiological investigations and clinical trials. In this article, we comprehensively review studies that investigate the impact of GLP-1RAs on the various aetiologies of cognitive impairment and dementia syndromes. Focusing on evidence from human studies, we highlight how brain energy homeostasis, neurogenesis, synaptic functioning, neuroinflammation and other cellular stress responses, pathological protein aggregates, proteostasis, cerebrovascular system and blood-brain barrier dynamics may underlie GLP-1RA putative neuroprotective effects. We then report and appraise evidence from clinical studies, including observational investigations, clinical trials and pooled analyses. Finally, we discuss current challenges and perspectives ahead for research and clinical implementation of GLP-1RAs for the care of people with major neurocognitive disorders, including their individual brain penetrance potential, the need for response biomarkers and disease stage-based indications, their possible non-specific effects on brain health, their profile in terms of adverse events and other unwanted effects, the lack of long-term data for efficacy and safety, and issues surrounding cost and availability of treatment. CI - (c) Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group. FAU - De Giorgi, Riccardo AU - De Giorgi R AD - Department of Psychiatry, University of Oxford, Oxford, UK. AD - Oxford Health NHS Foundation Trust, Oxford, UK. FAU - Ghenciulescu, Ana AU - Ghenciulescu A AD - Department of Psychiatry, University of Oxford, Oxford, UK. FAU - Yotter, Courtney AU - Yotter C AD - Department of Psychiatry, University of Oxford, Oxford, UK. FAU - Taquet, Maxime AU - Taquet M AD - Department of Psychiatry, University of Oxford, Oxford, UK. FAU - Koychev, Ivan AU - Koychev I AUID- ORCID: 0000-0001-6813-8493 AD - Department of Psychiatry, University of Oxford, Oxford, UK ivan.koychev@psych.ox.ac.uk. AD - Division of Brain Sciences, Imperial College London, London, UK. LA - eng PT - Journal Article PT - Review DEP - 20250814 PL - England TA - J Neurol Neurosurg Psychiatry JT - Journal of neurology, neurosurgery, and psychiatry JID - 2985191R RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Neurocognitive Disorders/drug therapy MH - *Neuroprotective Agents/therapeutic use MH - Animals MH - Cognitive Dysfunction/drug therapy MH - Brain/drug effects MH - Diabetes Mellitus, Type 2/drug therapy MH - Alzheimer Disease/drug therapy PMC - PMC12418562 OTO - NOTNLM OT - ALZHEIMER'S DISEASE OT - DEMENTIA OT - PARKINSON'S DISEASE COIS- Competing interests: RDG and IK are supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (NIHR203316). IK declares additional funding for this work through the UKRI Medical Research Council (MRC) (MR/T033371/1) and NIHR Development and Skills Enhancement Award (NIHR301616). IK is also in receipt of grant funding from Novo Nordisk for an investigator-initiated study of semaglutide in Alzheimer's disease; he is paid a medical advisor for digital healthcare companies in the dementia space (Five Lives SAS, Cognetivity Ltd, Cognes Ltd). EDAT- 2025/04/11 00:32 MHDA- 2025/08/31 19:54 PMCR- 2025/09/09 CRDT- 2025/04/10 21:33 PHST- 2025/02/15 00:00 [received] PHST- 2025/03/21 00:00 [accepted] PHST- 2025/08/31 19:54 [medline] PHST- 2025/04/11 00:32 [pubmed] PHST- 2025/04/10 21:33 [entrez] PHST- 2025/09/09 00:00 [pmc-release] AID - jnnp-2024-335593 [pii] AID - 10.1136/jnnp-2024-335593 [doi] PST - epublish SO - J Neurol Neurosurg Psychiatry. 2025 Aug 14;96(9):870-883. doi: 10.1136/jnnp-2024-335593. PMID- 40207412 OWN - NLM STAT- MEDLINE DCOM- 20250410 LR - 20260519 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 21 IP - 4 DP - 2025 Apr TI - Glycated hemoglobin and body mass index as mediators of GLP-1RAs and Alzheimer's disease and related dementias in patients with type 2 diabetes. PG - e70161 LID - 10.1002/alz.70161 [doi] LID - e70161 AB - INTRODUCTION: Whether reductions in glycated hemoglobin (HbA1c) levels and body mass index (BMI) mediate the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and Alzheimer's disease and related dementias (ADRD) risk is unknown. METHODS: This cohort study included 22,908 patients aged >/= 50 years with type 2 diabetes (T2D) newly prescribed GLP-1RA or other second-line glucose-lowering drugs (GLDs). Causal mediation analysis was used to estimate to what extent the effect of GLP-1RAs on ADRD risk was attributable to lowering HbA1c or BMI. RESULTS: Compared to other GLD users, GLP-1RA users had significant reductions in HbA1c levels by 0.16% and BMI by 0.23 kg/m(2), along with a 26% lower ADRD risk. The direct protective effect of GLP-1RAs on ADRD risk persisted even after accounting for HbA1c and BMI reductions, with minimal mediation effects observed through these factors. DISCUSSION: GLP-1RAs reduce ADRD risk, largely independent of their effects on HbA1c and BMI. HIGHLIGHTS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were associated with reductions in glycated hemoglobin (HbA1c) and body mass index (BMI) compared to other second-line glucose-lowering drugs(GLDs). GLP-1RA users were associated with a 26% lower risk of Alzheimer's disease and related dementias (ADRD) than other GLD users. The protective effect of GLP-1RAs against ADRD in adults with type 2 diabetes (T2D) is largely independent of their effects on HbA1c and BMI. CI - (c) 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Tang, Huilin AU - Tang H AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Donahoo, William T AU - Donahoo WT AD - Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. FAU - DeKosky, Steven T AU - DeKosky ST AD - Department of Neurology and McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA. AD - Florida Alzheimer's Disease Research Center (ADRC), University of Florida, Gainesville, Florida, USA. FAU - Lee, Yao An AU - Lee YA AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Svensson, Mikael AU - Svensson M AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. FAU - Bian, Jiang AU - Bian J AD - Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Guo, Jingchuan AU - Guo J AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. LA - eng GR - R01AG076234/AG/NIA NIH HHS/United States GR - R01AG089445/AG/NIA NIH HHS/United States GR - R01DK133465/DK/NIDDK NIH HHS/United States GR - R01 DK133465/DK/NIDDK NIH HHS/United States GR - R01 AG076234/AG/NIA NIH HHS/United States GR - NH/NIH HHS/United States GR - R01 AG089445/AG/NIA NIH HHS/United States GR - 2023PDVH1064032/Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Predoctoral Fellowship/ PT - Journal Article PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Glycated Hemoglobin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Glycated Hemoglobin/metabolism MH - *Body Mass Index MH - Male MH - Female MH - *Alzheimer Disease/epidemiology MH - Aged MH - Middle Aged MH - *Dementia/epidemiology MH - Cohort Studies MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use PMC - PMC11982930 OTO - NOTNLM OT - Alzheimer's disease and related dementias OT - GLP-1RAs OT - body mass index OT - causal mediation analysis OT - glycated hemoglobin OT - type 2 diabetes COIS- All authors declare no conflict of interest. Author disclosures are available in the supporting information. EDAT- 2025/04/10 06:25 MHDA- 2025/04/10 06:26 PMCR- 2025/04/10 CRDT- 2025/04/10 05:24 PHST- 2025/03/08 00:00 [revised] PHST- 2024/12/22 00:00 [received] PHST- 2025/03/11 00:00 [accepted] PHST- 2025/04/10 06:26 [medline] PHST- 2025/04/10 06:25 [pubmed] PHST- 2025/04/10 05:24 [entrez] PHST- 2025/04/10 00:00 [pmc-release] AID - ALZ70161 [pii] AID - 10.1002/alz.70161 [doi] PST - ppublish SO - Alzheimers Dement. 2025 Apr;21(4):e70161. doi: 10.1002/alz.70161. PMID- 40193122 OWN - NLM STAT- MEDLINE DCOM- 20250512 LR - 20260211 IS - 2168-6157 (Electronic) IS - 2168-6149 (Print) IS - 2168-6149 (Linking) VI - 82 IP - 5 DP - 2025 May 1 TI - Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis. PG - 450-460 LID - 10.1001/jamaneurol.2025.0360 [doi] AB - IMPORTANCE: Although diabetes is a risk factor for dementia, the effect of glucose-lowering therapy for prevention of incident dementia is uncertain. OBJECTIVE: To determine whether cardioprotective glucose-lowering therapy (sodium-glucose cotransporter-2 inhibitors [SGLT2is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], metformin, and pioglitazone), compared with controls, was associated with a reduction in risk of dementia or cognitive impairment, and among primary dementia subtypes. DATA SOURCES: The PubMed and Embase databases were searched for studies published from inception of the database to July 11, 2024. STUDY SELECTION: Randomized clinical trials comparing cardioprotective glucose-lowering therapy with controls that reported dementia or change in cognitive scores. Cardioprotective glucose-lowering therapies were defined as drug classes recommended by guidelines for reduction of cardiovascular events, based on evidence from phase III randomized clinical trials. Inclusion criteria were assessed independently and inconsistencies were resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently by 2 authors adhering to the PRISMA guidelines in August 2024. Random-effects meta-analysis models were used to estimate a pooled treatment effect. MAIN OUTCOMES AND MEASURES: The primary outcome measure was dementia or cognitive impairment. The secondary outcomes were primary dementia subtypes, including vascular and Alzheimer dementia, and change in cognitive scores. RESULTS: Twenty-six randomized clinical trials were eligible for inclusion (N = 164 531 participants), of which 23 trials (n = 160 191 participants) reported the incidence of dementia or cognitive impairment, including 12 trials evaluating SGLT2is, 10 trials evaluating GLP-1RAs, and 1 trial evaluating pioglitazone (no trials of metformin were identified). The mean (SD) age of trial participants was 64.4 (3.5) years and 57 470 (34.9%) were women. Overall, cardioprotective glucose-lowering therapy was not significantly associated with a reduction in cognitive impairment or dementia (odds ratio [OR], 0.83 [95% CI, 0.60-1.14]). Among drug classes, GLP-1RAs were associated with a statistically significant reduction in dementia (OR, 0.55 [95% CI, 0.35-0.86]), but not SGLT2is (OR, 1.20 [95% CI, 0.67-2.17]; P value for heterogeneity = .04). CONCLUSIONS AND RELEVANCE: While cardioprotective glucose-lowering therapies were not associated with an overall reduction in all-cause dementia, this meta-analysis of randomized clinical trials found that glucose lowering with GLP-1RAs was associated with a statistically significant reduction in all-cause dementia. FAU - Seminer, Allie AU - Seminer A AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. FAU - Mulihano, Alfredi AU - Mulihano A AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. FAU - O'Brien, Clare AU - O'Brien C AD - University Hospital Galway, Galway, Ireland. FAU - Krewer, Finn AU - Krewer F AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. FAU - Costello, Maria AU - Costello M AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. AD - University Hospital Galway, Galway, Ireland. FAU - Judge, Conor AU - Judge C AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. AD - University Hospital Galway, Galway, Ireland. FAU - O'Donnell, Martin AU - O'Donnell M AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. AD - University Hospital Galway, Galway, Ireland. FAU - Reddin, Catriona AU - Reddin C AD - HRB Clinical Research Facility, University of Galway, Galway, Ireland. AD - University Hospital Galway, Galway, Ireland. AD - Wellcome Trust-HRB, Irish Clinical Academic Training, Dublin, Ireland. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - United States TA - JAMA Neurol JT - JAMA neurology JID - 101589536 RN - 0 (Cardiotonic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - X4OV71U42S (Pioglitazone) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM CIN - JAMA Neurol. 2025 May 1;82(5):437-438. doi: 10.1001/jamaneurol.2025.0237. PMID: 40193095 MH - Humans MH - *Cardiotonic Agents/therapeutic use MH - Cognitive Dysfunction/prevention & control MH - *Dementia/prevention & control/epidemiology MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - Metformin/therapeutic use MH - Pioglitazone/therapeutic use MH - Randomized Controlled Trials as Topic MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use PMC - PMC11976645 COIS- Conflict of Interest Disclosures: Dr Krewer reported receiving grants from the Health Research Board (HRB; SDAP2023.036) outside the submitted work. Dr Reddin reported receiving grants from the Irish Clinical Academic Training Programme, Wellcome Trust, HRB (203930/B/16/Z), Health Service Executive, National Doctors Training and Planning, and Health and Social Care, Research and Development Division, Northern Ireland outside the submitted work. No other disclosures were reported. EDAT- 2025/04/07 13:17 MHDA- 2025/05/12 12:33 PMCR- 2025/04/07 CRDT- 2025/04/07 11:34 PHST- 2025/05/12 12:33 [medline] PHST- 2025/04/07 13:17 [pubmed] PHST- 2025/04/07 11:34 [entrez] PHST- 2025/04/07 00:00 [pmc-release] AID - 2831975 [pii] AID - noi250011 [pii] AID - 10.1001/jamaneurol.2025.0360 [doi] PST - ppublish SO - JAMA Neurol. 2025 May 1;82(5):450-460. doi: 10.1001/jamaneurol.2025.0360. PMID- 40193118 OWN - NLM STAT- MEDLINE DCOM- 20250512 LR - 20260408 IS - 2168-6157 (Electronic) IS - 2168-6149 (Print) IS - 2168-6149 (Linking) VI - 82 IP - 5 DP - 2025 May 1 TI - GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. PG - 439-449 LID - 10.1001/jamaneurol.2025.0353 [doi] AB - IMPORTANCE: The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) and risk of Alzheimer disease and related dementias (ADRD) remains to be confirmed. OBJECTIVE: To assess the risk of ADRD associated with GLP-1RAs and SGLT2is in people with type 2 diabetes (T2D). DESIGN, SETTING, AND PARTICIPANTS: This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium from January 2014 to June 2023. Patients were 50 years or older with T2D and no prior diagnosis of ADRD or antidementia treatment. Among the 396 963 eligible patients with T2D, 33 858 were included in the GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 in the SGLT2i vs other GLD cohort, and 24 117 in the GLP-1RA vs SGLT2i cohort. EXPOSURES: Initiation of treatment with a GLP-1RA, SGLT2i, or other second-line GLD. MAIN OUTCOMES AND MEASURES: ADRD was identified using clinical diagnosis codes. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression models with inverse probability of treatment weighting (IPTW) to adjust for potential confounders. RESULTS: This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], -2.26 per 1000 person-years [95% CI, -2.88 to -1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, -3.05 per 1000 person-years [95% CI, -3.68 to -2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of -0.09 per 1000 person-years (95% CI, -0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32). CONCLUSION AND RELEVANCE: In people with T2D, both GLP-1RAs and SGLT2is were statistically significantly associated with decreased risk of ADRD compared with other GLDs, and no difference was observed between both drugs. FAU - Tang, Huilin AU - Tang H AD - Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville. FAU - Donahoo, William T AU - Donahoo WT AD - Department of Medicine, College of Medicine, University of Florida, Gainesville. FAU - DeKosky, Steven T AU - DeKosky ST AD - Department of Neurology and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville. AD - 1Florida Alzheimer's Disease Research Center, University of Florida, Gainesville. FAU - Lee, Yao An AU - Lee YA AD - Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville. FAU - Kotecha, Pareeta AU - Kotecha P AD - Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville. FAU - Svensson, Mikael AU - Svensson M AD - Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville. FAU - Bian, Jiang AU - Bian J AD - Department of Health Outcomes & Biomedical Informatics, College of Medicine, University of Florida, Gainesville. FAU - Guo, Jingchuan AU - Guo J AD - Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville. LA - eng GR - R01 DK133465/DK/NIDDK NIH HHS/United States PT - Journal Article PL - United States TA - JAMA Neurol JT - JAMA neurology JID - 101589536 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM CIN - JAMA Neurol. 2025 May 1;82(5):437-438. doi: 10.1001/jamaneurol.2025.0237. PMID: 40193095 MH - Humans MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - Male MH - Female MH - Aged MH - *Alzheimer Disease/epidemiology/chemically induced MH - Middle Aged MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Dementia/epidemiology/chemically induced MH - Aged, 80 and over MH - Cohort Studies PMC - PMC11976648 COIS- Conflict of Interest Disclosures: Dr Tang reported receiving grants from Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation during the conduct of the study. Dr DeKosky reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study; personal fees from Acumen Pharmaceuticals, Biogen, and Vaccinex for serving as the data and safety monitoring board chair; Cognition Therapeutics for serving on the medical advisory board; Neurotherapeutics for serving as an associate editor; UpToDate for serving as a section editor for dementia; and consulting fees from Eisai, Lilly, Nido Biosciences, and Prevail Therapeutics outside the submitted work. Dr Kotecha reported receiving personal fees from Takeda Pharmaceuticals for serving as an intern in 2023 and Novo Nordisk for serving as a regulatory medical writer from 2021 to 2022 outside the submitted work. No other disclosures were reported. EDAT- 2025/04/07 13:16 MHDA- 2025/05/12 12:33 PMCR- 2026/04/07 CRDT- 2025/04/07 11:34 PHST- 2025/05/12 12:33 [medline] PHST- 2025/04/07 13:16 [pubmed] PHST- 2025/04/07 11:34 [entrez] PHST- 2026/04/07 00:00 [pmc-release] AID - 2831976 [pii] AID - noi250010 [pii] AID - 10.1001/jamaneurol.2025.0353 [doi] PST - ppublish SO - JAMA Neurol. 2025 May 1;82(5):439-449. doi: 10.1001/jamaneurol.2025.0353. PMID- 40145958 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20260430 LR - 20260813 IS - 1673-5374 (Print) IS - 1876-7958 (Electronic) IS - 1673-5374 (Linking) VI - 21 IP - 8 DP - 2026 Aug 1 TI - Neuroprotective effects of lixisenatide against propagation of alpha-synuclein pathology in Parkinson's disease. PG - 3788-3796 LID - 10.4103/NRR.NRR-D-24-00941 [doi] AB - Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of type 2 diabetes mellitus, have been suggested as a potential disease-modifying treatment for Parkinson's disease. Some clinical trials of glucagon-like peptide-1 receptor agonists have demonstrated that they can alleviate motor dysfunction and improve quality of life for patients with Parkinson's disease. However, the mechanisms underlying the neuroprotective effects of glucagon-like peptide-1 receptor agonists have yet to be elucidated. In this study, we used alpha-synuclein preformed fibrils to generate in vitro and in vivo models of Parkinson's disease and investigated the effects of a short-acting glucagon-like peptide-1 receptor agonist, lixisenatide, on the propagation of alpha-synuclein pathology. We found that lixisenatide reduced alpha-synuclein phosphorylation, aggregation, and propagation in cells treated with alpha-synuclein preformed fibrils, and that these effects were accompanied by decreased mitochondrial dysfunction and apoptosis. Additionally, lixisenatide treatment alleviated motor dysfunction and dopaminergic cell neurodegeneration 20 weeks after stereotactic injection of alpha-synuclein preformed fibrils into the striatum of wild-type mice. In addition, lixisenatide inhibited alpha-synuclein phosphorylation and seeding between neurons, mediated by neuronal lymphocyte-activation gene 3 expression. This study provides new insights into the mechanism underlying the disease-modifying effects of glucagon-like peptide-1 receptor agonists in the treatment of Parkinson's disease. FAU - Sun, Shangqi AU - Sun S AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. FAU - Huang, Liqin AU - Huang L AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. FAU - Jiang, Gege AU - Jiang G AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. FAU - Xie, Guanfeng AU - Xie G AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. FAU - Li, Xiaoyi AU - Li X AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. FAU - Wang, Xiufeng AU - Wang X AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. FAU - Guo, Hongxiu AU - Guo H AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. FAU - Wang, Cailin AU - Wang C AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. FAU - Zheng, Siyi AU - Zheng S AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. FAU - Li, Gang AU - Li G AUID- ORCID: 0000-0003-3758-5965 AD - Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. FAU - Xiong, Jing AU - Xiong J AUID- ORCID: 0000-0002-2221-5972 AD - Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. AD - Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei Province, China. LA - eng PT - Journal Article DEP - 20250325 PL - India TA - Neural Regen Res JT - Neural regeneration research JID - 101316351 PMC - PMC13452710 OTO - NOTNLM OT - Parkinson's disease OT - disease-modifying treatment OT - glucagon-like peptide-1 receptor agonists OT - lixisenatide OT - lymphocyte-activation gene 3 OT - mitochondrial dysfunction OT - alpha-synuclein propagation COIS- Conflicts of interest: The authors declare no competing financial interests. EDAT- 2025/03/27 13:17 MHDA- 2025/03/27 13:18 PMCR- 2025/03/25 CRDT- 2025/03/27 10:43 PHST- 2024/08/16 00:00 [received] PHST- 2025/01/20 00:00 [accepted] PHST- 2025/03/27 13:18 [medline] PHST- 2025/03/27 13:17 [pubmed] PHST- 2025/03/27 10:43 [entrez] PHST- 2025/03/25 00:00 [pmc-release] AID - 01300535-202608000-00070 [pii] AID - NRR-21-3788 [pii] AID - 10.4103/NRR.NRR-D-24-00941 [doi] PST - ppublish SO - Neural Regen Res. 2026 Aug 1;21(8):3788-3796. doi: 10.4103/NRR.NRR-D-24-00941. Epub 2025 Mar 25. PMID- 40142784 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250329 IS - 2077-0383 (Print) IS - 2077-0383 (Electronic) IS - 2077-0383 (Linking) VI - 14 IP - 6 DP - 2025 Mar 14 TI - Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss. LID - 10.3390/jcm14061978 [doi] LID - 1978 AB - The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes. FAU - Sundararaman, Lalitha AU - Sundararaman L AD - Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA. FAU - Gouda, Divakara AU - Gouda D AD - Inspira Health Network, 155 Bridgeton Pike ste c, Mullica Hill, NJ 08062, USA. FAU - Kumar, Anil AU - Kumar A AD - Department of Diabetes and Endocrinology, Karnataka Institute of Endocrinology and Research Bangalore, Binnamangala, Stage 1, Indiranagar, Bengaluru 560038, Karnataka, India. FAU - Sundararaman, Sumithra AU - Sundararaman S AD - Prana Holistic Center for Fertility and Integrated Medicine, 74/198, St'Mary's Road, Opp. St' Mary's Church, Trustpakkam, Abiramapuram, Chennai 600018, Tamil Nadu, India. FAU - Goudra, Basavana AU - Goudra B AUID- ORCID: 0000-0002-5146-0424 AD - Department of Anesthesiology, Sidney Kimmel Medical College, Jefferson Health, 111 S 11th Street, #8280, Philadelphia, PA 19107, USA. LA - eng PT - Journal Article PT - Review DEP - 20250314 PL - Switzerland TA - J Clin Med JT - Journal of clinical medicine JID - 101606588 PMC - PMC11943310 OTO - NOTNLM OT - GLPI-A OT - Parkinson OT - hypertension OT - obesity OT - renal failure OT - type 2 DM COIS- The authors declare no conflicts of interest. EDAT- 2025/03/27 06:28 MHDA- 2025/03/27 06:29 PMCR- 2025/03/14 CRDT- 2025/03/27 01:14 PHST- 2025/02/05 00:00 [received] PHST- 2025/03/03 00:00 [revised] PHST- 2025/03/06 00:00 [accepted] PHST- 2025/03/27 06:29 [medline] PHST- 2025/03/27 06:28 [pubmed] PHST- 2025/03/27 01:14 [entrez] PHST- 2025/03/14 00:00 [pmc-release] AID - jcm14061978 [pii] AID - jcm-14-01978 [pii] AID - 10.3390/jcm14061978 [doi] PST - epublish SO - J Clin Med. 2025 Mar 14;14(6):1978. doi: 10.3390/jcm14061978. PMID- 40134421 OWN - NLM STAT- MEDLINE DCOM- 20250514 LR - 20250514 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 16 DP - 2025 TI - The immunomodulatory effects of GLP-1 receptor agonists in neurogenerative diseases and ischemic stroke treatment. PG - 1525623 LID - 10.3389/fimmu.2025.1525623 [doi] LID - 1525623 AB - Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular system, adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated in clinical studies for various indications, including type 2 diabetes and obesity (accounts for 70% of the total studies), non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease. This review presented fundamental information regarding two categories of GLP-1 receptor agonists (GLP-1RAs): peptide-based and small molecule compounds, and elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, and ultimately improving cognitive function in various neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has a unique role in reducing the concurrent risk of stroke in T2D patients. Given the infiltration of various peripheral immune cells into brain tissue, particularly in the areas surrounding the infarct lesion, we further investigated the potential immune regulatory mechanisms. GLP-1RA could not only facilitate the M2 polarization of microglia through both direct and indirect pathways, but also modulate the quantity and function of T cell subtypes, including CD4, CD8, and regulatory T cells, resulting into the inhibition of inflammatory responses and the promotion of neuronal regeneration through interleukin-10 secretion. Therefore, we believe that the "Tregs-microglia-neuron/neural precursor cells" axis is instrumental in mediating immune suppression and neuroprotection in the context of ischemic stroke. Given the benefits of rapid diffusion, favorable blood-brain barrier permeability and versatile administration routes, these small molecule compounds will be one of the important candidates of GLP-1RA. We look forward to the further clinical evidence of small molecule GLP-1RA intervention in ischemic stroke or T2D complicated by ischemic stroke. CI - Copyright (c) 2025 Sun, Hao, Liu and Gao. FAU - Sun, Haohui AU - Sun H AD - School of Basic Medical Science, School of Medicine, Ningbo University, Ningbo, Zhejiang, China. FAU - Hao, Yue AU - Hao Y AD - School of Basic Medical Science, School of Medicine, Ningbo University, Ningbo, Zhejiang, China. FAU - Liu, Hao AU - Liu H AD - School of Basic Medical Science, School of Medicine, Ningbo University, Ningbo, Zhejiang, China. FAU - Gao, Feng AU - Gao F AD - School of Basic Medical Science, School of Medicine, Ningbo University, Ningbo, Zhejiang, China. LA - eng PT - Journal Article PT - Review DEP - 20250311 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Ischemic Stroke/drug therapy/immunology/metabolism MH - Animals MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Neuroprotective Agents/therapeutic use/pharmacology MH - *Neurodegenerative Diseases/drug therapy/immunology PMC - PMC11932860 OTO - NOTNLM OT - IL-10 OT - Treg cells OT - glucagon-like peptide-1 receptor agonists OT - ischemic stroke OT - microglia COIS- The authors declare that this study received funding from Ningbo Dachang Pharmaceutical Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. EDAT- 2025/03/26 13:06 MHDA- 2025/03/26 13:07 PMCR- 2025/01/01 CRDT- 2025/03/26 04:24 PHST- 2024/11/11 00:00 [received] PHST- 2025/02/19 00:00 [accepted] PHST- 2025/03/26 13:07 [medline] PHST- 2025/03/26 13:06 [pubmed] PHST- 2025/03/26 04:24 [entrez] PHST- 2025/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2025.1525623 [doi] PST - epublish SO - Front Immunol. 2025 Mar 11;16:1525623. doi: 10.3389/fimmu.2025.1525623. eCollection 2025. PMID- 40081498 OWN - NLM STAT- MEDLINE DCOM- 20250404 LR - 20260529 IS - 1873-5169 (Electronic) IS - 0196-9781 (Linking) VI - 187 DP - 2025 May TI - Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities. PG - 171380 LID - S0196-9781(25)00041-5 [pii] LID - 10.1016/j.peptides.2025.171380 [doi] AB - Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025). CI - Copyright (c) 2025 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Bailey, Clifford J AU - Bailey CJ AD - Life and Health Sciences, Aston University, Birmingham B4 7ET, UK. FAU - Flatt, Peter R AU - Flatt PR AD - Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK. FAU - Conlon, J Michael AU - Conlon JM AD - Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK. Electronic address: jmconlon1@gmail.com. LA - eng PT - Journal Article PT - Review DEP - 20250311 PL - United States TA - Peptides JT - Peptides JID - 8008690 RN - 0 (Incretins) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Obesity/drug therapy/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Incretins/therapeutic use MH - Glucagon-Like Peptides/therapeutic use MH - Comorbidity MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/therapeutic use MH - Gastric Inhibitory Polypeptide/therapeutic use MH - Glucagon-Like Peptide 1 MH - Semaglutide OTO - NOTNLM OT - Cardiovascular OT - Incretin OT - Multiagonist OT - Obesity OT - Renal OT - Type 2 diabetes COIS- Conflict of Interest CJB has served on steering committees for clinical trials and advisory boards for several pharmaceutical companies. PRF and JMC are named on patents held by Ulster University for peptide therapeutics and have served as advisor to several pharmaceutical companies. EDAT- 2025/03/14 11:19 MHDA- 2025/04/05 15:58 CRDT- 2025/03/13 20:13 PHST- 2025/01/27 00:00 [received] PHST- 2025/03/03 00:00 [revised] PHST- 2025/03/05 00:00 [accepted] PHST- 2025/04/05 15:58 [medline] PHST- 2025/03/14 11:19 [pubmed] PHST- 2025/03/13 20:13 [entrez] AID - S0196-9781(25)00041-5 [pii] AID - 10.1016/j.peptides.2025.171380 [doi] PST - ppublish SO - Peptides. 2025 May;187:171380. doi: 10.1016/j.peptides.2025.171380. Epub 2025 Mar 11. PMID- 40062098 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250311 IS - 2168-8184 (Print) IS - 2168-8184 (Electronic) IS - 2168-8184 (Linking) VI - 17 IP - 2 DP - 2025 Feb TI - A System-Based Review on Effects of Glucagon-Like Peptide-1 Receptor Agonists: Benefits vs Risks. PG - e78575 LID - 10.7759/cureus.78575 [doi] LID - e78575 AB - Glucagon-like peptide 1 (GLP-1), an incretin hormone primarily secreted by L-cells in the gut, prompts insulin release, thus reducing blood sugar levels and causing weight loss by inducing feelings of fullness while curbing appetite. GLP-1 receptor agonists (GLP-1 RAs) mimic its effects, proving highly effective in managing type 2 diabetes mellitus (T2DM) and facilitating weight loss. While predominantly approved for T2DM and obesity, GLP-1 RAs also hold promise for treating other conditions like heart and kidney disease, with ongoing research exploring additional therapeutic applications. These agonists exhibit diverse effects within different organ systems, influencing conditions such as psoriasis, polycystic ovarian syndrome (PCOS), thyroid disorders, neurodegenerative diseases, and cardiopulmonary dysfunction. This study aims to comprehensively review the impact of GLP-1 RAs on various body systems, emphasizing both positive and negative effects while addressing existing knowledge gaps in the literature. By enhancing understanding of the diverse effects of GLP-1 RAs, this study aims to contribute to a broader awareness of their therapeutic potential. This systemic review uses Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a robust and transparent search process, aiming to minimize bias and maximize the retrieval of pertinent studies for review, where past research on GLP-1 RAs' interactions with various bodily systems were analyzed. The hypothesis posits that a systems-based review of GLP-1 RA mechanisms will reveal positive and negative effects across multiple organ systems, providing comprehensive insights into the hormone's physiological impact. This systematic review will assess the appropriateness of GLP-1 RAs in various aforementioned patient health states, shedding light on their potential impacts on comorbidities. With the surge in popularity of GLP-1 RAs for weight loss and diabetes management, this study aims to enhance patient understanding and informed decision-making regarding these medications, countering trends driven by celebrity endorsements and promoting better healthcare outcomes. CI - Copyright (c) 2025, Fadel et al. FAU - Fadel, Lynn P AU - Fadel LP AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Thao, Gigi AU - Thao G AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Chitre, Tanvi AU - Chitre T AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Rojas, Edwin D AU - Rojas ED AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Nguyen Fricko, Maria AU - Nguyen Fricko M AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Domingo, Valerie AU - Domingo V AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Budginas, Brigita AU - Budginas B AD - Department of Biomedical Education, Noorda College of Osteopathic Medicine, Provo, USA. FAU - Guerrero, Lorenz Carmelo AU - Guerrero LC AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Ghatas, Maria AU - Ghatas M AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Arani, Niloufar T AU - Arani NT AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Tabatabai, Niki AU - Tabatabai N AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. FAU - Pemminati, Sudhakar AU - Pemminati S AD - Department of Biomedical Education, California Health Sciences University College of Osteopathic Medicine, Clovis, USA. LA - eng PT - Journal Article PT - Review DEP - 20250205 PL - United States TA - Cureus JT - Cureus JID - 101596737 PMC - PMC11888820 OTO - NOTNLM OT - endocrinology and diabetes OT - glucagon-like peptide-1 receptor agonists OT - polycystic ovarian disease OT - types 2 diabetes OT - weight loss and obesity COIS- Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. EDAT- 2025/03/10 12:32 MHDA- 2025/03/10 12:33 PMCR- 2025/02/05 CRDT- 2025/03/10 06:39 PHST- 2025/01/31 00:00 [accepted] PHST- 2025/03/10 12:33 [medline] PHST- 2025/03/10 12:32 [pubmed] PHST- 2025/03/10 06:39 [entrez] PHST- 2025/02/05 00:00 [pmc-release] AID - 10.7759/cureus.78575 [doi] PST - epublish SO - Cureus. 2025 Feb 5;17(2):e78575. doi: 10.7759/cureus.78575. eCollection 2025 Feb. PMID- 40059125 OWN - NLM STAT- MEDLINE DCOM- 20250512 LR - 20260127 IS - 1573-6830 (Electronic) IS - 0272-4340 (Print) IS - 0272-4340 (Linking) VI - 45 IP - 1 DP - 2025 Mar 10 TI - Beyond Diabetes: Semaglutide's Role in Modulating Mood Disorders through Neuroinflammation Pathways. PG - 22 LID - 10.1007/s10571-025-01534-4 [doi] LID - 22 AB - Diabetes and mood disorders are intricately interconnected, with each condition elevating the risk of the other. This bidirectional relationship, further exacerbated by neuroinflammation, fosters an environment conducive to the development of anxiety and depression. Glucagon-like peptide-1 receptor agonists, such as semaglutide, offer promising therapeutic options that not only target type 2 diabetes but also can positively influence mood. Our study's primary goal was to evaluate the effectiveness of semaglutide, in mitigating anxiety and depression within an animal model of diabetes. The neuroprotective properties of semaglutide were evaluated by examining its influence on the kynurenine pathway and neurobiological markers (GFAP, NEFL, NSE, and GAL3) in the perfrontal cortex, selected for its key role in cognitive function and emotional regulation, impaired in diabetes and mood disorders. Additionally, we examined semaglutide's impact on peripheral inflammation and stress parameters to elucidate its role in modulating systemic inflammatory responses linked to mood disorders. Additionally, we conducted behavioral assessments to better understand how semaglutide influences anxiety and depression-related behaviors in diabetic mice. Semaglutide therapy significantly improved behavioral patterns and neurochemical markers in diabetic mice. The frequency of administration significantly influenced the outcomes, whereas the dosage appeared to have a limited impact. Here we show that semaglutide expands its therapeutic potential beyond diabetes, significantly influencing mood disorders through neuroinflammatory pathways. Semaglutide has the potential to be a key element in formulating integrated treatment strategies that address both metabolic health and mental well-being, ultimately enhancing the quality of life for individuals navigating these interrelated challenges. CI - (c) 2025. The Author(s). FAU - Piatkowska-Chmiel, Iwona AU - Piatkowska-Chmiel I AD - Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8B Jaczewskiego Street, 20-090, Lublin, Poland. iwona.piatkowska-chmiel@umlub.pl. FAU - Wicha-Komsta, Katarzyna AU - Wicha-Komsta K AD - Department of Experimental and Clinical Pharmacology, Faculty of Medicine, Medical University of Lublin, Lublin, Poland. FAU - Pawlowski, Kamil AU - Pawlowski K AD - Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8B Jaczewskiego Street, 20-090, Lublin, Poland. FAU - Syrytczyk, Aleksandra AU - Syrytczyk A AD - Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8B Jaczewskiego Street, 20-090, Lublin, Poland. FAU - Kocki, Tomasz AU - Kocki T AD - Department of Experimental and Clinical Pharmacology, Faculty of Medicine, Medical University of Lublin, Lublin, Poland. FAU - Dudka, Jaroslaw AU - Dudka J AD - Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8B Jaczewskiego Street, 20-090, Lublin, Poland. FAU - Herbet, Mariola AU - Herbet M AD - Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8B Jaczewskiego Street, 20-090, Lublin, Poland. LA - eng PT - Journal Article DEP - 20250310 PL - Netherlands TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - *Mood Disorders/drug therapy/metabolism/complications MH - *Neuroinflammatory Diseases/drug therapy/complications/metabolism MH - Male MH - Mice MH - *Diabetes Mellitus, Experimental/drug therapy/complications/metabolism MH - Mice, Inbred C57BL MH - *Signal Transduction/drug effects MH - Anxiety/drug therapy/complications MH - Depression/drug therapy MH - Behavior, Animal/drug effects MH - Inflammation/drug therapy MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC11891103 OTO - NOTNLM OT - Anxiety OT - Depression OT - Diabetes OT - Mood disorders OT - Neuroinflammation OT - Semaglutide COIS- Declarations. Conflict of Interest: The authors declare no competing interests. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee for Animal Research (No. 43/2018, 26 March 2018). Informed Consent Statement: Not applicable. EDAT- 2025/03/10 08:00 MHDA- 2025/03/10 08:01 PMCR- 2025/03/10 CRDT- 2025/03/10 00:05 PHST- 2024/09/10 00:00 [received] PHST- 2025/01/25 00:00 [accepted] PHST- 2025/03/10 08:01 [medline] PHST- 2025/03/10 08:00 [pubmed] PHST- 2025/03/10 00:05 [entrez] PHST- 2025/03/10 00:00 [pmc-release] AID - 10.1007/s10571-025-01534-4 [pii] AID - 1534 [pii] AID - 10.1007/s10571-025-01534-4 [doi] PST - epublish SO - Cell Mol Neurobiol. 2025 Mar 10;45(1):22. doi: 10.1007/s10571-025-01534-4. PMID- 40047116 OWN - NLM STAT- MEDLINE DCOM- 20250511 LR - 20260824 IS - 0743-6661 (Print) IS - 0743-6661 (Linking) VI - 52 IP - 1 DP - 2025 Jul 1 TI - Sweet Solutions: Unlocking the Diabetes-Dementia Connection for Better Outcomes. PG - 14-20 LID - 10.17849/insm-52-1-14-20.1 [doi] AB - Type 2 diabetes and Alzheimer's dementia represent important health challenges in our society today. Understanding the relationship between these conditions is crucial. This article explores the research on whether they share common risk factors or if they may influence each other's development, which could lead to more effective prevention and treatment strategies. CI - Copyright (c) 2025 Journal of Insurance Medicine. FAU - Posan, Emoke AU - Posan E LA - eng PT - Journal Article PL - United States TA - J Insur Med JT - Journal of insurance medicine (New York, N.Y.) JID - 8401468 SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/epidemiology MH - *Alzheimer Disease/prevention & control/etiology/epidemiology MH - Risk Factors MH - *Dementia OTO - NOTNLM OT - Alzheimer's dementia OT - Alzheimer's disease OT - GLP1 OT - Type 2 diabetes OT - antidiabetic drugs OT - glucagon-like peptide 1 receptor agonists OT - insulin resistance OT - neuroinflammation OT - neuronal degeneration EDAT- 2025/03/06 06:21 MHDA- 2025/03/06 12:32 CRDT- 2025/03/06 05:33 PHST- 2024/09/16 00:00 [received] PHST- 2024/09/16 00:00 [accepted] PHST- 2025/03/06 12:32 [medline] PHST- 2025/03/06 06:21 [pubmed] PHST- 2025/03/06 05:33 [entrez] AID - 505934 [pii] AID - 10.17849/insm-52-1-14-20.1 [doi] PST - ppublish SO - J Insur Med. 2025 Jul 1;52(1):14-20. doi: 10.17849/insm-52-1-14-20.1. PMID- 40017057 OWN - NLM STAT- MEDLINE DCOM- 20250415 LR - 20260716 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 104 IP - 3 DP - 2025 Apr TI - Effect of diabetes medications on the risk of developing dementia, mild cognitive impairment, or cognitive decline: A systematic review and meta-analysis. PG - 627-648 LID - 10.1177/13872877251319054 [doi] AB - Background: Diabetes is a risk factor for dementia, but we do not know whether specific diabetes medications ameliorate this risk. Objective: To systematically review and meta-analyze such medication's effect on the risk of developing dementia, mild cognitive impairment (MCI), or cognitive decline. Methods: We searched three databases until 21 November 2023. We included randomized controlled trials (RCT), cohort, and case-control studies assessing association between antidiabetic medication and future dementia, MCI, or cognitive decline. We meta-analyzed studies separately for individual drug classes and their comparators (no medication, placebo, or another drug). We appraised study quality using the Newcastle-Ottawa Scale and Physiotherapy Evidence Database Scale. Results: 42 studies fulfilled inclusion criteria. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus placebo reduced dementia risk by 53% in three RCTs (n = 15,820, RR = 0.47[0.25, 0.86]) and 27% in three case-control studies (n = 312,856, RR = 0.73[0.54, 0.99], I(2 )= 96%). Repaglinide was superior to glibenclamide by 0.8 points on the Mini-Mental State Examination scale in another RCT. Meta-analysis of seven longitudinal studies showed glitazones (n = 1,081,519, RR = 0.78[0.76, 0.81], I(2 )= 0%) were associated with reduced dementia risk. Metformin (n = 999,349, RR = 0.94[0.79, 1.13], I(2 )= 98.4%), sulfonylureas (RR = 0.98[0.78, 1.22], I(2 )= 83.3%), dipeptidyl peptidase-IV inhibitors (DPP-1V) (n = 192,802, RR = 0.86[0.65, 1.15], I(2 )= 92.9%) and insulin (n = 571,274, RR = 1.09[0.95, 1.25], I(2 )= 94.8%) were not. Most studies were observational and limited by confounding by indication. Conclusions: In people with diabetes, RCTs consistently showed GLP-RAs reduce future dementia risk. Glitazones consistently showed protective effects, without heterogeneity, suggesting potential generalizability of these results. Metformin, sulfonylureas, insulin, and DPP-1V studies had inconsistent findings. If information is available future studies should consider dosage, severity, and duration. FAU - Hui, Esther K AU - Hui EK AUID- ORCID: 0000-0001-7815-5473 AD - Division of Psychiatry, University College London, London, UK. FAU - Mukadam, Naaheed AU - Mukadam N AUID- ORCID: 0000-0001-8635-9521 AD - Division of Psychiatry, University College London, London, UK. FAU - Kohl, Gianna AU - Kohl G AUID- ORCID: 0000-0002-8913-1247 AD - Division of Psychology and Language Sciences, University College London, London, UK. FAU - Livingston, Gill AU - Livingston G AUID- ORCID: 0000-0001-6741-5516 AD - Division of Psychiatry, University College London, London, UK. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20250227 PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - *Cognitive Dysfunction/epidemiology/prevention & control MH - *Dementia/epidemiology/prevention & control MH - *Hypoglycemic Agents/therapeutic use MH - Randomized Controlled Trials as Topic MH - Risk Factors MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Metformin/therapeutic use PMC - PMC12231844 OTO - NOTNLM OT - Alzheimer's disease OT - cognitive decline OT - cognitive impairment OT - dementia OT - diabetes OT - prevention OT - risk factors COIS- Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2025/02/28 06:22 MHDA- 2025/04/15 06:24 PMCR- 2025/07/07 CRDT- 2025/02/28 01:53 PHST- 2025/04/15 06:24 [medline] PHST- 2025/02/28 06:22 [pubmed] PHST- 2025/02/28 01:53 [entrez] PHST- 2025/07/07 00:00 [pmc-release] AID - 10.1177_13872877251319054 [pii] AID - 10.1177/13872877251319054 [doi] PST - ppublish SO - J Alzheimers Dis. 2025 Apr;104(3):627-648. doi: 10.1177/13872877251319054. Epub 2025 Feb 27. PMID- 40009763 OWN - NLM STAT- MEDLINE DCOM- 20250730 LR - 20250730 IS - 1473-6578 (Electronic) IS - 0951-7367 (Linking) VI - 38 IP - 5 DP - 2025 Sep 1 TI - Risk of depression and dementia among individuals treated with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. PG - 368-375 LID - 10.1097/YCO.0000000000001001 [doi] AB - PURPOSE OF REVIEW: To review whether sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists decrease the risk of depression, suicidal ideation and cognitive impairment in later life. RECENT FINDINGS: The results of studies using information derived from large registries and administrative health datasets suggest that GLP-1 receptor agonists (RAs) increase the risk of suicidality, although findings have been inconsistent. One nested-case control study reported that SGLT2i decreases the risk of depression among adults with diabetes, and findings from a small trial of the SGLT2i empagliflozin provided supportive evidence. Several observational studies reported that SGLT2i and GLP-1 RAs decrease dementia risk, with a target trial finding greater cognitive benefit associated with the use of GLP-1 RAs compared with other medicines commonly used to manage diabetes. SUMMARY: Recent results from large observational studies suggest that SGLT2i and GLP-1 RA may decrease the risk of cognitive impairment in later life. The effects of these medicines on mood have not been as well explored, but there are concerns about the potential increased risk of suicidality among GLP-1 RA users. Prescription bias could explain some of these associations, so that robust trial evidence is now needed to confirm or dismiss the reported findings. CI - Copyright (c) 2025 Wolters Kluwer Health, Inc. All rights reserved. FAU - Almeida, Osvaldo P AU - Almeida OP AD - Institute for Health Research, University of Notre Dame Australia. AD - WA Centre for Health & Ageing, Medical School, University of Western Australia. LA - eng PT - Journal Article PT - Review DEP - 20250219 PL - United States TA - Curr Opin Psychiatry JT - Current opinion in psychiatry JID - 8809880 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Dementia/chemically induced MH - *Depression/chemically induced MH - *Diabetes Mellitus, Type 2/drug therapy OTO - NOTNLM OT - dementia OT - depression OT - glucagon-like peptide 1 receptor agonist OT - sodium-glucose cotransporter 2 inhibitor OT - suicide EDAT- 2025/02/26 18:17 MHDA- 2025/07/30 12:30 CRDT- 2025/02/26 15:13 PHST- 2025/07/30 12:30 [medline] PHST- 2025/02/26 18:17 [pubmed] PHST- 2025/02/26 15:13 [entrez] AID - 00001504-990000000-00164 [pii] AID - 10.1097/YCO.0000000000001001 [doi] PST - ppublish SO - Curr Opin Psychiatry. 2025 Sep 1;38(5):368-375. doi: 10.1097/YCO.0000000000001001. Epub 2025 Feb 19. PMID- 40003982 OWN - NLM STAT- MEDLINE DCOM- 20250509 LR - 20250509 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 26 IP - 4 DP - 2025 Feb 11 TI - Targeting Ferroptosis in Parkinson's: Repurposing Diabetes Drugs as a Promising Treatment. LID - 10.3390/ijms26041516 [doi] LID - 1516 AB - This review explores the promising potential of repurposing type 2 diabetes (T2D) medications for the treatment of Parkinson's disease (PD), highlighting the shared pathophysiological mechanisms between these two age-related conditions, such as oxidative stress, mitochondrial dysfunction, and ferroptosis. The overlap suggests that existing diabetes drugs could target the common pathways involved in both conditions. Specifically, the review discusses how T2D medications, including metformin (Met), peroxisome-proliferator-activated receptor gamma (PPAR-gamma) agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, incretins, and dipeptidyl-peptidase 4 (DPP-4) inhibitors, can improve mitochondrial function, reduce neuroinflammation and oxidative stress, and potentially inhibit ferroptosis. The connection between ferroptosis and existing treatments, including diabetes medication, are only beginning to be explored. The limited data can be attributed also to the complexity of mechanisms involved in ferroptosis and Parkinson's disease and to the fact that the specific role of ferroptosis in Parkinson's disease pathogenesis has not been a primary focus until recent. Despite the promising preclinical evidence, clinical findings are mixed, underscoring the need for further research to elucidate these drugs' roles in neurodegeneration. Repurposing existing diabetes medications that have well-established safety profiles for Parkinson's disease treatment could significantly reduce the time and cost associated with drug development and could offer a more comprehensive approach to managing Parkinson's disease compared to treatments targeting a single mechanism. FAU - Duta, Carmen AU - Duta C AUID- ORCID: 0009-0001-0229-1177 AD - Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania. FAU - Muscurel, Corina AU - Muscurel C AD - Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania. FAU - Dogaru, Carmen Beatrice AU - Dogaru CB AD - Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania. FAU - Stoian, Irina AU - Stoian I AUID- ORCID: 0000-0002-0271-9946 AD - Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania. LA - eng PT - Journal Article PT - Review DEP - 20250211 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - *Ferroptosis/drug effects MH - *Parkinson Disease/drug therapy/metabolism MH - *Drug Repositioning/methods MH - Animals MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Oxidative Stress/drug effects MH - Mitochondria/drug effects/metabolism MH - Metformin/therapeutic use PMC - PMC11855881 OTO - NOTNLM OT - Parkinson's disease OT - ferroptosis OT - oxidative stress OT - type 2 diabetes medication COIS- The authors declare no conflicts of interest. EDAT- 2025/02/26 06:28 MHDA- 2025/02/26 06:29 PMCR- 2025/02/11 CRDT- 2025/02/26 01:15 PHST- 2024/12/31 00:00 [received] PHST- 2025/02/02 00:00 [revised] PHST- 2025/02/10 00:00 [accepted] PHST- 2025/02/26 06:29 [medline] PHST- 2025/02/26 06:28 [pubmed] PHST- 2025/02/26 01:15 [entrez] PHST- 2025/02/11 00:00 [pmc-release] AID - ijms26041516 [pii] AID - ijms-26-01516 [pii] AID - 10.3390/ijms26041516 [doi] PST - epublish SO - Int J Mol Sci. 2025 Feb 11;26(4):1516. doi: 10.3390/ijms26041516. PMID- 39983843 OWN - NLM STAT- MEDLINE DCOM- 20250413 LR - 20260530 IS - 1879-016X (Electronic) IS - 0163-7258 (Linking) VI - 269 DP - 2025 May TI - GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? PG - 108824 LID - S0163-7258(25)00036-1 [pii] LID - 10.1016/j.pharmthera.2025.108824 [doi] AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions. CI - Copyright (c) 2025 Elsevier Inc. All rights reserved. FAU - Arredouani, Abdelilah AU - Arredouani A AD - Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Qatar. Electronic address: aarredouani@hbku.edu.qa. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20250219 PL - England TA - Pharmacol Ther JT - Pharmacology & therapeutics JID - 7905840 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Animals MH - Cardiovascular Diseases/drug therapy MH - *Hypoglycemic Agents/therapeutic use/pharmacology/adverse effects MH - *Metabolic Diseases/drug therapy MH - Neurodegenerative Diseases/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy MH - Obesity/drug therapy OTO - NOTNLM OT - Diabetes OT - GLP-1 OT - GLP-1 receptor OT - GLP-1 receptor agonists OT - MASLD OT - Neurodegenerative diseases OT - Obesity COIS- Declaration of competing interest The author declares that there are no conflicts of interest. EDAT- 2025/02/22 00:21 MHDA- 2025/04/14 00:25 CRDT- 2025/02/21 19:34 PHST- 2024/08/30 00:00 [received] PHST- 2025/02/07 00:00 [revised] PHST- 2025/02/14 00:00 [accepted] PHST- 2025/04/14 00:25 [medline] PHST- 2025/02/22 00:21 [pubmed] PHST- 2025/02/21 19:34 [entrez] AID - S0163-7258(25)00036-1 [pii] AID - 10.1016/j.pharmthera.2025.108824 [doi] PST - ppublish SO - Pharmacol Ther. 2025 May;269:108824. doi: 10.1016/j.pharmthera.2025.108824. Epub 2025 Feb 19. PMID- 39952607 OWN - NLM STAT- MEDLINE DCOM- 20250301 LR - 20260507 IS - 1878-1780 (Electronic) IS - 1262-3636 (Linking) VI - 51 IP - 2 DP - 2025 Mar TI - Comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists in preventing Alzheimer's disease, vascular dementia, and other dementia types among patients with type 2 diabetes. PG - 101623 LID - S1262-3636(25)00018-7 [pii] LID - 10.1016/j.diabet.2025.101623 [doi] AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). While sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have shown neuroprotective potential, comparative data on their efficacy in dementia prevention remain scarce. METHODS: - We conducted a retrospective cohort study using the TriNetX database, including 307,103 SGLT2 inhibitor users and 348,686 GLP-1 receptor agonist users with T2DM. Propensity score matching yielded 221,883 pairs with balanced baseline characteristics. The primary outcome was overall dementia incidence, with secondary outcomes including AD, VaD, and all-cause mortality. Hazard ratios (HRs) were calculated using Cox proportional hazards models. RESULTS: SGLT2 inhibitors were associated with a significantly lower incidence of overall dementia compared to GLP-1 receptor agonists (2.7 % vs. 3.6 %; HR, 0.92; 95 % CI, 0.89-0.95). The risk of VaD (HR, 0.89; 95 % CI, 0.84-0.95) and AD (HR, 0.90; 95 % CI, 0.86-0.94) was also reduced with SGLT2 inhibitors. All-cause mortality was lower in the SGLT2 group (3.6 % vs. 4.6 %; HR, 0.95; 95 % CI, 0.92-0.98). No significant difference was observed in other dementia subtypes (HR, 0.96; 95 % CI, 0.91-1.01). CONCLUSIONS: In this large, real-world cohort, SGLT2 inhibitors demonstrated superior efficacy over GLP-1 receptor agonists in reducing the risks of overall dementia, VaD, and AD among patients with T2DM. These findings support the preferential use of SGLT2 inhibitors in mitigating dementia risk in this population, though randomized controlled trials are warranted for confirmation. CI - Copyright (c) 2025 Elsevier Masson SAS. All rights reserved. FAU - Sun, Mingyang AU - Sun M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Wang, Xiaoling AU - Wang X AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China. FAU - Lu, Zhongyuan AU - Lu Z AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China. FAU - Yang, Yitian AU - Yang Y AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Lv, Shuang AU - Lv S AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Miao, Mengrong AU - Miao M AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Chen, Wan-Ming AU - Chen WM AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan; Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan. FAU - Wu, Szu-Yuan AU - Wu SY AD - Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan; Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan; Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan; Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: szuyuanwu5399@gmail.com. FAU - Zhang, Jiaqiang AU - Zhang J AD - Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, China. Electronic address: zhangjiq@zzu.edu.cn. LA - eng PT - Comparative Study PT - Journal Article DEP - 20250212 PL - France TA - Diabetes Metab JT - Diabetes & metabolism JID - 9607599 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Male MH - Female MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Aged MH - *Alzheimer Disease/prevention & control/epidemiology MH - Retrospective Studies MH - *Dementia, Vascular/prevention & control/epidemiology MH - *Dementia/prevention & control/epidemiology MH - Middle Aged MH - Aged, 80 and over MH - Hypoglycemic Agents/therapeutic use MH - Incidence OTO - NOTNLM OT - Dementia prevention OT - GLP-1 receptor agonists OT - Neuroprotection OT - SGLT2 inhibitors OT - Type 2 Diabetes Mellitus COIS- Declaration of competing interest The authors have no potential conflicts of interest to declare. EDAT- 2025/02/15 15:10 MHDA- 2025/03/03 00:54 CRDT- 2025/02/14 19:33 PHST- 2025/01/13 00:00 [received] PHST- 2025/02/05 00:00 [revised] PHST- 2025/02/06 00:00 [accepted] PHST- 2025/03/03 00:54 [medline] PHST- 2025/02/15 15:10 [pubmed] PHST- 2025/02/14 19:33 [entrez] AID - S1262-3636(25)00018-7 [pii] AID - 10.1016/j.diabet.2025.101623 [doi] PST - ppublish SO - Diabetes Metab. 2025 Mar;51(2):101623. doi: 10.1016/j.diabet.2025.101623. Epub 2025 Feb 12. PMID- 39934020 OWN - NLM STAT- MEDLINE DCOM- 20250408 LR - 20250409 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) VI - 36 IP - 4 DP - 2025 Apr TI - Glucagon-like peptide-1 receptor agonism and end-organ protection. PG - 301-315 LID - S1043-2760(25)00002-5 [pii] LID - 10.1016/j.tem.2025.01.002 [doi] AB - Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases. One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes. We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas. CI - Copyright (c) 2025 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Daniels, Samuel AU - Daniels S AD - Early-stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. FAU - Karlsson, Cecilia AU - Karlsson C AD - Late-stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. FAU - Schrauwen, Patrick AU - Schrauwen P AD - Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Parker, Victoria E R AU - Parker VER AD - Late-stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Electronic address: victoria.parker@astrazeneca.com. LA - eng PT - Journal Article PT - Review DEP - 20250210 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Animals MH - Exenatide MH - Cardiovascular Diseases/drug therapy/prevention & control MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Hypoglycemic Agents/therapeutic use/pharmacology OTO - NOTNLM OT - cardiovascular OT - end-organ protection OT - glucagon-like peptide-1 (GLP-1) OT - kidney OT - liver OT - neurodegenerative OT - respiratory COIS- Declaration of interests S.D., C.K., and V.E.R.P. are employees of and stockholders in AstraZeneca; P.S. has received institutional research funding from AstraZeneca. V.E.R.P. holds patent WO2021140174A1 (Glucagon and GLP-1R co-agonists for the treatment of chronic kidney disease and diabetic kidney disease in type 2 diabetes). EDAT- 2025/02/12 00:20 MHDA- 2025/04/09 10:11 CRDT- 2025/02/11 22:34 PHST- 2024/09/27 00:00 [received] PHST- 2025/01/08 00:00 [revised] PHST- 2025/01/09 00:00 [accepted] PHST- 2025/04/09 10:11 [medline] PHST- 2025/02/12 00:20 [pubmed] PHST- 2025/02/11 22:34 [entrez] AID - S1043-2760(25)00002-5 [pii] AID - 10.1016/j.tem.2025.01.002 [doi] PST - ppublish SO - Trends Endocrinol Metab. 2025 Apr;36(4):301-315. doi: 10.1016/j.tem.2025.01.002. Epub 2025 Feb 10. PMID- 39932627 OWN - NLM STAT- MEDLINE DCOM- 20250507 LR - 20260826 IS - 1557-1904 (Electronic) IS - 1557-1890 (Print) IS - 1557-1890 (Linking) VI - 20 IP - 1 DP - 2025 Feb 11 TI - Reduction of Neuroinflammation as a Common Mechanism of Action of Anorexigenic and Orexigenic Peptide Analogues in the Triple Transgenic Mouse Model of Alzheimer s Disease. PG - 18 LID - 10.1007/s11481-025-10174-w [doi] LID - 18 AB - Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm(11)-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Abeta) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm(11)-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr(3)-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm(11)-PrRP31, Dpr(3)-ghrelin, and liraglutide reduced intraneuronal deposits of Abeta plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm(11)-PrRP31 and Dpr(3)-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm(11)-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders. CI - (c) 2025. The Author(s). FAU - Mengr, Anna AU - Mengr A AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. FAU - Smotkova, Zuzana AU - Smotkova Z AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. AD - First Faculty of Medicine, Charles University, Katerinska 32, 12108, Prague, Czech Republic. AD - Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic. FAU - Pacesova, Andrea AU - Pacesova A AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. FAU - Zelezna, Blanka AU - Zelezna B AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. FAU - Kunes, Jaroslav AU - Kunes J AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. AD - Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic. FAU - Maletinska, Lenka AU - Maletinska L AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, 160 00, Prague, Czech Republic. lenka.maletinska@uochb.cas.cz. LA - eng GR - 22-11155S/Grantova Agentura Ceske Republiky/ GR - 61388963/Akademie Ved Ceske Republiky/ GR - TN02000109/Technologicka Agentura Ceske Republiky/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20250211 PL - United States TA - J Neuroimmune Pharmacol JT - Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology JID - 101256586 RN - 0 (Prolactin-Releasing Hormone) RN - 0 (Ghrelin) SB - IM MH - Animals MH - *Alzheimer Disease/drug therapy/pathology/genetics/metabolism MH - Mice, Transgenic MH - Mice MH - Disease Models, Animal MH - *Prolactin-Releasing Hormone/pharmacology/therapeutic use/analogs & derivatives MH - *Neuroinflammatory Diseases/drug therapy/pathology MH - Humans MH - Mice, Inbred C57BL MH - Male MH - *Ghrelin/pharmacology/therapeutic use PMC - PMC11813825 OTO - NOTNLM OT - 3xTg-AD mice OT - Alzheimer's disease OT - Anorexigenic peptide analogues OT - Neuroinflammation OT - Orexigenic peptide analogues COIS- Declarations. Competing Interests: The authors declare no competing interests. Clinical Trial Number: Not applicable. EDAT- 2025/02/11 12:24 MHDA- 2025/02/11 12:25 PMCR- 2025/02/11 CRDT- 2025/02/11 11:20 PHST- 2024/10/13 00:00 [received] PHST- 2025/01/24 00:00 [accepted] PHST- 2025/02/11 12:25 [medline] PHST- 2025/02/11 12:24 [pubmed] PHST- 2025/02/11 11:20 [entrez] PHST- 2025/02/11 00:00 [pmc-release] AID - 10.1007/s11481-025-10174-w [pii] AID - 10174 [pii] AID - 10.1007/s11481-025-10174-w [doi] PST - epublish SO - J Neuroimmune Pharmacol. 2025 Feb 11;20(1):18. doi: 10.1007/s11481-025-10174-w. PMID- 39902055 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250206 IS - 2688-5654 (Electronic) IS - 2688-5654 (Linking) VI - 8 IP - 1 DP - 2025 TI - Semaglutide: Double-edged Sword with Risks and Benefits. PG - 1-13 LID - 10.26502/aimr.0189 [doi] AB - Type 2 Diabetes Mellitus therapy has evolved over the years to now include a new class of therapeutics, semaglutide. This article reviews the mechanism of action and formulation of semaglutide therapy, potential benefits, contraindications, adverse effects, and drug interactions. Oral and subcutaneous semaglutide therapies have shown effectiveness in improving glycemic control, weight loss, and reducing cardiovascular risks associated with diabetes mellitus. Semaglutide has also shown potential in being used as a therapeutic strategy in Alzheimer's disease due to its anti-neuroinflammatory effects and being used to treat polycystic ovary syndrome. However, semaglutide therapy is also associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy. Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy. Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics, due to anti-psychotics associated weight gain. The findings of this article emphasize the need for a cross-disciplinary approach to understand the molecular mechanisms and clinical implications of semaglutide on patients with complex medical histories and treatment regimens. The potential anesthetic risks of semaglutide therapy warrant careful consideratiion with ethical concerns. Further studies can assess if there is a need to modify pre-operative guidelines to account for patient using semaglutide and how delayed gastric emptying and constitpation will affect surgical outcomes and complications. While semaglutide therapy for diabetes mellitus has been established, there is a need for extensive research on repurposing semaglutide in neurodegenerative disease treatment. FAU - Pillarisetti, Lekha AU - Pillarisetti L AD - Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA. FAU - Agrawal, Devendra K AU - Agrawal DK AD - Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA. LA - eng GR - R01 HL144125/HL/NHLBI NIH HHS/United States GR - R01 HL147662/HL/NHLBI NIH HHS/United States GR - R25 AI179582/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20250110 PL - United States TA - Arch Intern Med Res JT - Archives of internal medicine research JID - 9918300879806676 PMC - PMC11790292 MID - NIHMS2048394 OTO - NOTNLM OT - Alzheimer's Disease OT - Diabetes mellitus OT - Diabetic retinopathy OT - Drug interactions OT - Hyperglycemia OT - Insulin resistance OT - Medullary thyroid carcinoma OT - Pancreatitis OT - Pulmonary aspiration OT - Semaglutide OT - Stroke OT - Weight loss COIS- Competing Interests: Both authors have read the manuscript and declare no conflict of interest. No writing assistance was utilized in the production of this manuscript. EDAT- 2025/02/04 06:20 MHDA- 2025/02/04 06:21 PMCR- 2025/02/03 CRDT- 2025/02/04 04:06 PHST- 2025/02/04 06:21 [medline] PHST- 2025/02/04 06:20 [pubmed] PHST- 2025/02/04 04:06 [entrez] PHST- 2025/02/03 00:00 [pmc-release] AID - 10.26502/aimr.0189 [doi] PST - ppublish SO - Arch Intern Med Res. 2025;8(1):1-13. doi: 10.26502/aimr.0189. Epub 2025 Jan 10. PMID- 39886945 OWN - NLM STAT- MEDLINE DCOM- 20250504 LR - 20260127 IS - 1791-244X (Electronic) IS - 1107-3756 (Print) IS - 1107-3756 (Linking) VI - 55 IP - 4 DP - 2025 Apr TI - Transcriptomics and proteomics characterizing the antioxidant mechanisms of semaglutide in diabetic mice with cognitive impairment. LID - 56 [pii] LID - 10.3892/ijmm.2025.5497 [doi] AB - The aim of the present study was to investigate the neuroprotective effects of semaglutide in diabetes‑associated cognitive decline (DACD), while also exploring the underlying mechanisms targeting anti‑oxidative effects. The present study evaluated the antioxidant properties of semaglutide using a DACD model of inflammation. To investigate the underlying mechanisms, omics technologies were employed. Comprehensive transcriptomic and proteomic analysis of the cells was conducted to identify the pathways responsible for the observed antioxidant effects. Semaglutide demonstrated the potential to enhance learning and memory functions while mitigating hippocampal pathological damage. RNA‑sequencing and data‑independent acquisition proteomics analyses identified 13,511 differentially expressed genes and 588 differentially expressed proteins between the control and type 2 diabetes mellitus (T2DM) groups. In addition, 1,378 genes and 2,394 proteins exhibited a differential expression between the T2DM and semaglutide (10 microg/kg) treatment groups. A combined transcriptomic and proteomic analysis unveiled 40 common pathways. Acyl‑CoA oxidase 1 (ACOX1) was observed to be activated during oxidative stress and subsequently suppressed by semaglutide. Of note, the antioxidant and anti‑apoptotic properties of semaglutide in high glucose (HG) conditions were partially reversed upon ACOX1 overexpression. Overall, the present data provided molecular evidence to elucidate the physiological connections between semaglutide and neuronal function, and contribute to clarifying the role of semaglutide in combating oxidative stress and HG‑induced cognitive impairment. FAU - Yang, Ying AU - Yang Y AD - Department of Endocrinology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China. FAU - Song, Lulu AU - Song L AD - Department of Endocrinology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China. FAU - Yu, Liping AU - Yu L AD - Department of Endocrinology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China. FAU - Zhang, Jinping AU - Zhang J AD - Department of Endocrinology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China. FAU - Zhang, Bo AU - Zhang B AD - Department of Endocrinology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China. LA - eng PT - Journal Article DEP - 20250131 PL - Greece TA - Int J Mol Med JT - International journal of molecular medicine JID - 9810955 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Antioxidants) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - *Proteomics/methods MH - *Antioxidants/pharmacology/therapeutic use MH - *Cognitive Dysfunction/drug therapy/metabolism/genetics/etiology MH - Mice MH - Male MH - *Diabetes Mellitus, Experimental/complications/genetics/metabolism/drug therapy MH - *Transcriptome/drug effects MH - Oxidative Stress/drug effects MH - Hippocampus/drug effects/metabolism/pathology MH - Gene Expression Profiling MH - Mice, Inbred C57BL MH - *Diabetes Mellitus, Type 2/complications/genetics/metabolism MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC11819768 OTO - NOTNLM OT - cognitive OT - diabetes OT - oxidative stress OT - proteomic OT - transcriptomic COIS- The authors declare that they have no competing interests. EDAT- 2025/01/31 12:23 MHDA- 2025/01/31 12:24 PMCR- 2025/01/30 CRDT- 2025/01/31 07:12 PHST- 2024/10/16 00:00 [received] PHST- 2025/01/16 00:00 [accepted] PHST- 2025/01/31 12:24 [medline] PHST- 2025/01/31 12:23 [pubmed] PHST- 2025/01/31 07:12 [entrez] PHST- 2025/01/30 00:00 [pmc-release] AID - 56 [pii] AID - ijmm-55-04-05497 [pii] AID - 10.3892/ijmm.2025.5497 [doi] PST - ppublish SO - Int J Mol Med. 2025 Apr;55(4):56. doi: 10.3892/ijmm.2025.5497. Epub 2025 Jan 31. PMID- 39876043 OWN - NLM STAT- MEDLINE DCOM- 20250519 LR - 20250522 IS - 1502-7724 (Electronic) IS - 0281-3432 (Print) IS - 0281-3432 (Linking) VI - 43 IP - 2 DP - 2025 Jun TI - Cognitive dysfunction in diabetes - the 'forgotten' diabetes complication: a narrative review. PG - 448-454 LID - 10.1080/02813432.2025.2455136 [doi] AB - BACKGROUND: In addition to peripheral neuropathy of various kinds, diabetes can also cause central neuropathy, which among other things can manifest itself as premature cognitive dysfunction, often linked to vascular dysfunction. Although the link between diabetes and cognitive dysfunction was discovered more than 100 years ago and has important clinical implications, this diabetes complication remains relatively unknown. Recent years have seen research that has clarified cerebral insulin resistance and defective insulin signaling as examples of pathogenic factors behind this cognitive impairment in diabetes. METHOD: We provide a narrative review of select and contemporary publications with relevance for the interface between diabetes/prediabetes and cognitive function. RESULTS: Recently published studies show that physical activity can reverse insulin resistance in the brain as well as cognitive impairment and pathological appetite regulation. Pharmacological interventions with, for example, nasal insulin, GLP-1 receptor agonists, SGLT-2 inhibitors, or PPAR-gamma agonists have also shown promising results. CONCLUSION: Optimization of lifestyle factors (e.g. physical activity), as well as several pharmaceutical agents already in clinical use against diabetes, have shown promising results in improving cognitive function in diabetic patients. An important task for primary health care, where most patients with type 2 diabetes are diagnosed, treated, and followed, is to increase awareness and early detection of cognitive dysfunction in these patients for optimizing risk factor control. FAU - Sjoholm, Ake AU - Sjoholm A AUID- ORCID: 0000-0002-5274-9748 AD - Department of Internal Medicine, Division of Endocrinology and Diabetology, Gavle Hospital and University of Gavle, Gavle, Sweden. FAU - Bennet, Louise AU - Bennet L AD - Department of Clinical Sciences, Lund University, Clinical Studies Sweden, Forum South, Skane University Hospital, Lund, Sweden. FAU - Nilsson, Peter M AU - Nilsson PM AUID- ORCID: 0000-0002-5652-8459 AD - Department of Clinical Sciences, Lund University, Skane University Hospital, Malmo, Sweden. LA - eng PT - Journal Article PT - Review DEP - 20250128 PL - United States TA - Scand J Prim Health Care JT - Scandinavian journal of primary health care JID - 8510679 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Humans MH - *Cognitive Dysfunction/etiology MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Insulin Resistance MH - Hypoglycemic Agents/therapeutic use MH - Exercise MH - Insulin/therapeutic use MH - Life Style MH - *Diabetes Complications PMC - PMC12090258 OTO - NOTNLM OT - Antidiabetic drugs OT - cognition OT - dementia OT - diabetes OT - epidemiology COIS- A.S. has received lecture and consultancy fees from Boehringer-Ingelheim, Novo Nordisk, Novartis, Amarin, MSD, Amgen, Lilly, Bayer, AstraZeneca, Sanofi, Abbott Diabetes Care, Grunenthal Nordic and Pfizer. P.M.N. has received corresponding fees from Boehringer-Ingelheim, Novo Nordisk, Novartis, Amgen, Bayer, AstraZeneca and Sanofi. L.B. declares no conflicts of interest. EDAT- 2025/01/29 06:20 MHDA- 2025/05/19 12:30 PMCR- 2025/01/28 CRDT- 2025/01/29 00:02 PHST- 2025/05/19 12:30 [medline] PHST- 2025/01/29 06:20 [pubmed] PHST- 2025/01/29 00:02 [entrez] PHST- 2025/01/28 00:00 [pmc-release] AID - 2455136 [pii] AID - 10.1080/02813432.2025.2455136 [doi] PST - ppublish SO - Scand J Prim Health Care. 2025 Jun;43(2):448-454. doi: 10.1080/02813432.2025.2455136. Epub 2025 Jan 28. PMID- 39873719 OWN - NLM STAT- MEDLINE DCOM- 20250717 LR - 20261010 IS - 1432-1912 (Electronic) IS - 0028-1298 (Linking) VI - 398 IP - 7 DP - 2025 Jul TI - Tirzepatide mitigates cognitive decline in zebrafish model of type 2 diabetes mellitus induced by high-fat diet. PG - 8861-8883 LID - 10.1007/s00210-025-03827-3 [doi] AB - In examining the enduring consequences of diabetes, recent research has focused on the anticipated outcomes of the condition. Specifically, cognitive impairment has been linked to diabetes mellitus dating back to the discovery of insulin. This study delves into the neuroprotective effects of TZP, i.e. tirzepatide a dual GIP and GLP-1 receptor agonist that works by mimicking these two gut hormones, against cognitive impairment associated with type 2 diabetes mellitus (T2DM). T2DM-like zebrafish model of varying age groups was created through a 6-week administration of a high-fat diet (HFD). Parameters such as body weight, body mass index, and blood glucose levels were monitored, and behavioural assessments (T-maze, novel tank diving test, and inhibitory avoidance test) were conducted at the conclusion of the protocol to assess learning and memory. Additionally, lipid profile biochemical parameters (MDA, AChEs, and GSH), molecular markers (IL-1beta, IL-10, TNF-alpha, Bcl-2, Bax, GSK-3beta, and AMPK), and histopathological examinations were performed. Treatment with the novel GLP-1 and GIP dual agonist TZP (10 nM/kg, i.p.) significantly ameliorated cognitive impairment, as evidenced by behavioural parameters, and restored antioxidant like GSH (p < 0.05) and catalase (p < 0.05) and anti-inflammatory marker levels, i.e. IL-10 (p < 0.05) compared to the HFD group. TZP also mitigated abnormal glucose (73.2 +/- 5.889) and lipid profiles (TG 0.159 +/- 0.0075 and TC 0.100 +/- 0.0020) in hyperglycaemic zebrafish. This study suggests that the positive effects of TZP on cognition and memory may stem from its neuroprotective capabilities, potentially attributed to its antioxidant, anti-inflammatory, and anti-apoptotic properties, as well as its ability to enhance AMPK levels as GLP-1 agonist has the potential to increase the level of AMPK. CI - (c) 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Misra, Sakshi AU - Misra S AD - Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, GT Road, Moga, 142001, Punjab, India. FAU - Rajput, Prabha AU - Rajput P AD - Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, GT Road, Moga, 142001, Punjab, India. prabharajput1351991@gmail.com. AD - Department of Pharmacology, School of Pharmacy & Technology Management, SVKM's NMIMS University, Shirpur Campus, Shirpur, India. prabharajput1351991@gmail.com. FAU - Kaur, Amandeep AU - Kaur A AD - Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, GT Road, Moga, 142001, Punjab, India. LA - eng PT - Journal Article DEP - 20250128 PL - Germany TA - Naunyn Schmiedebergs Arch Pharmacol JT - Naunyn-Schmiedeberg's archives of pharmacology JID - 0326264 RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 0 (Blood Glucose) RN - OYN3CCI6QE (Tirzepatide) SB - IM MH - Animals MH - Zebrafish MH - Diet, High-Fat/adverse effects MH - *Cognitive Dysfunction/drug therapy/etiology/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - Disease Models, Animal MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Hypoglycemic Agents/pharmacology/therapeutic use MH - Gastric Inhibitory Polypeptide/agonists MH - Behavior, Animal/drug effects MH - Maze Learning/drug effects MH - *Cognition/drug effects MH - Male MH - Blood Glucose/drug effects MH - Tirzepatide OTO - NOTNLM OT - Cognitive impairment OT - Diabetes mellitus OT - Neurodegeneration OT - Tirzepatide OT - Zebrafish COIS- Declarations. Competing interests: The authors declare no competing interests. EDAT- 2025/01/28 12:35 MHDA- 2025/07/17 06:27 CRDT- 2025/01/28 11:13 PHST- 2024/11/27 00:00 [received] PHST- 2025/01/17 00:00 [accepted] PHST- 2025/07/17 06:27 [medline] PHST- 2025/01/28 12:35 [pubmed] PHST- 2025/01/28 11:13 [entrez] AID - 10.1007/s00210-025-03827-3 [pii] AID - 10.1007/s00210-025-03827-3 [doi] PST - ppublish SO - Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul;398(7):8861-8883. doi: 10.1007/s00210-025-03827-3. Epub 2025 Jan 28. PMID- 39857716 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250130 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 13 IP - 1 DP - 2025 Jan 8 TI - Dysregulation of Metabolic Peptides in the Gut-Brain Axis Promotes Hyperinsulinemia, Obesity, and Neurodegeneration. LID - 10.3390/biomedicines13010132 [doi] LID - 132 AB - Metabolic peptides can influence metabolic processes and contribute to both inflammatory and/or anti-inflammatory responses. Studies have shown that there are thousands of metabolic peptides, made up of short chains of amino acids, that the human body produces. These peptides are crucial for regulating many different processes like metabolism and cell signaling, as they bind to receptors on various cells. This review will cover the role of three specific metabolic peptides and their roles in hyperinsulinemia, diabetes, inflammation, and neurodegeneration, as well as their roles in type 3 diabetes and dementia. The metabolic peptides glucagon-like peptide 1 (GLP-1), gastric inhibitor polypeptide (GIP), and pancreatic peptide (PP) will be discussed, as dysregulation within their processes can lead to the development of various inflammatory and neurodegenerative diseases. Research has been able to closely investigate the connections between these metabolic peptides and their links to the gut-brain axis, highlighting changes made in the gut that can lead to dysfunction in processes in the brain, as well as changes made in the brain that can lead to dysregulation in the gut. The role of metabolic peptides in the development and potentially reversal of diseases such as obesity, hyperinsulinemia, and type 2 diabetes will also be discussed. Furthermore, we review the potential links between these conditions and neuroinflammation and the development of neurodegenerative diseases like dementia, specifically Parkinson's disease and Alzheimer's disease. FAU - Green, Camille AU - Green C AUID- ORCID: 0009-0007-1349-2031 AD - Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. FAU - Zaman, Vandana AU - Zaman V AD - Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. AD - Ralph H. Johnson Veterans Administration Medical Center, 109 Bee Street, Charleston, SC 29401, USA. FAU - Blumenstock, Kayce AU - Blumenstock K AD - Ralph H. Johnson Veterans Administration Medical Center, 109 Bee Street, Charleston, SC 29401, USA. AD - Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. FAU - Banik, Narendra L AU - Banik NL AD - Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. AD - Ralph H. Johnson Veterans Administration Medical Center, 109 Bee Street, Charleston, SC 29401, USA. AD - Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. FAU - Haque, Azizul AU - Haque A AUID- ORCID: 0000-0002-6386-9390 AD - Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. AD - Ralph H. Johnson Veterans Administration Medical Center, 109 Bee Street, Charleston, SC 29401, USA. AD - Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. LA - eng GR - R21 NS118393/NS/NINDS NIH HHS/United States GR - I01 BX001262/BX/BLRD VA/United States GR - BX001262/Veterans Administration/ GR - 1R21NS118393-01/NH/NIH HHS/United States GR - BX006101/Veterans Administration/ GR - I01 BX006101/BX/BLRD VA/United States GR - IK6 BX005964/BX/BLRD VA/United States PT - Journal Article PT - Review DEP - 20250108 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC11763097 OTO - NOTNLM OT - diabetes OT - gut-brain axis OT - hormonal peptides OT - hyperinsulinemia OT - inflammation OT - neurodegeneration COIS- The authors have no financial conflicts of interest. EDAT- 2025/01/25 13:54 MHDA- 2025/01/25 13:55 PMCR- 2025/01/08 CRDT- 2025/01/25 01:07 PHST- 2024/12/08 00:00 [received] PHST- 2024/12/31 00:00 [revised] PHST- 2025/01/05 00:00 [accepted] PHST- 2025/01/25 13:55 [medline] PHST- 2025/01/25 13:54 [pubmed] PHST- 2025/01/25 01:07 [entrez] PHST- 2025/01/08 00:00 [pmc-release] AID - biomedicines13010132 [pii] AID - biomedicines-13-00132 [pii] AID - 10.3390/biomedicines13010132 [doi] PST - epublish SO - Biomedicines. 2025 Jan 8;13(1):132. doi: 10.3390/biomedicines13010132. PMID- 39833406 OWN - NLM STAT- MEDLINE DCOM- 20250502 LR - 20261010 IS - 1546-170X (Electronic) IS - 1078-8956 (Linking) VI - 31 IP - 3 DP - 2025 Mar TI - Mapping the effectiveness and risks of GLP-1 receptor agonists. PG - 951-962 LID - 10.1038/s41591-024-03412-w [doi] AB - Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas. CI - (c) 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Xie, Yan AU - Xie Y AUID- ORCID: 0000-0002-2457-9382 AD - Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, USA. AD - Veterans Research and Education Foundation of St. Louis, St. Louis, MO, USA. AD - Division of Pharmacoepidemiology, Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, USA. AD - Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. FAU - Choi, Taeyoung AU - Choi T AD - Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, USA. AD - Veterans Research and Education Foundation of St. Louis, St. Louis, MO, USA. FAU - Al-Aly, Ziyad AU - Al-Aly Z AUID- ORCID: 0000-0002-2600-0434 AD - Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, USA. zalaly@gmail.com. AD - Veterans Research and Education Foundation of St. Louis, St. Louis, MO, USA. zalaly@gmail.com. AD - Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. zalaly@gmail.com. AD - Nephrology Section, Medicine Service, VA St. Louis Health Care System, St. Louis, MO, USA. zalaly@gmail.com. AD - Institute for Public Health, Washington University in St. Louis, St. Louis, MO, USA. zalaly@gmail.com. LA - eng PT - Journal Article DEP - 20250120 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sulfonylurea Compounds) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM EIN - Nat Med. 2025 Mar;31(3):1038. doi: 10.1038/s41591-025-03542-9. PMID: 39891006 MH - Humans MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Male MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Female MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - Middle Aged MH - Sulfonylurea Compounds/therapeutic use/adverse effects MH - Aged MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - United States COIS- Competing interests: Y.X. and Z.A.A. are uncompensated consultants for Pfizer. No other potential competing interests relevant to this article are reported. EDAT- 2025/01/21 09:02 MHDA- 2025/03/20 06:24 CRDT- 2025/01/20 23:24 PHST- 2024/06/14 00:00 [received] PHST- 2024/11/12 00:00 [accepted] PHST- 2025/03/20 06:24 [medline] PHST- 2025/01/21 09:02 [pubmed] PHST- 2025/01/20 23:24 [entrez] AID - 10.1038/s41591-024-03412-w [pii] AID - 10.1038/s41591-024-03412-w [doi] PST - ppublish SO - Nat Med. 2025 Mar;31(3):951-962. doi: 10.1038/s41591-024-03412-w. Epub 2025 Jan 20. PMID- 39820580 OWN - NLM STAT- MEDLINE DCOM- 20250327 LR - 20260127 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 68 IP - 4 DP - 2025 Apr TI - Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial. PG - 739-751 LID - 10.1007/s00125-024-06348-5 [doi] AB - AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA(1c) 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA(1c) from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.0 mmol/l) or severe (level 3; associated with severe cognitive impairment requiring external assistance for recovery) hypoglycaemia (baseline to week 57). RESULTS: Overall, 683 participants were randomised using a Randomisation and Trial Supply Management system to IcoSema (n=342) or semaglutide 1.0 mg (n=341). Mean +/- SD baseline characteristics were as follows: HbA(1c) 64.0+/-8.2 mmol/mol (8.0+/-0.7%); diabetes duration 12.6+/-6.9 years; and BMI 31.1+/-4.7 kg/m(2). From baseline to week 52, mean change in HbA(1c) was -14.7 mmol/mol (-1.35%-points) in the IcoSema group and -9.88 mmol/mol (-0.90%-points) in the semaglutide group; the estimated treatment difference (ETD) was -4.85 (95% CI -6.13, -3.57) mmol/mol (-0.44 [95% CI -0.56, -0.33]%-points), confirming superiority of IcoSema to semaglutide (p<0.0001). The estimated mean change in fasting plasma glucose from baseline to week 52 was statistically significantly reduced with IcoSema vs semaglutide (-2.48 mmol/l vs -1.43 mmol/l, respectively; ETD -1.05 [95% CI -1.36, -0.75] mmol; p<0.0001). Mean change in body weight from baseline to week 52 was statistically significantly different between groups: +0.84 kg for IcoSema vs -3.70 kg for semaglutide (ETD 4.54 kg [95% CI 3.84, 5.23]; p<0.0001). There was no statistically significant difference in the rate of combined clinically significant or severe hypoglycaemia between IcoSema and semaglutide (0.042 vs 0.036 episodes per person-year of exposure; estimated rate ratio 1.20 [95% CI 0.53, 2.69]; p=0.66). The proportion of participants experiencing gastrointestinal adverse events was similar between treatment groups (IcoSema 31.4%; semaglutide 34.4%). CONCLUSIONS/INTERPRETATION: In people living with type 2 diabetes inadequately managed with GLP-1 RA therapy, with or without additional oral glucose-lowering medications, switching to once-weekly IcoSema in comparison with once-weekly semaglutide 1.0 mg demonstrated superiority in HbA(1c) reduction, similar rates of clinically significant or severe hypoglycaemia, and similar frequency of gastrointestinal adverse events. However, weight change from baseline to week 52 was statistically significantly in favour of semaglutide 1.0 mg. TRIAL REGISTRATION: ClinicalTrials.gov NCT05259033 FUNDING: This trial was funded by Novo Nordisk. CI - (c) 2025. The Author(s). FAU - Lingvay, Ildiko AU - Lingvay I AUID- ORCID: 0000-0001-7006-7401 AD - Endocrinology Division, Department of Internal Medicine and Peter O'Donnell Jr School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. Ildiko.Lingvay@UTSouthwestern.edu. FAU - Benamar, Malik AU - Benamar M AUID- ORCID: 0009-0001-1820-1527 AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Chen, Liming AU - Chen L AUID- ORCID: 0000-0002-5682-2340 AD - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China. FAU - Fu, Ariel AU - Fu A AUID- ORCID: 0009-0007-0220-5877 AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Jodar, Esteban AU - Jodar E AUID- ORCID: 0000-0002-1234-8560 AD - Universitary Hospital QuironSalud Madrid, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain. FAU - Nishida, Tomoyuki AU - Nishida T AUID- ORCID: 0009-0004-5812-7167 AD - Novo Nordisk Pharma Ltd, Tokyo, Japan. FAU - Riveline, Jean-Pierre AU - Riveline JP AUID- ORCID: 0000-0001-7991-0741 AD - Department of Endocrinology and Diabetology, Lariboisiere Hospital, APHP, Paris-Cite University Paris, Paris, France. AD - Institut Necker Enfants Malades, Inserm U1151, CNRS UMR 8253, IMMEDIAB Laboratory, Paris, France. FAU - Yabe, Daisuke AU - Yabe D AUID- ORCID: 0000-0002-5334-7687 AD - Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Zueger, Thomas AU - Zueger T AUID- ORCID: 0000-0001-6190-7405 AD - Department of Endocrinology, Diabetes and Metabolic Diseases, Kantonsspital Olten, Olten, Switzerland. AD - Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. FAU - Rea, Rosangela AU - Rea R AUID- ORCID: 0000-0002-2102-0495 AD - Internal Medicine Department, Endocrine Division (SEMPR), Universidade Federal do Parana, Curitiba, Brazil. LA - eng SI - ClinicalTrials.gov/NCT05259033 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20250117 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin) RN - 2ZM8CX04RZ (Insulin Glargine) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM EIN - Diabetologia. 2025 Jul;68(7):1586-1588. doi: 10.1007/s00125-025-06435-1. PMID: 40323333 MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/blood MH - Female MH - *Glucagon-Like Peptides/administration & dosage/therapeutic use MH - Male MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use/administration & dosage MH - Aged MH - Blood Glucose/drug effects/metabolism MH - Glycated Hemoglobin/metabolism MH - Adult MH - Drug Administration Schedule MH - Treatment Outcome MH - Drug Therapy, Combination MH - Insulin Glargine/therapeutic use/administration & dosage MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC11950020 OTO - NOTNLM OT - Fixed-ratio combination OT - GLP-1 RA OT - Glycaemic control OT - Hypoglycaemia OT - IcoSema OT - Insulin icodec OT - Once-weekly OT - Safety OT - Semaglutide OT - Type 2 diabetes COIS- Acknowledgements: The authors thank all trial participants and staff. Medical writing support was provided by G. Rogers and J. Geatrell of Oxford PharmaGenesis, Oxford, UK, funded by Novo Nordisk A/S. Data availability: Individual participant data will be shared in data sets in a de-identified/anonymised format. Shared data will include data sets from Novo Nordisk-sponsored clinical research completed after 2001 for product indications approved in both the EU and the USA. The trial protocol and redacted clinical trial report will be made available according to Novo Nordisk data sharing commitments. These data will be available after research completion and approval of product and product use in both the EU and the USA (no end date). Data will be shared with bona fide researchers submitting a research proposal requesting access to data, for use as approved by the Independent Review Board (IRB) according to the IRB charter (see novonordisk-trials.com). These data can be accessed via an access request proposal form; the access criteria can be found at novonordisk-trials.com. The data will be made available on a specialised SAS data platform. The results tables will be made available according to US and EU law, via Clinicaltrials.gov and EU Clinical Trials Register. Clinical trials synopsis will be uploaded to novonordisk-trials.com for clinical projects that have been discontinued. Funding: This trial was funded by Novo Nordisk A/S. Representatives of Novo Nordisk A/S were involved in the design and conduct of the trial; collection, management, analysis and interpretation of the data; and preparation, review and approval of the manuscript. Investigators were responsible for trial-related medical decisions and data collection; Novo Nordisk undertook site monitoring, data collation and analysis. Medical writers (G. Rogers and J. Geatrell from Oxford PharmaGenesis, Oxford, UK), funded by Novo Nordisk, assisted with drafting the manuscript under direction of the authors. Novo Nordisk did not have the right to veto publication or to control the decision regarding the journal to which the manuscript was submitted; these decisions were made by the authors. Authors' relationships and activities: IL has received research funding (paid to the institution they are affiliated with) from Boehringer Ingelheim, Merck, Mylan, Novo Nordisk, Pfizer and Sanofi, and has received advisory/consulting fees and/or other support from AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GI Dynamics, Intarcia Therapeutics, Intercept Pharmaceuticals, Johnson & Johnson, MannKind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, Target Pharma, Valeritas and Zealand Pharma. MB and AF are employees of Novo Nordisk A/S. LC has received research funding (paid to the institution they are affiliated with) from AstraZeneca and Eli Lilly. EJ has received research funding (paid to the institution they are affiliated with) from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Faes Farma, MSD, Novartis and Novo Nordisk, and has received advisory/consulting fees and/or other support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, Technofarma, UCB and Viatris. TN is an employee of Novo Nordisk Pharma Ltd. J-PR is an advisory panel member for Abbott, Air Liquide International, Alphadiab, AstraZeneca, Dexcom, Eli Lilly, Medtronic, MSD, Novo Nordisk and Sanofi, and has received research funding from and provided research support to Abbott, Air Liquide International, Medtronic, Novo Nordisk and Sanofi. DY has received consulting or speaker fees from Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, MSD K.K., Nippon Boehringer Ingelheim, Novo Nordisk Pharma Ltd and Sumitomo Pharma, and clinically commissioned/received joint research grants from Arklay, Nippon Boehringer Ingelheim, Novo Nordisk Pharma Ltd and Taisho Pharmaceutical. TZ has received research funding (paid to the institution they are affiliated with) from Akero Therapeutics, Novartis and Novo Nordisk, and has received advisory/consulting fees and/or other support (paid to the institution they are affiliated with) from AstraZeneca, Eli Lilly, Novo Nordisk, and Sanofi. RR is an advisory panel member for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Novo Nordisk, has participated in speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD and Novo Nordisk, and has received research grants from Boehringer Ingelheim, Eli Lilly and Novo Nordisk. Contribution statement: All authors had full access to the data associated with this trial and contributed to interpreting the data and drafting the manuscript. The authors jointly decided to submit the manuscript, approved it before submission and take full responsibility for its content. IL is the guarantor of this work. EDAT- 2025/01/17 18:22 MHDA- 2025/03/27 18:26 PMCR- 2025/01/17 CRDT- 2025/01/17 13:22 PHST- 2024/08/16 00:00 [received] PHST- 2024/11/08 00:00 [accepted] PHST- 2025/03/27 18:26 [medline] PHST- 2025/01/17 18:22 [pubmed] PHST- 2025/01/17 13:22 [entrez] PHST- 2025/01/17 00:00 [pmc-release] AID - 10.1007/s00125-024-06348-5 [pii] AID - 6348 [pii] AID - 10.1007/s00125-024-06348-5 [doi] PST - ppublish SO - Diabetologia. 2025 Apr;68(4):739-751. doi: 10.1007/s00125-024-06348-5. Epub 2025 Jan 17. PMID- 39780249 OWN - NLM STAT- MEDLINE DCOM- 20250109 LR - 20260514 IS - 1758-9193 (Electronic) VI - 17 IP - 1 DP - 2025 Jan 8 TI - evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease. PG - 14 LID - 10.1186/s13195-024-01666-7 [doi] LID - 14 AB - BACKGROUND: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD. METHODS: evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation. RESULTS: Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials' main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026. CONCLUSION: evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021. CI - (c) 2024. The Author(s). FAU - Cummings, Jeffrey L AU - Cummings JL AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, USA. jcummings@cnsinnovations.com. AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, NV, USA. jcummings@cnsinnovations.com. FAU - Atri, Alireza AU - Atri A AD - Banner Sun Health Research Institute, Sun City, AZ, USA. AD - Banner Alzheimer's Institute, Phoenix, AZ, USA. AD - Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Feldman, Howard H AU - Feldman HH AD - Department of Neurosciences, University of California San Diego, La Jolla, San Diego, CA, USA. FAU - Hansson, Oskar AU - Hansson O AD - Clinical Memory Research Unit, Department of Clinical Sciences Malmo, Lund University, Lund, Sweden. AD - Memory Clinic, Skane University Hospital, Malmo, Sweden. FAU - Sano, Mary AU - Sano M AD - Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Knop, Filip K AU - Knop FK AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. AD - Steno Diabetes Center Copenhagen, Herlev, Denmark. AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Johannsen, Peter AU - Johannsen P AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Leon, Teresa AU - Leon T AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Scheltens, Philip AU - Scheltens P AD - Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. AD - EQT Life Sciences, Amsterdam, The Netherlands. LA - eng SI - ClinicalTrials.gov/NCT04777396 SI - ClinicalTrials.gov/NCT04777409 GR - P30 AG072980/AG/NIA NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20250108 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Glucagon-Like Peptides/therapeutic use/adverse effects MH - *Alzheimer Disease/drug therapy MH - Double-Blind Method MH - Aged MH - Female MH - Male MH - Middle Aged MH - Aged, 80 and over MH - Treatment Outcome MH - Semaglutide PMC - PMC11708093 OTO - NOTNLM OT - Alzheimer's disease OT - Clinical trial OT - Design OT - Neuroinflammation OT - Semaglutide OT - evoke OT - evoke+ COIS- Declarations. Ethics approval and consent to participate: The evoke and evoke+ trials are being conducted in accordance with the consensus ethical principles derived from international guidelines including the Declaration of Helsinki and applicable ICH Good Clinical Practice (GCP) Guideline, as well as local laws and regulations. The trials were approved by local ethics committees and institutional review boards (listed in Additional file 1 in Supplementary Information). All participants and study partners provided written informed consent to participate in the trials. Consent for publication: Not applicable. Competing interests: JC: provided consultation to Acadia, Actinogen, Acumen, Alpha Cognition, Aprinoia, AriBio, Artery, Biogen, BioVie, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GemVax, Genentech, GAP Innovations, Janssen, Jocasta, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, PRODEO, Prothena, reMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren Therapeutics. AA: has received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer's Association, Axovant, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Novo Nordisk, ONO, Prothena, Qynapse, Roche/Genentech, Sunovion, Suven, and Synexus. AA receives book royalties from Oxford University Press for a medical book on dementia. AA receives institutional research grant/contract funding from National Institute on Aging/National Institutes of Health (1P30AG072980), NIA/NIH U24AG057437, AZ DHS (CTR040636), Foundation for NIH (FNIH), Washington University in St. Louis, and Gates Ventures. AA's institution receives/received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves/served as contracted site principal investigator. AA has received/receives honoraria from Novo Nordisk for consulting activities including for service on the evoke/evoke+ program Steering Committee. HHF: reports grants to the University of California San Diego (UCSD) from LuMind Foundation, Annovis (QR Pharma), AC Immune, Biohaven Pharmaceuticals, and Vivoryon (Probiodrug). He also reports service agreements through UCSD for consulting with Arrowhead Pharmaceuticals, Axon Neuroscience, LuMind Foundation, and Novo Nordisk. He reports serving on a data monitoring committee and data and safety monitoring board for Janssen Research & Development LLC and Roche/Genentech Pharmaceuticals with service agreements through UCSD, as well as serving on the Scientific Advisory Board for the Tau Consortium. He reports travel expenses through UCSD from Novo Nordisk and Royal Society of Canada. He receives personal funds for Detecting and Treating Dementia Serial Number 12/3- 2691 U.S. Patent No. PCT/US2007/07008, Washington DC, U.S. Patent and Trademark Office. He also received philanthropic support for Alzheimer's therapeutic research through the Epstein Family Alzheimer's Research Collaboration. OH: acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eisai, Eli Lilly, Fujirebio, GE Healthcare, Pfizer, and Roche; and received consultancy/speaker fees from AC Immune, ALZpath, Amylyx, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche, and Siemens. FKK: has served on scientific advisory panels and/or been part of speaker's bureaus for, served as a consultant to, and/or received research support from 89bio, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; is a co-founder of and minority shareholder in Antag Therapeutics, and owns shares in Eli Lilly, Novo Nordisk, and Zealand Pharma; is an employee of Novo Nordisk A/S. MS: has served as a scientific advisory board member for Medivation and as a consultant for Bayer Schering Pharma, Bristol Myers Squibb, Elan, Genentech, Janssen, Medivation, Medpace, Otsuka, Pfizer, Takeda, and United BioSource. PJ: is an employee of Novo Nordisk A/S. TL: is an employee of Novo Nordisk A/S. PS: is a full-time employee of EQT Life Sciences (formerly LSP). He reports having received consultancy fees (paid to Vrije Universiteit Amsterdam) from AC Immune, Alzheon, BrainStorm Cell, FUJIFILM/Toyama, Green Valley, and Novo Nordisk. No remuneration was received by any author for the development of this manuscript. EDAT- 2025/01/09 06:21 MHDA- 2025/01/09 06:22 PMCR- 2025/01/08 CRDT- 2025/01/09 00:02 PHST- 2024/09/06 00:00 [received] PHST- 2024/12/23 00:00 [accepted] PHST- 2025/01/09 06:22 [medline] PHST- 2025/01/09 06:21 [pubmed] PHST- 2025/01/09 00:02 [entrez] PHST- 2025/01/08 00:00 [pmc-release] AID - 10.1186/s13195-024-01666-7 [pii] AID - 1666 [pii] AID - 10.1186/s13195-024-01666-7 [doi] PST - epublish SO - Alzheimers Res Ther. 2025 Jan 8;17(1):14. doi: 10.1186/s13195-024-01666-7. PMID- 39773090 OWN - NLM STAT- MEDLINE DCOM- 20250430 LR - 20260710 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 103 IP - 2 DP - 2025 Jan TI - Association of dipeptidyl peptidase-4 with Alzheimer's disease: A new therapeutic prospect. PG - 319-332 LID - 10.1177/13872877241304673 [doi] AB - Alzheimer's disease (AD) is the most common disease associated with cognitive dysfunction, which is closely associated with type 2 diabetes mellitus (T2DM) in clinical manifestations, pathological changes and prevention. Inhibition of dipeptidyl peptidase 4 (DPP-4) can lower blood glucose levels by stimulating insulin secretion. Besides, it can affect cognitive function through the neuroprotective effect of DPP-4 substrates, such as glucose-dependent insulin peptide and glucagon-like peptide-1, the proteolytic effect on amyloid-beta and the protective effect on neuronal structure. This review discusses the relationship between cognitive impairment in T2DM and in AD, summarizes the effect of DPP-4 inhibitor (DPP-4i) on improving cognitive impairment in these two diseases based on the current studies. Given the lack of clinical randomized trials that evaluate the effect of DPP-4i on AD, this review is expected to provide preclinical evidence for DPP-4i as a potential therapy for the treatment and prevention of AD. FAU - Wang, Xinyi AU - Wang X AUID- ORCID: 0009-0003-5429-9853 AD - Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China. AD - State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China. FAU - Chen, Li AU - Chen L AUID- ORCID: 0009-0008-3254-456X AD - Department of Pathology, Northeast Yunnan Regional Central Hospital, Zhaotong, China. FAU - Li, Weijian AU - Li W AD - Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China. FAU - He, Zhi AU - He Z AUID- ORCID: 0000-0001-7567-8287 AD - Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China. FAU - Jiang, Haiying AU - Jiang H AUID- ORCID: 0000-0001-6687-6900 AD - Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20250108 PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/enzymology/metabolism MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology MH - *Dipeptidyl Peptidase 4/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Animals OTO - NOTNLM OT - Alzheimer's disease OT - aging OT - dipeptidyl peptidase-4 OT - neurodegenerative disease OT - type 2 diabetes mellitus COIS- Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2025/01/08 18:22 MHDA- 2025/02/05 06:20 CRDT- 2025/01/08 14:58 PHST- 2025/02/05 06:20 [medline] PHST- 2025/01/08 18:22 [pubmed] PHST- 2025/01/08 14:58 [entrez] AID - 10.1177/13872877241304673 [doi] PST - ppublish SO - J Alzheimers Dis. 2025 Jan;103(2):319-332. doi: 10.1177/13872877241304673. Epub 2025 Jan 8. PMID- 39770025 OWN - NLM STAT- MEDLINE DCOM- 20250108 LR - 20250113 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 29 IP - 24 DP - 2024 Dec 16 TI - Pathology and Treatments of Alzheimer's Disease Based on Considering Changes in Brain Energy Metabolism Due to Type 2 Diabetes. LID - 10.3390/molecules29245936 [doi] LID - 5936 AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD. FAU - Yanai, Hidekatsu AU - Yanai H AUID- ORCID: 0000-0002-4199-3665 AD - Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan. FAU - Adachi, Hiroki AU - Adachi H AD - Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan. FAU - Hakoshima, Mariko AU - Hakoshima M AD - Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan. FAU - Katsuyama, Hisayuki AU - Katsuyama H AUID- ORCID: 0000-0003-2871-8340 AD - Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan. LA - eng PT - Journal Article PT - Review DEP - 20241216 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (tau Proteins) SB - IM MH - *Alzheimer Disease/metabolism/pathology/etiology MH - *Diabetes Mellitus, Type 2/metabolism/complications MH - Humans MH - *Energy Metabolism MH - *Brain/metabolism/pathology MH - Animals MH - tau Proteins/metabolism MH - Oxidative Stress PMC - PMC11677283 OTO - NOTNLM OT - Alzheimer's disease OT - amyloid beta OT - glucagon-like peptide 1 receptor agonists OT - insulin resistance OT - oxidative stress OT - type 2 diabetes COIS- The authors declare no conflicts of interest in relation to the present review paper. EDAT- 2025/01/08 06:20 MHDA- 2025/01/08 06:21 PMCR- 2024/12/16 CRDT- 2025/01/08 01:29 PHST- 2024/10/22 00:00 [received] PHST- 2024/11/22 00:00 [revised] PHST- 2024/12/12 00:00 [accepted] PHST- 2025/01/08 06:21 [medline] PHST- 2025/01/08 06:20 [pubmed] PHST- 2025/01/08 01:29 [entrez] PHST- 2024/12/16 00:00 [pmc-release] AID - molecules29245936 [pii] AID - molecules-29-05936 [pii] AID - 10.3390/molecules29245936 [doi] PST - epublish SO - Molecules. 2024 Dec 16;29(24):5936. doi: 10.3390/molecules29245936. PMID- 39764175 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250107 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 74 DP - 2024 Aug TI - 12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study. PG - 102726 LID - 10.1016/j.eclinm.2024.102726 [doi] LID - 102726 AB - BACKGROUND: While semaglutide, approved for type-2 diabetes mellitus (T2DM), is being investigated as a treatment for brain disorders, concerns over adverse neuropsychiatric events have emerged. More data are therefore needed to assess the effects of semaglutide on brain health. This study provides robust estimates of the risk of neurological and psychiatric outcomes following semaglutide use compared to three other antidiabetic medications. METHODS: This retrospective cohort study used electronic health records from TriNetX US Collaborative Network, covering >100 million patients in the USA. Due to the exploratory nature of this study, we did not use a pre-registered protocol or statistical analysis plan. Three cohorts with T2DM prescribed semaglutide between 1st December 2017 and 31st May 2021 were propensity-score matched (1:1 using a greedy nearest-neighbour algorithm with calliper distance of 0.1) with cohorts receiving sitagliptin, empagliflozin, and glipizide. Using Cox regression analysis, we compared the risks of 22 neurological and psychiatric outcomes within one year since the index prescription: encephalitis, parkinsonism, cognitive deficit, dementia, epilepsy/seizure, migraine, insomnia, nerve disorder, myoneural junction/muscle disease, intracranial haemorrhage, ischaemic stroke, alcohol misuse, opioid misuse, cannabis misuse, stimulants misuse, nicotine misuse, psychosis, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, and suicidality. Negative control outcomes (NCOs) were used to assess unmeasured confounding. FINDINGS: Each matched cohort included 23,386 (semaglutide vs sitagliptin), 22,584 (vs empagliflozin), and 19,206 (vs glipizide) patients. Semaglutide was not associated with an increased risk of neurological and psychiatric outcomes. Instead, after multiple-testing correction, semaglutide was associated with reduced risk for several such outcomes, notably cognitive deficit compared to sitagliptin (HR 0.72, 95% CI 0.64-0.80) and glipizide (HR 0.72, 95% CI 0.63-0.81), dementia compared to sitagliptin (HR 0.52, 95% CI 0.40-0.68), and nicotine misuse across most comparisons (HR 0.72, 95% CI 0.61-0.85 against glipizide; HR 0.77, 95% CI 0.65-0.90 against empagliflozin; HR 0.82, 95% CI 0.70-0.95 against sitagliptin, though the latter was no longer statistically significant after adjustment for multiple comparisons). Empagliflozin showed fewest differences from semaglutide. No differences in NCOs were observed between cohorts. INTERPRETATION: Semaglutide is not associated with higher 12-month risk of adverse neuropsychiatric outcomes compared to other antidiabetic medications. Potential beneficial associations with some outcomes, especially cognitive deficit and nicotine misuse, should stimulate validation in clinical trials. FUNDING: National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre, Medical Research Council. CI - (c) 2024 The Author(s). FAU - De Giorgi, Riccardo AU - De Giorgi R AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Oxford Health NHS Foundation Trust, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. FAU - Koychev, Ivan AU - Koychev I AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Department of Psychological Medicine, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, United Kingdom. FAU - Adler, Amanda I AU - Adler AI AD - Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, United Kingdom. FAU - Cowen, Philip J AU - Cowen PJ AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Oxford Health NHS Foundation Trust, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. FAU - Harmer, Catherine J AU - Harmer CJ AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Oxford Health NHS Foundation Trust, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. FAU - Harrison, Paul J AU - Harrison PJ AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Oxford Health NHS Foundation Trust, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. FAU - Taquet, Maxime AU - Taquet M AD - Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. AD - Oxford Health NHS Foundation Trust, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom. LA - eng PT - Journal Article DEP - 20240710 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC11701436 OTO - NOTNLM OT - Cognition OT - Neurological outcomes OT - Pharmacoepidemiology OT - Psychiatric outcomes OT - Semaglutide COIS- RDG, IK, CJH, PJC, PJH are supported by the NIHR Oxford Health Biomedical Research Centre (NIHR203316). MT is an NIHR clinical lecturer. AIA is supported by the NIHR Oxford Biomedical Research Centre. IK declares additional funding for this work through the Medical Research Council (MR/T033371/1), and NIHR Development and Skills Enhancement Award (NIHR301616). IK is in receipt of grant funding from Novo Nordisk for an investigator-initiated study of semaglutide in Alzheimer's disease; he is paid a medical advisor for digital healthcare companies in the dementia space (Five Lives SAS, Cognetivity Ltd, Cognes Ltd). PJC declares additional funding for this work through the Medical Research Council (MR/K022202). CJH has received consultancy fees from P1vital, Lundbeck, Servier, UCB, Zogenix, J&J, and Syndesi outside of the current work. The other authors declare that they have no conflict of interest. EDAT- 2025/01/07 10:54 MHDA- 2025/01/07 10:55 PMCR- 2024/07/10 CRDT- 2025/01/07 04:39 PHST- 2024/03/27 00:00 [received] PHST- 2024/06/05 00:00 [revised] PHST- 2024/06/24 00:00 [accepted] PHST- 2025/01/07 10:55 [medline] PHST- 2025/01/07 10:54 [pubmed] PHST- 2025/01/07 04:39 [entrez] PHST- 2024/07/10 00:00 [pmc-release] AID - S2589-5370(24)00305-5 [pii] AID - 102726 [pii] AID - 10.1016/j.eclinm.2024.102726 [doi] PST - epublish SO - EClinicalMedicine. 2024 Jul 10;74:102726. doi: 10.1016/j.eclinm.2024.102726. eCollection 2024 Aug. PMID- 39755491 OWN - NLM STAT- MEDLINE DCOM- 20251007 LR - 20251008 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) VI - 36 IP - 10 DP - 2025 Oct TI - The growing range of complications of diabetes mellitus. PG - 943-954 LID - S1043-2760(24)00328-X [pii] LID - 10.1016/j.tem.2024.12.006 [doi] AB - With the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity, several previously under-recognised complications associated with T2DM are becoming more evident. The most common of these emerging complications are metabolic dysfunction-associated steatotic liver disease (MASLD), cancer, dementia, sarcopenia, and frailty, as well as other conditions involving the lung, heart, and intestinal tract. Likely causative factors are chronic inflammation and insulin resistance, whereas blood glucose levels appear to play a lesser role. We discuss these complications and the new approaches being developed to prevent and manage them, especially incretin-based therapies. We argue that these new interventions may work in a complementary way to other proven cardiorenal protective therapies to reduce the burden of T2DM complications. CI - Copyright (c) 2024 Elsevier Ltd. All rights reserved. FAU - Hamblin, Peter S AU - Hamblin PS AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC, Australia; Department of Endocrinology and Diabetes, Western Health, St Albans, VIC, Australia. Electronic address: Peter.Hamblin@monash.edu. FAU - Russell, Anthony W AU - Russell AW AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC, Australia. FAU - Talic, Stella AU - Talic S AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. FAU - Zoungas, Sophia AU - Zoungas S AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. LA - eng PT - Journal Article PT - Review DEP - 20250103 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/metabolism MH - Insulin Resistance/physiology MH - *Diabetes Complications/metabolism MH - Neoplasms/metabolism OTO - NOTNLM OT - cancer OT - dementia OT - diabetes OT - frailty OT - liver OT - sarcopenia COIS- Declaration of interests A.W.R. reports speaker honoraria from Boehringer-Ingelheim and Astra Zeneca paid to a University research account. S.T. reports grant support from the Medical Research Future Fund (MRFF) Cardiovascular Health Mission paid to Monash University, and travel and meeting support from Monash University Cardiovascular Research and Education in Therapeutics (CCRET), all independently of this work. S.Z. has received payment to Monash University from Eli Lilly Australia, Boehringer-Ingelheim, CSL Sequiris, AstraZeneca, Novo Nordisk, Sanofi, and Moderna for consultancy work and travel, and accommodation support from Eli Lilly and Novo Nordisk as well as funding from the National Health and Medical Research Council (NHMRC), the Australian Government Department of Health and Aged Care, the Juvenile Diabetes Research Foundation (JDRF) Centre of Excellence, and the MRFF, all independently of this work. P.S.H. declares no competing interests. EDAT- 2025/01/05 06:12 MHDA- 2025/10/08 00:29 CRDT- 2025/01/04 21:55 PHST- 2024/09/29 00:00 [received] PHST- 2024/11/30 00:00 [revised] PHST- 2024/12/11 00:00 [accepted] PHST- 2025/10/08 00:29 [medline] PHST- 2025/01/05 06:12 [pubmed] PHST- 2025/01/04 21:55 [entrez] AID - S1043-2760(24)00328-X [pii] AID - 10.1016/j.tem.2024.12.006 [doi] PST - ppublish SO - Trends Endocrinol Metab. 2025 Oct;36(10):943-954. doi: 10.1016/j.tem.2024.12.006. Epub 2025 Jan 3. PMID- 39754628 OWN - NLM STAT- MEDLINE DCOM- 20250408 LR - 20260813 IS - 1995-8218 (Electronic) IS - 1673-7067 (Print) IS - 1995-8218 (Linking) VI - 41 IP - 4 DP - 2025 Apr TI - Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors. PG - 676-690 LID - 10.1007/s12264-024-01342-8 [doi] AB - Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain. CI - (c) 2025. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences. FAU - Liu, Shufen AU - Liu S AD - Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China. AD - School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China. FAU - Liu, Tingting AU - Liu T AD - Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China. AD - School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China. FAU - Li, Jingwen AU - Li J AD - School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China. FAU - Hong, Jun AU - Hong J AD - School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China. FAU - Moosavi-Movahedi, Ali A AU - Moosavi-Movahedi AA AD - Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 999067, Iran. FAU - Wei, Jianshe AU - Wei J AUID- ORCID: 0000-0002-3560-3392 AD - Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China. jswei@henu.edu.cn. AD - School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China. jswei@henu.edu.cn. LA - eng PT - Journal Article PT - Review DEP - 20250104 PL - Singapore TA - Neurosci Bull JT - Neuroscience bulletin JID - 101256850 RN - EC 2.7.10.1 (Receptor, Insulin) RN - 0 (Insulin) SB - IM MH - Humans MH - *Parkinson Disease/metabolism/pathology/drug therapy MH - *Diabetes Mellitus, Type 2/metabolism/drug therapy/complications/pathology MH - *Signal Transduction/physiology MH - *Receptor, Insulin/metabolism MH - Animals MH - Insulin Resistance/physiology MH - Insulin/metabolism PMC - PMC11978575 OTO - NOTNLM OT - Insulin OT - Parkinson's disease OT - Therapeutic agents OT - Type 2 diabetes mellitus COIS- Conflict of interest: The authors declare that there are no conflicts of interest. EDAT- 2025/01/04 20:12 MHDA- 2025/04/09 10:13 PMCR- 2026/04/01 CRDT- 2025/01/04 11:03 PHST- 2024/08/10 00:00 [received] PHST- 2024/10/15 00:00 [accepted] PHST- 2025/04/09 10:13 [medline] PHST- 2025/01/04 20:12 [pubmed] PHST- 2025/01/04 11:03 [entrez] PHST- 2026/04/01 00:00 [pmc-release] AID - 10.1007/s12264-024-01342-8 [pii] AID - 1342 [pii] AID - 10.1007/s12264-024-01342-8 [doi] PST - ppublish SO - Neurosci Bull. 2025 Apr;41(4):676-690. doi: 10.1007/s12264-024-01342-8. Epub 2025 Jan 4. PMID- 39743126 OWN - NLM STAT- MEDLINE DCOM- 20250523 LR - 20260525 IS - 1873-1740 (Electronic) IS - 0033-0620 (Print) IS - 0033-0620 (Linking) VI - 89 DP - 2025 Mar-Apr TI - Anti-consumption agents: Tirzepatide and semaglutide for treating obesity-related diseases and addictions, and improving life expectancy. PG - 102-112 LID - S0033-0620(24)00179-8 [pii] LID - 10.1016/j.pcad.2024.12.010 [doi] AB - American culture encourages overconsumption, fueled by ubiquitous availability and pervasive marketing of ultra-processed foods and other addictive substances. This chronic overindulgence has contributed to rising rates of obesity, type 2 diabetes (T2D), substance abuse, mental health disorders and premature mortality. Glucose-like peptide-1 agonists (GLP-1RAs) affect the brain's reward pathway that mediates addiction to foods and various other substances. Evolving data suggest that tirzepatide and semaglutide may be the first effective "anti-consumption" agents with potential applications in reducing food cravings, obesity, alcohol consumption, nicotine addiction, recreational drug use, and even uncontrollable shopping behaviors. Tirzepatide and semaglutide, unlike prior weight-loss drugs, are effective and relatively safe/well-tolerated medications that are associated with reduced risks for myocardial infarction, stroke, cardiovascular death, heart failure, progressive kidney and liver disease, obstructive sleep apnea, debilitating osteoarthritis, polycystic ovarian syndrome, neurodegenerative disease and premature mortality. Observational studies show that GLP-1RAs are associated with spontaneous nonvolitional reductions in use of alcohol, nicotine, and recreational drugs. Because obesity and substance abuse are so prevalent in the United States, GLP-1RA drugs may be uniquely helpful in addressing overconsumption and addiction issues thereby improving overall health and life expectancy. CI - Copyright (c) 2025 The Authors. Published by Elsevier Inc. All rights reserved. FAU - O'Keefe, James H AU - O'Keefe JH AD - Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, United States of America. Electronic address: ljwilson@saintlukeskc.org. FAU - Franco, W Grant AU - Franco WG AD - Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, United States of America. FAU - O'Keefe, Evan L AU - O'Keefe EL AD - Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, United States of America. LA - eng GR - T32 HL110837/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Review DEP - 20241230 PL - United States TA - Prog Cardiovasc Dis JT - Progress in cardiovascular diseases JID - 0376442 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Anti-Obesity Agents) RN - OYN3CCI6QE (Tirzepatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Obesity/drug therapy/psychology/physiopathology/mortality MH - *Glucagon-Like Peptides/therapeutic use/adverse effects MH - *Life Expectancy MH - *Substance-Related Disorders/drug therapy/psychology MH - Treatment Outcome MH - *Anti-Obesity Agents/therapeutic use/adverse effects MH - *Behavior, Addictive/drug therapy/psychology MH - Animals MH - Tirzepatide MH - Glucagon-Like Peptide 1 MH - Semaglutide PMC - PMC12103286 MID - NIHMS2048886 OTO - NOTNLM OT - Diabetes OT - Obesity OT - Semaglutide OT - Survival OT - Tirzepatide COIS- Declaration of competing interest JHO - Speaker bureau for Amgen, Boehringer, and Lilly. WFG - no disclosures. ELO - The National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number T32HL110837 supported the research reported in this publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NIH era commons number 79260132. EDAT- 2025/01/02 00:21 MHDA- 2025/05/24 00:45 PMCR- 2025/05/25 CRDT- 2025/01/01 19:16 PHST- 2024/12/29 00:00 [received] PHST- 2024/12/29 00:00 [accepted] PHST- 2025/05/24 00:45 [medline] PHST- 2025/01/02 00:21 [pubmed] PHST- 2025/01/01 19:16 [entrez] PHST- 2025/05/25 00:00 [pmc-release] AID - S0033-0620(24)00179-8 [pii] AID - 10.1016/j.pcad.2024.12.010 [doi] PST - ppublish SO - Prog Cardiovasc Dis. 2025 Mar-Apr;89:102-112. doi: 10.1016/j.pcad.2024.12.010. Epub 2024 Dec 30. PMID- 41835241 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260920 IS - 2575-9655 (Electronic) IS - 2575-9655 (Linking) VI - 9 IP - 6 DP - 2025 TI - A Critical Analysis of the Clinical Use of Incretin-Based Therapies: Efficacy and Adverse Events. PG - 242-253 LID - 10.26502/acmcr.96550740 [doi] AB - Obesity is a major public health challenge in the United States, despite widespread implementation of regulated diet plans, exercise programs, behavioral interventions, and surgical procedures. The emergence of incretin-based therapies, particularly GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) receptor agonists, has transformed the therapeutic landscape for initially type 2 diabetes and now obesity. Beyond their metabolic effects, incretin therapies exert meaningful cardiovascular, gastrointestinal, and neuroprotective actions. Semaglutide, a GLP-1 receptor agonist, and tripeptide, a dual GLP-1/GIP agonist, demonstrate substantial weight reduction, improved glycemic control, and reductions in cardiometabolic risk factors. Tirzepatide consistently produces greater weight loss effects than semaglutide, likely due to synergistic dual-receptor effects. However, these therapies are accompanied by adverse effects, most commonly gastrointestinal disturbances, and, less frequently, gallbladder disease, pancreatitis, or rare ophthalmologic concerns. Long-term safety data remain limited, particularly in older adults, pediatric patients, pregnant women, and individuals with comorbid disease. Emerging evidence also suggests potential roles in cancer prevention, hypertension, and neurodegenerative disease. As the indications for incretin-based therapies continue to expand, longer-duration trials and more diverse study populations will be essential to fully examine their long-term clinical effects. Though these agents hold considerable promise, careful and informed use remain vital. FAU - Radparvar, Ilana AU - Radparvar I AD - Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA. FAU - Agrawal, Devendra K AU - Agrawal DK AD - Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA. LA - eng GR - R25 AI179582/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20251230 PL - United States TA - Arch Clin Med Case Rep JT - Archives of clinical and medical case reports JID - 101741210 PMC - PMC12981728 MID - NIHMS2142093 OTO - NOTNLM OT - Adverse effects OT - Cardiometabolic disease OT - GLP-1 Receptor agonists OT - Incretin hormones OT - Obesity OT - Tirzepatide OT - Type 2 diabetes OT - Weight loss therapy OT - semaglutide COIS- Competing interests Both authors have read the manuscript and declare no conflict of interest. No writing assistance was utilized in the production of this manuscript. EDAT- 2025/01/01 00:00 MHDA- 2025/01/01 00:01 PMCR- 2026/03/13 CRDT- 2026/03/16 05:57 PHST- 2025/01/01 00:01 [medline] PHST- 2025/01/01 00:00 [pubmed] PHST- 2026/03/16 05:57 [entrez] PHST- 2026/03/13 00:00 [pmc-release] AID - 10.26502/acmcr.96550740 [doi] PST - ppublish SO - Arch Clin Med Case Rep. 2025;9(6):242-253. doi: 10.26502/acmcr.96550740. Epub 2025 Dec 30. PMID- 39740304 OWN - NLM STAT- MEDLINE DCOM- 20250429 LR - 20260818 IS - 1873-460X (Electronic) IS - 1056-8727 (Linking) VI - 39 IP - 2 DP - 2025 Feb TI - Identifying predictors of sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide 1 receptor agonist use in hospital among adults with diabetes. PG - 108945 LID - S1056-8727(24)00271-X [pii] LID - 10.1016/j.jdiacomp.2024.108945 [doi] AB - AIMS: To identify factors associated with use of novel diabetes medications among patients hospitalized under general internal medicine. METHODS: We conducted a cohort study of patients with type 2 diabetes mellitus (T2DM) hospitalized in Ontario, Canada between 2015 and 2020. We evaluated the patient- and physician-level factors associated with sodium-glucose cotransporter 2 inhibitor (SGLT2) and glucagon-like peptide 1 receptor agonist (GLP1R) use using a multivariable logistic regression model. RESULTS: There were 253,152 hospitalizations and 68,126 involved patients who had T2DM. Prior to discharge, 3.7 % (N = 2490) of patients with T2DM received an SGLT2 and 0.2 % (N = 121) received a GLP1R. The strongest predictors for receiving a novel diabetes medication were hemoglobin A1C > 9.0 % (Odds Ratio (OR) = 1.81, 95 % Confidence Interval (CI) 1.28, 2.60) and patients aged 40-60 compared with patients <40 years old (OR = 1.81, 95 % CI 1.33, 2.68). The strongest predictors for not receiving a novel diabetes medication were dementia (OR = 0.47, 95 % CI 0.39, 0.56) and creatinine >/=200 mumol/L (OR = 0.11, 95 % CI 0.08, 0.15). Overall, 46.8 % of patients hospitalized with T2DM not receiving a novel diabetes medication would potentially benefit from an SGLT2 inhibitor. CONCLUSIONS: Novel diabetes medications were rarely continued or initiated during hospitalization despite a high prevalence of cardiovascular disease, raising the concern for systematic under-utilization after discharge. CI - Copyright (c) 2024 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Raudanskis, Ashley AU - Raudanskis A AD - Sinai Health System, Division of General Internal Medicine, Toronto, Ontario, Canada. FAU - Sarma, Shohinee AU - Sarma S AD - Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, United States of America. FAU - Biering-Sorensen, Tor AU - Biering-Sorensen T AD - Department of Cardiology, Copenhagen University Hospital - Herlev & Gentofte, Copenhagen, Denmark. FAU - Zorcic, Katarina AU - Zorcic K AD - Sinai Health System, Division of General Internal Medicine, Toronto, Ontario, Canada. FAU - Razak, Fahad AU - Razak F AD - Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario; St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Verma, Amol AU - Verma A AD - Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario; St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Jensen, Magnus Thorsten AU - Jensen MT AD - Steno Diabetes Center Copenhagen, Copenhagen, Denmark. FAU - Perkins, Bruce A AU - Perkins BA AD - Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Colacci, Michael AU - Colacci M AD - Sinai Health System, Division of General Internal Medicine, Toronto, Ontario, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario. FAU - Fralick, Michael AU - Fralick M AD - Sinai Health System, Division of General Internal Medicine, Toronto, Ontario, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario. Electronic address: mike.fralick@mail.utoronto.ca. LA - eng PT - Journal Article DEP - 20241220 PL - United States TA - J Diabetes Complications JT - Journal of diabetes and its complications JID - 9204583 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) SB - IM MH - Humans MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology/blood/complications MH - Male MH - Female MH - Middle Aged MH - *Hospitalization/statistics & numerical data MH - Aged MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Adult MH - Ontario/epidemiology MH - *Hypoglycemic Agents/therapeutic use MH - Cohort Studies MH - Glycated Hemoglobin/analysis OTO - NOTNLM OT - Diabetes OT - Diabetes medication OT - Glucagon-like peptide 1 receptor [GLP1R] agonists OT - Sodium-glucose cotransporter 2 [SGLT2] inhibitors OT - Type 2 diabetes mellitus [T2DM] COIS- Declaration of competing interest Michael Fralick was a consultant for ProofDx, a start-up company creating a point of care diagnostic test for COVID-19. Michael Fralick is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. Tor Biering-Sorensen discloses the following relationships: steering committee member of the Amgen-financed GALACTIC-HF trial, of the Boehringer Ingelheim financed SHARP3 trial, of "LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System" trial; advisory board: Amgen, CSL Seqirus and GSK; chief investigator of the Sanofi Pasteur financed "NUDGE-FLU", "DANFLU-1", and "DANFLU-2" trials; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, GE healthcare and GSK; consultant appointments: Novo Nordisk, IQVIA and Parexel; and research grants: GE Healthcare, AstraZeneca, Novo Nordisk and Sanofi Pasteur. Fahad Razak is a part-time employee of Ontario Health. The development of the GEMINI data platform has been supported with funding from sources such as the Canadian Cancer Society, the Canadian Frailty Network, the Canadian Institutes of Health Research, the Canadian Medical Protective Agency, Green Shield Canada Foundation, the Natural Sciences and Engineering Research Council of Canada, Ontario Health, the St. Michael's Hospital Association Innovation Fund, the University of Toronto Department of Medicine, and in-kind support from partner hospitals and the Vector Institute. Fahad Razak holds a salary award from Canada Research Chairs Program, University of Toronto and the PSI Graham Farquharson Knowledge Translation Fellowship. No funding sources from Fahad Razak influenced the writing of this manuscript. Outside of the submitted work, Amol Verma is a part-time employee of Ontario Health and a co-inventor of an AI-based early warning system for patient deterioration that was acquired by the start-up company Signal1. Magnus Thorsten Jensen is the CEO of Steno Diabetes Center Copenhagen which is funded through a partnership between the Capital Region of Denmark and the Novo Nordisk Foundation. Bruce A. Perkins has received honoraria for educational events from Medtronic, Novo Nordisk, Sanofi, Insulet and Abbott. His research institute has received funding from BMO Bank of Montreal and Novo Nordisk for research support. He has served as an advisor to Boehringer Ingelheim, Sanofi, Insulet, Abbott, and Vertex. Ashley Raudanskis, Shohinee Sarma, Katarina Zorcic, and Michael Colacci have no reported conflicts of interest. EDAT- 2025/01/01 12:42 MHDA- 2025/02/11 00:19 CRDT- 2024/12/31 18:02 PHST- 2024/08/28 00:00 [received] PHST- 2024/12/18 00:00 [revised] PHST- 2024/12/19 00:00 [accepted] PHST- 2025/02/11 00:19 [medline] PHST- 2025/01/01 12:42 [pubmed] PHST- 2024/12/31 18:02 [entrez] AID - S1056-8727(24)00271-X [pii] AID - 10.1016/j.jdiacomp.2024.108945 [doi] PST - ppublish SO - J Diabetes Complications. 2025 Feb;39(2):108945. doi: 10.1016/j.jdiacomp.2024.108945. Epub 2024 Dec 20. PMID- 39723481 OWN - NLM STAT- MEDLINE DCOM- 20250206 LR - 20260808 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 27 IP - 3 DP - 2025 Mar TI - Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials. PG - 1444-1455 LID - 10.1111/dom.16147 [doi] AB - AIM: To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). MATERIALS AND METHODS: A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs. RESULTS: Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns. CONCLUSIONS: Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors. CI - (c) 2024 John Wiley & Sons Ltd. FAU - Tang, Huilin AU - Tang H AUID- ORCID: 0000-0002-5814-6657 AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Zhang, Bingyu AU - Zhang B AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Lu, Yiwen AU - Lu Y AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Donahoo, William T AU - Donahoo WT AD - Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. FAU - Singh Ospina, Naykky AU - Singh Ospina N AD - Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. FAU - Kotecha, Pareeta AU - Kotecha P AUID- ORCID: 0009-0009-4864-9662 AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Lu, Ying AU - Lu Y AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Tong, Jiayi AU - Tong J AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. FAU - Smith, Steven M AU - Smith SM AUID- ORCID: 0000-0002-0201-839X AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. FAU - Rosenberg, Eric I AU - Rosenberg EI AD - Division of General Internal Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Kimmel, Stephen E AU - Kimmel SE AD - Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Bian, Jiang AU - Bian J AD - Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Guo, Jingchuan AU - Guo J AUID- ORCID: 0000-0001-9799-2592 AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. FAU - Chen, Yong AU - Chen Y AD - The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA. AD - Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. AD - Leonard Davis Institute of Health Economics, Philadelphia, Pennsylvania, USA. AD - Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, Pennsylvania, USA. AD - Penn Institute for Biomedical Informatics (IBI), Philadelphia, Pennsylvania, USA. LA - eng GR - K08 CA248972/CA/NCI NIH HHS/United States GR - R01 DK133465/DK/NIDDK NIH HHS/United States GR - R01DK133465/Division of Diabetes, Endocrinology, and Metabolic Diseases/ PT - Journal Article PT - Network Meta-Analysis PT - Systematic Review DEP - 20241226 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Blood Glucose) SB - IM MH - Humans MH - Randomized Controlled Trials as Topic MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Risk Assessment MH - Cardiovascular Diseases/epidemiology/prevention & control MH - Blood Glucose/drug effects PMC - PMC12135018 MID - NIHMS2042370 OTO - NOTNLM OT - DPP-IV inhibitor OT - GLP-1 analogue OT - SGLT2 inhibitor OT - meta-analysis OT - type 2 diabetes COIS- JG received consulting fees from Pfizer and received research funding from PhRMA foundation. NSO was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA248972. The authors declare that there are no conflicts of interest relevant to this work. EDAT- 2024/12/26 06:20 MHDA- 2025/02/07 00:20 PMCR- 2026/03/01 CRDT- 2024/12/26 04:33 PHST- 2024/12/07 00:00 [revised] PHST- 2024/11/10 00:00 [received] PHST- 2024/12/10 00:00 [accepted] PHST- 2025/02/07 00:20 [medline] PHST- 2024/12/26 06:20 [pubmed] PHST- 2024/12/26 04:33 [entrez] PHST- 2026/03/01 00:00 [pmc-release] AID - 10.1111/dom.16147 [doi] PST - ppublish SO - Diabetes Obes Metab. 2025 Mar;27(3):1444-1455. doi: 10.1111/dom.16147. Epub 2024 Dec 26. PMID- 39719978 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260923 IS - 1664-2295 (Print) IS - 1664-2295 (Electronic) IS - 1664-2295 (Linking) VI - 15 DP - 2024 TI - Neuroprotective effects of GLP-1 class drugs in Parkinson's disease. PG - 1462240 LID - 10.3389/fneur.2024.1462240 [doi] LID - 1462240 AB - Parkinson's disease (PD) is a chronic, progressive neurological disorder primarily affecting motor control, clinically characterized by resting tremor, bradykinesia, rigidity, and other symptoms that significantly diminish the quality of life. Currently, available treatments only alleviate symptoms without halting or delaying disease progression. There is a significant association between PD and type 2 diabetes mellitus (T2DM), possibly due to shared pathological mechanisms such as insulin resistance, chronic inflammation, and mitochondrial dysfunction. PD is caused by a deficiency of dopamine, a neurotransmitter in the brain that plays a critical role in the control of movement. Glucose metabolism and energy metabolism disorders also play an important role in the pathogenesis of PD. This review investigates the neuroprotective mechanisms of glucagon-like peptide-1 (GLP-1) and its receptor agonists, offering novel insights into potential therapeutic strategies for PD. GLP-1 class drugs, primarily used in diabetes management, show promise in addressing PD's underlying pathophysiological mechanisms, including energy metabolism and neuroprotection. These drugs can cross the blood-brain barrier, improve insulin resistance, stabilize mitochondrial function, and enhance neuronal survival and function. Additionally, they exhibit significant anti-inflammatory and antioxidative stress effects, which are crucial in neurodegenerative diseases like PD. Research indicates that GLP-1 receptor agonists could improve both motor and cognitive symptoms in PD patients, marking a potential breakthrough in PD treatment and prevention. Further exploration of GLP-1's molecular mechanisms in PD could provide new preventive and therapeutic approaches, especially for PD patients with concurrent T2DM. By targeting both metabolic and neurodegenerative pathways, GLP-1 receptor agonists represent a multifaceted approach to PD treatment, offering hope for better disease management and improved patient outcomes. CI - Copyright (c) 2024 Lv, Feng, Guan, Liu, Li, Xue, Bai and Holscher. FAU - Lv, Dongliang AU - Lv D AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Feng, Peng AU - Feng P AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Guan, Xueying AU - Guan X AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Liu, Zhaona AU - Liu Z AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Li, Dongfang AU - Li D AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Xue, Cunshui AU - Xue C AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Bai, Bo AU - Bai B AD - Second Hospital, Shanxi Medical University, Taiyuan, China. FAU - Holscher, Christian AU - Holscher C AD - Henan Academy of Innovations in Medical Science, Brain Institute, Zhengzhou, China. LA - eng PT - Journal Article PT - Review DEP - 20241210 PL - Switzerland TA - Front Neurol JT - Frontiers in neurology JID - 101546899 PMC - PMC11667896 OTO - NOTNLM OT - Parkinson's disease OT - diabetes OT - energy metabolism OT - glucagon-like peptide 1 OT - insulin OT - neuroprotection COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/12/25 06:19 MHDA- 2024/12/25 06:20 PMCR- 2024/12/10 CRDT- 2024/12/25 04:14 PHST- 2024/07/09 00:00 [received] PHST- 2024/11/14 00:00 [accepted] PHST- 2024/12/25 06:20 [medline] PHST- 2024/12/25 06:19 [pubmed] PHST- 2024/12/25 04:14 [entrez] PHST- 2024/12/10 00:00 [pmc-release] AID - 10.3389/fneur.2024.1462240 [doi] PST - epublish SO - Front Neurol. 2024 Dec 10;15:1462240. doi: 10.3389/fneur.2024.1462240. eCollection 2024. PMID- 39716328 OWN - NLM STAT- MEDLINE DCOM- 20241224 LR - 20260416 IS - 1758-9193 (Electronic) VI - 16 IP - 1 DP - 2024 Dec 23 TI - Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials. PG - 272 LID - 10.1186/s13195-024-01645-y [doi] LID - 272 AB - OBJECTIVE: To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D). METHODS: Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI). RESULTS: A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > alpha-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo. CONCLUSION: Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D. CI - (c) 2024. The Author(s). FAU - Li, Zonglin AU - Li Z AUID- ORCID: 0000-0002-8949-9455 AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. FAU - Lin, Chu AU - Lin C AUID- ORCID: 0000-0002-2365-9831 AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. FAU - Cai, Xiaoling AU - Cai X AUID- ORCID: 0000-0002-7881-0543 AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. dr_junel@sina.com. FAU - Lv, Fang AU - Lv F AUID- ORCID: 0000-0002-1872-781X AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. FAU - Yang, Wenjia AU - Yang W AUID- ORCID: 0000-0003-0610-5121 AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. FAU - Ji, Linong AU - Ji L AUID- ORCID: 0000-0002-3262-2168 AD - Department of Endocrinology and Metabolism, Peking University People's Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People's Republic of China. jiln@bjmu.edu.cn. LA - eng GR - 7202216/Natural Science Foundation of Beijing Municipality/ GR - 81970698/National Natural Science Foundation of China/ PT - Journal Article PT - Network Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20241223 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - *Dementia/epidemiology/etiology/prevention & control MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Hypoglycemic Agents/therapeutic use MH - Observational Studies as Topic MH - Randomized Controlled Trials as Topic MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use PMC - PMC11668108 OTO - NOTNLM OT - Alzheimer's disease OT - Anti-diabetic agents OT - Dementia OT - Glucagon-like peptide-1 receptor agonist OT - Sodium-glucose cotransporter-2 inhibitor COIS- Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: For financial competing interests, LJ has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda; when LJ has no non-financial competing interests to disclose. There are no financial or non-financial conflicts of interests to reveal in any other co-authors. No other support from any organization for the submitted work other than that described above. EDAT- 2024/12/24 06:20 MHDA- 2024/12/24 06:21 PMCR- 2024/12/23 CRDT- 2024/12/24 00:07 PHST- 2024/07/10 00:00 [received] PHST- 2024/12/11 00:00 [accepted] PHST- 2024/12/24 06:21 [medline] PHST- 2024/12/24 06:20 [pubmed] PHST- 2024/12/24 00:07 [entrez] PHST- 2024/12/23 00:00 [pmc-release] AID - 10.1186/s13195-024-01645-y [pii] AID - 1645 [pii] AID - 10.1186/s13195-024-01645-y [doi] PST - epublish SO - Alzheimers Res Ther. 2024 Dec 23;16(1):272. doi: 10.1186/s13195-024-01645-y. PMID- 39696300 OWN - NLM STAT- MEDLINE DCOM- 20241219 LR - 20250825 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 22 IP - 1 DP - 2024 Dec 18 TI - The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes. PG - 582 LID - 10.1186/s12916-024-03763-8 [doi] LID - 582 AB - The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners. CI - (c) 2024. The Author(s). FAU - Schwartz, Stanley S AU - Schwartz SS AD - University of Pennsylvania School of Medicine, 771 County Line Road, Villanova, PA, 19085, USA. FAU - Herman, Mary E AU - Herman ME AD - Social Alchemy: Building Physician Competency Across the Globe, 5 Ave Sur #36, Antigua, Sacatepequez, Guatemala. mariaon4@mail.com. FAU - Tun, May Thet Hmu AU - Tun MTH AD - Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY, 11219, USA. FAU - Barone, Eugenio AU - Barone E AD - Sapienza University of Rome, Via Degli Equi 42, Scala A, Int. 5, 00185, Rome, Italy. FAU - Butterfield, D Allan AU - Butterfield DA AD - Sanders-Brown Center On Aging, Department of Chemistry, University of Kentucky, 249 Chemistry-Physics Building, Lexington, KY, 40506-0055, USA. LA - eng PT - Journal Article PT - Review DEP - 20241218 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (Blood Glucose) RN - IY9XDZ35W2 (Glucose) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - Blood Glucose/drug effects/metabolism MH - *Brain/metabolism MH - *Diabetes Mellitus, Type 2/metabolism/drug therapy MH - Glucose/metabolism MH - *Homeostasis/drug effects/physiology MH - Hypoglycemic Agents/pharmacology/therapeutic use PMC - PMC11657227 OTO - NOTNLM OT - Agents, Brain insulin resistance OT - Brain glucotoxicity OT - Cognitive impairment OT - Injectable OT - Insulin, Noninsulin oral OT - Type 2 diabetes COIS- Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. EDAT- 2024/12/19 06:22 MHDA- 2024/12/19 06:23 PMCR- 2024/12/18 CRDT- 2024/12/19 00:38 PHST- 2024/03/14 00:00 [received] PHST- 2024/11/11 00:00 [accepted] PHST- 2024/12/19 06:23 [medline] PHST- 2024/12/19 06:22 [pubmed] PHST- 2024/12/19 00:38 [entrez] PHST- 2024/12/18 00:00 [pmc-release] AID - 10.1186/s12916-024-03763-8 [pii] AID - 3763 [pii] AID - 10.1186/s12916-024-03763-8 [doi] PST - epublish SO - BMC Med. 2024 Dec 18;22(1):582. doi: 10.1186/s12916-024-03763-8. PMID- 39658957 OWN - NLM STAT- MEDLINE DCOM- 20241211 LR - 20250103 IS - 0253-9772 (Print) IS - 0253-9772 (Linking) VI - 46 IP - 12 DP - 2024 Dec TI - The mechanism and related research progress of GLP-1 receptor agonists in treating Alzheimer's disease. PG - 1017-1027 LID - 10.16288/j.yczz.24-178 [doi] AB - GLP-1 receptor agonists are primarily used clinically for the treatment of type 2 diabetes and have the potential for weight loss, while they are currently expanding their horizons in the treatment of hypertension, non-alcoholic liver disease, depression, and neurodegenerative diseases. In particular, in the treatment of Alzheimer's disease, a large number of animal models and a handful of clinical studies have demonstrated the potential efficacy of GLP-1 receptor agonists, making it highly probable that they will become a new entrant in the drug list for Alzheimer's disease. At present, the research on the mechanism of GLP-1 receptor agonist in the treatment of Alzheimer's disease is mainly based on in-depth analysis of the pathogenesis of Alzheimer's disease and exploration of the mechanism of its comorbidity with diabetes. This article mainly reviews the latest advances in the mechanism of GLP-1 receptor agonists in the treatment of Alzheimer's disease, introduces the latest achievements in animal studies and clinical studies, and aims to provide reference for the subsequent relevant basic research and clinical application. FAU - Zhu, Xiao-Cheng AU - Zhu XC AD - Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. FAU - Wang, Yi-Wen AU - Wang YW AD - Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. FAU - Zhou, Hong-Wen AU - Zhou HW AD - Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. LA - eng PT - Journal Article PT - Review PL - China TA - Yi Chuan JT - Yi chuan = Hereditas JID - 9436478 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Alzheimer Disease/drug therapy MH - Humans MH - Animals MH - Diabetes Mellitus, Type 2/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - pharmacology EDAT- 2024/12/11 06:25 MHDA- 2024/12/11 06:26 CRDT- 2024/12/11 01:23 PHST- 2024/12/11 06:26 [medline] PHST- 2024/12/11 06:25 [pubmed] PHST- 2024/12/11 01:23 [entrez] AID - 24-178 [pii] AID - 10.16288/j.yczz.24-178 [doi] PST - ppublish SO - Yi Chuan. 2024 Dec;46(12):1017-1027. doi: 10.16288/j.yczz.24-178. PMID- 39639832 OWN - NLM STAT- MEDLINE DCOM- 20241218 LR - 20241218 IS - 1752-2978 (Electronic) IS - 1752-296X (Linking) VI - 32 IP - 1 DP - 2025 Feb 1 TI - Interactions between antidiabetes medications and heart-brain axis. PG - 34-43 LID - 10.1097/MED.0000000000000896 [doi] AB - PURPOSE OF REVIEW: The heart - brain axis (HBA) is the physiological interactions between the cardiovascular and nervous systems through autonomic nerves, hormones, and cytokines. Patients diagnosed with diabetes mellitus have an increased risk of the cardiovascular and neurological diseases. However, recent evidence demonstrated that different antidiabetic drugs may delay cognitive impairment and improve cardiovascular outcomes. This review examines the impact of antidiabetic drugs on the HBA in patients with diabetes. RECENT FINDINGS: Metformin improves the cardiovascular and cognitive outcomes through adenosine 5'-monophosphate-activated protein kinase activation. Sodium-glucose cotransporter-2 inhibitors reduce inflammation, oxidative stress by inhibiting the NLRP3 inflammasome thereby reducing the incidence of heart failure and formation of beta-amyloid and neurofibrillary tangles in the brain. Dipeptidyl peptidase-4 inhibitors exhibit neuroprotective effects in Alzheimer's disease by reducing amyloid-beta and tau pathology and inflammation but may exacerbate heart failure risk due to increased sympathetic activity and prolonged beta-adrenergic stimulation. Glucagon-like peptide-1 receptor agonists exhibit neuroprotective effects in Alzheimer's and Parkinson's diseases by reducing neuroinflammation, but may increase sympathetic activity, potentially elevating heart rate and blood pressure, despite their cardioprotective benefits. SUMMARY: Antidiabetes medications have the potential to improve cardiovascular and cognitive outcomes; however, additional studies are required to substantiate these effects. CI - Copyright (c) 2024 Wolters Kluwer Health, Inc. All rights reserved. FAU - Ong, Leong Tung AU - Ong LT AD - Department of Cardiology, National University Heart Centre, Singapore. FAU - Sia, Ching-Hui AU - Sia CH LA - eng PT - Journal Article PT - Review DEP - 20241206 PL - England TA - Curr Opin Endocrinol Diabetes Obes JT - Current opinion in endocrinology, diabetes, and obesity JID - 101308636 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Humans MH - *Hypoglycemic Agents/therapeutic use MH - *Brain/drug effects/metabolism MH - Heart/drug effects MH - Metformin/therapeutic use/pharmacology MH - Cardiovascular Diseases/prevention & control/etiology/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology EDAT- 2024/12/06 06:23 MHDA- 2024/12/18 12:25 CRDT- 2024/12/06 04:23 PHST- 2024/12/18 12:25 [medline] PHST- 2024/12/06 06:23 [pubmed] PHST- 2024/12/06 04:23 [entrez] AID - 01266029-990000000-00117 [pii] AID - 10.1097/MED.0000000000000896 [doi] PST - ppublish SO - Curr Opin Endocrinol Diabetes Obes. 2025 Feb 1;32(1):34-43. doi: 10.1097/MED.0000000000000896. Epub 2024 Dec 6. PMID- 39610591 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241130 IS - 2168-8184 (Print) IS - 2168-8184 (Electronic) IS - 2168-8184 (Linking) VI - 16 IP - 10 DP - 2024 Oct TI - Exploring the Therapeutic Potential of DPP4 Inhibitors in Alzheimer's Disease: Molecular Insight and Clinical Outcome. PG - e72648 LID - 10.7759/cureus.72648 [doi] LID - e72648 AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Abeta) plaques, neurofibrillary tangles, and cognitive decline. Given the shared neuropathophysiological traits between AD and type 2 diabetes mellitus (T2DM), repurposing antidiabetic medications, such as dipeptidyl peptidase 4 inhibitors (DPP4i), has emerged as a promising therapeutic strategy. This review comprehensively evaluates the preclinical and clinical evidence supporting the potential of DPP4i in preventing or treating AD by modulating Abeta and tau pathology, improving cognitive function, reducing neuroinflammation and oxidative stress, and promoting neuronal survival. The beneficial effects of DPP4i are likely mediated through the modulation of insulin signaling, anti-inflammatory and antioxidant properties, glucagon-like peptide-1 (GLP-1) upregulation, and modulation of the amyloidogenic pathway. While further research is needed to establish their clinical efficacy in AD patients, DPP4i offers a promising avenue for therapeutic intervention for this devastating neurodegenerative disease. CI - Copyright (c) 2024, Sulangi et al. FAU - Sulangi, Albert Joseph AU - Sulangi AJ AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA. FAU - Lyons, Sarah E AU - Lyons SE AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Abdou, Amy A AU - Abdou AA AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Patel, Hemangi AU - Patel H AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Nagliya, Deepika AU - Nagliya D AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Joseph, Eileen AU - Joseph E AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Joseph, Carmel AU - Joseph C AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Kumar, Divya AU - Kumar D AD - Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, USA. FAU - Patel, Shivani AU - Patel S AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Jinwala, Isha AU - Jinwala I AD - Osteopathic Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA. FAU - Parmar, Mayur S AU - Parmar MS AD - Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA. LA - eng PT - Journal Article PT - Review DEP - 20241029 PL - United States TA - Cureus JT - Cureus JID - 101596737 PMC - PMC11604213 OTO - NOTNLM OT - alzheimer's dementia OT - amyloid plaques OT - dipeptidyl peptidase-4 inhibitors OT - drugs repurposing OT - neurofibrillary tangles (nfts) OT - types 2 diabetes COIS- Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. EDAT- 2024/11/29 06:21 MHDA- 2024/11/29 06:22 PMCR- 2024/10/29 CRDT- 2024/11/29 04:17 PHST- 2024/09/14 00:00 [received] PHST- 2024/10/22 00:00 [accepted] PHST- 2024/11/29 06:22 [medline] PHST- 2024/11/29 06:21 [pubmed] PHST- 2024/11/29 04:17 [entrez] PHST- 2024/10/29 00:00 [pmc-release] AID - 10.7759/cureus.72648 [doi] PST - epublish SO - Cureus. 2024 Oct 29;16(10):e72648. doi: 10.7759/cureus.72648. eCollection 2024 Oct. PMID- 39594606 OWN - NLM STAT- MEDLINE DCOM- 20241127 LR - 20260127 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 13 IP - 22 DP - 2024 Nov 8 TI - Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord. LID - 10.3390/cells13221857 [doi] LID - 1857 AB - Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats. METHODS: Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1x SEMA (1.44 mg/kg, orally) or 2x SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. RESULTS: SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. CONCLUSIONS: These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects. FAU - Lee, Sing-Ong AU - Lee SO AD - Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan. AD - Department of Health and Leisure Management, Yuanpei University of Medical Technology, Hsinchu City 306, Taiwan. FAU - Kuthati, Yaswanth AU - Kuthati Y AUID- ORCID: 0000-0002-5018-3736 AD - Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan. FAU - Huang, Wei-Hsiu AU - Huang WH AD - Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan. AD - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan. FAU - Wong, Chih-Shung AU - Wong CS AD - Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan. AD - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan. LA - eng GR - 110-2314-B-281-007-MY3/Ministry of Science and Technology (Taiwan)/ GR - CGH-MR-A10905 and CGH-MR- A11311/Cathay research grant/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20241108 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - Male MH - Rats MH - *Rats, Wistar MH - *Diabetic Neuropathies/drug therapy/pathology/metabolism MH - *Spinal Cord/drug effects/pathology/metabolism MH - *Diabetes Mellitus, Experimental/complications/drug therapy MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - *Neuralgia/drug therapy/pathology/metabolism MH - Neuroinflammatory Diseases/drug therapy/metabolism MH - Semaglutide PMC - PMC11593193 OTO - NOTNLM OT - GLP-1RA OT - SEMA OT - astrocytes OT - diabetic neuropathic pain OT - microglia OT - pro-inflammatory cytokines COIS- The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2024/11/27 06:19 MHDA- 2024/11/27 06:20 PMCR- 2024/11/08 CRDT- 2024/11/27 01:13 PHST- 2024/10/10 00:00 [received] PHST- 2024/11/07 00:00 [revised] PHST- 2024/11/07 00:00 [accepted] PHST- 2024/11/27 06:20 [medline] PHST- 2024/11/27 06:19 [pubmed] PHST- 2024/11/27 01:13 [entrez] PHST- 2024/11/08 00:00 [pmc-release] AID - cells13221857 [pii] AID - cells-13-01857 [pii] AID - 10.3390/cells13221857 [doi] PST - epublish SO - Cells. 2024 Nov 8;13(22):1857. doi: 10.3390/cells13221857. PMID- 39582489 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260923 IS - 2666-7762 (Electronic) IS - 2666-7762 (Linking) VI - 47 DP - 2024 Dec TI - Recent achievements and future directions of anti-obesity medications. PG - 101100 LID - 10.1016/j.lanepe.2024.101100 [doi] LID - 101100 AB - Pharmacological management of obesity long suffered from a reputation of a 'Mission Impossible,' with inefficient weight loss and/or unacceptable tolerability. However, the tide has turned with recent progress in biochemical engineering and the development of long-acting agonists at the receptor for glucagon-like peptide-1 (GLP-1), and with unimolecular peptides that simultaneously possess activity at the receptors for GLP-1, the glucose-dependent insulinotropic polypeptide (GIP) and glucagon. Some of these novel therapeutics not only improve body weight and glycemic control in individuals with obesity and type 2 diabetes with hitherto unmet efficacy and tolerable safety, but also exhibit potential therapeutic value in diverse areas such as neurodegenerative diseases, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular diseases. In this review, we highlight recent advances in incretin-based therapies and discuss their pharmacological potential within and beyond the treatment of obesity and diabetes, as well as their limitations in use, side effects, and underlying molecular mechanisms. CI - (c) 2024 The Authors. FAU - Grandl, Gerald AU - Grandl G AD - Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany. AD - German Center for Diabetes Research (DZD), Neuherberg, Germany. FAU - Novikoff, Aaron AU - Novikoff A AD - Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany. AD - German Center for Diabetes Research (DZD), Neuherberg, Germany. FAU - Liu, Xue AU - Liu X AD - Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany. AD - German Center for Diabetes Research (DZD), Neuherberg, Germany. FAU - Muller, Timo D AU - Muller TD AD - Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany. AD - German Center for Diabetes Research (DZD), Neuherberg, Germany. AD - Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Germany. LA - eng PT - Journal Article PT - Review DEP - 20241109 PL - England TA - Lancet Reg Health Eur JT - The Lancet regional health. Europe JID - 101777707 PMC - PMC11585837 OTO - NOTNLM OT - Anti-obesity medication (AOM) OT - Diabetes OT - GIP OT - GLP-1 OT - Obesity COIS- TDM receives research funding by Novo Nordisk but these funds are unrelated the here described work. TDM received speaking fees within the last 3 years from Novo Nordisk, Eli Lilly, AstraZeneca, Merck, Berlin Chemie AG, and Mercodia. EDAT- 2024/11/25 11:33 MHDA- 2024/11/25 11:34 PMCR- 2024/11/09 CRDT- 2024/11/25 04:54 PHST- 2024/08/07 00:00 [received] PHST- 2024/09/06 00:00 [revised] PHST- 2024/10/03 00:00 [accepted] PHST- 2024/11/25 11:34 [medline] PHST- 2024/11/25 11:33 [pubmed] PHST- 2024/11/25 04:54 [entrez] PHST- 2024/11/09 00:00 [pmc-release] AID - S2666-7762(24)00267-9 [pii] AID - 101100 [pii] AID - 10.1016/j.lanepe.2024.101100 [doi] PST - epublish SO - Lancet Reg Health Eur. 2024 Nov 9;47:101100. doi: 10.1016/j.lanepe.2024.101100. eCollection 2024 Dec. PMID- 39574978 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241123 IS - 2168-8184 (Print) IS - 2168-8184 (Electronic) IS - 2168-8184 (Linking) VI - 16 IP - 10 DP - 2024 Oct TI - Recent Advances and Therapeutic Benefits of Glucagon-Like Peptide-1 (GLP-1) Agonists in the Management of Type 2 Diabetes and Associated Metabolic Disorders. PG - e72080 LID - 10.7759/cureus.72080 [doi] LID - e72080 AB - Glucagon-like peptide-1 (GLP-1) agonists have emerged as a groundbreaking class of medications for managing type 2 diabetes and associated metabolic disorders. These agents not only improve glycemic control by increasing insulin secretion and reducing glucagon levels but also promote significant weight loss, enhance cardiovascular and renal health, and offer potential neuroprotective benefits. Their multifaceted mechanisms include appetite suppression, increased energy expenditure, and direct neuroprotective effects. GLP-1 agonists have shown recent benefits in Obstructive Sleep Apnea, and the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as reducing the risk of stroke. This review highlights the therapeutic potential of GLP-1 agonists in diabetes management and beyond, advocating for continued research to optimize their clinical use and explore new therapeutic avenues. CI - Copyright (c) 2024, Olukorode et al. FAU - Olukorode, John O AU - Olukorode JO AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Orimoloye, Dolapo A AU - Orimoloye DA AD - Internal Medicine, College of Medicine, University of Lagos, Lagos, NGA. FAU - Nwachukwu, Nwachukwu O AU - Nwachukwu NO AD - Public Health, Liverpool John Moores University, Liverpool, GBR. FAU - Onwuzo, Chidera N AU - Onwuzo CN AD - Internal Medicine, SUNY Upstate Medical University, Syracuse, USA. AD - Internal Medicine, Benjamin S. Carson College of Health and Medical Sciences, Ilishan-Remo, NGA. AD - Internal Medicine, General Hospital Lagos Island, Lagos, NGA. FAU - Oloyede, Praise O AU - Oloyede PO AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Fayemi, Temiloluwa AU - Fayemi T AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Odunaike, Oluwatobi S AU - Odunaike OS AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Ayobami-Ojo, Petra S AU - Ayobami-Ojo PS AD - Internal Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, GBR. FAU - Divine, Nwachi AU - Divine N AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Alo, Demilade J AU - Alo DJ AD - Internal Medicine, Babcock University Teaching Hospital, Ilishan-Remo, NGA. FAU - Alex, Chukwurah U AU - Alex CU AD - Internal Medicine, Danylo Halytsky Lviv National Medical University, Lviv, UKR. LA - eng PT - Journal Article PT - Review DEP - 20241021 PL - United States TA - Cureus JT - Cureus JID - 101596737 PMC - PMC11579408 OTO - NOTNLM OT - benefits of glp-1 agonists OT - diabetes OT - glp-1 agonist OT - glucagon-like peptide OT - liraglutide OT - management of type 2 diabetes OT - obstructive sleep apnea OT - tirzepatide COIS- Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. EDAT- 2024/11/22 11:25 MHDA- 2024/11/22 11:26 PMCR- 2024/10/21 CRDT- 2024/11/22 04:26 PHST- 2024/10/21 00:00 [accepted] PHST- 2024/11/22 11:26 [medline] PHST- 2024/11/22 11:25 [pubmed] PHST- 2024/11/22 04:26 [entrez] PHST- 2024/10/21 00:00 [pmc-release] AID - 10.7759/cureus.72080 [doi] PST - epublish SO - Cureus. 2024 Oct 21;16(10):e72080. doi: 10.7759/cureus.72080. eCollection 2024 Oct. PMID- 39497615 OWN - NLM STAT- MEDLINE DCOM- 20250425 LR - 20250516 IS - 1464-5491 (Electronic) IS - 0742-3071 (Print) IS - 0742-3071 (Linking) VI - 42 IP - 2 DP - 2025 Feb TI - Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes. PG - e15464 LID - 10.1111/dme.15464 [doi] LID - e15464 AB - AIM: Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes. METHODS: We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists. RESULTS: Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing. CONCLUSIONS: A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes. CI - (c) 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK. FAU - Fountoulakis, Nikolaos AU - Fountoulakis N AD - School of Cardiovascular, Metabolic Medicine and Sciences, King's College London, London, UK. FAU - Miyamoto, Yoshihisa AU - Miyamoto Y AD - Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Pavkov, Meda E AU - Pavkov ME AD - Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Karalliedde, Janaka AU - Karalliedde J AUID- ORCID: 0000-0002-2617-8320 AD - School of Cardiovascular, Metabolic Medicine and Sciences, King's College London, London, UK. FAU - Maltese, Giuseppe AU - Maltese G AUID- ORCID: 0000-0001-6770-3569 AD - School of Cardiovascular, Metabolic Medicine and Sciences, King's College London, London, UK. LA - eng PT - Journal Article PT - Review DEP - 20241105 PL - England TA - Diabet Med JT - Diabetic medicine : a journal of the British Diabetic Association JID - 8500858 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - EC 3.2.1.31 (Klotho Proteins) SB - IM MH - Humans MH - *Renal Insufficiency, Chronic/prevention & control/physiopathology/etiology MH - Disease Progression MH - *Aging/physiology MH - *Diabetic Nephropathies/prevention & control/physiopathology/drug therapy MH - Vascular Stiffness/drug effects/physiology MH - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Klotho Proteins MH - Cellular Senescence/drug effects/physiology MH - Renin-Angiotensin System/drug effects MH - *Cardiovascular Diseases/prevention & control MH - *Diabetes Mellitus, Type 2/complications/drug therapy PMC - PMC11733662 OTO - NOTNLM OT - Ageing OT - Diabetes OT - Diabetic Kidney Disease OT - GLP-1 receptor agonists OT - SGLT-2 inhibitors COIS- The authors declare no conflict of interest. EDAT- 2024/11/05 10:18 MHDA- 2025/01/15 06:21 PMCR- 2025/01/15 CRDT- 2024/11/05 03:53 PHST- 2024/10/15 00:00 [revised] PHST- 2024/07/30 00:00 [received] PHST- 2024/10/16 00:00 [accepted] PHST- 2025/01/15 06:21 [medline] PHST- 2024/11/05 10:18 [pubmed] PHST- 2024/11/05 03:53 [entrez] PHST- 2025/01/15 00:00 [pmc-release] AID - DME15464 [pii] AID - 10.1111/dme.15464 [doi] PST - ppublish SO - Diabet Med. 2025 Feb;42(2):e15464. doi: 10.1111/dme.15464. Epub 2024 Nov 5. PMID- 39493064 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241105 IS - 2168-8184 (Print) IS - 2168-8184 (Electronic) IS - 2168-8184 (Linking) VI - 16 IP - 10 DP - 2024 Oct TI - From Glucose to Neuroprotection: Exploring Antidiabetic Medications as a Novel Approach to Alzheimer's Disease Treatment. PG - e70710 LID - 10.7759/cureus.70710 [doi] LID - e70710 AB - Alzheimer's disease (AD) is a major neurological disorder and a leading cause of dementia, which is characterized by progressive cognitive decline. Emerging research highlights the link between AD and type 2 diabetes mellitus (T2DM), suggesting that shared pathophysiological mechanisms, such as insulin resistance, inflammation, and oxidative stress, contribute to both conditions. This connection has led to the concept of type 3 diabetes. Given these overlaps, antidiabetic drugs are being explored for repurposing as potential AD treatments. Intranasal insulin, metformin, thiazolidinediones, and GLP-1 analogs like liraglutide have shown promise in reducing amyloid-beta levels and inflammation, and improving cognitive functions. Despite encouraging preclinical and early clinical results, challenges remain in translating these findings into safe and effective treatments. Continued research could lead to innovative therapies that address both AD and T2DM, offering improved patient outcomes. CI - Copyright (c) 2024, Pandiyan et al. FAU - Pandiyan, Chandaraa Kumar AU - Pandiyan CK AD - Department of Pharmacy/Pharmacology, Sri Ramaswamy Memorial College of Pharmacy, Sri Ramaswamy Memorial Institute of Science and Technology, Kattankulathur, IND. FAU - Manivannan, Arjun Gokulan AU - Manivannan AG AD - Department of Pharmacy/Pharmacology, Sri Ramaswamy Memorial College of Pharmacy, Sri Ramaswamy Memorial Institute of Science and Technology, Kattankulathur, IND. FAU - Jaishankar, Narayanan AU - Jaishankar N AD - Department of Pharmacy/Pharmacology, Sri Ramaswamy Memorial College of Pharmacy, Sri Ramaswamy Memorial Institute of Science and Technology, Kattankulathur, IND. FAU - Vellapandian, Chitra AU - Vellapandian C AD - Department of Pharmacy/Pharmacology, Sri Ramaswamy Memorial College of Pharmacy, Sri Ramaswamy Memorial Institute of Science and Technology, Kattankulathur, IND. LA - eng PT - Journal Article PT - Review DEP - 20241002 PL - United States TA - Cureus JT - Cureus JID - 101596737 PMC - PMC11530258 OTO - NOTNLM OT - alzheimer's disease OT - antidiabetic drugs OT - diabetes mellitus type 2 OT - insulin OT - metformin COIS- Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. EDAT- 2024/11/04 06:23 MHDA- 2024/11/04 06:24 PMCR- 2024/10/02 CRDT- 2024/11/04 04:58 PHST- 2024/09/11 00:00 [received] PHST- 2024/10/02 00:00 [accepted] PHST- 2024/11/04 06:24 [medline] PHST- 2024/11/04 06:23 [pubmed] PHST- 2024/11/04 04:58 [entrez] PHST- 2024/10/02 00:00 [pmc-release] AID - 10.7759/cureus.70710 [doi] PST - epublish SO - Cureus. 2024 Oct 2;16(10):e70710. doi: 10.7759/cureus.70710. eCollection 2024 Oct. PMID- 39486172 OWN - NLM STAT- MEDLINE DCOM- 20241207 LR - 20250103 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 143 IP - Pt 3 DP - 2024 Dec 25 TI - Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study. PG - 113537 LID - S1567-5769(24)02059-9 [pii] LID - 10.1016/j.intimp.2024.113537 [doi] AB - BACKGROUND: GLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. OBJECTIVE: To evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. METHODS: This comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. RESULTS: Obese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer's disease (RR = 0.627, 95 %CI = 0.481-0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462-0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327-0.588). The risk reduction for Parkinson's disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580-1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369-0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493-0.558). CONCLUSION: This study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment. CI - Copyright (c) 2024 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Siddeeque, Nabeela AU - Siddeeque N AD - Tulane University School of Medicine, New Orleans, LA, 70112, USA. FAU - Hussein, Mohammad H AU - Hussein MH AD - Ochsner Clinic Foundation, New Orleans, LA 70112, USA. FAU - Abdelmaksoud, Ahmed AU - Abdelmaksoud A AD - Department of Internal Medicine, University of California, Riverside, CA 92521, USA. FAU - Bishop, Julia AU - Bishop J AD - Tulane University School of Medicine, New Orleans, LA, 70112, USA. FAU - Attia, Abdallah S AU - Attia AS AD - Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA. FAU - Elshazli, Rami M AU - Elshazli RM AD - Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA; Biochemistry and Molecular Genetic Unit, Department of Basic Sciences, Faculty of Physical Therapy, Horus University - Egypt, New Damietta 34517, Egypt; Department of Biological Sciences, Faculty of Science, New Mansoura University, New Mansoura City 35742, Egypt. FAU - Fawzy, Manal S AU - Fawzy MS AD - Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia; Center for Health Research, Northern Border University, Arar 1321, Saudi Arabia. FAU - Toraih, Eman A AU - Toraih EA AD - Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA; Medical Genetics Unit, Department of Histology and Cell Biology, Suez Canal University, Ismailia 41522, Egypt. Electronic address: etoraih@tulane.edu. LA - eng PT - Journal Article DEP - 20241031 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Neurodegenerative Diseases/drug therapy MH - Male MH - *Neuroprotective Agents/therapeutic use/pharmacology MH - Female MH - Retrospective Studies MH - Middle Aged MH - Aged MH - Obesity/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy MH - Cohort Studies MH - Propensity Score MH - Adult MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Neurodegenerative disorders OT - Neuroprotection OT - Obesity OT - Parkinson's disease COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/11/02 23:13 MHDA- 2024/12/07 14:47 CRDT- 2024/11/01 19:04 PHST- 2024/09/04 00:00 [received] PHST- 2024/10/27 00:00 [revised] PHST- 2024/10/28 00:00 [accepted] PHST- 2024/12/07 14:47 [medline] PHST- 2024/11/02 23:13 [pubmed] PHST- 2024/11/01 19:04 [entrez] AID - S1567-5769(24)02059-9 [pii] AID - 10.1016/j.intimp.2024.113537 [doi] PST - ppublish SO - Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113537. doi: 10.1016/j.intimp.2024.113537. Epub 2024 Oct 31. PMID- 39484764 OWN - NLM STAT- MEDLINE DCOM- 20260630 LR - 20260630 IS - 1873-4294 (Electronic) IS - 1568-0266 (Linking) VI - 26 IP - 6 DP - 2026 TI - Triazole Scaffold-based DPP-IV Inhibitors for the Management of Type-II Diabetes Mellitus: Insight into Molecular Docking and SAR. PG - 545-581 LID - 10.2174/0115680266339313241021053225 [doi] AB - Diabetes mellitus, characterized as a chronic metabolic disorder or a polygenic syndrome; is increasing at a very fast pace among every group of the population worldwide. It arises due to the inability of the body to produce enough insulin (the hormone responsible for controlling blood sugar levels) or inability to utilize the insulin, leading to hyperglycaemic condition, which, if left uncontrolled gives rise to chronic microvascular and macrovascular complications like retinopathy, neuropathy, nephropathy, coronary artery disease, cognitive impairment, etc. Several therapeutic approaches are available for the treatment of diabetes; among which dipeptidyl peptidase (DPP-IV) inhibitors (gliptins) hold a significant place. DPP-IV is a multifunctional enzyme or a serine exopeptidase that plays an imperative role in cleaving bioactive molecules. DPP-IV causes the breakdown of incretin hormone (GLP-1: Glucagon-like peptide 1 and GIP: Glucose-dependent insulinotropic peptide) that is essential for controlling glycaemic levels in the body. Inhibition of DPP-IV enzyme (DPP-IV inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) prevents this breakdown, thereby controlling blood glucose levels and saving the patients from deleterious effects of prolonged hyperglycaemic conditions. Triazole-based DPP-IV inhibitors are a significant class of drugs used to treat Type 2 diabetes mellitus in a dose-dependent manner. Clinical trials have demonstrated their efficacy as monotherapy or in combination with other antidiabetic agents. This review highlights the molecular docking studies and structure-activity relationship of potential synthetic derivatives that may act as lead molecules for future drug discovery and yield drug molecules with enhanced efficacy, potency and reduced toxicity profile. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Shamim, Saniya AU - Shamim S AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Alam, Ozair AU - Alam O AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Jha, Mukund AU - Jha M AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Nazar, Shagufi AU - Nazar S AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Mathur, Vishal AU - Mathur V AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Ali, Shaheen AU - Ali S AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Ilyas, Anam AU - Ilyas A AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Chandra, Kailash AU - Chandra K AD - Department of Biochemistry, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Jamil Ahmed, Shaikh Mohd Aatif AU - Jamil Ahmed SMA AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Naim, Mohd Javed AU - Naim MJ AD - Pharmacy Department, Tishk International University, Erbil, Iraq. FAU - Parveen, Bushra AU - Parveen B AD - Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. LA - eng GR - ISRM/12(08)2022/Indian Council of Medical Research (ICMR), New Delhi, Government of India/ PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Top Med Chem JT - Current topics in medicinal chemistry JID - 101119673 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Triazoles) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Dipeptidyl-Peptidase IV Inhibitors/chemistry/pharmacology/therapeutic use/chemical synthesis MH - *Triazoles/chemistry/pharmacology/therapeutic use/chemical synthesis MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Molecular Docking Simulation MH - *Dipeptidyl Peptidase 4/metabolism MH - Structure-Activity Relationship MH - *Hypoglycemic Agents/chemistry/pharmacology/chemical synthesis/therapeutic use MH - Molecular Structure OTO - NOTNLM OT - Dipeptidyl peptidase-IV inhibitors OT - Drug discovery OT - Structure-activity relationship OT - Triazole OT - Type-II diabetes mellitus OT - molecular docking EDAT- 2024/11/01 12:25 MHDA- 2026/06/30 06:31 CRDT- 2024/11/01 06:34 PHST- 2024/07/24 00:00 [received] PHST- 2024/09/09 00:00 [revised] PHST- 2024/10/02 00:00 [accepted] PHST- 2026/06/30 06:31 [medline] PHST- 2024/11/01 12:25 [pubmed] PHST- 2024/11/01 06:34 [entrez] AID - CTMC-EPUB-144314 [pii] AID - 10.2174/0115680266339313241021053225 [doi] PST - ppublish SO - Curr Top Med Chem. 2026;26(6):545-581. doi: 10.2174/0115680266339313241021053225. PMID- 39445596 OWN - NLM STAT- MEDLINE DCOM- 20241224 LR - 20260414 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 20 IP - 12 DP - 2024 Dec TI - Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. PG - 8661-8672 LID - 10.1002/alz.14313 [doi] AB - INTRODUCTION: Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. METHODS: We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS: Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. DISCUSSION: These findings support further studies to assess semaglutide's potential in preventing AD. HIGHLIGHTS: Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD. CI - (c) 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Wang, William AU - Wang W AD - Center for Science, Health, and Society, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. FAU - Wang, QuangQiu AU - Wang Q AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. FAU - Qi, Xin AU - Qi X AD - Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. FAU - Gurney, Mark AU - Gurney M AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. FAU - Perry, George AU - Perry G AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. AD - Department of Neuroscience, Development and Regenerative Biology, College of Sciences, The University of Texas at San Antonio, San Antonio, Texas, USA. FAU - Volkow, Nora D AU - Volkow ND AD - National Institute on Drug Abuse, National Institutes of Health, Maryland, USA. FAU - Davis, Pamela B AU - Davis PB AD - Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. FAU - Kaelber, David C AU - Kaelber DC AD - Center for Clinical Informatics Research and Education, The MetroHealth System, Ohio, USA. FAU - Xu, Rong AU - Xu R AD - Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. LA - eng GR - R01 AG057557/AG/NIA NIH HHS/United States GR - R01 AG076051/AG/NIA NIH HHS/United States GR - R56 AG062272/AG/NIA NIH HHS/United States GR - RF1 AG074346/AG/NIA NIH HHS/United States GR - R01 AG061388/AG/NIA NIH HHS/United States GR - AG057557 AG061388 AG062272 AG076649/AG/NIA NIH HHS/United States GR - R01 AG065240/AG/NIA NIH HHS/United States GR - UM1 TR004528/TR/NCATS NIH HHS/United States GR - RF1 AG076649/AG/NIA NIH HHS/United States GR - TR004528/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20241024 PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Glucagon-Like Peptides/therapeutic use MH - *Alzheimer Disease/drug therapy MH - Female MH - Male MH - Aged MH - *Hypoglycemic Agents/therapeutic use MH - United States MH - Middle Aged MH - Aged, 80 and over MH - Semaglutide PMC - PMC11667504 OTO - NOTNLM OT - Alzheimer's disease OT - emulation target trial OT - patient electronic health records OT - prevention OT - real-world data OT - semaglutide OT - type 2 diabetes COIS- All authors declare no competing interests. Author disclosures are available in the Supporting Information. EDAT- 2024/10/24 16:21 MHDA- 2024/12/24 12:21 PMCR- 2024/10/24 CRDT- 2024/10/24 07:03 PHST- 2024/09/10 00:00 [revised] PHST- 2024/07/29 00:00 [received] PHST- 2024/09/12 00:00 [accepted] PHST- 2024/12/24 12:21 [medline] PHST- 2024/10/24 16:21 [pubmed] PHST- 2024/10/24 07:03 [entrez] PHST- 2024/10/24 00:00 [pmc-release] AID - ALZ14313 [pii] AID - 10.1002/alz.14313 [doi] PST - ppublish SO - Alzheimers Dement. 2024 Dec;20(12):8661-8672. doi: 10.1002/alz.14313. Epub 2024 Oct 24. PMID- 39429814 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241024 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 73 DP - 2024 Jul TI - Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study. PG - 102689 LID - 10.1016/j.eclinm.2024.102689 [doi] LID - 102689 AB - BACKGROUND: The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown. METHODS: We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment. FINDINGS: The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n = 12,351), DPP-4 inhibitors (n = 43,850), or sulfonylureas (n = 32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p < 0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p < 0.0001). INTERPRETATION: Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings. FUNDING: Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond. CI - (c) 2024 The Author(s). FAU - Tang, Bowen AU - Tang B AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Sjolander, Arvid AU - Sjolander A AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Wastesson, Jonas W AU - Wastesson JW AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Maura, Geric AU - Maura G AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Blotiere, Pierre-Olivier AU - Blotiere PO AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Szilcz, Mate AU - Szilcz M AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Mak, Jonathan K L AU - Mak JKL AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. AD - Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China. FAU - Qin, Chenxi AU - Qin C AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Alvarsson, Michael AU - Alvarsson M AD - Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. FAU - Religa, Dorota AU - Religa D AD - Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden. FAU - Johnell, Kristina AU - Johnell K AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Hagg, Sara AU - Hagg S AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. LA - eng GR - R01 AG067996/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20240620 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC11490655 OTO - NOTNLM OT - Antidiabetic drugs OT - Dementia OT - Emulated trial study COIS- All authors have provided signed conflict of interest forms and declared no competing interests. EDAT- 2024/10/21 10:51 MHDA- 2024/10/21 10:52 PMCR- 2024/06/20 CRDT- 2024/10/21 05:31 PHST- 2024/03/14 00:00 [received] PHST- 2024/05/25 00:00 [revised] PHST- 2024/05/30 00:00 [accepted] PHST- 2024/10/21 10:52 [medline] PHST- 2024/10/21 10:51 [pubmed] PHST- 2024/10/21 05:31 [entrez] PHST- 2024/06/20 00:00 [pmc-release] AID - S2589-5370(24)00268-2 [pii] AID - 102689 [pii] AID - 10.1016/j.eclinm.2024.102689 [doi] PST - epublish SO - EClinicalMedicine. 2024 Jun 20;73:102689. doi: 10.1016/j.eclinm.2024.102689. eCollection 2024 Jul. PMID- 39422964 OWN - NLM STAT- MEDLINE DCOM- 20241018 LR - 20260713 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 101 IP - s1 DP - 2024 TI - Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer's Disease. PG - S357-S370 LID - 10.3233/JAD-240730 [doi] AB - Alzheimer's disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer's disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer's disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer's disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer's disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson's disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer's disease and other neurodegenerative diseases. FAU - Crook, Harry AU - Crook H AD - Faculty of Medicine, Imperial College London, London, UK. FAU - Edison, Paul AU - Edison P AD - Faculty of Medicine, Imperial College London, London, UK. AD - Cardiff University, Cardiff, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy MH - *Incretins/therapeutic use MH - Animals MH - Diabetes Mellitus, Type 2/drug therapy/complications MH - Neuroprotective Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - drug repositioning OT - gastric inhibitory polypeptide OT - glucagon-like peptide-1 OT - type 2 diabetes mellitus EDAT- 2024/10/18 12:25 MHDA- 2024/10/18 18:22 CRDT- 2024/10/18 11:43 PHST- 2024/10/18 18:22 [medline] PHST- 2024/10/18 12:25 [pubmed] PHST- 2024/10/18 11:43 [entrez] AID - JAD240730 [pii] AID - 10.3233/JAD-240730 [doi] PST - ppublish SO - J Alzheimers Dis. 2024;101(s1):S357-S370. doi: 10.3233/JAD-240730. PMID- 39422949 OWN - NLM STAT- MEDLINE DCOM- 20250305 LR - 20260713 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 101 IP - s1 DP - 2024 TI - Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today? PG - S317-S343 LID - 10.3233/JAD-240069 [doi] AB - Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-beta and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration. FAU - de la Monte, Suzanne M AU - de la Monte SM AD - Departments of Pathology and Laboratory Medicine, Medicine, Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA. LA - eng GR - R01 AA011431/AA/NIAAA NIH HHS/United States GR - R01 AA028408/AA/NIAAA NIH HHS/United States GR - R37 AA011431/AA/NIAAA NIH HHS/United States GR - R56 AA011431/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Insulin) RN - 0 (Hypoglycemic Agents) RN - 0 (Peroxisome Proliferator-Activated Receptors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism/pathology MH - *Insulin/metabolism/pharmacology/therapeutic use MH - Signal Transduction/drug effects MH - Energy Metabolism/drug effects MH - Insulin Resistance MH - Neuronal Plasticity/drug effects MH - Brain/drug effects/pathology MH - Humans MH - Animals MH - Drug Repositioning MH - *Hypoglycemic Agents/pharmacology/therapeutic use MH - Clinical Trials as Topic MH - Cognitive Dysfunction/metabolism/pathology/prevention & control MH - Peroxisome Proliferator-Activated Receptors/agonists/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists/pharmacology/therapeutic use MH - Disease Models, Animal PMC - PMC11807374 MID - NIHMS2052156 OTO - NOTNLM OT - Alzheimer's disease OT - PPAR agonist OT - diabetes drugs OT - incretin OT - insulin resistance OT - insulin sensitizer OT - intranasal insulin OT - neurodegeneration OT - type 3 diabetes OT - vascular dementia COIS- CONFLICT OF INTEREST S. M. de la Monte is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The author has no conflict of interest to report. EDAT- 2024/10/18 12:26 MHDA- 2024/10/18 12:27 PMCR- 2025/02/09 CRDT- 2024/10/18 11:43 PHST- 2024/10/18 12:27 [medline] PHST- 2024/10/18 12:26 [pubmed] PHST- 2024/10/18 11:43 [entrez] PHST- 2025/02/09 00:00 [pmc-release] AID - JAD240069 [pii] AID - 10.3233/JAD-240069 [doi] PST - ppublish SO - J Alzheimers Dis. 2024;101(s1):S317-S343. doi: 10.3233/JAD-240069. PMID- 39358806 OWN - NLM STAT- MEDLINE DCOM- 20241003 LR - 20260923 IS - 1758-9193 (Electronic) VI - 16 IP - 1 DP - 2024 Oct 2 TI - Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial. PG - 212 LID - 10.1186/s13195-024-01573-x [doi] LID - 212 AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. METHODS: The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. RESULTS: EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. CONCLUSIONS: EQW treatment was associated with significant change in inflammatory proteins associated with AD. TRIAL REGISTRATION: EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010. CI - (c) 2024. The Author(s). FAU - Koychev, Ivan AU - Koychev I AUID- ORCID: 0000-0001-6813-8493 AD - Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, UK. ivan.koychev@psych.ox.ac.uk. FAU - Reid, Graham AU - Reid G AUID- ORCID: 0000-0002-6079-9323 AD - Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, UK. FAU - Nguyen, Maggie AU - Nguyen M AD - Duke Center for Precision Health, Duke University School of Medicine, Durham, NC, USA. FAU - Mentz, Robert J AU - Mentz RJ AD - Duke Clinical Research Institute, Durham, NC, USA. FAU - Joyce, Dan AU - Joyce D AD - Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, UK. FAU - Shah, Svati H AU - Shah SH AD - Duke Center for Precision Health, Duke University School of Medicine, Durham, NC, USA. AD - Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA. FAU - Holman, Rury R AU - Holman RR AD - Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. LA - eng SI - ClinicalTrials.gov/NCT01144338 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20241002 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 9P1872D4OL (Exenatide) RN - 0 (Hypoglycemic Agents) RN - 0 (Plasminogen Activator Inhibitor 1) RN - 9007-41-4 (C-Reactive Protein) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/blood MH - Male MH - Female MH - Aged MH - *Diabetes Mellitus, Type 2/drug therapy/blood MH - *Exenatide/therapeutic use MH - Middle Aged MH - Hypoglycemic Agents/therapeutic use MH - Double-Blind Method MH - Plasminogen Activator Inhibitor 1/blood MH - C-Reactive Protein/analysis/metabolism MH - Inflammation/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC11448378 OTO - NOTNLM OT - Alzheimer's disease OT - Glucagon-like peptide-1 receptor agonists OT - Proteomics COIS- IK received research support and honoraria from Novo Nordisk. He is a paid medical advisor for biotechnology (cfdx Ltd) and digital healthcare companies working in dementia (Five Lives SAS, Cognetivity, Mantrah Ltd). RJM received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. RRH reports personal fees from Anji Pharmaceuticals, AstraZeneca, and Novartis. EDAT- 2024/10/03 00:42 MHDA- 2024/10/03 07:18 PMCR- 2024/10/02 CRDT- 2024/10/02 23:49 PHST- 2024/05/21 00:00 [received] PHST- 2024/09/09 00:00 [accepted] PHST- 2024/10/03 07:18 [medline] PHST- 2024/10/03 00:42 [pubmed] PHST- 2024/10/02 23:49 [entrez] PHST- 2024/10/02 00:00 [pmc-release] AID - 10.1186/s13195-024-01573-x [pii] AID - 1573 [pii] AID - 10.1186/s13195-024-01573-x [doi] PST - epublish SO - Alzheimers Res Ther. 2024 Oct 2;16(1):212. doi: 10.1186/s13195-024-01573-x. PMID- 39302577 OWN - NLM STAT- MEDLINE DCOM- 20250131 LR - 20261010 IS - 1720-8386 (Electronic) IS - 0391-4097 (Linking) VI - 48 IP - 2 DP - 2025 Feb TI - Comparative outcomes of systemic diseases in people with type 2 diabetes, or obesity alone treated with and without GLP-1 receptor agonists: a retrospective cohort study from the Global Collaborative Network : Author list. PG - 483-497 LID - 10.1007/s40618-024-02466-4 [doi] AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to manage type 2 diabetes (T2D) and obesity. Despite their recognized benefits in glycemic control and weight management, their impact on broader systemic has been less explored. OBJECTIVE: This study aimed to evaluate the impact of GLP-1RAs on a variety of systemic diseases in people with T2D or obesity. METHODS: We conducted a retrospective cohort study using data from the Global Collaborative Network, accessed through the TriNetX analytics platform. The study comprised two primary groups: individuals with T2D and those with obesity. Each group was further divided into subgroups based on whether they received GLP-1RA treatment or not. Data were analyzed over more than a 5-year follow-up period, comparing incidences of systemic diseases; systemic lupus erythematosus (SLE), systemic sclerosis (SS), rheumatoid arthritis (RA), ulcerative colitis (UC), crohn's disease (CD), alzheimer's disease (AD), parkinson's disease (PD), dementia, bronchial asthma (BA), osteoporosis, and several cancers. RESULTS: In the T2D cohorts, GLP-1RA treatment was associated with significantly lower incidences of several systemic and metabolic conditions as compared to those without GLP-1RA, specifically, dementia (Risk Difference (RD): -0.010, p < 0.001), AD (RD: -0.003, p < 0.001), PD (RD: -0.002, p < 0.001), and pancreatic cancer (RD: -0.003, p < 0.001). SLE and SS also saw statistically significant reductions, though the differences were minor in magnitude (RD: -0.001 and - 0.000 respectively, p < 0.001 for both). Conversely, BA a showed a slight increase in risk (RD: 0.002, p < 0.001). CONCLUSIONS: GLP-1RAs demonstrate potential benefits in reducing the risk of several systemic conditions in people with T2D or obesity. Further prospective studies are needed to confirm these effects fully and understand the mechanisms. CI - (c) 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE). FAU - Nassar, Mahmoud AU - Nassar M AUID- ORCID: 0000-0002-5401-9562 AD - Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. Dr.Nassar@Aucegypt.edu. FAU - Nassar, Omar AU - Nassar O AD - Williamsville East High School, Buffalo, NY, USA. FAU - Abosheaishaa, Hazem AU - Abosheaishaa H AD - Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Misra, Anoop AU - Misra A AD - Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India. AD - National Diabetes, Obesity and Cholesterol Foundation (N-DOC), New Delhi, India. AD - Diabetes Foundation (India) (DFI) India, New Delhi, India. LA - eng PT - Comparative Study PT - Journal Article DEP - 20240920 PL - Italy TA - J Endocrinol Invest JT - Journal of endocrinological investigation JID - 7806594 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology MH - Retrospective Studies MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - *Obesity/drug therapy/complications/epidemiology MH - Female MH - Male MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use MH - Aged MH - Follow-Up Studies MH - Treatment Outcome MH - Adult OTO - NOTNLM OT - Bronchial asthma OT - Crohn's disease OT - Dementia OT - Lupus OT - Obesity OT - Osteoporosis. OT - Pancreatic cancer OT - Retrospective cohort study OT - Rheumatoid arthritis OT - Systemic diseases OT - Systemic sclerosis OT - TriNetX OT - Type 2 diabetes OT - Ulcerative colitis COIS- Declarations. Conflict of Interest Statement: On behalf of all authors, the corresponding author states that there is no conflict of interest. EDAT- 2024/09/20 13:00 MHDA- 2025/01/31 12:24 CRDT- 2024/09/20 11:20 PHST- 2024/06/26 00:00 [received] PHST- 2024/09/04 00:00 [accepted] PHST- 2025/01/31 12:24 [medline] PHST- 2024/09/20 13:00 [pubmed] PHST- 2024/09/20 11:20 [entrez] AID - 10.1007/s40618-024-02466-4 [pii] AID - 10.1007/s40618-024-02466-4 [doi] PST - ppublish SO - J Endocrinol Invest. 2025 Feb;48(2):483-497. doi: 10.1007/s40618-024-02466-4. Epub 2024 Sep 20. PMID- 39265262 OWN - NLM STAT- MEDLINE DCOM- 20241204 LR - 20250711 IS - 1573-2509 (Electronic) IS - 0920-9964 (Linking) VI - 274 DP - 2024 Dec TI - Insulin-resistance as a modifiable pathway to cognitive dysfunction in schizophrenia: A systematic review. PG - 78-89 LID - S0920-9964(24)00417-1 [pii] LID - 10.1016/j.schres.2024.09.008 [doi] AB - BACKGROUND: Cognitive deficits are difficult to treat and negatively influence quality of life and functional outcomes of persons with schizophrenia. In the last twenty years, extensive literature demonstrated that persons with diabetes and insulin resistance (IR) also display cognitive deficits. Being type 2 diabetes (T2DM) and IR highly frequent in persons with schizophrenia, it is plausible to hypothesize that these conditions might play a role in determining dyscognition. If that is the case, acting on glucose dysmetabolism may eventually improve cognitive functioning. This review aims at: 1. evaluating the association between IR or T2DM and cognitive dysfunction in schizophrenia; 2. reviewing the evidence that pharmacological treatment of IR or T2DM may improve dyscognition in schizophrenia. METHODS: Two systematic searches were conducted in PubMed, PsycInfo, and Scopus. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. RESULTS: From the first search we included 17 studies, 8 on the effects of T2DM and 9 on the effects of IR-other prediabetes measures on cognition in persons with schizophrenia. From the second search we included 12 studies investigating the effect on cognition of glucose (4 studies), insulin (2 studies), metformin (2 studies), PPAR-gamma agonists (2 studies), GLP-1 agonist (1 study), bromocriptine (1 study). CONCLUSIONS: T2DM was associated with worse cognitive function in persons with schizophrenia, while IR was less strongly associated with cognitive dysfunction. Evidence regarding the efficacy of glucose-lowering medications on cognition in schizophrenia is inconclusive, yet methodological issues likely contribute to explain conflicting results. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Salvi, Virginio AU - Salvi V AD - Department of Mental Health and Addiction, ASST Crema, L.go Ugo Dossena 2, 26013 Crema, CR, Italy. Electronic address: virginiosalvi@gmail.com. FAU - Tripodi, Beniamino AU - Tripodi B AD - Department of Mental Health and Addiction, ASST Crema, L.go Ugo Dossena 2, 26013 Crema, CR, Italy. FAU - Cerveri, Giancarlo AU - Cerveri G AD - Department of Mental Health and Addiction, ASST Lodi, Via Mose Bianchi 26, 26900 Lodi, Italy. FAU - Migliarese, Giovanni AU - Migliarese G AD - Department of Mental Health and Addiction, ASST Pavia, C.so Milano 19, 27029 Vigevano, PV, Italy. FAU - Bertoni, Lorenzo AU - Bertoni L AD - Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. FAU - Nibbio, Gabriele AU - Nibbio G AD - Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. FAU - Barlati, Stefano AU - Barlati S AD - Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. FAU - Vita, Antonio AU - Vita A AD - Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. FAU - Mencacci, Claudio AU - Mencacci C AD - Director Emeritus, Department of Neurosciences-Mental Health, ASST Fatebenefratelli-Sacco, Milan, Italy. LA - eng PT - Journal Article PT - Systematic Review DEP - 20240911 PL - Netherlands TA - Schizophr Res JT - Schizophrenia research JID - 8804207 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Schizophrenia/drug therapy/physiopathology/complications MH - *Insulin Resistance/physiology MH - *Cognitive Dysfunction/etiology/physiopathology/drug therapy MH - *Diabetes Mellitus, Type 2/complications/drug therapy/physiopathology MH - Hypoglycemic Agents/pharmacology OTO - NOTNLM OT - Cognition OT - Diabetes OT - Insulin-resistance OT - Schizophrenia OT - T2DM COIS- Declaration of competing interest The authors declare no conflict of interest for the present article. EDAT- 2024/09/13 00:46 MHDA- 2024/12/05 05:31 CRDT- 2024/09/12 18:03 PHST- 2024/02/23 00:00 [received] PHST- 2024/07/21 00:00 [revised] PHST- 2024/09/06 00:00 [accepted] PHST- 2024/12/05 05:31 [medline] PHST- 2024/09/13 00:46 [pubmed] PHST- 2024/09/12 18:03 [entrez] AID - S0920-9964(24)00417-1 [pii] AID - 10.1016/j.schres.2024.09.008 [doi] PST - ppublish SO - Schizophr Res. 2024 Dec;274:78-89. doi: 10.1016/j.schres.2024.09.008. Epub 2024 Sep 11. PMID- 39257395 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240914 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 15 DP - 2024 TI - Daphnetin modulates GLP-1R to alleviate cognitive dysfunction in diabetes: implications for inflammation and oxidative stress. PG - 1438926 LID - 10.3389/fphar.2024.1438926 [doi] LID - 1438926 AB - Daphnetin exerts certain pharmacological function on a variety of diseases, but its role in diabetic cognitive dysfunction has not been elucidated. In this study, we carried a series of pharmacological studies of GLP-1R with daphnetin. In rats and PC12 cells, we found that daphnetin could alleviate diabetic cognitive dysfunction and increase the expression level of GLP-1R. Additionally, the anti-diabetic cognitive dysfunction effect of DAP was accompanied by the inhibition of inflammation and oxidative stress. Further in-depth studies demonstrated that the inhibition GLP-1R enhanced the protective effect of daphnetin, whilst, the overexpression of GLP-1R weakened the protective effect of daphnetin. These results indicated that daphnetin protects diabetes cognitive dysfunction by regulating GLP-1R-mediated inflammation and oxidative stress, act as a GLP-1R agonist. The study further demonstrated that daphnetin has great value in preventing cognitive dysfunction in type 2 diabetes, and GLP-1R is a key potential target for the treatment of related diseases. CI - Copyright (c) 2024 Liang, Tian and Ding. FAU - Liang, Feng AU - Liang F AD - Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China. FAU - Tian, Xinyi AU - Tian X AD - College of Chemistry and Pharmacy, Northwest A&F University, Xianyang, China. FAU - Ding, Lining AU - Ding L AD - College of Chemistry and Pharmacy, Northwest A&F University, Xianyang, China. AD - Guangdong Pharmaceutical University, Guangzhou, China. LA - eng PT - Journal Article DEP - 20240827 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC11384579 OTO - NOTNLM OT - GLP-1 receptor OT - daphnetin OT - diabetes cognitive dysfunction OT - inflammation and oxidative stress OT - pharmacological effects COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/09/11 07:43 MHDA- 2024/09/11 07:44 PMCR- 2024/08/27 CRDT- 2024/09/11 04:13 PHST- 2024/05/27 00:00 [received] PHST- 2024/08/14 00:00 [accepted] PHST- 2024/09/11 07:44 [medline] PHST- 2024/09/11 07:43 [pubmed] PHST- 2024/09/11 04:13 [entrez] PHST- 2024/08/27 00:00 [pmc-release] AID - 1438926 [pii] AID - 10.3389/fphar.2024.1438926 [doi] PST - epublish SO - Front Pharmacol. 2024 Aug 27;15:1438926. doi: 10.3389/fphar.2024.1438926. eCollection 2024. PMID- 39248211 OWN - NLM STAT- MEDLINE DCOM- 20241004 LR - 20260323 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 26 IP - 11 DP - 2024 Nov TI - Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks. PG - 5420-5430 LID - 10.1111/dom.15918 [doi] AB - BACKGROUND: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged >/=50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA. CI - (c) 2024 John Wiley & Sons Ltd. FAU - Pai, Yen-Wei AU - Pai YW AD - Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan. AD - Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Chen, I-Chieh AU - Chen IC AUID- ORCID: 0000-0002-8345-5304 AD - Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Lin, Jun-Fu AU - Lin JF AUID- ORCID: 0009-0006-5287-7893 AD - Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Chen, Xiao-Hui AU - Chen XH AD - Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Chen, Hsin-Hua AU - Chen HH AUID- ORCID: 0000-0002-7304-4587 AD - Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Chang, Ming-Hong AU - Chang MH AD - Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan. AD - Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Huang, Jin-An AU - Huang JA AD - Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan. AD - Department of Health Business Administration, Hungkuang University, Taichung, Taiwan. FAU - Lin, Ching-Heng AU - Lin CH AUID- ORCID: 0000-0002-2450-6108 AD - Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. AD - Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan. AD - Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan. AD - Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. LA - eng GR - TCVGH-NCHU1137618/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-YM1130105/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-1137315C/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-1127303C/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-112G211/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-113G211/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-NHRI11301/Taichung Veterans General Hospital Research Fund/ GR - TCVGH-YM1120103/Taichung Veterans General Hospital Research Fund/ PT - Journal Article DEP - 20240909 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/mortality/complications MH - Female MH - Male MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - Retrospective Studies MH - Aged MH - *Dementia/epidemiology/mortality MH - Middle Aged MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects MH - Incidence MH - Hypoglycemic Agents/therapeutic use MH - United States/epidemiology MH - Aged, 80 and over MH - Mortality MH - Cohort Studies MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - DPP-4 inhibitor OT - GLP-1 RA OT - SGLT-2 inhibitor OT - incident dementia OT - mortality OT - type 2 diabetes EDAT- 2024/09/09 12:44 MHDA- 2024/10/04 12:43 CRDT- 2024/09/09 06:52 PHST- 2024/08/08 00:00 [revised] PHST- 2024/06/12 00:00 [received] PHST- 2024/08/15 00:00 [accepted] PHST- 2024/10/04 12:43 [medline] PHST- 2024/09/09 12:44 [pubmed] PHST- 2024/09/09 06:52 [entrez] AID - 10.1111/dom.15918 [doi] PST - ppublish SO - Diabetes Obes Metab. 2024 Nov;26(11):5420-5430. doi: 10.1111/dom.15918. Epub 2024 Sep 9. PMID- 39216535 OWN - NLM STAT- MEDLINE DCOM- 20241006 LR - 20261010 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 89 DP - 2024 Nov TI - The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice. PG - 102019 LID - S2212-8778(24)00150-9 [pii] LID - 10.1016/j.molmet.2024.102019 [doi] LID - 102019 AB - OBJECTIVE: The development of glucagon-like peptide-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has been accompanied by evidence for anti-inflammatory and cytoprotective actions in the heart, blood vessels, kidney, and brain. Whether GLP-1R agonists might be useful clinically for attenuating deterioration of cognitive dysfunction and reducing the progression of Alzheimer's disease remains uncertain. METHODS: Here we evaluated the actions of semaglutide and tirzepatide, clinically distinct GLP-1 medicines, in two mouse models of neurodegeneration. RESULTS: Semaglutide reduced body weight and improved glucose tolerance in 12-month-old male and female 5XFAD and APP/PS1 mice, consistent with pharmacological engagement of the GLP-1R. Nevertheless, amyloid plaque density was not different in the cerebral cortex, hippocampus, or subiculum of semaglutide-treated 12-month-old 5XFAD and APP/PS1 mice. IBA1 and GFAP expression were increased in the hippocampus of 5XFAD and APP/PS1 mice but were not reduced by semaglutide. Moreover, parameters of neurobehavioral and cognitive function evaluated using Open Field testing or the Morris water maze were not improved following treatment with semaglutide. To explore whether incretin therapies might be more effective in younger mice, we studied semaglutide and tirzepatide action in 6-month-old male and female 5XFAD mice. Neither semaglutide nor tirzepatide modified the extent of plaque accumulation, hippocampal IBA1+ or GFAP+ cells, or parameters of neurobehavioral testing, despite improving glucose tolerance and reducing body weight. mRNA biomarkers of inflammation and neurodegeneration were increased in the hippocampus of male and female 5XFAD mice but were not reduced after treatment with semaglutide or tirzepatide. CONCLUSIONS: Collectively, these findings reveal preservation of the metabolic actions of two GLP-1 medicines, semaglutide and tirzepatide, yet inability to detect improvement in structural and functional parameters of neurodegeneration in two mouse models of Alzheimer's disease. CI - Copyright (c) 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved. FAU - Forny Germano, Leticia AU - Forny Germano L AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Koehler, Jacqueline A AU - Koehler JA AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Baggio, Laurie L AU - Baggio LL AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Cui, Fiona AU - Cui F AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Wong, Chi Kin AU - Wong CK AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Rittig, Nikolaj AU - Rittig N AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Cao, Xiemin AU - Cao X AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Matthews, Dianne AU - Matthews D AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. FAU - Drucker, Daniel J AU - Drucker DJ AD - Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, M5G1X5, Canada. Electronic address: drucker@lunenfeld.ca. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240830 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - Mice MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - Male MH - Female MH - *Alzheimer Disease/drug therapy/metabolism MH - *Mice, Transgenic MH - *Cognition/drug effects MH - Disease Models, Animal MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Plaque, Amyloid/metabolism/drug therapy MH - Cognitive Dysfunction/drug therapy/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Semaglutide PMC - PMC11408156 OTO - NOTNLM OT - Alzheimer's OT - Diabetes OT - GLP-1 OT - Glucagon-like peptides OT - Inflammation OT - Neurodegeneration OT - Obesity COIS- Declaration of competing interest Dr. Drucker has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, AstraZeneca Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk Inc., Pfizer Inc. and Zealand Pharma Inc. Laurie Baggio is currently an employee of Avalere Health. None of the authors have anything else to declare. EDAT- 2024/09/01 16:17 MHDA- 2024/10/07 00:35 PMCR- 2024/08/30 CRDT- 2024/08/31 19:24 PHST- 2024/06/26 00:00 [received] PHST- 2024/08/17 00:00 [revised] PHST- 2024/08/25 00:00 [accepted] PHST- 2024/10/07 00:35 [medline] PHST- 2024/09/01 16:17 [pubmed] PHST- 2024/08/31 19:24 [entrez] PHST- 2024/08/30 00:00 [pmc-release] AID - S2212-8778(24)00150-9 [pii] AID - 102019 [pii] AID - 10.1016/j.molmet.2024.102019 [doi] PST - ppublish SO - Mol Metab. 2024 Nov;89:102019. doi: 10.1016/j.molmet.2024.102019. Epub 2024 Aug 30. PMID- 39186787 OWN - NLM STAT- MEDLINE DCOM- 20241014 LR - 20260703 IS - 1539-3704 (Electronic) IS - 0003-4819 (Linking) VI - 177 IP - 10 DP - 2024 Oct TI - Sodium-Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia : A Population-Based Cohort Study. PG - 1319-1329 LID - 10.7326/M23-3220 [doi] AB - BACKGROUND: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain. OBJECTIVE: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA). DESIGN: Target trial emulation study. SETTING: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022. PATIENTS: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide. MEASUREMENTS: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score-matched cohort adjusted for confounders. RESULTS: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was -0.91 percentage point (95% CI, -2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16). LIMITATION: Residual confounding is possible; there was no adjustment for hemoglobin A(1c) levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly. CONCLUSION: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required. PRIMARY FUNDING SOURCE: Ministry of Food and Drug Safety of South Korea. FAU - Hong, Bin AU - Hong B AD - School of Pharmacy, Sungkyunkwan University, Suwon, South Korea (B.H., H.Y.K.). FAU - Bea, Sungho AU - Bea S AUID- ORCID: 0000-0003-2622-6553 AD - School of Pharmacy, Sungkyunkwan University, Suwon, South Korea, and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.B.). FAU - Ko, Hwa Yeon AU - Ko HY AUID- ORCID: 0000-0001-5297-8826 AD - School of Pharmacy, Sungkyunkwan University, Suwon, South Korea (B.H., H.Y.K.). FAU - Kim, Woo Jung AU - Kim WJ AUID- ORCID: 0000-0002-4963-4819 AD - Department of Psychiatry, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin; Institute of Behavioral Sciences in Medicine, Yonsei University College of Medicine, Seoul; and Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, South Korea (W.J.K.). FAU - Cho, Young Min AU - Cho YM AUID- ORCID: 0000-0002-2331-6126 AD - Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (Y.M.C.). FAU - Shin, Ju-Young AU - Shin JY AUID- ORCID: 0000-0003-1010-7525 AD - School of Pharmacy and Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, and Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea (J.-Y.S.). LA - eng PT - Journal Article DEP - 20240827 PL - United States TA - Ann Intern Med JT - Annals of internal medicine JID - 0372351 RN - 0 (Recombinant Fusion Proteins) RN - 0 (Immunoglobulin Fc Fragments) RN - WTT295HSY5 (dulaglutide) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucosides) RN - 0 (Hypoglycemic Agents) RN - 0 (Benzhydryl Compounds) RN - HDC1R2M35U (empagliflozin) RN - 1ULL0QJ8UC (dapagliflozin) SB - IM MH - Humans MH - *Recombinant Fusion Proteins/therapeutic use/adverse effects MH - *Immunoglobulin Fc Fragments/therapeutic use/adverse effects MH - *Glucagon-Like Peptides/analogs & derivatives/therapeutic use/adverse effects MH - Male MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - Female MH - *Diabetes Mellitus, Type 2/drug therapy MH - Aged MH - *Dementia/epidemiology MH - *Glucosides/therapeutic use/adverse effects MH - Middle Aged MH - Republic of Korea/epidemiology MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - Benzhydryl Compounds/therapeutic use/adverse effects MH - Risk Factors MH - Propensity Score MH - Cohort Studies COIS- Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3220. EDAT- 2024/08/26 19:49 MHDA- 2024/10/14 19:00 CRDT- 2024/08/26 17:02 PHST- 2024/10/14 19:00 [medline] PHST- 2024/08/26 19:49 [pubmed] PHST- 2024/08/26 17:02 [entrez] AID - 10.7326/M23-3220 [doi] PST - ppublish SO - Ann Intern Med. 2024 Oct;177(10):1319-1329. doi: 10.7326/M23-3220. Epub 2024 Aug 27. PMID- 39182542 OWN - NLM STAT- MEDLINE DCOM- 20240914 LR - 20250103 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 982 DP - 2024 Nov 5 TI - Beyond insulin: The Intriguing role of GLP-1 in Parkinson's disease. PG - 176936 LID - S0014-2999(24)00625-3 [pii] LID - 10.1016/j.ejphar.2024.176936 [doi] AB - GLP-1 (Glucagon-like peptide 1) serves as both a peptide hormone and a growth factor, is released upon nutrient intake and contributes to insulin secretion stimulated by glucose levels. Also, GLP-1 is synthesized within several brain areas and plays a vital function in providing neuroprotection and reducing inflammation through the activation of the GLP-1 receptor. Parkinson's Disease (PD) is a neurodegenerative illness that worsens with time and is defined by considerable morbidity. Presently, there are few pharmaceutical choices available, and none of the existing therapies are capable of modifying the course of the disease. There is a suggestion that type 2 diabetes mellitus (T2DM) could increase the risk of PD, and the presence of both conditions concurrently might exacerbate PD symptoms and hasten neurodegeneration. GLP-1 receptor (GLP-1R) agonists exhibit numerous implications like enhancement of glucose-dependent insulin release and biosynthesis, suppression of glucagon secretion and gastric emptying. Also, some GLP-1R agonists have received clinical approval for the management of T2DM. Moreover, the use of GLP-1R agonists has demonstrated counter-inflammatory, neurotrophic, and neuroprotective actions in various preclinical models of neurodegenerative disorders. Considering the significant amount of evidence backing the potential of GLP-1R agonists to protect the nervous system across different research settings, this article delves into examining the hopeful prospect of GLP-1R agonists as a treatment option for PD. This review sheds light on combined neuroprotective benefits of GLP-1R agonists and the possible mechanisms driving the protective effects on the PD brain, through the collection of data from various preclinical and clinical investigations. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Verma, Aanchal AU - Verma A AD - Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India. FAU - Goyal, Ahsas AU - Goyal A AD - Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India. Electronic address: ahsasgoyal1990@gmail.com. LA - eng PT - Journal Article PT - Review DEP - 20240823 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Parkinson Disease/metabolism/drug therapy MH - Animals MH - *Glucagon-Like Peptide 1/metabolism MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - *Insulin/metabolism MH - Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Neuroprotective Agents/therapeutic use/pharmacology MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - GLP-1 receptor agonist OT - Glucagon-like peptide 1 OT - Neurodegeneration OT - Neuroinflammation OT - Oxidative stress OT - Parkinson's COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/08/26 12:38 MHDA- 2024/09/15 14:09 CRDT- 2024/08/25 19:23 PHST- 2024/04/09 00:00 [received] PHST- 2024/08/12 00:00 [revised] PHST- 2024/08/22 00:00 [accepted] PHST- 2024/09/15 14:09 [medline] PHST- 2024/08/26 12:38 [pubmed] PHST- 2024/08/25 19:23 [entrez] AID - S0014-2999(24)00625-3 [pii] AID - 10.1016/j.ejphar.2024.176936 [doi] PST - ppublish SO - Eur J Pharmacol. 2024 Nov 5;982:176936. doi: 10.1016/j.ejphar.2024.176936. Epub 2024 Aug 23. PMID- 39173996 OWN - NLM STAT- MEDLINE DCOM- 20240903 LR - 20240903 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 355 DP - 2024 Oct 15 TI - Repurposing antidiabetic drugs for Alzheimer's disease: A review of preclinical and clinical evidence and overcoming challenges. PG - 123001 LID - S0024-3205(24)00591-5 [pii] LID - 10.1016/j.lfs.2024.123001 [doi] AB - Repurposing antidiabetic drugs for the treatment of Alzheimer's disease (AD) has emerged as a promising therapeutic strategy. This review examines the potential of repurposing antidiabetic drugs for AD treatment, focusing on preclinical evidence, clinical trials, and observational studies. In addition, the review aims to explore challenges and opportunities in repurposing antidiabetic drugs for AD, emphasizing the importance of well-designed clinical trials that consider patient selection criteria, refined outcome measures, adverse effects, and combination therapies to enhance therapeutic efficacy. Preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, metformin, thiazolidinediones, and sodium-glucose co-transporter-2 (SGLT2) inhibitors exhibit neuroprotective effects in AD preclinical models. In preclinical studies, antidiabetic drugs have demonstrated neuroprotective effects by reducing amyloid beta (Abeta) plaques, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. Antidiabetic drug classes, notably GLP-1 analogs and SGLT2 inhibitors, and a reduced risk of dementia in patients with diabetes mellitus. While the evidence for DPP4 inhibitors is mixed, some studies suggest a potential protective effect. On the other hand, alpha-glucosidase inhibitors (AGIs) and sulfonylureas may potentially increase the risk, especially in those experiencing recurrent hypoglycemic events. Repurposing antidiabetic drugs for AD is a promising therapeutic strategy, but challenges such as disease heterogeneity, limited biomarkers, and benefits versus risk evaluation need to be addressed. Ongoing clinical trials in mild cognitive impairment (MCI) and early AD patients without diabetes will be crucial in determining the clinical efficacy and safety of the antidiabetic drugs, paving the way for potential treatments for AD. CI - Copyright (c) 2024 Elsevier Inc. All rights reserved. FAU - Tran, Jacky AU - Tran J AD - Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA. FAU - Parekh, Sneh AU - Parekh S AD - Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA. FAU - Rockcole, Julia AU - Rockcole J AD - Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA. FAU - Wilson, Danielle AU - Wilson D AD - Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA. FAU - Parmar, Mayur S AU - Parmar MS AD - Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA. Electronic address: mparmar@nova.edu. LA - eng PT - Journal Article PT - Review DEP - 20240821 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) SB - IM MH - *Alzheimer Disease/drug therapy MH - Humans MH - *Drug Repositioning MH - *Hypoglycemic Agents/therapeutic use/pharmacology MH - Animals MH - Neuroprotective Agents/therapeutic use/pharmacology MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology OTO - NOTNLM OT - Alzheimer's disease OT - Antidiabetic drugs OT - Cognitive impairment OT - Dipeptidyl peptidase-4 inhibitors (DPP4i) OT - Drug repurposing OT - Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) OT - Sodium-glucose cotransporter-2 inhibitors (SGLT2i) OT - Type 2 diabetes mellitus COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/08/23 00:43 MHDA- 2024/09/04 01:01 CRDT- 2024/08/22 19:23 PHST- 2024/07/05 00:00 [received] PHST- 2024/08/13 00:00 [revised] PHST- 2024/08/19 00:00 [accepted] PHST- 2024/09/04 01:01 [medline] PHST- 2024/08/23 00:43 [pubmed] PHST- 2024/08/22 19:23 [entrez] AID - S0024-3205(24)00591-5 [pii] AID - 10.1016/j.lfs.2024.123001 [doi] PST - ppublish SO - Life Sci. 2024 Oct 15;355:123001. doi: 10.1016/j.lfs.2024.123001. Epub 2024 Aug 21. PMID- 39139128 OWN - NLM STAT- MEDLINE DCOM- 20240814 LR - 20250731 IS - 1752-8984 (Electronic) IS - 1479-1641 (Print) IS - 1479-1641 (Linking) VI - 21 IP - 4 DP - 2024 Jul-Aug TI - Patient-important outcomes in type 2 diabetes: The paradigm of the sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. PG - 14791641241269743 LID - 10.1177/14791641241269743 [doi] LID - 14791641241269743 AB - The newfound knowledge in type 2 diabetes (T2D) during the past decade for the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is wealthy in favorable results for key patient-important outcomes including morbidity, mortality and health-related quality of life (HRQoL). The SGLT-2i and GLP-1RA offer cardiovascular and renal protection beyond their glucose lowering effect, reduce body weight and hypoglycemia and improve diabetes-related distress, physical function and HRQoL. Along with the fixed-ratio combinations of basal insulin/GLP-1RA, they make feasible a regimen simplification and de-escalation from high dose and multiple injections of insulin reducing treatment burden. Besides cardiorenal risk reduction, the SGLT-2i and GLP-1RA reduce the incidence of depression, cognitive decline, respiratory disease, gout, arrhythmias and other co-occurring conditions of T2D, namely multimorbidity, which frequently complicates T2D and adversely affects HRQoL. The alleviation of multimorbidity by the pleiotropic effects of the SGLT-2i and GLP-1RA, could improve patients' HRQoL. The use of the SGLT-2i and GLP-1RA should be increased within a shared decision-making in which they are reframed as cardiorenal risk-reducing medications with the potential to lower blood glucose. By improving outcomes that patients may highly perceive and value, the SGLT-2i and GLP-1RA may facilitate the contemporary person-centered management of T2D. FAU - Kintzoglanakis, Kyriakos AU - Kintzoglanakis K AUID- ORCID: 0000-0003-1265-3351 AD - Department of Primary Care, Local Health-Team Unit of Thebes, Thebes, Greece. FAU - Diamantis, Christos AU - Diamantis C AD - Department of Primary Care, General Hospital of Livadeia, Livadeia, Greece. FAU - Mariolis, Anargiros AU - Mariolis A AD - Department of Primary Care, Health Center of Areopolis, Areopolis, Laconia, Greece. FAU - Paschou, Stavroula A AU - Paschou SA AD - Departement of Endocrinology, Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, Athens, Greece. LA - eng PT - Journal Article PT - Review PL - England TA - Diab Vasc Dis Res JT - Diabetes & vascular disease research JID - 101234011 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Blood Glucose) RN - 0 (Incretins) RN - 0 (Biomarkers) RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/diagnosis/blood MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - *Quality of Life MH - Treatment Outcome MH - *Hypoglycemic Agents/therapeutic use/adverse effects MH - *Blood Glucose/metabolism/drug effects MH - Risk Factors MH - Glycemic Control/adverse effects MH - Incretins/therapeutic use/adverse effects MH - Biomarkers/blood MH - Patient Reported Outcome Measures MH - Risk Assessment MH - Health Status MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC11325323 OTO - NOTNLM OT - Type 2 diabetes mellitus OT - fixed ratio combination of basal insulin/glucagon-like peptide-1 receptor agonists OT - glucagon-like peptide-1 receptor agonists OT - health-related quality of life OT - patient-important outcomes OT - sodium-glucose cotransporter-2 inhibitors COIS- Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2024/08/14 06:42 MHDA- 2024/08/14 06:43 PMCR- 2024/08/14 CRDT- 2024/08/14 04:03 PHST- 2024/08/14 06:43 [medline] PHST- 2024/08/14 06:42 [pubmed] PHST- 2024/08/14 04:03 [entrez] PHST- 2024/08/14 00:00 [pmc-release] AID - 10.1177_14791641241269743 [pii] AID - 10.1177/14791641241269743 [doi] PST - ppublish SO - Diab Vasc Dis Res. 2024 Jul-Aug;21(4):14791641241269743. doi: 10.1177/14791641241269743. PMID- 39062586 OWN - NLM STAT- MEDLINE DCOM- 20240728 LR - 20260410 IS - 2218-273X (Electronic) IS - 2218-273X (Linking) VI - 14 IP - 7 DP - 2024 Jul 19 TI - Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration. LID - 10.3390/biom14070872 [doi] LID - 872 AB - Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. FAU - Kopp, Katherine O AU - Kopp KO AUID- ORCID: 0000-0003-3011-8854 AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Li, Yazhou AU - Li Y AUID- ORCID: 0000-0002-6048-3660 AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Glotfelty, Elliot J AU - Glotfelty EJ AUID- ORCID: 0000-0001-5125-8720 AD - Cellular Stress and Inflammation Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Tweedie, David AU - Tweedie D AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Greig, Nigel H AU - Greig NH AUID- ORCID: 0000-0002-3032-1468 AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. LA - eng GR - AG000333/National Institute on Aging, Intramural Research Program, NIH, USA/ PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20240719 PL - Switzerland TA - Biomolecules JT - Biomolecules JID - 101596414 RN - 0 (Neuroprotective Agents) RN - 0 (Incretins) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Anti-Inflammatory Agents) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 9P1872D4OL (Exenatide) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Animals MH - *Neuroprotective Agents/pharmacology/chemistry MH - *Incretins/pharmacology MH - Mice MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - *Anti-Inflammatory Agents/pharmacology/chemistry MH - Cell Line MH - Receptors, Gastrointestinal Hormone/agonists/metabolism MH - Exenatide/pharmacology MH - Microglia/drug effects/metabolism MH - Neurodegenerative Diseases/drug therapy/metabolism MH - Cell Line, Tumor MH - Peptides/pharmacology/chemistry MH - Receptors, Glucagon/agonists/metabolism MH - Glucagon-Like Peptide 1/metabolism/agonists MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC11275108 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - glucagon OT - glucagon-like peptide-1 (GLP-1) OT - glucose-dependent insulinotropic polypeptide (GIP) OT - incretin mimetic OT - microglia OT - neurodegeneration OT - neuroinflammation COIS- The Intramural Research Program of the National Institute on Aging (NIA), NIH, holds patent rights in relation to the use of exenatide in neurodegenerative disorders via the work NHG. These are assigned to NIA, NIH, in entirety, and not to NHG. All other authors report no conflicts of interest. EDAT- 2024/07/27 10:47 MHDA- 2024/07/28 14:53 PMCR- 2024/07/19 CRDT- 2024/07/27 01:09 PHST- 2024/05/29 00:00 [received] PHST- 2024/07/03 00:00 [revised] PHST- 2024/07/15 00:00 [accepted] PHST- 2024/07/28 14:53 [medline] PHST- 2024/07/27 10:47 [pubmed] PHST- 2024/07/27 01:09 [entrez] PHST- 2024/07/19 00:00 [pmc-release] AID - biom14070872 [pii] AID - biomolecules-14-00872 [pii] AID - 10.3390/biom14070872 [doi] PST - epublish SO - Biomolecules. 2024 Jul 19;14(7):872. doi: 10.3390/biom14070872. PMID- 39062126 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260923 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 12 IP - 7 DP - 2024 Jul 12 TI - Ketosis Suppression and Ageing (KetoSAge) Part 2: The Effect of Suppressing Ketosis on Biomarkers Associated with Ageing, HOMA-IR, Leptin, Osteocalcin, and GLP-1, in Healthy Females. LID - 10.3390/biomedicines12071553 [doi] LID - 1553 AB - Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m(2) +/- 1.4), metabolically healthy, pre-menopausal women (age 32.3 +/- 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (+/- 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia. FAU - Cooper, Isabella D AU - Cooper ID AUID- ORCID: 0000-0001-7374-4340 AD - Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. FAU - Kyriakidou, Yvoni AU - Kyriakidou Y AUID- ORCID: 0000-0002-8883-2228 AD - Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. FAU - Petagine, Lucy AU - Petagine L AUID- ORCID: 0000-0003-2457-4001 AD - Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. FAU - Edwards, Kurtis AU - Edwards K AUID- ORCID: 0000-0003-2481-4909 AD - Cancer Biomarkers and Mechanisms Group, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. FAU - Soto-Mota, Adrian AU - Soto-Mota A AUID- ORCID: 0000-0002-9173-7440 AD - Metabolic Diseases Research Unit, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City 14080, Mexico. AD - School of Medicine, Tecnologico de Monterrey, Mexico City 14380, Mexico. FAU - Brookler, Kenneth AU - Brookler K AUID- ORCID: 0000-0002-3088-9897 AD - Retired former Research Collaborator, Aerospace Medicine and Vestibular Research Laboratory, Mayo Clinic, Scottsdale, AZ 85259, USA. FAU - Elliott, Bradley T AU - Elliott BT AUID- ORCID: 0000-0003-4295-3785 AD - Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. LA - eng PT - Journal Article DEP - 20240712 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC11274887 OTO - NOTNLM OT - GLP-1 OT - HOMA-IR OT - ageing OT - cortisol OT - hyperinsulinaemia OT - insulin resistance OT - ketosis OT - leptin OT - metabolic syndrome OT - osteocalcin COIS- The authors declare no conflicts of interest. EDAT- 2024/07/27 10:47 MHDA- 2024/07/27 10:48 PMCR- 2024/07/12 CRDT- 2024/07/27 01:07 PHST- 2024/06/05 00:00 [received] PHST- 2024/07/08 00:00 [revised] PHST- 2024/07/09 00:00 [accepted] PHST- 2024/07/27 10:48 [medline] PHST- 2024/07/27 10:47 [pubmed] PHST- 2024/07/27 01:07 [entrez] PHST- 2024/07/12 00:00 [pmc-release] AID - biomedicines12071553 [pii] AID - biomedicines-12-01553 [pii] AID - 10.3390/biomedicines12071553 [doi] PST - epublish SO - Biomedicines. 2024 Jul 12;12(7):1553. doi: 10.3390/biomedicines12071553. PMID- 39059989 OWN - NLM STAT- MEDLINE DCOM- 20240727 LR - 20260303 IS - 1876-1631 (Electronic) IS - 1876-1623 (Linking) VI - 142 DP - 2024 TI - Therapeutic potentials of glucose-dependent insulinotropic polypeptide (GIP) in T2DM: Past, present, and future. PG - 293-328 LID - S1876-1623(23)00129-3 [pii] LID - 10.1016/bs.apcsb.2023.12.017 [doi] AB - Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic beta-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice. CI - Copyright (c) 2024. Published by Elsevier Inc. FAU - Das, Soumik AU - Das S AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Ravi, Harini AU - Ravi H AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Babu, Achsha AU - Babu A AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Banerjee, Manosi AU - Banerjee M AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Kanagavalli, R AU - Kanagavalli R AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Dhanasekaran, Sivaraman AU - Dhanasekaran S AD - School of Energy Technology, Pandit Deendayal Energy University, Knowledge Corridor, Gandhinagar, Gujarat, India. FAU - Devi Rajeswari, V AU - Devi Rajeswari V AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Venkatraman, Ganesh AU - Venkatraman G AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. FAU - Ramanathan, Gnanasambandan AU - Ramanathan G AD - Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. Electronic address: gnanasambandan.r@vit.ac.in. LA - eng PT - Journal Article PT - Review DEP - 20240604 PL - Netherlands TA - Adv Protein Chem Struct Biol JT - Advances in protein chemistry and structural biology JID - 101497281 RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 0 (Hypoglycemic Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/metabolism/drug therapy MH - *Gastric Inhibitory Polypeptide/metabolism MH - Animals MH - Hypoglycemic Agents/therapeutic use/chemistry MH - Receptors, Gastrointestinal Hormone/metabolism OTO - NOTNLM OT - Clinical trials OT - Glucose-dependent insulinotropic polypeptide OT - Incretin OT - Osteoblasts OT - Type 2 diabetes mellitus EDAT- 2024/07/27 10:42 MHDA- 2024/07/28 14:48 CRDT- 2024/07/26 21:00 PHST- 2024/07/28 14:48 [medline] PHST- 2024/07/27 10:42 [pubmed] PHST- 2024/07/26 21:00 [entrez] AID - S1876-1623(23)00129-3 [pii] AID - 10.1016/bs.apcsb.2023.12.017 [doi] PST - ppublish SO - Adv Protein Chem Struct Biol. 2024;142:293-328. doi: 10.1016/bs.apcsb.2023.12.017. Epub 2024 Jun 4. PMID- 39049060 OWN - NLM STAT- MEDLINE DCOM- 20240725 LR - 20260127 IS - 1472-6823 (Electronic) IS - 1472-6823 (Linking) VI - 24 IP - 1 DP - 2024 Jul 24 TI - Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study). PG - 124 LID - 10.1186/s12902-024-01658-6 [doi] LID - 124 AB - BACKGROUND: Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. METHODS: We retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65-74) versus late (>/= 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. RESULTS: We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (- 13.1 +/- 7.5 mmol/mol and - 3.0 +/- 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = -0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = -0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4). CONCLUSIONS: Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of >/= 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence. CI - (c) 2024. The Author(s). FAU - Oe, Yuki AU - Oe Y AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. AD - Department of Diabetes, Otaru General Hospital, Wakamatsu-1-1-1, Otaru, Hokkaido, 047-0017, Japan. FAU - Nomoto, Hiroshi AU - Nomoto H AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. hnomoto@med.hokudai.ac.jp. AD - Division of Endocrinology, Metabolism, and Rheumatology, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa-City, Hokkaido, 078-8510, Japan. hnomoto@med.hokudai.ac.jp. FAU - Cho, Kyu Yong AU - Cho KY AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. FAU - Yokozeki, Kei AU - Yokozeki K AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. AD - Department of Diabetes, Otaru General Hospital, Wakamatsu-1-1-1, Otaru, Hokkaido, 047-0017, Japan. FAU - Ono, Tsubasa AU - Ono T AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. AD - Department of Diabetes, Otaru General Hospital, Wakamatsu-1-1-1, Otaru, Hokkaido, 047-0017, Japan. FAU - Miya, Aika AU - Miya A AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. FAU - Kameda, Hiraku AU - Kameda H AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. FAU - Nakamura, Akinobu AU - Nakamura A AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. FAU - Arimura, Yoshiaki AU - Arimura Y AD - Department of Gastroenterology, Otaru General Hospital, Wakamatsu-1-1-1, Otaru, Hokkaido, 047-0017, Japan. FAU - Atsumi, Tatsuya AU - Atsumi T AD - Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, North-15, West-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. LA - eng PT - Journal Article PT - Observational Study DEP - 20240724 PL - England TA - BMC Endocr Disord JT - BMC endocrine disorders JID - 101088676 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Glycated Hemoglobin) RN - 0 (Blood Glucose) RN - 53AXN4NNHX (Semaglutide) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Male MH - Female MH - Retrospective Studies MH - Aged MH - *Glucagon-Like Peptides/administration & dosage/therapeutic use/adverse effects MH - *Hypoglycemic Agents/therapeutic use/administration & dosage/adverse effects MH - *Glycated Hemoglobin/analysis MH - Aged, 80 and over MH - Administration, Oral MH - Blood Glucose/analysis/drug effects MH - Treatment Outcome MH - Hypoglycemia/chemically induced MH - Follow-Up Studies MH - Cognition/drug effects MH - Semaglutide PMC - PMC11267784 OTO - NOTNLM OT - Aged OT - Cognitive test OT - Glucagon-like peptide 1 receptor OT - Oral medicine OT - Type 2 diabetes COIS- YO has received honoraria for lectures from Novo Nordisk Pharma Ltd.. HN has received honoraria for lectures from Novo Nordisk Pharma Ltd. and Sumitomo Pharma Co., Ltd; and has obtained research support from Kowa Pharmaceutical Co.. AN has received honoraria for lectures from Mitsubishi Tanabe Pharma and has obtained research support from Kowa Co., Ltd. TA has received honoraria for lectures from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd. Eisai Co. Ltd., AbbVie Inc., UCB Japan Co. Ltd., Novartis Pharma K.K., Pfizer Inc. Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., AstraZeneca plc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; and research grants from Eli Lilly Japan K.K., AbbVie Inc., Bristol-Myers Squibb Co., Daiichi Sankyo Co., Ltd., Asahi Kasei Pharma Co., Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca plc., Novartis Pharma K.K., Pfizer Inc. and UCB Japan Co., Ltd.; and consultancy fees from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Boehringer Ingelheim., Bristol-Myers Squibb Co., Amgen K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc. and Daiichi Sankyo Co., Ltd.. KYC, KY, TO, AM, HK, and YA have no conflicts of interest to declare. EDAT- 2024/07/26 12:40 MHDA- 2024/07/26 12:41 PMCR- 2024/07/24 CRDT- 2024/07/25 00:09 PHST- 2024/02/04 00:00 [received] PHST- 2024/07/16 00:00 [accepted] PHST- 2024/07/26 12:41 [medline] PHST- 2024/07/26 12:40 [pubmed] PHST- 2024/07/25 00:09 [entrez] PHST- 2024/07/24 00:00 [pmc-release] AID - 10.1186/s12902-024-01658-6 [pii] AID - 1658 [pii] AID - 10.1186/s12902-024-01658-6 [doi] PST - epublish SO - BMC Endocr Disord. 2024 Jul 24;24(1):124. doi: 10.1186/s12902-024-01658-6. PMID- 39042202 OWN - NLM STAT- MEDLINE DCOM- 20240723 LR - 20261010 IS - 1557-1904 (Electronic) IS - 1557-1890 (Linking) VI - 19 IP - 1 DP - 2024 Jul 23 TI - Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis. PG - 36 LID - 10.1007/s11481-024-10142-w [doi] AB - Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1beta and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety. CI - (c) 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - de Paiva, Igor Henrique Rodrigues AU - de Paiva IHR AD - Laboratory of Ultrastructure, Aggeu Magalhaes Institute (IAM), Av. Moraes Rego s/n, Recife CEP, PE, 50670-420, Brazil. igorhenriqueigor231@gmail.com. AD - Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil. igorhenriqueigor231@gmail.com. FAU - da Silva, Rodrigo Soares AU - da Silva RS AD - Laboratory of Ultrastructure, Aggeu Magalhaes Institute (IAM), Av. Moraes Rego s/n, Recife CEP, PE, 50670-420, Brazil. AD - Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil. FAU - Mendonca, Ingrid Prata AU - Mendonca IP AD - Laboratory of Ultrastructure, Aggeu Magalhaes Institute (IAM), Av. Moraes Rego s/n, Recife CEP, PE, 50670-420, Brazil. AD - Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil. FAU - de Souza, Jose Roberto Botelho AU - de Souza JRB AD - Department of Zoology, Federal University of Pernambuco, Recife, PE, Brazil. FAU - Peixoto, Christina Alves AU - Peixoto CA AD - Laboratory of Ultrastructure, Aggeu Magalhaes Institute (IAM), Av. Moraes Rego s/n, Recife CEP, PE, 50670-420, Brazil. christina.peixoto@fiocruz.br. AD - Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Recife, Brazil. christina.peixoto@fiocruz.br. LA - eng GR - PROEP#400208/2019-9/Centro de Pesquisas Aggeu Magalhaes, Fundacao Oswaldo Cruz/ GR - VPPCB-007-FIO-18-2-17/Fundacao Oswaldo Cruz/ GR - #301777/2012-8/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240723 PL - United States TA - J Neuroimmune Pharmacol JT - Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology JID - 101256586 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Antidepressive Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - *Glucagon-Like Peptides/pharmacology MH - *Diabetes Mellitus, Type 2/complications/drug therapy/psychology/metabolism MH - Mice MH - *Cognitive Dysfunction/drug therapy/prevention & control/etiology/metabolism MH - *Depression/drug therapy/psychology/metabolism MH - Male MH - *Anxiety/drug therapy/psychology/etiology MH - *Gastrointestinal Microbiome/drug effects MH - *Mice, Inbred C57BL MH - *Brain-Gut Axis/drug effects MH - Diabetes Mellitus, Experimental/complications/drug therapy/psychology/metabolism MH - Disease Models, Animal MH - Antidepressive Agents/pharmacology/therapeutic use MH - Semaglutide OTO - NOTNLM OT - Anxiety OT - Cognition OT - Depression OT - Diabetes mellitus 2 OT - Gut microbiota OT - Semaglutide EDAT- 2024/07/23 12:42 MHDA- 2024/07/23 12:43 CRDT- 2024/07/23 11:05 PHST- 2023/08/09 00:00 [received] PHST- 2024/07/14 00:00 [accepted] PHST- 2024/07/23 12:43 [medline] PHST- 2024/07/23 12:42 [pubmed] PHST- 2024/07/23 11:05 [entrez] AID - 10.1007/s11481-024-10142-w [pii] AID - 10.1007/s11481-024-10142-w [doi] PST - epublish SO - J Neuroimmune Pharmacol. 2024 Jul 23;19(1):36. doi: 10.1007/s11481-024-10142-w. PMID- 39028784 OWN - NLM STAT- MEDLINE DCOM- 20240719 LR - 20240920 IS - 1532-0650 (Electronic) IS - 0002-838X (Linking) VI - 110 IP - 1 DP - 2024 Jul TI - Top 20 Research Studies of 2023 for Primary Care Physicians. PG - 65-73 AB - This article summarizes the top 20 research studies of 2023 identified as POEMs (patient-oriented evidence that matters) and the most highly rated guidelines. A large randomized controlled trial found that the time antihypertensive medications are taken has no effect on important outcomes. A fixed-dose approach to statin prescribing is not inferior to a treat-to-target strategy for management of lipid levels. Blood pressure measurements using 24-hour ambulatory monitoring are better than office measurements for predicting mortality. In patients 80 years and older with atrial fibrillation, direct oral anticoagulants have fewer harms than vitamin K antagonists and similar benefits. In people at high risk of cardiovascular disease, the Mediterranean and low-fat diets are the better options among seven dietary programs. An observational study of people with acute COVID-19 in the Omicron phase showed that nirmatrelvir/ritonavir was effective in reducing hospitalizations and death. The diagnosis of urinary tract infection requires a higher optimal cutoff to define pyuria on automated microscopy than was thought. A new regimen has been found using one of the most effective treatments for toenail onychomycosis. Dextromethorphan, honey, and inhaled ipratropium do not appear to be effective for acute cough. Serotonin-norepinephrine reuptake inhibitors are effective for some types of pain syndromes. In a 6-week trial, adults with acute, nonspecific low back or neck pain treated with opioids had similar pain relief as those treated with placebo. In patients with knee osteoarthritis who want to participate in sports and recreation, 70 to 90 minutes of exercise produces better results than 20 to 30 minutes three times per week. Healthy behaviors are associated with a lower risk of developing type 2 diabetes mellitus. In patients 50 years and older with type 2 diabetes, cumulative glycemic control with A1C levels of greater than 9% is associated with an increased risk of dementia. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists are best for improving patient-oriented outcomes for type 2 diabetes. Mindfulness-based stress reduction is not inferior to escitalopram in adults with anxiety disorders. Framing depression as an adaptation to current circumstances can lead to better patient outcomes. People labeled as having a penicillin allergy can complete an amoxicillin oral provocation challenge in the primary care office and, following a negative result, have this label removed. A 5-year surveillance interval can be safely reconsidered in many older patients with colon polyps. Nonprescription hearing aids can be effective without a fitting by an audiologist. We wrap this up with the top guidelines of the year as determined by POEM readers. FAU - Grad, Roland AU - Grad R AD - McGill University, Montreal, Quebec, Canada. FAU - Ebell, Mark H AU - Ebell MH AD - University of Georgia, Athens. LA - eng PT - Journal Article PT - Review PL - United States TA - Am Fam Physician JT - American family physician JID - 1272646 SB - IM MH - Humans MH - COVID-19 MH - Physicians, Primary Care MH - Practice Guidelines as Topic MH - *Primary Health Care MH - SARS-CoV-2 EDAT- 2024/07/19 18:41 MHDA- 2024/07/19 18:42 CRDT- 2024/07/19 13:52 PHST- 2024/07/19 18:42 [medline] PHST- 2024/07/19 18:41 [pubmed] PHST- 2024/07/19 13:52 [entrez] AID - b4c9f484-651d-4f62-bc59-3c6e15e28a96 [pii] PST - ppublish SO - Am Fam Physician. 2024 Jul;110(1):65-73. PMID- 38977507 OWN - NLM STAT- MEDLINE DCOM- 20240708 LR - 20241216 IS - 1573-6830 (Electronic) IS - 0272-4340 (Print) IS - 0272-4340 (Linking) VI - 44 IP - 1 DP - 2024 Jul 8 TI - Hypoglycemia and Alzheimer Disease Risk: The Possible Role of Dasiglucagon. PG - 55 LID - 10.1007/s10571-024-01489-y [doi] LID - 55 AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory impairment and cognitive dysfunctions. It has been shown that hypoglycemia can adversely affect AD neuropathology. It is well-known that chronic hyperglycemia in type 2 diabetes (T2D) is regarded as a potential risk factor for the development and progression of AD. However, the effect of recurrent hypoglycemia on the pathogenesis of AD was not deeply discussed, and how recurrent hypoglycemia affects AD at cellular and molecular levels was not intensely interpreted by the previous studies. The underlying mechanisms for hypoglycaemia-induced AD are diverse such as endothelial dysfunction, thrombosis, and neuronal injury that causing tau protein hyperphosphorylation and the accumulation of amyloid beta (Abeta) in the brain neurons. Of note, the glucagon hormone, which controls blood glucose, can also regulate the cognitive functions. Glucagon increases blood glucose by antagonizing the metabolic effect of insulin. Therefore, glucagon, through attenuation of hypoglycemia, may prevent AD neuropathology. Glucagon/GLP-1 has been shown to promote synaptogenesis, hippocampal synaptic plasticity, and learning and memory, while attenuating amyloid and tau pathologies. Therefore, activation of glucagon receptors in the brain may reduce AD neuropathology. A recent glucagon receptor agonist dasiglucagon which used in the management of hypoglycemia may be effective in preventing hypoglycemia and AD neuropathology. This review aims to discuss the potential role of dasiglucagon in treating hypoglycemia in AD, and how this drug reduce AD neuropathology. CI - (c) 2024. The Author(s). FAU - Ali, Naif H AU - Ali NH AD - Assistant Professor of Neurology, Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia. FAU - Al-Kuraishy, Hayder M AU - Al-Kuraishy HM AUID- ORCID: 0000-0003-3097-2962 AD - Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. FAU - Al-Gareeb, Ali I AU - Al-Gareeb AI AUID- ORCID: 0000-0001-8284-8897 AD - Head of Jabir Ibn, Hayyan Medical University, Al-Ameer Qu./Najaf-Iraq, PO.Box13, Kufa, Iraq. FAU - Hadi, Najah R AU - Hadi NR AUID- ORCID: 0000-0001-9084-591X AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Kufa, Kufa, Iraq. FAU - Assiri, Abdullah A AU - Assiri AA AUID- ORCID: 0000-0002-8721-1331 AD - Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia. FAU - Alrouji, Mohammed AU - Alrouji M AUID- ORCID: 0000-0001-9645-0572 AD - Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, 11961, Kingdom of Saudi Arabia. FAU - Welson, Nermeen N AU - Welson NN AUID- ORCID: 0000-0001-7854-2086 AD - Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Beni Suef, 62511, Egypt. FAU - Alexiou, Athanasios AU - Alexiou A AD - Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia. AD - AFNP Med, 1030, Vienna, Austria. AD - University Centre for Research & Development, Chandigarh University, Punjab, India. AD - Department of Research & Development, Funogen, Athens, Greece. FAU - Papadakis, Marios AU - Papadakis M AUID- ORCID: 0000-0002-9020-874X AD - Department of Surgery II, University Hospital Witten-Herdecke, Heusnerstrasse 40, University of Witten-Herdecke, 42283, Wuppertal, Germany. FAU - Batiha, Gaber El-Saber AU - Batiha GE AUID- ORCID: 0000-0002-7817-425X AD - Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, 22511, Egypt. LA - eng GR - D753/Universitat Witten/Herdecke/ PT - Journal Article PT - Review DEP - 20240708 PL - Netherlands TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 SB - IM MH - Humans MH - *Alzheimer Disease/metabolism/pathology MH - *Hypoglycemia/metabolism/complications MH - Animals MH - Risk Factors PMC - PMC11230952 OTO - NOTNLM OT - Alzheimer disease OT - Dasiglucagon OT - Dementia OT - Glucagon COIS- The authors have no relevant financial or non-financial interests to disclose. EDAT- 2024/07/09 00:42 MHDA- 2024/07/09 00:43 PMCR- 2024/07/08 CRDT- 2024/07/08 23:15 PHST- 2024/03/05 00:00 [received] PHST- 2024/06/21 00:00 [accepted] PHST- 2024/07/09 00:43 [medline] PHST- 2024/07/09 00:42 [pubmed] PHST- 2024/07/08 23:15 [entrez] PHST- 2024/07/08 00:00 [pmc-release] AID - 10.1007/s10571-024-01489-y [pii] AID - 1489 [pii] AID - 10.1007/s10571-024-01489-y [doi] PST - epublish SO - Cell Mol Neurobiol. 2024 Jul 8;44(1):55. doi: 10.1007/s10571-024-01489-y. PMID- 38948473 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240702 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 15 DP - 2024 TI - Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects. PG - 1422740 LID - 10.3389/fphar.2024.1422740 [doi] LID - 1422740 AB - Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research. CI - Copyright (c) 2024 Riemma, Mele, Donniacuo, Telesca, Bellocchio, Castaldo, Rossi, De Angelis, Cappetta, Urbanek and Berrino. FAU - Riemma, Maria Antonietta AU - Riemma MA AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Mele, Elena AU - Mele E AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Donniacuo, Maria AU - Donniacuo M AD - Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy. FAU - Telesca, Marialucia AU - Telesca M AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Bellocchio, Gabriella AU - Bellocchio G AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Castaldo, Giuseppe AU - Castaldo G AD - Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy. AD - CEINGE-Advanced Biotechnologies, Naples, Italy. FAU - Rossi, Francesco AU - Rossi F AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - De Angelis, Antonella AU - De Angelis A AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Cappetta, Donato AU - Cappetta D AD - Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy. FAU - Urbanek, Konrad AU - Urbanek K AD - Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy. AD - CEINGE-Advanced Biotechnologies, Naples, Italy. FAU - Berrino, Liberato AU - Berrino L AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. LA - eng PT - Journal Article PT - Review DEP - 20240614 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC11212466 OTO - NOTNLM OT - cognitive impairment OT - glucagon-like peptide-1 receptor agonists OT - heart failure OT - sodium-glucose cotransporter 2 inhibitors OT - type 2 diabetes COIS- Authors GC and KU were employed by CEINGE-Advanced Biotechnologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2024/07/01 06:42 MHDA- 2024/07/01 06:43 PMCR- 2024/06/14 CRDT- 2024/07/01 05:57 PHST- 2024/04/24 00:00 [received] PHST- 2024/05/21 00:00 [accepted] PHST- 2024/07/01 06:43 [medline] PHST- 2024/07/01 06:42 [pubmed] PHST- 2024/07/01 05:57 [entrez] PHST- 2024/06/14 00:00 [pmc-release] AID - 1422740 [pii] AID - 10.3389/fphar.2024.1422740 [doi] PST - epublish SO - Front Pharmacol. 2024 Jun 14;15:1422740. doi: 10.3389/fphar.2024.1422740. eCollection 2024. PMID- 38915346 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260922 IS - 1663-4365 (Print) IS - 1663-4365 (Electronic) IS - 1663-4365 (Linking) VI - 16 DP - 2024 TI - Reduced GLP-1R availability in the caudate nucleus with Alzheimer's disease. PG - 1350239 LID - 10.3389/fnagi.2024.1350239 [doi] LID - 1350239 AB - The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD. CI - Copyright (c) 2024 Barrett, Ivey, Cunningham, Coffman, Pemberton, Lee, Patra, Day, Lee and Shim. FAU - Barrett, Emma AU - Barrett E AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Ivey, Gabrielle AU - Ivey G AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Cunningham, Adam AU - Cunningham A AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Coffman, Gary AU - Coffman G AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Pemberton, Tyera AU - Pemberton T AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Lee, Chan AU - Lee C AD - Department of Anesthesia, Indiana University Health Arnett Hospital, Lafayette, IN, United States. FAU - Patra, Prabir AU - Patra P AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. FAU - Day, James B AU - Day JB AD - Department of Orthopedic Surgery, Cabell Huntington Hospital and Marshall University School of Medicine, Huntington, WV, United States. FAU - Lee, Peter H U AU - Lee PHU AD - Department of Cardiothoracic Surgery, Southcoast Health, Fall River, MA, United States. AD - Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States. FAU - Shim, Joon W AU - Shim JW AD - Department of Biomedical Engineering, Marshall University, Huntington, WV, United States. LA - eng GR - P20 GM103434/GM/NIGMS NIH HHS/United States GR - P20 GM121299/GM/NIGMS NIH HHS/United States GR - U54 GM104942/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20240610 PL - Switzerland TA - Front Aging Neurosci JT - Frontiers in aging neuroscience JID - 101525824 PMC - PMC11194438 OTO - NOTNLM OT - Alzheimer's disease OT - DCX OT - GLP-1R OT - chronic hydrocephalus OT - hemoglobin COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/06/25 06:42 MHDA- 2024/06/25 06:43 PMCR- 2024/01/01 CRDT- 2024/06/25 04:04 PHST- 2023/12/05 00:00 [received] PHST- 2024/05/15 00:00 [accepted] PHST- 2024/06/25 06:43 [medline] PHST- 2024/06/25 06:42 [pubmed] PHST- 2024/06/25 04:04 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - 10.3389/fnagi.2024.1350239 [doi] PST - epublish SO - Front Aging Neurosci. 2024 Jun 10;16:1350239. doi: 10.3389/fnagi.2024.1350239. eCollection 2024. PMID- 38908839 OWN - NLM STAT- MEDLINE DCOM- 20240622 LR - 20260127 IS - 2044-6055 (Electronic) IS - 2044-6055 (Linking) VI - 14 IP - 6 DP - 2024 Jun 21 TI - Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults. PG - e081401 LID - 10.1136/bmjopen-2023-081401 [doi] LID - e081401 AB - INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD. METHODS AND ANALYSIS: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged >/=55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN71283871. CI - (c) Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. FAU - Koychev, Ivan AU - Koychev I AUID- ORCID: 0000-0001-6813-8493 AD - Department of Psychiatry, University of Oxford, Oxford, UK ivan.koychev@psych.ox.ac.uk. FAU - Adler, Amanda I AU - Adler AI AD - Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. FAU - Edison, Paul AU - Edison P AD - Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, UK. FAU - Tom, Brian AU - Tom B AD - Medical Research Council Biostatistics Unit, University of Cambridge, UK. FAU - Milton, Joanne E AU - Milton JE AD - Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. FAU - Butchart, Joe AU - Butchart J AD - Royal Devon University Healthcare Foundation Trust, Exeter, UK. AD - University of Exeter Medical School, Exeter, UK. FAU - Hampshire, Adam AU - Hampshire A AD - Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, UK. FAU - Marshall, Charles AU - Marshall C AD - Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London, London, UK. FAU - Coulthard, Elizabeth AU - Coulthard E AD - Bristol Medical School, University of Bristol, Bristol, UK. FAU - Zetterberg, Henrik AU - Zetterberg H AD - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden. AD - Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden. AD - Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK. AD - UK Dementia Research Institute at UCL, London, UK. AD - Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, People's Republic of China. AD - Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA18 Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK. FAU - Hellyer, Peter AU - Hellyer P AD - Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, UK. FAU - Cormack, Francesca AU - Cormack F AD - Cambridge Cognition Ltd, Cambridge, UK. FAU - Underwood, Benjamin R AU - Underwood BR AD - Department of Psychiatry, University of Cambridge, Cambridge, UK. AD - Cambridgeshire and Peterborough NHS Foundation trust, Cambridge, UK. FAU - Mummery, Catherine J AU - Mummery CJ AD - Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK. FAU - Holman, Rury R AU - Holman RR AD - Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. LA - eng SI - ISRCTN/ISRCTN71283871 PT - Clinical Trial Protocol PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240621 PL - England TA - BMJ Open JT - BMJ open JID - 101552874 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (tau Proteins) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - Administration, Oral MH - *Alzheimer Disease/drug therapy MH - Brain/diagnostic imaging/metabolism/drug effects MH - Double-Blind Method MH - *Glucagon-Like Peptides/administration & dosage/therapeutic use MH - *Positron-Emission Tomography/methods MH - Randomized Controlled Trials as Topic MH - tau Proteins MH - United Kingdom MH - Equivalence Trials as Topic MH - Semaglutide PMC - PMC11328662 OTO - NOTNLM OT - dementia OT - nuclear medicine OT - protocols & guidelines COIS- Competing interests: IK has received speaker fees and grant funding (ISAP trial) from Novo Nordisk and is a remunerated medical advisor to digital healthcare companies (Five Lives SAS, Cognetivity, Mantrah) in the dementia field. RRH reports personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. AIA has received grant funding (ISAP trial) from Novo Nordisk. HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, Wave, has given lectures with honoraria in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). PE was a consultant to Pfizer, Novo Nordisk, Roche, AstraZeneca, Piramal Life Science, GE Healthcare. He has received speaker fees from Novo Nordisk, Pfizer, Nordea, Piramal Life Science. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was a member of the Scientific Advisory Board for Novo Nordisk and Cytodyn. CM consults for Biogen, Roche, Eli Lilly, Eisai, IONIS, Alnylam, Prevail, WAVE. She has been awarded an investigator grant from Biogen for ultrafast MRI programme. EDAT- 2024/06/23 00:42 MHDA- 2024/06/23 00:43 PMCR- 2024/06/20 CRDT- 2024/06/22 20:43 PHST- 2024/06/23 00:43 [medline] PHST- 2024/06/23 00:42 [pubmed] PHST- 2024/06/22 20:43 [entrez] PHST- 2024/06/20 00:00 [pmc-release] AID - bmjopen-2023-081401 [pii] AID - 10.1136/bmjopen-2023-081401 [doi] PST - epublish SO - BMJ Open. 2024 Jun 21;14(6):e081401. doi: 10.1136/bmjopen-2023-081401. PMID- 38843460 OWN - NLM STAT- MEDLINE DCOM- 20241021 LR - 20260625 IS - 1935-5548 (Electronic) IS - 0149-5992 (Linking) VI - 47 IP - 11 DP - 2024 Nov 1 TI - Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. PG - 1873-1888 LID - 10.2337/dci24-0003 [doi] AB - The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1-based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders. CI - (c) 2024 by the American Diabetes Association. FAU - Drucker, Daniel J AU - Drucker DJ AUID- ORCID: 0000-0001-6688-8127 AD - Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada. LA - eng GR - 154321/Canadian Institutes for Health Research/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Obesity/drug therapy MH - *Glucagon-Like Peptide 1/therapeutic use/analogs & derivatives MH - Hypoglycemic Agents/therapeutic use/adverse effects MH - *Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2024/06/06 19:05 MHDA- 2024/10/22 00:21 CRDT- 2024/06/06 15:23 PHST- 2024/03/11 00:00 [received] PHST- 2024/04/14 00:00 [accepted] PHST- 2024/10/22 00:21 [medline] PHST- 2024/06/06 19:05 [pubmed] PHST- 2024/06/06 15:23 [entrez] AID - 156807 [pii] AID - 10.2337/dci24-0003 [doi] PST - ppublish SO - Diabetes Care. 2024 Nov 1;47(11):1873-1888. doi: 10.2337/dci24-0003. PMID- 38815535 OWN - NLM STAT- MEDLINE DCOM- 20240615 LR - 20250103 IS - 1873-4111 (Electronic) IS - 0378-5122 (Linking) VI - 186 DP - 2024 Aug TI - Unlocking longevity with GLP-1: A key to turn back the clock? PG - 108028 LID - S0378-5122(24)00123-3 [pii] LID - 10.1016/j.maturitas.2024.108028 [doi] AB - Traditionally known for managing blood sugar, GLP-1, a gut hormone, is emerging as a potential key to both lengthening lifespan and combating age-related ailments. While widely recognized for its role in blood sugar control, GLP-1 is increasingly recognized for its diverse effects on various biological pathways beyond glucose metabolism. Research across organisms and humans suggests that activating GLP-1 receptors significantly impacts cellular processes linked to aging. Its ability to boost mitochondrial function, enhance cellular stress resistance, and quell inflammation hints at its wider influence on aging mechanisms. This intricate interplay between GLP-1 and longevity appears to act through multiple pathways. One key effect is its ability to modulate insulin sensitivity, potentially curbing age-related metabolic issues like type 2 diabetes. Its neuroprotective properties also make it a promising candidate for addressing age-related cognitive decline and neurodegenerative diseases. Furthermore, preclinical studies using GLP-1 analogs or agonists have shown promising results in extending lifespan and improving healthspan in various model organisms. These findings provide a compelling rationale for exploring GLP-1-based interventions in humans to extend healthy aging. However, despite the exciting therapeutic prospects of GLP-1 in promoting longevity, challenges remain. Determining optimal dosages, establishing long-term safety profiles, and investigating potential adverse effects require comprehensive clinical investigations before we can confidently translate these findings to humans. This article emphasises the wide applicability of GLP-1. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Chavda, Vivek P AU - Chavda VP AD - Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad 380008, Gujarat, India. Electronic address: vivek.chavda@lmcp.ac.in. FAU - Balar, Pankti C AU - Balar PC AD - Pharmacy Section, L M College of Pharmacy, Ahmedabad 380008, Gujarat, India. FAU - Vaghela, Dixa A AU - Vaghela DA AD - Pharmacy Section, L M College of Pharmacy, Ahmedabad 380008, Gujarat, India. FAU - Dodiya, Payal AU - Dodiya P AD - Pharmacy Section, L M College of Pharmacy, Ahmedabad 380008, Gujarat, India. LA - eng PT - Journal Article PT - Review DEP - 20240521 PL - Ireland TA - Maturitas JT - Maturitas JID - 7807333 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/metabolism MH - *Longevity MH - Animals MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - Diabetes Mellitus, Type 2/metabolism/drug therapy MH - Aging/physiology MH - Insulin Resistance/physiology MH - Neurodegenerative Diseases/drug therapy MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Age-related diseases OT - Bone health OT - Cancer OT - Cardiovascular health OT - Cellular senescence OT - Cognitive function OT - Frailty OT - GLP-1 OT - Glucagon-like peptide-1 OT - Healthy aging OT - Incretin hormones OT - Insulin sensitivity OT - Longevity OT - Metabolic health OT - Mitochondrial dysfunction OT - Neuroprotective effects OT - Sarcopenia COIS- Declaration of competing interest The authors declare that they have no competing interest. EDAT- 2024/05/31 00:42 MHDA- 2024/06/15 10:44 CRDT- 2024/05/30 18:10 PHST- 2024/01/17 00:00 [received] PHST- 2024/05/05 00:00 [revised] PHST- 2024/05/11 00:00 [accepted] PHST- 2024/06/15 10:44 [medline] PHST- 2024/05/31 00:42 [pubmed] PHST- 2024/05/30 18:10 [entrez] AID - S0378-5122(24)00123-3 [pii] AID - 10.1016/j.maturitas.2024.108028 [doi] PST - ppublish SO - Maturitas. 2024 Aug;186:108028. doi: 10.1016/j.maturitas.2024.108028. Epub 2024 May 21. PMID- 38803170 OWN - NLM STAT- MEDLINE DCOM- 20240920 LR - 20240920 IS - 1873-4294 (Electronic) IS - 1568-0266 (Linking) VI - 24 IP - 19 DP - 2024 TI - GLP-1/GIP Agonist as an Intriguing and Ultimate Remedy for Combating Alzheimer's Disease through its Supporting DPP4 Inhibitors: A Review. PG - 1635-1664 LID - 10.2174/0115680266293416240515075450 [doi] AB - BACKGROUND: Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease. AIM: This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD. METHODS: This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD. RESULTS: The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions. CONCLUSION: With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Abubakar, Mohammad AU - Abubakar M AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Nama, Lokesh AU - Nama L AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Ansari, Mohammad Arif AU - Ansari MA AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Ansari, Mohammad Mazharuddin AU - Ansari MM AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Bhardwaj, Shivani AU - Bhardwaj S AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Daksh, Rajni AU - Daksh R AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Syamala, Katta Leela Venkata AU - Syamala KLV AD - Department of Regulatory and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Jamadade, Mohini Santosh AU - Jamadade MS AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Chhabra, Vishal AU - Chhabra V AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. FAU - Kumar, Dileep AU - Kumar D AD - Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India. AD - Department of Entomology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA. FAU - Kumar, Nitesh AU - Kumar N AD - Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Top Med Chem JT - Current topics in medicinal chemistry JID - 101119673 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - EC 3.4.14.5 (DPP4 protein, human) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - Humans MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/chemistry/chemical synthesis MH - *Glucagon-Like Peptide 1/metabolism MH - *Dipeptidyl Peptidase 4/metabolism MH - Animals MH - Gastric Inhibitory Polypeptide/pharmacology/metabolism OTO - NOTNLM OT - Blood-brain barrier OT - Cognitive OT - DPP4 OT - Gastric inhibitory peptide OT - Glucagon-like peptide-1 OT - Incretins OT - Insulin OT - Tau phosphorylation OT - Type 2 diabetes mellitus. EDAT- 2024/05/28 06:43 MHDA- 2024/09/21 13:19 CRDT- 2024/05/28 02:23 PHST- 2023/11/17 00:00 [received] PHST- 2024/04/14 00:00 [revised] PHST- 2024/04/22 00:00 [accepted] PHST- 2024/09/21 13:19 [medline] PHST- 2024/05/28 06:43 [pubmed] PHST- 2024/05/28 02:23 [entrez] AID - CTMC-EPUB-140639 [pii] AID - 10.2174/0115680266293416240515075450 [doi] PST - ppublish SO - Curr Top Med Chem. 2024;24(19):1635-1664. doi: 10.2174/0115680266293416240515075450. PMID- 38795310 OWN - NLM STAT- MEDLINE DCOM- 20240622 LR - 20260323 IS - 1179-1969 (Electronic) IS - 1170-229X (Print) IS - 1170-229X (Linking) VI - 41 IP - 6 DP - 2024 Jun TI - Relationship Between Frailty and Diabetic Pharmacologic Therapy in Older Adults with Type 2 Diabetes: A Cross-Sectional Study. PG - 531-542 LID - 10.1007/s40266-024-01119-8 [doi] AB - BACKGROUND: Older adults with diabetes mellitus require drug treatment considering their frailty, cognitive function, and hypoglycemia. OBJECTIVE: We investigated the association between diabetic pharmacologic therapy and both diabetic complications and frailty across eight diabetes-specific outpatient clinics nationwide. METHODS: Participants (aged 60-80 years) who had type 2 diabetes and did not require nursing care were included in the study. Basic attributes, patient background, complications, hypoglycemic status, body weight, body composition, blood tests, grip strength, and Kihon Checklist (a frailty index) and self-care scores were obtained. Descriptive statistics, t-test, chi-square test, and regression analyses were employed for evaluation. RESULTS: Overall, 417 participants were included (224 men, 193 women, mean age 70.1 +/- 5.4 years, diabetes duration 14.9 +/- 10.9 years, body mass index 24.5 +/- 3.8, glycated hemoglobin 7.22 +/- 0.98%, proportion of individuals with frailty and prefrailty, 19.9% and 41.0%, respectively). All drugs were used more frequently in prefrailty conditions. Each diabetes medication was related to complications, body composition, and frailty, as follows: sulfonylurea (lower hypoglycemia); glinide (severe hypoglycemia, retinopathy, weaker grip strength, high Kihon Checklist score, decreased physical activities); alpha-glucosidase inhibitors (no association); biguanide (high body mass index, high body fat, stronger grip strength); thiazolidinedione (decreased instrumental activities of daily living); dipeptidyl-peptidase-4 inhibitors (no association); sodium-glucose cotransporter 2 inhibitors; retinopathy, high body mass index and Kihon Checklist score, and depressive mood); glucagon-like peptide-1 receptor agonists (high body mass index and body fat and poor nutritional status); and insulin preparations (hypoglycemia, retinopathy, neuropathy, nephropathy, cardiovascular diseases, weaker grip strength, and high Kihon Checklist score and physical inactivity). CONCLUSIONS: Some formulations, such as glinide, sodium-glucose cotransporter 2 inhibitors, and insulin, are associated with an increased frequency of frailty, warranting careful and individualized diabetes treatment. CI - (c) 2024. The Author(s). FAU - Nishimura, Akiko AU - Nishimura A AD - School of Nursing, Faculty of Medicine and Graduate School of Medicine, Kagawa University, Miki-cho, Kagawa, Japan. AD - Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto, Japan. AD - Department of Internal Medicine and Diabetes, Goshominami Harashima Clinic, Kyoto City, Kyoto, Japan. FAU - Masuda, Chie AU - Masuda C AD - Department of Nursing, Asahikawa City Hospital, Asahikawa City, Hokkaido, Japan. FAU - Murauchi, Chiyo AU - Murauchi C AD - Faculty of Nursing and Graduate School of Nursing, Kansai Medical University, Hirakata City, Osaka, Japan. FAU - Ishii, Miho AU - Ishii M AD - Jonan Branch, Town Home-Visit Medical Care Clinic, Ota-ku, Tokyo, Japan. FAU - Murata, Yuko AU - Murata Y AD - Department of Nursing, Takashima Municipal Hospital, Takashima City, Shiga, Japan. FAU - Kawasaki, Terumi AU - Kawasaki T AD - Department of Nursing, Sapporo City General Hospital, Sapporo City, Hokkaido, Japan. FAU - Azuma, Mayumi AU - Azuma M AD - School of Nursing, Faculty of Medicine and Graduate School of Medicine, Kagawa University, Miki-cho, Kagawa, Japan. AD - Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto, Japan. AD - Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki City, Miyazaki, Japan. FAU - Harashima, Shin-Ichi AU - Harashima SI AUID- ORCID: 0000-0003-4813-0085 AD - School of Nursing, Faculty of Medicine and Graduate School of Medicine, Kagawa University, Miki-cho, Kagawa, Japan. harashima.shinichi.38m@st.kyoto-u.ac.jp. AD - Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto, Japan. harashima.shinichi.38m@st.kyoto-u.ac.jp. AD - Department of Internal Medicine and Diabetes, Goshominami Harashima Clinic, Kyoto City, Kyoto, Japan. harashima.shinichi.38m@st.kyoto-u.ac.jp. AD - Clinical Research Planning and Administration Division, National Hospital Organization, Kyoto Medical Center, Kyoto City, Kyoto, Japan. harashima.shinichi.38m@st.kyoto-u.ac.jp. AD - Research Center for Healthcare, Nagahama City Hospital, Nagahama City, Shiga, Japan. harashima.shinichi.38m@st.kyoto-u.ac.jp. LA - eng GR - JP 20H03983/Japan Society for the Promotion of Science/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240525 PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Male MH - Female MH - Aged MH - Cross-Sectional Studies MH - *Frailty MH - Aged, 80 and over MH - Middle Aged MH - *Hypoglycemic Agents/therapeutic use/adverse effects PMC - PMC11193829 COIS- Akiko Nishimura, Chie Masuda, Chiyo Murauchi, Miho Ishii, Yuko Murata, Terumi Kawasaki, Mayumi Azuma, and Shin-ichi Harashima declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/05/25 20:48 MHDA- 2024/06/22 19:45 PMCR- 2024/05/25 CRDT- 2024/05/25 11:11 PHST- 2024/04/24 00:00 [accepted] PHST- 2024/06/22 19:45 [medline] PHST- 2024/05/25 20:48 [pubmed] PHST- 2024/05/25 11:11 [entrez] PHST- 2024/05/25 00:00 [pmc-release] AID - 10.1007/s40266-024-01119-8 [pii] AID - 1119 [pii] AID - 10.1007/s40266-024-01119-8 [doi] PST - ppublish SO - Drugs Aging. 2024 Jun;41(6):531-542. doi: 10.1007/s40266-024-01119-8. Epub 2024 May 25. PMID- 38762101 OWN - NLM STAT- MEDLINE DCOM- 20240610 LR - 20250702 IS - 1872-9649 (Electronic) IS - 1568-1637 (Print) IS - 1568-1637 (Linking) VI - 98 DP - 2024 Jul TI - Type 2 diabetes mellitus/obesity drugs: A neurodegenerative disorders savior or a bridge too far? PG - 102343 LID - S1568-1637(24)00161-2 [pii] LID - 10.1016/j.arr.2024.102343 [doi] AB - Glucagon-like peptide-1 (GLP-1) receptor agonist-based drugs (incretin mimetics) have meaningfully impacted current treatment of type 2 diabetes mellitus (T2DM), and their actions on satiety and weight loss have led to their use as an obesity medication. With multiple pleotropic actions beyond their insulinotropic and weight loss ones, including anti-inflammatory and anti-insulin-resistant effects selectively mediated by their receptors present within numerous organs, this drug class offers potential efficacy for an increasing number of systemic and neurological disorders whose current treatment is inadequate. Among these are a host of neurodegenerative disorders that are prevalent in the elderly, such as Parkinson's and Alzheimer's disease, which have bucked previous therapeutic approaches. An increasing preclinical, clinical, and epidemiological literature suggests that select incretin mimetics may provide an effective treatment strategy, but 'which ones' for 'which disorders' and 'when' remain key open questions. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Kopp, Katherine O AU - Kopp KO AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: katherine.kopp@nih.gov. FAU - Glotfelty, Elliot J AU - Glotfelty EJ AD - Cellular Stress and Inflammation Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Lahiri, Debomoy K AU - Lahiri DK AD - Department of Psychiatry, Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical & Molecular Genetics, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: Greign@grc.nia.nih.gov. LA - eng GR - ZIA AG000333/ImNIH/Intramural NIH HHS/United States GR - R21 AG056007/AG/NIA NIH HHS/United States GR - R21 AG076202/AG/NIA NIH HHS/United States GR - R56 AG072810/AG/NIA NIH HHS/United States GR - P30 AG072976/AG/NIA NIH HHS/United States GR - P30 AG010133/AG/NIA NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20240516 PL - England TA - Ageing Res Rev JT - Ageing research reviews JID - 101128963 RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Anti-Obesity Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Neurodegenerative Diseases/drug therapy MH - *Obesity/drug therapy MH - Animals MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - Incretins/therapeutic use MH - Anti-Obesity Agents/therapeutic use/pharmacology MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC11378160 MID - NIHMS1999289 OTO - NOTNLM OT - Alzheimer's disease OT - Glucagon-like peptide-1 (GLP-1) OT - Glucose-dependent insulinotropic polypeptide (GIP) OT - Incretin mimetic OT - Insulin resistance OT - Neurodegeneration OT - Neuroinflammation OT - Parkinson's disease OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The Intramural Research Program of the National Institute on Aging (NIA), NIH, holds patent rights in relation to the use of Exenatide in neurodegenerative disorders via the work of NHG. These are assigned to NIA, NIH alone, and not to NHG. All other authors report no conflicts of interest. EDAT- 2024/05/19 00:42 MHDA- 2024/06/11 00:42 PMCR- 2025/07/01 CRDT- 2024/05/18 19:30 PHST- 2024/03/11 00:00 [received] PHST- 2024/05/15 00:00 [accepted] PHST- 2024/06/11 00:42 [medline] PHST- 2024/05/19 00:42 [pubmed] PHST- 2024/05/18 19:30 [entrez] PHST- 2025/07/01 00:00 [pmc-release] AID - S1568-1637(24)00161-2 [pii] AID - 10.1016/j.arr.2024.102343 [doi] PST - ppublish SO - Ageing Res Rev. 2024 Jul;98:102343. doi: 10.1016/j.arr.2024.102343. Epub 2024 May 16. PMID- 38732190 OWN - NLM STAT- MEDLINE DCOM- 20240511 LR - 20260127 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 25 IP - 9 DP - 2024 May 2 TI - A Systematic Review of Semaglutide's Influence on Cognitive Function in Preclinical Animal Models and Cell-Line Studies. LID - 10.3390/ijms25094972 [doi] LID - 4972 AB - Since we aim to test new options to find medication for cognitive disorders, we have begun to assess the effect of semaglutide and to conduct a review gathering studies that have attempted this purpose. This systematic review focuses on the cognitive effects of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), in the context of neurological and cognitive impairment. Semaglutide, a synthetic GLP-1 analog, showcased neuroprotective effects beyond metabolic regulation. It mitigated apoptosis and improved cognitive dysfunction in cerebrovascular disease, suggesting broader implications for neurological well-being. Also, studies highlighted GLP-1 RAs' positive impact on olfactory function in obese individuals with type 2 diabetes, on neurodegenerative disorders, multiple sclerosis, and endotoxemia. In order to analyze current studies that assess the impact of semaglutide on cognitive function, a literature search was conducted up to February 2024 on two online databases, MEDLINE (via PubMed) and Web of Science Core Collection, as well as various websites. Fifteen studies on mice populations and two studies on cell lines were included, analyzed, and assessed with bias-specific tools. The neuroprotective and anti-apoptotic properties of GLP-1 and its analogs were emphasized, with animal models and cell line studies demonstrating enhanced cognitive function. While promising, limitations include fewer studies, highlighting the need for extensive research, particularly in the human population. Even though this medication seems promising, there are significant limitations, one of which is the lack of studies on human subjects. Therefore, this review aims to gather current evidence. FAU - Tipa, Raluca Oana AU - Tipa RO AD - Department of Psychiatry, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. AD - "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, 041914 Bucharest, Romania. FAU - Balan, Daniela-Gabriela AU - Balan DG AD - Discipline of Physiology, Faculty of Dentistry, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania. FAU - Georgescu, Mihai-Teodor AU - Georgescu MT AUID- ORCID: 0000-0003-1601-0580 AD - Discipline of Oncology, Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. FAU - Ignat, Luciana Angela AU - Ignat LA AD - "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, 041914 Bucharest, Romania. AD - Doctoral School, "George Emil Palade" University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania. FAU - Vacaroiu, Ileana Adela AU - Vacaroiu IA AD - Discipline of Nephrology, Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. FAU - Georgescu, Dragos Eugen AU - Georgescu DE AUID- ORCID: 0009-0005-5389-2254 AD - Discipline of General Surgery, Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. FAU - Raducu, Laura AU - Raducu L AUID- ORCID: 0000-0001-9376-6774 AD - Discipline of Plastic and Reconstructive Surgery, Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. FAU - Mihai, Doina Andrada AU - Mihai DA AD - Discipline of Diabetes, Nutrition, and Metabolic Diseases, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania. FAU - Chiperi, Liviu-Vasile AU - Chiperi LV AD - Discipline of Physiology, Faculty of Dentistry, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania. FAU - Balcangiu-Stroescu, Andra-Elena AU - Balcangiu-Stroescu AE AD - Discipline of Physiology, Faculty of Dentistry, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania. LA - eng PT - Journal Article PT - Systematic Review DEP - 20240502 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - *Cognition/drug effects MH - Humans MH - Disease Models, Animal MH - Neuroprotective Agents/pharmacology/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Mice MH - Cell Line MH - Cognitive Dysfunction/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Semaglutide PMC - PMC11084700 OTO - NOTNLM OT - cognitive OT - effect OT - potential OT - review OT - semaglutide COIS- The authors declare no conflicts of interest. EDAT- 2024/05/11 19:44 MHDA- 2024/05/11 19:45 PMCR- 2024/05/02 CRDT- 2024/05/11 01:10 PHST- 2024/03/15 00:00 [received] PHST- 2024/04/17 00:00 [revised] PHST- 2024/04/24 00:00 [accepted] PHST- 2024/05/11 19:45 [medline] PHST- 2024/05/11 19:44 [pubmed] PHST- 2024/05/11 01:10 [entrez] PHST- 2024/05/02 00:00 [pmc-release] AID - ijms25094972 [pii] AID - ijms-25-04972 [pii] AID - 10.3390/ijms25094972 [doi] PST - epublish SO - Int J Mol Sci. 2024 May 2;25(9):4972. doi: 10.3390/ijms25094972. PMID- 38710803 OWN - NLM STAT- MEDLINE DCOM- 20250422 LR - 20260619 IS - 1476-5497 (Electronic) IS - 0307-0565 (Print) IS - 0307-0565 (Linking) VI - 49 IP - 3 DP - 2025 Mar TI - Obesity pharmacotherapy in older adults: a narrative review of evidence. PG - 369-380 LID - 10.1038/s41366-024-01529-z [doi] AB - The prevalence of obesity in older adults (people aged >60 years) is increasing in line with the demographic shift in global populations. Despite knowledge of obesity-related complications in younger adults (increased risk of type 2 diabetes, liver and cardiovascular disease and malignancy), these considerations may be outweighed, in older adults, by concerns regarding weight-loss induced reduction in skeletal muscle and bone mass, and the awareness of the 'obesity paradox'. Obesity in the elderly contributes to various obesity-related complications from cardiometabolic disease and cancer, to functional decline, worsening cognition, and quality of life, that will have already suffered an age-related decline. Lifestyle interventions remain the cornerstone of obesity management in older adults, with emphasis on resistance training for muscle strength and bone mineral density preservation. However, in older adults with obesity refractory to lifestyle strategies, pharmacotherapy, using anti-obesity medicines (AOMs), can be a useful adjunct. Recent evidence suggests that intentional weight loss in older adults with overweight and obesity is effective and safe, hence a diminishing reluctance to use AOMs in this more vulnerable population. Despite nine AOMs being currently approved for the treatment of obesity, limited clinical trial evidence in older adults predominantly focuses on incretin therapy with glucagon-like peptide-1 receptor agonists (liraglutide, semaglutide, and tirzepatide). AOMs enhance weight loss and reduce cardiometabolic events, while maintaining muscle mass. Future randomised controlled trials should specifically evaluate the effectiveness of novel AOMs for long-term weight management in older adults with obesity, carefully considering the impact on body composition and functional ability, as well as health economics. CI - (c) 2024. Crown. FAU - Henney, Alex E AU - Henney AE AUID- ORCID: 0000-0002-8066-9470 AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK. alexander.henney@aintree.nhs.uk. AD - Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. alexander.henney@aintree.nhs.uk. AD - Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. alexander.henney@aintree.nhs.uk. FAU - Wilding, John P H AU - Wilding JPH AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK. AD - Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. AD - Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. FAU - Alam, Uazman AU - Alam U AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK. AD - Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. AD - Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. FAU - Cuthbertson, Daniel J AU - Cuthbertson DJ AD - Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK. AD - Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. AD - Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. LA - eng PT - Journal Article PT - Review DEP - 20240506 PL - England TA - Int J Obes (Lond) JT - International journal of obesity (2005) JID - 101256108 RN - 0 (Anti-Obesity Agents) SB - IM MH - Humans MH - *Obesity/drug therapy/epidemiology MH - Aged MH - *Anti-Obesity Agents/therapeutic use MH - Middle Aged MH - Weight Loss/drug effects PMC - PMC11971046 COIS- Competing interests: DJC has received investigator-initiated grants from Astra Zeneca and Novo Nordisk, as well as speaker fees for lectures. UA has received investigator-led grant from Proctor and Gamble, as well as speaker fees for lectures. He has also received honoraria from Boehringer Ingelheim, Eli Lilly, Napp, Proctor and Gamble and Sanofi for educational meetings. JPHW consults widely for pharmaceutical companies in relation to obesity and diabetes (fees paid to the University of Liverpool) and via his institution has received research grants from industry. He is received lecture fees from commercial organisations including the pharmaceutical industry and has provided unpaid support to various charities in relation to his interest in obesity and diabetes. AEH has no conflicts of interest to declare. EDAT- 2024/05/07 00:50 MHDA- 2025/04/05 15:59 PMCR- 2024/05/06 CRDT- 2024/05/06 23:25 PHST- 2024/01/25 00:00 [received] PHST- 2024/04/24 00:00 [accepted] PHST- 2024/04/22 00:00 [revised] PHST- 2025/04/05 15:59 [medline] PHST- 2024/05/07 00:50 [pubmed] PHST- 2024/05/06 23:25 [entrez] PHST- 2024/05/06 00:00 [pmc-release] AID - 10.1038/s41366-024-01529-z [pii] AID - 1529 [pii] AID - 10.1038/s41366-024-01529-z [doi] PST - ppublish SO - Int J Obes (Lond). 2025 Mar;49(3):369-380. doi: 10.1038/s41366-024-01529-z. Epub 2024 May 6. PMID- 38675438 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240429 IS - 1424-8247 (Print) IS - 1424-8247 (Electronic) IS - 1424-8247 (Linking) VI - 17 IP - 4 DP - 2024 Apr 8 TI - View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences. LID - 10.3390/ph17040478 [doi] LID - 478 AB - Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use. FAU - Froldi, Guglielmina AU - Froldi G AUID- ORCID: 0000-0002-5936-1789 AD - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy. LA - eng PT - Journal Article PT - Review DEP - 20240408 PL - Switzerland TA - Pharmaceuticals (Basel) JT - Pharmaceuticals (Basel, Switzerland) JID - 101238453 PMC - PMC11054066 OTO - NOTNLM OT - ADMET OT - ADRs OT - AMPK OT - T2DM OT - antidiabetic drugs OT - miRNA OT - pharmacovigilance OT - sex differences COIS- The author declares no conflict of interest. EDAT- 2024/04/27 09:53 MHDA- 2024/04/27 09:54 PMCR- 2024/04/08 CRDT- 2024/04/27 01:22 PHST- 2024/03/12 00:00 [received] PHST- 2024/03/29 00:00 [revised] PHST- 2024/04/03 00:00 [accepted] PHST- 2024/04/27 09:54 [medline] PHST- 2024/04/27 09:53 [pubmed] PHST- 2024/04/27 01:22 [entrez] PHST- 2024/04/08 00:00 [pmc-release] AID - ph17040478 [pii] AID - pharmaceuticals-17-00478 [pii] AID - 10.3390/ph17040478 [doi] PST - epublish SO - Pharmaceuticals (Basel). 2024 Apr 8;17(4):478. doi: 10.3390/ph17040478. PMID- 38639975 OWN - NLM STAT- MEDLINE DCOM- 20240514 LR - 20250103 IS - 1538-3598 (Electronic) IS - 0098-7484 (Linking) VI - 331 IP - 18 DP - 2024 May 14 TI - Could GLP-1 Receptor Agonists Like Semaglutide Treat Addiction, Alzheimer Disease, and Other Conditions? PG - 1519-1521 LID - 10.1001/jama.2024.1017 [doi] FAU - Rubin, Rita AU - Rubin R AD - Lead Senior Staff Writer, Medical News & Perspectives, JAMA. LA - eng PT - News PL - United States TA - JAMA JT - JAMA JID - 7501160 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Smoking Cessation Agents) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy MH - Chronic Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists/adverse effects/therapeutic use MH - Glucagon-Like Peptides/therapeutic use/adverse effects MH - Parkinson Disease/drug therapy MH - Renal Insufficiency, Chronic/drug therapy MH - Smoking Cessation Agents/adverse effects/therapeutic use MH - *Substance-Related Disorders/drug therapy OAB - This Medical News story examines other potential uses of GLP-1 receptor agonists, the popular type 2 diabetes and weight-loss drugs. OABL- eng EDAT- 2024/04/19 12:43 MHDA- 2024/05/15 05:45 CRDT- 2024/04/19 11:43 PHST- 2024/05/15 05:45 [medline] PHST- 2024/04/19 12:43 [pubmed] PHST- 2024/04/19 11:43 [entrez] AID - 2817996 [pii] AID - 10.1001/jama.2024.1017 [doi] PST - ppublish SO - JAMA. 2024 May 14;331(18):1519-1521. doi: 10.1001/jama.2024.1017. PMID- 38612620 OWN - NLM STAT- MEDLINE DCOM- 20240415 LR - 20240425 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 25 IP - 7 DP - 2024 Mar 29 TI - GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease. LID - 10.3390/ijms25073812 [doi] LID - 3812 AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay between the gut-brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies is also very promising, enhancing the possibility of adding GLP1-R agonists to the current armamentarium of drugs available for PD treatment. FAU - Kalinderi, Kallirhoe AU - Kalinderi K AD - Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Papaliagkas, Vasileios AU - Papaliagkas V AUID- ORCID: 0000-0003-1064-0290 AD - Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece. FAU - Fidani, Liana AU - Fidani L AD - Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. LA - eng PT - Journal Article PT - Review DEP - 20240329 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - *Parkinson Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/drug therapy MH - Brain-Gut Axis MH - Databases, Factual MH - Dopamine PMC - PMC11011817 OTO - NOTNLM OT - GLP-1 OT - GLP1-R agonists OT - Parkinson's disease OT - clinical trials OT - exendin-4 OT - liraglutide OT - lixisenatide OT - neurodegeneration OT - semaglutide OT - type 2 diabetes mellitus COIS- The authors declare no conflicts of interest. EDAT- 2024/04/13 10:43 MHDA- 2024/04/15 06:43 PMCR- 2024/03/29 CRDT- 2024/04/13 01:14 PHST- 2024/02/13 00:00 [received] PHST- 2024/03/26 00:00 [revised] PHST- 2024/03/27 00:00 [accepted] PHST- 2024/04/15 06:43 [medline] PHST- 2024/04/13 10:43 [pubmed] PHST- 2024/04/13 01:14 [entrez] PHST- 2024/03/29 00:00 [pmc-release] AID - ijms25073812 [pii] AID - ijms-25-03812 [pii] AID - 10.3390/ijms25073812 [doi] PST - epublish SO - Int J Mol Sci. 2024 Mar 29;25(7):3812. doi: 10.3390/ijms25073812. PMID- 38563864 OWN - NLM STAT- MEDLINE DCOM- 20240820 LR - 20260511 IS - 2509-2723 (Electronic) IS - 2509-2715 (Print) IS - 2509-2723 (Linking) VI - 46 IP - 5 DP - 2024 Oct TI - DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson's disease. PG - 4349-4371 LID - 10.1007/s11357-024-01116-0 [doi] AB - Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70-80% plasma and 20-30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD. CI - (c) 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Yu, Seong-Jin AU - Yu SJ AD - Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan. FAU - Wang, Yun AU - Wang Y AD - Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan. ywang@nhri.edu.tw. AD - National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. ywang@nhri.edu.tw. FAU - Shen, Hui AU - Shen H AD - National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. FAU - Bae, Eun-Kyung AU - Bae EK AD - Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan. FAU - Li, Yazhou AU - Li Y AD - National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. FAU - Sambamurti, Kumar AU - Sambamurti K AD - Department of Neurosciences, the Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Tones, Michael A AU - Tones MA AD - Cadre Bioscience, Saint Louis, MO, 63110, USA. FAU - Zaleska, Margaret M AU - Zaleska MM AD - Neuro-D Consulting LLC, Penn Valley, PA, 19072, USA. FAU - Hoffer, Barry J AU - Hoffer BJ AD - Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. FAU - Greig, Nigel H AU - Greig NH AUID- ORCID: 0000-0002-3032-1468 AD - National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. Greign@grc.nia.nih.gov. LA - eng GR - Intramural Research Program AG000333/AG/NIA NIH HHS/United States GR - NHG/Michael J. Fox Foundation for Parkinson's Research/ GR - Intramural Research Program AG000333/AG/NIA NIH HHS/United States GR - Intramural Research Grant/National Health Research Institutes, Taiwan/ GR - MOST-110-2320-B-400-007/Ministry of Science and Technology, Taiwan/ GR - MOST-111-2320-B-400-010/Ministry of Science and Technology, Taiwan/ PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20240402 PL - Switzerland TA - Geroscience JT - GeroScience JID - 101686284 RN - TS63EW8X6F (Sitagliptin Phosphate) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 8HW4YBZ748 (Oxidopamine) RN - 0 (Incretins) SB - IM MH - Animals MH - *Sitagliptin Phosphate/pharmacology MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology MH - *Oxidopamine MH - Male MH - *Dopaminergic Neurons/drug effects/metabolism MH - Rats MH - Humans MH - Rats, Sprague-Dawley MH - Disease Models, Animal MH - Neuroinflammatory Diseases/drug therapy MH - Parkinsonian Disorders/drug therapy/metabolism/chemically induced MH - Incretins/pharmacology PMC - PMC11336009 OTO - NOTNLM OT - 6-hydroxydopamine OT - Dopamine OT - GIP OT - Gliptins OT - Incretins, GLP-1 OT - Neurodegeneration OT - Neurogenesis OT - Neuroinflammation OT - PF-00734,200 OT - Parkinson's disease OT - Sitagliptin COIS- The authors declare that they have no competing interests. EDAT- 2024/04/02 12:45 MHDA- 2024/08/21 03:50 PMCR- 2024/04/02 CRDT- 2024/04/02 11:06 PHST- 2023/12/12 00:00 [received] PHST- 2024/02/28 00:00 [accepted] PHST- 2024/08/21 03:50 [medline] PHST- 2024/04/02 12:45 [pubmed] PHST- 2024/04/02 11:06 [entrez] PHST- 2024/04/02 00:00 [pmc-release] AID - 10.1007/s11357-024-01116-0 [pii] AID - 1116 [pii] AID - 10.1007/s11357-024-01116-0 [doi] PST - ppublish SO - Geroscience. 2024 Oct;46(5):4349-4371. doi: 10.1007/s11357-024-01116-0. Epub 2024 Apr 2. PMID- 38536493 OWN - NLM STAT- MEDLINE DCOM- 20240423 LR - 20260523 IS - 1432-2013 (Electronic) IS - 0031-6768 (Print) IS - 0031-6768 (Linking) VI - 476 IP - 5 DP - 2024 May TI - Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3beta/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model. PG - 779-795 LID - 10.1007/s00424-024-02933-0 [doi] AB - The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-beta deposition, glycogen synthase kinase 3 beta (GSK3beta), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3beta/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 mug/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3beta/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms. CI - (c) 2024. The Author(s). FAU - Moghazy, Hoda M AU - Moghazy HM AD - Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt. FAU - Abdelhaliem, Nesreen G AU - Abdelhaliem NG AD - Department of Histology, Faculty of Medicine, Sohag University, Sohag, Egypt. FAU - Mohammed, Sherine Ahmed AU - Mohammed SA AD - Department of Histology, Faculty of Medicine, Sohag University, Sohag, Egypt. FAU - Hassan, Asmaa AU - Hassan A AD - Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt. FAU - Abdelrahman, Amany AU - Abdelrahman A AUID- ORCID: 0000-0003-1909-242X AD - Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt. amany_abdelhameed@med.sohag.edu.eg. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240327 PL - Germany TA - Pflugers Arch JT - Pflugers Archiv : European journal of physiology JID - 0154720 RN - 0 (tau Proteins) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - 839I73S42A (Liraglutide) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - D3FM8FA78T (pramlintide) RN - 0 (Islet Amyloid Polypeptide) RN - 0 (Hypoglycemic Agents) RN - 5W494URQ81 (Streptozocin) SB - IM EIN - Pflugers Arch. 2024 May;476(5):873. doi: 10.1007/s00424-024-02959-4. PMID: 38575720 MH - Animals MH - *tau Proteins/metabolism MH - Rats MH - *Glycogen Synthase Kinase 3 beta/metabolism MH - *Liraglutide/pharmacology/therapeutic use MH - *Diet, High-Fat/adverse effects MH - Male MH - *Cognitive Dysfunction/prevention & control/drug therapy/metabolism/etiology MH - *Proto-Oncogene Proteins c-akt/metabolism MH - *Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation/drug effects MH - Signal Transduction/drug effects MH - Diabetes Mellitus, Experimental/metabolism/drug therapy MH - Islet Amyloid Polypeptide/metabolism/pharmacology MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Rats, Sprague-Dawley MH - Streptozocin MH - Diabetes Mellitus, Type 2/metabolism/drug therapy PMC - PMC11033245 OTO - NOTNLM OT - GSK-3beta OT - Liraglutide OT - Pramlintide OT - TTBK1 COIS- The authors declare no competing interests. EDAT- 2024/03/27 18:45 MHDA- 2024/04/23 15:50 PMCR- 2024/03/27 CRDT- 2024/03/27 12:17 PHST- 2023/09/16 00:00 [received] PHST- 2024/02/22 00:00 [accepted] PHST- 2024/02/13 00:00 [revised] PHST- 2024/04/23 15:50 [medline] PHST- 2024/03/27 18:45 [pubmed] PHST- 2024/03/27 12:17 [entrez] PHST- 2024/03/27 00:00 [pmc-release] AID - 10.1007/s00424-024-02933-0 [pii] AID - 2933 [pii] AID - 10.1007/s00424-024-02933-0 [doi] PST - ppublish SO - Pflugers Arch. 2024 May;476(5):779-795. doi: 10.1007/s00424-024-02933-0. Epub 2024 Mar 27. PMID- 38517522 OWN - NLM STAT- MEDLINE DCOM- 20240529 LR - 20240621 IS - 1432-1459 (Electronic) IS - 0340-5354 (Print) IS - 0340-5354 (Linking) VI - 271 IP - 6 DP - 2024 Jun TI - Comparing major and mild cognitive impairment risks in older type-2 diabetic patients: a Danish register-based study on dipeptidyl peptidase-4 inhibitors vs. glucagon-like peptide-1 analogues. PG - 3417-3425 LID - 10.1007/s00415-024-12300-9 [doi] AB - INTRODUCTION: The prevalence of major and mild cognitive impairment (CI) in type-2 diabetes older patients is 15-25% and 30-60%, respectively, thus affecting quality of life and health outcomes. There is, therefore, the need of head-to-head studies aiming at identifying the optimal treatment for individuals with type-2 diabetes at increased risk of mild and major CI. This study focuses on the risk of developing mild and major CI in Danish patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 analogues (GLP-1a) using administrative and healthcare registers. METHODS: An active comparator design with a 3-year follow-up period was used. The main outcome was the hospital admission with a diagnosis of mild CI or major CI. Multivariate Cox Regression analysis was performed using the high-dimensional propensity score to obtain adjusted Hazard Ratio (HR) estimates. Inverse probability of treatment weighting (IPTW) and marginal structured model were used to calculate risk differences while accounting for the variations of confounders throughout the follow-up period. RESULTS: Our results show a significant higher risk of major CI between DPP-4i and GLP-1a in unadjusted [HR (95% CI) = 3.13 (2.45-4.00), p < 0.001] and adjusted analyses [HR (95% CI) = 1.58 (1.22-2.06), p = 0.001]. No statistically significant differences were observed for mild CI. IPTW resulted stable throughout the follow-up period. Marginal structure modeling (beta (95% CI) = 0.022 (0.020-0.024), p < 0.001) resulted in a higher risk of major CI for DPP-4i when compared to GLP-1a. DISCUSSION: DPP-4i was associated with an increased risk of developing major CI when compared to GLP-1a among older individuals with type-2 diabetes. CI - (c) 2024. The Author(s). FAU - Battini, Vera AU - Battini V AUID- ORCID: 0000-0002-3513-9593 AD - Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark. AD - Pharmacovigilance and Clinical Research, International Centre for Pesticides and Health Risk Prevention, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Universita Degli Studi Di Milano, Milan, Italy. FAU - Barbieri, Maria Antonietta AU - Barbieri MA AUID- ORCID: 0000-0002-2019-4696 AD - Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark. AD - Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy. FAU - Carnovale, Carla AU - Carnovale C AUID- ORCID: 0000-0002-4107-196X AD - Pharmacovigilance and Clinical Research, International Centre for Pesticides and Health Risk Prevention, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Universita Degli Studi Di Milano, Milan, Italy. FAU - Spina, Edoardo AU - Spina E AUID- ORCID: 0000-0002-2509-7449 AD - Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy. FAU - Clementi, Emilio AU - Clementi E AUID- ORCID: 0000-0001-7333-8270 AD - Pharmacovigilance and Clinical Research, International Centre for Pesticides and Health Risk Prevention, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Universita Degli Studi Di Milano, Milan, Italy. AD - Scientific Institute, IRCCS E. Medea, Bosisio Parini, LC, Italy. FAU - Sessa, Maurizio AU - Sessa M AUID- ORCID: 0000-0003-0874-4744 AD - Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark. maurizio.sessa@sund.ku.dk. LA - eng PT - Comparative Study PT - Journal Article DEP - 20240322 PL - Germany TA - J Neurol JT - Journal of neurology JID - 0423161 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology/complications MH - Male MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects/therapeutic use MH - Female MH - Denmark/epidemiology MH - Aged MH - *Cognitive Dysfunction/epidemiology/etiology MH - *Glucagon-Like Peptide 1 MH - *Registries MH - Hypoglycemic Agents/adverse effects MH - Aged, 80 and over MH - Follow-Up Studies MH - Middle Aged PMC - PMC11136777 OTO - NOTNLM OT - Dipeptidyl peptidase-4 inhibitors OT - Glucagon-like peptide-1 analogues OT - Major cognitive impairment OT - Mild cognitive impairment OT - Older individuals OT - Register-based study COIS- All the authors declare that there is no conflict of interest. EDAT- 2024/03/22 18:44 MHDA- 2024/05/29 12:44 PMCR- 2024/03/22 CRDT- 2024/03/22 12:14 PHST- 2023/12/23 00:00 [received] PHST- 2024/03/02 00:00 [accepted] PHST- 2024/03/01 00:00 [revised] PHST- 2024/05/29 12:44 [medline] PHST- 2024/03/22 18:44 [pubmed] PHST- 2024/03/22 12:14 [entrez] PHST- 2024/03/22 00:00 [pmc-release] AID - 10.1007/s00415-024-12300-9 [pii] AID - 12300 [pii] AID - 10.1007/s00415-024-12300-9 [doi] PST - ppublish SO - J Neurol. 2024 Jun;271(6):3417-3425. doi: 10.1007/s00415-024-12300-9. Epub 2024 Mar 22. PMID- 38509913 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260214 IS - 2405-8440 (Print) IS - 2405-8440 (Electronic) IS - 2405-8440 (Linking) VI - 10 IP - 6 DP - 2024 Mar 30 TI - Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes. PG - e27412 LID - 10.1016/j.heliyon.2024.e27412 [doi] LID - e27412 AB - Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1. CI - (c) 2024 The Authors. FAU - Canario, Nadia S AU - Canario NS AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. AD - Faculty of Medicine, University of Coimbra, Portugal. FAU - Crisostomo, Joana AU - Crisostomo J AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. FAU - Moreno, Carolina AU - Moreno C AD - Department of Endocrinology, Centro Hospitalar e Universitario de Coimbra (CHUC), Coimbra, Portugal. FAU - Duarte, Joao V AU - Duarte JV AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. AD - Faculty of Medicine, University of Coimbra, Portugal. FAU - Duarte, Isabel C AU - Duarte IC AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. FAU - Ribeiro, Mario J AU - Ribeiro MJ AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. AD - The Faculty of Science and Technology, University of Coimbra, Portugal. FAU - Caramelo, Beatriz AU - Caramelo B AD - Faculty of Medicine, University of Coimbra, Portugal. AD - Coimbra Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine and Center of Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal. FAU - Gomes, Leonor V AU - Gomes LV AD - Department of Endocrinology, Centro Hospitalar e Universitario de Coimbra (CHUC), Coimbra, Portugal. FAU - Matafome, Paulo AU - Matafome P AD - Faculty of Medicine, University of Coimbra, Portugal. AD - Coimbra Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine and Center of Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal. FAU - Oliveira, Francisco P AU - Oliveira FP AD - Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal. FAU - Castelo-Branco, Miguel AU - Castelo-Branco M AD - Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health, Portugal. AD - Faculty of Medicine, University of Coimbra, Portugal. LA - eng GR - U58 DP004950/DP/NCCDPHP CDC HHS/United States PT - Journal Article DEP - 20240303 PL - England TA - Heliyon JT - Heliyon JID - 101672560 PMC - PMC10950584 COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/03/21 06:43 MHDA- 2024/03/21 06:44 PMCR- 2024/03/03 CRDT- 2024/03/21 03:57 PHST- 2023/08/29 00:00 [received] PHST- 2024/02/22 00:00 [revised] PHST- 2024/02/28 00:00 [accepted] PHST- 2024/03/21 06:44 [medline] PHST- 2024/03/21 06:43 [pubmed] PHST- 2024/03/21 03:57 [entrez] PHST- 2024/03/03 00:00 [pmc-release] AID - S2405-8440(24)03443-1 [pii] AID - e27412 [pii] AID - 10.1016/j.heliyon.2024.e27412 [doi] PST - epublish SO - Heliyon. 2024 Mar 3;10(6):e27412. doi: 10.1016/j.heliyon.2024.e27412. eCollection 2024 Mar 30. PMID- 38425117 OWN - NLM STAT- MEDLINE DCOM- 20241216 LR - 20241216 IS - 1875-6417 (Electronic) IS - 1573-3998 (Linking) VI - 21 IP - 4 DP - 2024 TI - Incretin Therapy and Insulin Signaling: Therapeutic Targets for Diabetes And Associated Dementia. PG - 57-63 LID - 10.2174/0115733998279875240216093902 [doi] AB - Dementia is the primary cause of disability and dependence among the elderly population worldwide. The population living with dementia is anticipated to double in the next 17 years. Recent studies show the fact that compared to people without diabetes, people with Type 2 Diabetes (T2D) have about a 60% increased chance of developing dementia. In addition to cholinergic function being downregulated, improper insulin signalling also has a negative impact on synaptic plasticity and neuronal survival. Type 2 diabetes and dementia share various similar pathophysiological components. The ageing of the population and the ensuing rise in dementia prevalence are both results of ongoing medical advancements. It is possible that restoring insulin signaling could be a helpful therapy against dementia, as it is linked to both diminished cognitive function and the development of dementia, including AD. This review article comprehensively focused on scientific literature to analyze the relationship of Dementia with diabetes, recent experimental studies, and insight into incretin-based drug therapy for diabetes-related dementia. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Joshi, Deepika AU - Joshi D AD - Siddhartha Institute of Pharmacy, Sahastradhara Road, Dehradun, Uttarakhand, India. AD - School of Pharmacy, Graphic Era Hill University, Clement Town Dehradun, Uttarakhand, India. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Diabetes Rev JT - Current diabetes reviews JID - 101253260 RN - 0 (Incretins) RN - 0 (Insulin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Incretins/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Dementia/drug therapy MH - *Insulin/metabolism/therapeutic use MH - *Signal Transduction/drug effects MH - Animals MH - Hypoglycemic Agents/therapeutic use OTO - NOTNLM OT - Dementia OT - cognitive OT - diabetes-related-dementia OT - gliptins OT - incretin. OT - insulin EDAT- 2024/03/01 06:43 MHDA- 2024/12/16 11:35 CRDT- 2024/03/01 02:12 PHST- 2023/10/19 00:00 [received] PHST- 2024/01/27 00:00 [revised] PHST- 2024/02/07 00:00 [accepted] PHST- 2024/12/16 11:35 [medline] PHST- 2024/03/01 06:43 [pubmed] PHST- 2024/03/01 02:12 [entrez] AID - CDR-EPUB-138878 [pii] AID - 10.2174/0115733998279875240216093902 [doi] PST - ppublish SO - Curr Diabetes Rev. 2024;21(4):57-63. doi: 10.2174/0115733998279875240216093902. PMID- 38408478 OWN - NLM STAT- MEDLINE DCOM- 20240304 LR - 20240516 IS - 2194-9387 (Electronic) IS - 2194-9379 (Linking) VI - 74 IP - 3 DP - 2024 Mar TI - Encyclopaedic Review of Glipizide Pre-clinical and Clinical Status. PG - 123-132 LID - 10.1055/a-2237-8566 [doi] AB - Glipizide is an oral glucose-lowering medication that is beneficial for the treatment of type 2 diabetes. This study compiles exhaustively all accessible information on glipizide, from preclinical to clinical studies. Glipizide may be used in concert with TRAIL to treat cancer cells; in vitro studies have shown that it suppresses angiogenesis and vasculogenesis while shielding cells from glycation-induced damage. Anticonvulsant effects and modifications in the pharmacokinetics of other medications, such as Divalproex Sodium, were seen in glipizide in vivo experiments. Propranolol amplifies glipizide's hypoglycemic effect briefly in normal animals but consistently enhances it in diabetic ones. In the treatment of cancer and neurodegenerative poly(Q) illnesses, glipizide has demonstrated to offer potential therapeutic advantages. It is ineffective in preventing DENA-induced liver cancer and may cause DNA damage over time. The way glipizide interacts with genetic variants may increase the risk of hypoglycemia. Combining Syzygium cumini and ARBE to glipizide may enhance glycemic and lipid control in type 2 diabetes. Individuals with coronary artery disease who take glipizide or glyburide have an increased risk of death. The risk of muscular responses and acute pancreatitis is minimal when glipizide and dulaglutide are combined. In conclusion, glipizide has shown promising therapeutic efficacy across a variety of disorders. CI - Thieme. All rights reserved. FAU - Mohammed, Saad AU - Mohammed S AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Mahmood, Tarique AU - Mahmood T AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Shamim, Arshiya AU - Shamim A AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Ahsan, Farogh AU - Ahsan F AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Shariq, Mohammad AU - Shariq M AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Parveen, Saba AU - Parveen S AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Waseem, Rufaida AU - Waseem R AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. FAU - Singh, Aditya AU - Singh A AD - Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India. LA - eng PT - Journal Article DEP - 20240226 PL - Germany TA - Drug Res (Stuttg) JT - Drug research JID - 101602406 RN - X7WDT95N5C (Glipizide) RN - 0 (Blood Glucose) SB - IM EIN - Drug Res (Stuttg). 2024 Mar;74(3):e2. doi: 10.1055/a-2321-8886. PMID: 38749472 MH - Humans MH - Glipizide/adverse effects MH - *Diabetes Mellitus, Type 2/drug therapy/chemically induced MH - Acute Disease MH - Blood Glucose MH - *Pancreatitis/chemically induced/drug therapy COIS- The authors declare that they have no conflict of interest. EDAT- 2024/02/27 00:42 MHDA- 2024/03/04 06:47 CRDT- 2024/02/26 19:02 PHST- 2024/03/04 06:47 [medline] PHST- 2024/02/27 00:42 [pubmed] PHST- 2024/02/26 19:02 [entrez] AID - 10.1055/a-2237-8566 [doi] PST - ppublish SO - Drug Res (Stuttg). 2024 Mar;74(3):123-132. doi: 10.1055/a-2237-8566. Epub 2024 Feb 26. PMID- 38405664 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240227 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 15 DP - 2024 TI - Neuroprotective effects of dipeptidyl peptidase 4 inhibitor on Alzheimer's disease: a narrative review. PG - 1361651 LID - 10.3389/fphar.2024.1361651 [doi] LID - 1361651 AB - Insulin resistance in brain and amyloidogenesis are principal pathological features of diabetes-related cognitive decline and development of Alzheimer's disease (AD). A growing body of evidence suggests that maintaining glucose under control in diabetic patients is beneficial for preventing AD development. Dipeptidyl peptidase 4 inhibitors (DDP4is) are a class of novel glucose-lowering medications through increasing insulin excretion and decreasing glucagon levels that have shown neuroprotective potential in recent studies. This review consolidates extant evidence from earlier and new studies investigating the association between DPP4i use, AD, and other cognitive outcomes. Beyond DPP4i's benefits in alleviating insulin resistance and glucose-lowering, underlying mechanisms for the potential neuroprotection with DPP4i medications were categorized into the following sections: (Ferrari et al., Physiol Rev, 2021, 101, 1,047-1,081): the benefits of DPP4is on directly ameliorating the burden of beta-amyloid plaques and reducing the formation of neurofibrillary tangles; DPP4i increasing the bioactivity of neuroprotective DPP4 substrates including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and stromal-derived factor-1alpha (SDF-1alpha) etc.; pleiotropic effects of DPP4is on neuronal cells and intracerebral structure including anti-inflammation, anti-oxidation, and anti-apoptosis. We further revisited recently published epidemiological studies that provided supportive data to compliment preclinical evidence. Given that there remains a lack of completed randomized trials that aim at assessing the effect of DPP4is in preventing AD development and progression, this review is expected to provide a useful insight into DPP4 inhibition as a potential therapeutic target for AD prevention and treatment. The evidence is helpful for informing the rationales of future clinical research and guiding evidence-based clinical practice. CI - Copyright (c) 2024 Jiang, Li, Yao, Ding, Gu and Zhou. FAU - Jiang, Xin AU - Jiang X AD - Baoying People's Hospital, Yangzhou, China. FAU - Li, Ji AU - Li J AD - Baoying People's Hospital, Yangzhou, China. AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. FAU - Yao, Xiaohui AU - Yao X AD - Baoying People's Hospital, Yangzhou, China. FAU - Ding, Hao AU - Ding H AD - Baoying People's Hospital, Yangzhou, China. FAU - Gu, Aihong AU - Gu A AD - Baoying People's Hospital, Yangzhou, China. FAU - Zhou, Zhen AU - Zhou Z AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. LA - eng PT - Journal Article PT - Review DEP - 20240209 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC10884281 OTO - NOTNLM OT - Alzheimer's disease OT - dipeptidyl peptidase 4 OT - glucagon-like peptide-1 OT - neurodegenerative diseases OT - type 2 diabetes mellitus COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/02/26 06:45 MHDA- 2024/02/26 06:46 PMCR- 2024/02/09 CRDT- 2024/02/26 04:47 PHST- 2023/12/26 00:00 [received] PHST- 2024/01/30 00:00 [accepted] PHST- 2024/02/26 06:46 [medline] PHST- 2024/02/26 06:45 [pubmed] PHST- 2024/02/26 04:47 [entrez] PHST- 2024/02/09 00:00 [pmc-release] AID - 1361651 [pii] AID - 10.3389/fphar.2024.1361651 [doi] PST - epublish SO - Front Pharmacol. 2024 Feb 9;15:1361651. doi: 10.3389/fphar.2024.1361651. eCollection 2024. PMID- 38288136 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20260922 IS - 2042-0188 (Print) IS - 2042-0196 (Electronic) IS - 2042-0188 (Linking) VI - 15 DP - 2024 TI - Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. PG - 20420188231222367 LID - 10.1177/20420188231222367 [doi] LID - 20420188231222367 AB - Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic agents with potent anti-inflammatory properties and diverse clinical implications. This in-depth review article explores the mechanisms behind the anti-inflammatory actions of GLP-1RAs and assesses their prospective applicability in a wide range of disease scenarios. The current review establishes the significance of comprehending the anti-inflammatory role of GLP-1RAs and identifies pertinent research gaps. A concise overview of inflammation and its clinical consequences underscores the critical need for effective anti-inflammatory interventions. Subsequently, the article elucidates the intricate mechanisms through which GLP-1RAs modulate immune cell signaling and regulate the nuclear factor-kappa B (NF-kappaB) pathway. Detailed discussions encompass their impact on inflammatory responses, cytokine production, and attenuation of oxidative stress. The exposition is substantiated by a collection of pertinent examples and an extensive array of references from both preclinical and clinical investigations. The historical trajectory of GLP-1RA drugs, including exenatide, lixisenatide, liraglutide, and semaglutide, is traced to delineate their development as therapeutic agents. Moreover, the review emphasizes the therapeutic potential of GLP-1RAs in specific disease contexts like type 2 diabetes, a neurodegenerative disorder, and inflammatory bowel disease (IBD), shedding light on their anti-inflammatory effects through rigorous examination of preclinical and clinical studies. The article also provides an outlook on future perspectives for GLP-1RAs, encompassing the domains of diabetes, neurodegenerative diseases, and IBD. In conclusion, GLP-1RAs exhibit substantial anti-inflammatory effects, rendering them promising therapeutic agents with broad clinical implications. They are very useful in a wide variety of diseases because they regulate immunological responses, block NF-kappaB activation, and decrease production of pro-inflammatory cytokines. Ongoing research endeavors aim to optimize their therapeutic use, delineate patient-specific treatment paradigms, and explore novel therapeutic applications. GLP-1RAs represent a significant breakthrough in anti-inflammatory therapy, offering novel treatment options, and improved patient outcomes. CI - (c) The Author(s), 2024. FAU - Alharbi, Saleh Hadi AU - Alharbi SH AUID- ORCID: 0000-0002-9635-3307 AD - Department of Medicine, Imam Mohammed Ibn Saud Islamic University, Riyadh 11652, Saudi Arabia. LA - eng PT - Journal Article PT - Review DEP - 20240127 PL - United States TA - Ther Adv Endocrinol Metab JT - Therapeutic advances in endocrinology and metabolism JID - 101532143 PMC - PMC10823863 OTO - NOTNLM OT - Glucagon-like peptide 1 receptor agonists OT - inflammation OT - inflammatory bowel disease OT - neurodegenerative disorder OT - nuclear factor-kappa B OT - obesity OT - type-2 diabetes COIS- The author declares that there is no conflict of interest. EDAT- 2024/01/30 06:42 MHDA- 2024/01/30 06:43 PMCR- 2024/01/27 CRDT- 2024/01/30 03:38 PHST- 2023/07/11 00:00 [received] PHST- 2023/11/28 00:00 [accepted] PHST- 2024/01/30 06:43 [medline] PHST- 2024/01/30 06:42 [pubmed] PHST- 2024/01/30 03:38 [entrez] PHST- 2024/01/27 00:00 [pmc-release] AID - 10.1177_20420188231222367 [pii] AID - 10.1177/20420188231222367 [doi] PST - epublish SO - Ther Adv Endocrinol Metab. 2024 Jan 27;15:20420188231222367. doi: 10.1177/20420188231222367. eCollection 2024. PMID- 38287296 OWN - NLM STAT- MEDLINE DCOM- 20240131 LR - 20250103 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 22 IP - 1 DP - 2024 Jan 29 TI - Tirzepatide prevents neurodegeneration through multiple molecular pathways. PG - 114 LID - 10.1186/s12967-024-04927-z [doi] LID - 114 AB - BACKGROUND: Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders. METHODS: We investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means +/- SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures. RESULTS: For the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level. CONCLUSIONS: We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy. CI - (c) 2024. The Author(s). FAU - Fontanella, Rosaria Anna AU - Fontanella RA AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Ghosh, Puja AU - Ghosh P AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Pesapane, Ada AU - Pesapane A AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Taktaz, Fatemeh AU - Taktaz F AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Puocci, Armando AU - Puocci A AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Franzese, Martina AU - Franzese M AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Feliciano, Maria Federica AU - Feliciano MF AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Tortorella, Giovanni AU - Tortorella G AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Scisciola, Lucia AU - Scisciola L AUID- ORCID: 0000-0003-3636-4298 AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. lucia.scisciola@unicampania.it. FAU - Sommella, Eduardo AU - Sommella E AD - Department of Pharmacy, University of Salerno, Fisciano, SA, Italy. FAU - Ambrosino, Concetta AU - Ambrosino C AD - Biogem Institute of Molecular Biology and Genetics, Ariano Irpino, Italy. AD - Department of Science and Technology, University of Sannio, Benevento, Italy. FAU - Paolisso, Giuseppe AU - Paolisso G AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. AD - UniCamillus, International Medical University, Rome, Italy. FAU - Barbieri, Michelangela AU - Barbieri M AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. LA - eng GR - PNC0000003/AdvaNced Technologies for Human-centrEd Medicine (project acronym: ANTHEM)/ GR - 2017CPLH3/Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240129 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - OYN3CCI6QE (Tirzepatide) RN - 0 (Insulin) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Blood Glucose) RN - 0 (MicroRNAs) RN - 0 (Hypoglycemic Agents) RN - 0 (MIRN212 microRNA, human) RN - 0 (Glucagon-Like Peptide-2 Receptor) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism MH - Insulin/metabolism MH - *Insulin Resistance MH - Brain-Derived Neurotrophic Factor MH - Blood Glucose/metabolism MH - *MicroRNAs MH - Hypoglycemic Agents/pharmacology MH - *Glucagon-Like Peptide-2 Receptor MH - *Gastric Inhibitory Polypeptide MH - Tirzepatide MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC10823712 OTO - NOTNLM OT - Diabetes mellitus type 2 OT - Glucose homeostasis OT - Insulin resistance OT - Neurodegeneration OT - Neurodifferentiation OT - Neuronal growth COIS- The authors declare that they have no competing interests. EDAT- 2024/01/30 00:42 MHDA- 2024/01/31 06:43 PMCR- 2024/01/29 CRDT- 2024/01/29 23:56 PHST- 2023/12/20 00:00 [received] PHST- 2024/01/23 00:00 [accepted] PHST- 2024/01/31 06:43 [medline] PHST- 2024/01/30 00:42 [pubmed] PHST- 2024/01/29 23:56 [entrez] PHST- 2024/01/29 00:00 [pmc-release] AID - 10.1186/s12967-024-04927-z [pii] AID - 4927 [pii] AID - 10.1186/s12967-024-04927-z [doi] PST - epublish SO - J Transl Med. 2024 Jan 29;22(1):114. doi: 10.1186/s12967-024-04927-z. PMID- 38272546 OWN - NLM STAT- MEDLINE DCOM- 20240129 LR - 20241023 IS - 2044-6055 (Electronic) IS - 2044-6055 (Linking) VI - 14 IP - 1 DP - 2024 Jan 25 TI - Clinical characteristics and healthcare utilisation associated with undiagnosed cognitive impairment in elderly patients with diabetes in a primary care setting: a population-based cohort study. PG - e078996 LID - 10.1136/bmjopen-2023-078996 [doi] LID - e078996 AB - OBJECTIVES: The objective of this study is to report the prevalence, clinical characteristics and healthcare utilisation of patients with type 2 diabetes (T2DM) and previously undiagnosed cognitive impairment who were identified as having a low Montreal Cognitive Assessment (MoCA) score. DESIGN: A population-based cohort study comparing clinical characteristics, medications, outpatient and inpatient care of patients with a MoCA score <19 to MoCA >26 using descriptive statistics, linear regression and multivariate logistic regression. SETTING: Electronic medical records of a large health maintenance organisation in Israel. PARTICIPANTS: 350 patients, age >65 with T2DM who participated in a cognitive function screening initiative using MoCA, and had a follow-up visit during the 12 months after screening. RESULTS: 130 (37.1%) had a MoCA score >26 and 68 (19.4%) <19. Patients with MoCA<19 had more diabetes-related complications, poorer glycaemic and lipid control, fewer visits to their main primary care physician (PCP; 3.9+/-3.2 vs 7.3+/-4.2 visits/year p=0.008), shorter duration of PCP visits (8.3+/-4.5 vs 4.0+/-3.5 min, p=0.007), fewer nutritionist and endocrinologist visits, and lower participation in diabetes or smoking cessation workshops. They were less likely to be treated with glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 inhibitor (DPP-4), or sodium-glucose transport protein 2 (SGLT-2) inhibitors and more likely to receive insulin or sulfonylurea. Moreover, they had more emergency room visits (ER; 15 (11.5%) vs 16 (23.5%), p=0.019), hospitalisations (8 (6.2%) vs 22 (32.4%), p=0.001), and longer hospital stays (4.3+/-3.2 vs 14.5+/-9.8, p=0.001). Using statistical models, MoCA<19 was identified as a risk factor for fewer and shorter PCP visits and more ER visits and hospitalisations. CONCLUSIONS: This study highlights the high prevalence of undiagnosed severe cognitive impairment in elderly patients with T2DM and its association with poor outpatient care. Appropriate interventions are needed to improve outcomes and prevent hospitalisation in this high-risk population. CI - (c) Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Merzon, Eugene AU - Merzon E AUID- ORCID: 0000-0001-5469-0236 AD - Medical Division, Leumit Health Care Services, Tel Aviv, Israel. AD - Dr Miriam and Sheldon G Adelson School of Medicine, Ariel University, Ariel, Israel. FAU - Shpigelman, Miriam AU - Shpigelman M AD - Clalit Health Services, Dan Petach Tikva, Israel. FAU - Vinker, Shlomo AU - Vinker S AD - Medical Division, Leumit Health Care Services, Tel Aviv, Israel. AD - Department of Family Medicine, School of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Golan Cohen, Avivit AU - Golan Cohen A AD - Medical Division, Leumit Health Care Services, Tel Aviv, Israel. AD - Department of Family Medicine, School of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Green, Ilan AU - Green I AD - Medical Division, Leumit Health Care Services, Tel Aviv, Israel. AD - Department of Family Medicine, School of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Israel, Ariel AU - Israel A AD - Medical Division, Leumit Health Care Services, Tel Aviv, Israel. FAU - Cukierman-Yaffe, T AU - Cukierman-Yaffe T AD - Division of Endocrinology, Diabetes and Metabolism, Gertner Institute, Sheba Medical Center, Ramat Gan, Israel. AD - Epidmiology Department, Herczeg Institute on Aging, School of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Eldor, Roy AU - Eldor R AUID- ORCID: 0000-0002-1151-1370 AD - Diabetes Units, Institute for Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel eldorroy@yahoo.com. AD - School of Medicine, Tel Aviv University, Tel Aviv, Israel. LA - eng PT - Journal Article DEP - 20240125 PL - England TA - BMJ Open JT - BMJ open JID - 101552874 RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) SB - IM MH - Humans MH - Aged MH - Child, Preschool MH - *Diabetes Mellitus, Type 2/complications/epidemiology/drug therapy MH - Cohort Studies MH - Hypoglycemic Agents/therapeutic use MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - *Cognitive Dysfunction/diagnosis/epidemiology/complications MH - Patient Acceptance of Health Care MH - Primary Health Care PMC - PMC10824016 OTO - NOTNLM OT - Aged OT - Dementia OT - General diabetes OT - Primary Health Care COIS- Competing interests: None declared. EDAT- 2024/01/26 00:43 MHDA- 2024/01/29 06:43 PMCR- 2024/01/25 CRDT- 2024/01/25 20:52 PHST- 2024/01/29 06:43 [medline] PHST- 2024/01/26 00:43 [pubmed] PHST- 2024/01/25 20:52 [entrez] PHST- 2024/01/25 00:00 [pmc-release] AID - bmjopen-2023-078996 [pii] AID - 10.1136/bmjopen-2023-078996 [doi] PST - epublish SO - BMJ Open. 2024 Jan 25;14(1):e078996. doi: 10.1136/bmjopen-2023-078996. PMID- 38267691 OWN - NLM STAT- MEDLINE DCOM- 20240229 LR - 20261010 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 49 IP - 4 DP - 2024 Apr TI - Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice. PG - 1061-1075 LID - 10.1007/s11064-023-04093-6 [doi] AB - Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice. CI - (c) 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Liu, Weizhen AU - Liu W AD - Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. AD - The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450001, Henan, China. FAU - Wang, Ziliang AU - Wang Z AD - Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. AD - The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450001, Henan, China. FAU - Wang, Wang AU - Wang W AD - Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. AD - The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450001, Henan, China. FAU - Wang, Zhiju AU - Wang Z AD - Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. FAU - Xing, Ying AU - Xing Y AD - Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. Xingy@zzu.edu.cn. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - Henan Academy of Innovation in Medical Science, XinZheng, 451100, Henan, China. c.holscher@hactcm.edu.cn. LA - eng PT - Journal Article DEP - 20240124 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 3K9958V90M (Ethanol) RN - 0 (Intercellular Signaling Peptides and Proteins) SB - IM MH - Mice MH - Male MH - Animals MH - Liraglutide/pharmacology/therapeutic use MH - *Alcoholism/drug therapy MH - *Diabetes Mellitus, Type 2 MH - *Substance Withdrawal Syndrome/drug therapy MH - Mice, Inbred C57BL MH - Glucagon-Like Peptide 1/pharmacology/therapeutic use MH - Anxiety/drug therapy MH - Memory Disorders/chemically induced/drug therapy MH - Ethanol/pharmacology MH - Alcohol Drinking/drug therapy MH - Synapses MH - Intercellular Signaling Peptides and Proteins/pharmacology MH - Recurrence OTO - NOTNLM OT - Alcohol addiction OT - Golgi stain OT - Learning OT - Liraglutide OT - Synapses EDAT- 2024/01/25 00:42 MHDA- 2024/02/29 06:44 CRDT- 2024/01/24 23:27 PHST- 2023/08/18 00:00 [received] PHST- 2023/12/22 00:00 [accepted] PHST- 2023/12/02 00:00 [revised] PHST- 2024/02/29 06:44 [medline] PHST- 2024/01/25 00:42 [pubmed] PHST- 2024/01/24 23:27 [entrez] AID - 10.1007/s11064-023-04093-6 [pii] AID - 10.1007/s11064-023-04093-6 [doi] PST - ppublish SO - Neurochem Res. 2024 Apr;49(4):1061-1075. doi: 10.1007/s11064-023-04093-6. Epub 2024 Jan 24. PMID- 38256482 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241023 IS - 2077-0383 (Print) IS - 2077-0383 (Electronic) IS - 2077-0383 (Linking) VI - 13 IP - 2 DP - 2024 Jan 8 TI - Chronic Kidney Disease in the Older Adult Patient with Diabetes. LID - 10.3390/jcm13020348 [doi] LID - 348 AB - Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and older adult individuals. DM may accelerate the aging process, and the age-related declines in the estimated glomerular filtration rate (eGFR) can pose a challenge to diagnosing diabetic kidney disease (DKD) using standard diagnostic criteria especially with the absence of severe albuminuria among older adults. In the presence of CKD and DM, older adult patients may need multidisciplinary care due to susceptibility to various health issues, e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to older adults. We review the evidence that the benefits from these newer therapies apply equally to older and younger patients with CKD and diabetes type 2 and propose a comprehensive management. This framework will address nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), sodium glucose co-transporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and glucagon like peptide 1 receptor agonists (GLP1-RAs). FAU - Ravender, Raja AU - Ravender R AD - Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, MSC 04-2785, Albuquerque, NM 87131, USA. FAU - Roumelioti, Maria-Eleni AU - Roumelioti ME AD - Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, MSC 04-2785, Albuquerque, NM 87131, USA. FAU - Schmidt, Darren W AU - Schmidt DW AD - Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, MSC 04-2785, Albuquerque, NM 87131, USA. FAU - Unruh, Mark L AU - Unruh ML AD - Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, MSC 04-2785, Albuquerque, NM 87131, USA. FAU - Argyropoulos, Christos AU - Argyropoulos C AUID- ORCID: 0000-0002-9679-7805 AD - Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, MSC 04-2785, Albuquerque, NM 87131, USA. LA - eng PT - Journal Article PT - Review DEP - 20240108 PL - Switzerland TA - J Clin Med JT - Journal of clinical medicine JID - 101606588 PMC - PMC10816477 OTO - NOTNLM OT - GLP1 receptor agonists OT - SGLT2 inhibitors OT - chronic kidney disease OT - diabetes OT - dialysis OT - elderly OT - geriatric OT - non-steroidal mineralocorticoid antagonists OT - treatment COIS- C.A. has received consultant fees from Bayer (manufacturer of finerenone Hanover, NJ, USA). EDAT- 2024/01/23 06:43 MHDA- 2024/01/23 06:44 PMCR- 2024/01/08 CRDT- 2024/01/23 01:14 PHST- 2023/10/06 00:00 [received] PHST- 2023/12/27 00:00 [revised] PHST- 2024/01/04 00:00 [accepted] PHST- 2024/01/23 06:44 [medline] PHST- 2024/01/23 06:43 [pubmed] PHST- 2024/01/23 01:14 [entrez] PHST- 2024/01/08 00:00 [pmc-release] AID - jcm13020348 [pii] AID - jcm-13-00348 [pii] AID - 10.3390/jcm13020348 [doi] PST - epublish SO - J Clin Med. 2024 Jan 8;13(2):348. doi: 10.3390/jcm13020348. PMID- 38255204 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20241023 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 12 IP - 1 DP - 2024 Jan 3 TI - Pharmacological Approaches Using Diabetic Drugs Repurposed for Alzheimer's Disease. LID - 10.3390/biomedicines12010099 [doi] LID - 99 AB - Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are chronic, progressive disorders affecting the elderly, which fosters global healthcare concern with the growing aging population. Both T2DM and AD have been linked with increasing age, advanced glycosylation end products, obesity, and insulin resistance. Insulin resistance in the periphery is significant in the development of T2DM and it has been posited that insulin resistance in the brain plays a key role in AD pathogenesis, earning AD the name "type 3 diabetes". These clinical and epidemiological links between AD and T2DM have become increasingly pronounced throughout the years, and serve as a means to investigate the effects of antidiabetic therapies in AD, such as metformin, intranasal insulin, incretins, DPP4 inhibitors, PPAR-gamma agonists, SGLT2 inhibitors. The majority of these drugs have shown benefit in preclinical trials, and have shown some promising results in clinical trials, with the improvement of cognitive faculties in participants with mild cognitive impairment and AD. In this review, we have summarize the benefits, risks, and conflicting data that currently exist for diabetic drugs being repurposed for the treatment of AD. FAU - Adem, Muna A AU - Adem MA AD - Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Rd., Phoenix, AZ 85013, USA. FAU - Decourt, Boris AU - Decourt B AUID- ORCID: 0000-0001-7637-5034 AD - Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. FAU - Sabbagh, Marwan N AU - Sabbagh MN AUID- ORCID: 0000-0001-8139-3309 AD - Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Rd., Phoenix, AZ 85013, USA. LA - eng GR - P30 AG072980/AG/NIA NIH HHS/United States GR - R01 AG059008/AG/NIA NIH HHS/United States GR - R01 AG073212/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20240103 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC10813018 OTO - NOTNLM OT - Alzheimer's disease OT - clinical trials OT - dementia OT - diabetes OT - drugs OT - insulin OT - medications OT - type 2 diabetes COIS- Adem has no conflicts of interest to report. DeCourt declares that he is a consultant for Seq Biomarque. Sabbagh discloses that he has ownership interest (stock or stock options) in NeuroTau, uMethod Health, Lighthouse Pharmaceuticals, and Athira; he consults for Alzheon, Biogen, Roche-Genentech, T3D, Novo Nordisk, Signant Health, Prothena, Eisai, Lilly, and KeifeRx. EDAT- 2024/01/23 06:42 MHDA- 2024/01/23 06:43 PMCR- 2024/01/03 CRDT- 2024/01/23 01:06 PHST- 2023/11/30 00:00 [received] PHST- 2023/12/19 00:00 [revised] PHST- 2023/12/20 00:00 [accepted] PHST- 2024/01/23 06:43 [medline] PHST- 2024/01/23 06:42 [pubmed] PHST- 2024/01/23 01:06 [entrez] PHST- 2024/01/03 00:00 [pmc-release] AID - biomedicines12010099 [pii] AID - biomedicines-12-00099 [pii] AID - 10.3390/biomedicines12010099 [doi] PST - epublish SO - Biomedicines. 2024 Jan 3;12(1):99. doi: 10.3390/biomedicines12010099. PMID- 38226157 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240117 IS - 2589-0042 (Electronic) IS - 2589-0042 (Linking) VI - 27 IP - 1 DP - 2024 Jan 19 TI - High glucose impairs cognitive function through inducing mitochondrial calcium overload in Treg cells. PG - 108689 LID - 10.1016/j.isci.2023.108689 [doi] LID - 108689 AB - High glucose has been proved to impair cognitive function in type 2 diabetes, but the underlying mechanisms remain elusive. Here, we found that high glucose increased transcription factors' SP1 O-GlcNAcylation in regulatory T (Treg) cells. Glycosylated SP1 further enhanced HDAC2 recruitment and histone deacetylation on Na(+)/Ca(2+)/Li(+) exchanger (NCLX) promoter, which downregulated NCLX expression and led to mitochondrial calcium overload and oxidative damage, thereby promoting Treg cell dysfunction, M1 microglia polarization, and diabetes-associated cognitive impairment. Importantly, GLP-1 receptor agonist alleviated these deleterious effects via GLP-1-receptor-mediated upregulation of OGA and inhibition of SP1 O-GlcNAcylation in Treg cells. Our study highlighted a link between high-glucose-mediated SP1 O-GlcNAcylation and HDAC2/NCLX signaling in control of mitochondrial calcium concentrations in Treg cells. It also revealed a mechanism for linking Treg cell dysfunction and cognitive impairment in type 2 diabetes and provides an insight into the mechanism underlying the neuroprotective effects of GLP-1 receptor agonist. CI - (c) 2023 The Author(s). FAU - Hui, Ya AU - Hui Y AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Clinical Research Center for Diabetes and Metabolic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, P.R. China. FAU - Kuang, Liuyu AU - Kuang L AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P.R. China. FAU - Zhong, Yuanmei AU - Zhong Y AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. FAU - Tang, Yunyun AU - Tang Y AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Clinical Research Center for Diabetes and Metabolic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. FAU - Xu, Zhiqiang AU - Xu Z AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. FAU - Zheng, Tianpeng AU - Zheng T AD - Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Clinical Research Center for Diabetes and Metabolic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. AD - Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China. LA - eng PT - Journal Article DEP - 20231213 PL - United States TA - iScience JT - iScience JID - 101724038 PMC - PMC10788441 OTO - NOTNLM OT - Human metabolism OT - Immunology COIS- The authors declare no competing interests. EDAT- 2024/01/16 06:42 MHDA- 2024/01/16 06:43 PMCR- 2023/12/13 CRDT- 2024/01/16 03:40 PHST- 2023/07/04 00:00 [received] PHST- 2023/11/02 00:00 [revised] PHST- 2023/12/05 00:00 [accepted] PHST- 2024/01/16 06:43 [medline] PHST- 2024/01/16 06:42 [pubmed] PHST- 2024/01/16 03:40 [entrez] PHST- 2023/12/13 00:00 [pmc-release] AID - S2589-0042(23)02766-9 [pii] AID - 108689 [pii] AID - 10.1016/j.isci.2023.108689 [doi] PST - epublish SO - iScience. 2023 Dec 13;27(1):108689. doi: 10.1016/j.isci.2023.108689. eCollection 2024 Jan 19. PMID- 38211482 OWN - NLM STAT- MEDLINE DCOM- 20240311 LR - 20250103 IS - 1878-0334 (Electronic) IS - 1871-4021 (Linking) VI - 18 IP - 1 DP - 2024 Jan TI - GLP-1 receptor agonists, SGLT2 inhibitors and noncardiovascular mortality in type 2 diabetes: Insights from a meta-analysis. PG - 102943 LID - S1871-4021(24)00004-3 [pii] LID - 10.1016/j.dsx.2024.102943 [doi] AB - OBJECTIVE: Type-2 diabetes (T2D) poses a higher risk of noncardiovascular mortality in addition to the burden of cardiovascular mortality. The well-established cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) could solely explain their apparent effects on all-cause mortality in T2D. The present meta-analysis aims to pool their effects on noncardiovascular mortality in T2D and summarize the recent evidence on plausible pathways mediating these effects. METHODS: PubMed, Embase, Web of Science, and clinical trial registries were searched for randomized controlled trials (RCTs) with >/=1-year duration in adults with T2D reporting both cardiovascular and all-cause mortality in treatment versus placebo arms (PROSPERO: CRD42022337559). Noncardiovascular mortality was calculated by subtracting cardiovascular mortality events from all-cause mortality and risk ratios (RRs) were calculated. Random-effects meta-analysis was done. GRADE framework was used to assess evidence quality. RESULTS: We identified 17 eligible RCTs pooling data retrieved from 109,892 patients. Randomization to GLP-1 RA treatment versus placebo was associated with reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.81-0.99; I(2) = 0 %; p < 0.05), consistent with their effects on cardiovascular mortality (RR = 0.88; 95%CI: 0.81-0.95; I(2) = 0 %; p < 0.01) in T2D. Compared to placebo, SGLT2i significantly reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.82-0.99; I(2) = 0 %; p < 0.05) along with cardiovascular mortality (RR = 0.84; 95%CI: 0.77-0.92; I(2) = 28 %; p < 0.001). Subgroup analysis showed no significant effects of heart failure or renal function on treatment benefits of SGLT2i on noncardiovascular mortality (p value > 0.2 for subgroup differences). CONCLUSION: The impact of GLP-1RAs and SGLT2i on mortality in people with T2D extends beyond their cardiovascular benefits. CI - Copyright (c) 2024. Published by Elsevier Ltd. FAU - Banerjee, Mainak AU - Banerjee M AD - Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, 700020, India. Electronic address: mainak18y@gmail.com. FAU - Pal, Rimesh AU - Pal R AD - Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India. FAU - Maisnam, Indira AU - Maisnam I AD - Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, 700020, India. FAU - Mukhopadhyay, Satinath AU - Mukhopadhyay S AD - Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, 700020, India. Electronic address: satinath.Mukhopadhyay@gmail.com. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review DEP - 20240105 PL - Netherlands TA - Diabetes Metab Syndr JT - Diabetes & metabolic syndrome JID - 101462250 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Diabetes Mellitus, Type 2/complications/drug therapy/chemically induced MH - Glucagon-Like Peptide 1 MH - *Cardiovascular Diseases/complications MH - Hypoglycemic Agents/therapeutic use OTO - NOTNLM OT - CKD OT - Cancer OT - Dementia OT - Depression OT - Infections OT - Liver disease OT - T2DM COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/01/12 00:42 MHDA- 2024/03/11 06:44 CRDT- 2024/01/11 18:10 PHST- 2023/07/27 00:00 [received] PHST- 2023/12/31 00:00 [revised] PHST- 2024/01/04 00:00 [accepted] PHST- 2024/03/11 06:44 [medline] PHST- 2024/01/12 00:42 [pubmed] PHST- 2024/01/11 18:10 [entrez] AID - S1871-4021(24)00004-3 [pii] AID - 10.1016/j.dsx.2024.102943 [doi] PST - ppublish SO - Diabetes Metab Syndr. 2024 Jan;18(1):102943. doi: 10.1016/j.dsx.2024.102943. Epub 2024 Jan 5. PMID- 38201269 OWN - NLM STAT- MEDLINE DCOM- 20240112 LR - 20240210 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 13 IP - 1 DP - 2023 Dec 28 TI - GLP1 Receptor Agonists-Effects beyond Obesity and Diabetes. LID - 10.3390/cells13010065 [doi] LID - 65 AB - Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits of GLP1RA may be indirect due to their effects on obesity and glucose metabolism. However, there is building evidence that GLP1RA may also act directly on multiple organs implicated in aging-related pathology. This review aims to compile the studies reporting the effects of GLP1RA on aging-related diseases and discuss potential underlying mechanisms. FAU - Wilbon, Sydney S AU - Wilbon SS AD - The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. FAU - Kolonin, Mikhail G AU - Kolonin MG AUID- ORCID: 0000-0002-3743-7869 AD - The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. LA - eng GR - R01 DK125922/DK/NIDDK NIH HHS/United States GR - R21 DK122234/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20231228 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Blood Glucose) SB - IM MH - Animals MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Biological Availability MH - Obesity/drug therapy MH - Aging MH - Blood Glucose PMC - PMC10778154 OTO - NOTNLM OT - GLP-1 receptor agonist OT - aging OT - cancer OT - cardiovascular disease OT - diabetes OT - incretin OT - neurodegenerative disease OT - obesity COIS- The authors declare no conflict of interest. EDAT- 2024/01/11 07:42 MHDA- 2024/01/12 06:42 PMCR- 2023/12/28 CRDT- 2024/01/11 01:04 PHST- 2023/11/22 00:00 [received] PHST- 2023/12/22 00:00 [revised] PHST- 2023/12/24 00:00 [accepted] PHST- 2024/01/12 06:42 [medline] PHST- 2024/01/11 07:42 [pubmed] PHST- 2024/01/11 01:04 [entrez] PHST- 2023/12/28 00:00 [pmc-release] AID - cells13010065 [pii] AID - cells-13-00065 [pii] AID - 10.3390/cells13010065 [doi] PST - epublish SO - Cells. 2023 Dec 28;13(1):65. doi: 10.3390/cells13010065. PMID- 38198966 OWN - NLM STAT- MEDLINE DCOM- 20240209 LR - 20240320 IS - 1932-7420 (Electronic) IS - 1550-4131 (Linking) VI - 36 IP - 2 DP - 2024 Feb 6 TI - Prevention of cardiorenal complications in people with type 2 diabetes and obesity. PG - 338-353 LID - S1550-4131(23)00469-2 [pii] LID - 10.1016/j.cmet.2023.12.018 [doi] AB - Traditional approaches to prevention of the complications of type 2 diabetes (T2D) and obesity have focused on reduction of blood glucose and body weight. The development of new classes of medications, together with evidence from dietary weight loss and bariatric surgery trials, provides new options for prevention of heart failure, chronic kidney disease, myocardial infarction, stroke, metabolic liver disease, cancer, T2D, and neurodegenerative disorders. Here I review evidence for use of lifestyle modification, SGLT-2 inhibitors, GLP-1 receptor agonists, selective mineralocorticoid receptor antagonists, and bariatric surgery, for prevention of cardiorenal and metabolic complications in people with T2D or obesity, highlighting the contributions of weight loss, as well as weight loss-independent mechanisms of action. Collectively, the evidence supports a tailored approach to selection of therapeutic interventions for T2D and obesity based on the likelihood of developing specific complications, rather than a stepwise approach focused exclusively on glycemic or weight control. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Drucker, Daniel Joshua AU - Drucker DJ AD - The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada. Electronic address: drucker@lunenfeld.ca. LA - eng PT - Journal Article PT - Review DEP - 20240109 PL - United States TA - Cell Metab JT - Cell metabolism JID - 101233170 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/metabolism MH - Obesity/complications/drug therapy MH - Body Weight MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Weight Loss MH - Glucagon-Like Peptide-1 Receptor MH - Hypoglycemic Agents/therapeutic use COIS- Declaration of interests D.J.D. has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, Arrowhead, Boehringer Ingelheim, Eli Lilly Inc., Kallyope, Merck Research Laboratories, Novo Nordisk Inc., and Pfizer Inc. Neither D.J.D. nor his family members hold issued stock directly or indirectly in any of these companies. D.J.D. holds non-exercised options in Kallyope. GLP-2 is the subject of a patent license agreement between Takeda Inc. and the University of Toronto, Toronto General Hospital (UHN), and D.J.D. EDAT- 2024/01/11 00:41 MHDA- 2024/02/09 06:42 CRDT- 2024/01/10 19:47 PHST- 2023/10/16 00:00 [received] PHST- 2023/12/06 00:00 [revised] PHST- 2023/12/13 00:00 [accepted] PHST- 2024/02/09 06:42 [medline] PHST- 2024/01/11 00:41 [pubmed] PHST- 2024/01/10 19:47 [entrez] AID - S1550-4131(23)00469-2 [pii] AID - 10.1016/j.cmet.2023.12.018 [doi] PST - ppublish SO - Cell Metab. 2024 Feb 6;36(2):338-353. doi: 10.1016/j.cmet.2023.12.018. Epub 2024 Jan 9. PMID- 38159613 OWN - NLM STAT- MEDLINE DCOM- 20240313 LR - 20260515 IS - 1872-6216 (Electronic) IS - 0047-6374 (Linking) VI - 218 DP - 2024 Apr TI - A feasibility study of the combination of intranasal insulin with oral semaglutide for cognition in older adults with metabolic syndrome at high dementia risk- Study rationale and design. PG - 111898 LID - S0047-6374(23)00124-0 [pii] LID - 10.1016/j.mad.2023.111898 [doi] AB - INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with semaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/oral semaglutide, intranasal placebo/oral semaglutide, INI/oral placebo, and intranasal placebo/oral placebo. Feasibility of combining INI with semaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with semaglutide (14 once daily), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial (RCT) of the cognitive benefits of the combination of INI with semaglutide in individuals enriched for CVD and at high dementia risk. CI - Copyright (c) 2024. Published by Elsevier B.V. FAU - Davidy, Tal AU - Davidy T AD - The Joseph Sagol Neuroscience, Center Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Neurology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: Tal.davidy@mail.huji.ac.il. FAU - Yore, Iscka AU - Yore I AD - The Joseph Sagol Neuroscience, Center Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Gertner Institute for Epidemiology and Health Policy Research, Endocrinology Institute Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. FAU - Ravona-Springer, Ramit AU - Ravona-Springer R AD - The Joseph Sagol Neuroscience, Center Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Memory Clinic, Sheba Medical Center, Ramat Gan, Israel. FAU - Livny, Abigail AU - Livny A AD - The Joseph Sagol Neuroscience, Center Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. FAU - Lesman-Segev, Orit H AU - Lesman-Segev OH AD - The Joseph Sagol Neuroscience, Center Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. FAU - Azuri, Yossi AU - Azuri Y AD - Maccabi Healthcare Services, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. FAU - Carmichael, Owen AU - Carmichael O AD - Pennington Biomedical Research Center, Baton Rouge, LA, USA. FAU - Kapogiannis, Dimitrios AU - Kapogiannis D AD - Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging (NIA/NIH), Baltimore, MD, USA. FAU - Zetterberg, Henrik AU - Zetterberg H AD - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden. FAU - Lin, HungMo AU - Lin H AD - Department of Anesthesiology and Yale Center for Analytical Sciences, USA. FAU - Sano, Mary AU - Sano M AD - James J. Peters VA Medical Research Center, New York, NY, USA. FAU - Beeri, Michal Schnaider AU - Beeri MS AD - The Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, NJ, USA. LA - eng PT - Clinical Trial Protocol PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231229 PL - Ireland TA - Mech Ageing Dev JT - Mechanisms of ageing and development JID - 0347227 RN - 0 (Insulin) RN - 0 (Hypoglycemic Agents) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Humans MH - Aged MH - Insulin MH - Feasibility Studies MH - *Metabolic Syndrome/drug therapy MH - Cognition MH - *Dementia MH - *Cardiovascular Diseases MH - Hypoglycemic Agents/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy MH - Double-Blind Method MH - *Glucagon-Like Peptides MH - Randomized Controlled Trials as Topic MH - Semaglutide OTO - NOTNLM OT - Cerebral blood flow OT - Cognition OT - Dulaglutide OT - Intranasal insulin OT - Metabolic syndrome OT - Mild cognitive impairment EDAT- 2024/01/02 11:46 MHDA- 2024/03/13 06:47 CRDT- 2023/12/30 19:13 PHST- 2023/12/17 00:00 [received] PHST- 2023/12/25 00:00 [accepted] PHST- 2024/03/13 06:47 [medline] PHST- 2024/01/02 11:46 [pubmed] PHST- 2023/12/30 19:13 [entrez] AID - S0047-6374(23)00124-0 [pii] AID - 10.1016/j.mad.2023.111898 [doi] PST - ppublish SO - Mech Ageing Dev. 2024 Apr;218:111898. doi: 10.1016/j.mad.2023.111898. Epub 2023 Dec 29. PMID- 38144199 OWN - NLM STAT- MEDLINE DCOM- 20231226 LR - 20251222 IS - 2167-8359 (Electronic) IS - 2167-8359 (Linking) VI - 11 DP - 2023 TI - Correlation between long-term glycemic variability and cognitive function in middle-aged and elderly patients with type 2 diabetes mellitus: a retrospective study. PG - e16698 LID - 10.7717/peerj.16698 [doi] LID - e16698 AB - OBJECTIVE: To investigate the correlation between long-term glycemic variability and cognitive function in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis includes 222 patients hospitalized at Second Affiliated Hospital of Anhui Medical University from June 2021 to June 2023. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All patients were categorized into the MCI group and the non-MCI group based on their MoCA score. Long-term blood glucose fluctuations were measured using glycated hemoglobin A1c standard deviation (HbA1c-SD) and fasting plasma glucose standard deviation (FPG-SD). The study compared general clinical data, blood biochemical indicators, and glycemic variability indicators between the two groups. The differences between the groups were compared using t-test, Chi-Square Test, or Mann-Whitney U test. Kendall's correlation analysis, multivariate logistic regression analysis and ROC curve correlation analysis were further used to analyze the correlation and diagnostic power. RESULTS: The differences in age, MoCA scores, MMSE scores, HOMA-beta, HbA1c-M, HbA1c-SD, FPG-M, FPG-SD, eGFR, Smoking, GLP-1RA and SGLT-2i usage were statistically significant between the two groups (P < 0.05). Kendall's correlation analysis showed that age, HbA1c-M, HbA1c-SD, FPG-M, and FPG-SD was negatively correlated with MoCA scores; meanwhile, the HOMA-beta, and eGFR was positively correlated with MoCA scores. Multiple logistic regression analysis revealed that HbA1c-SD, FPG-SD and Smoking were risk factors for cognitive dysfunction, while eGFR, GLP-1RA and SGLT-2i usage was a protective effect. The area under the curve (AUC) values for predicting MCI prevalence were 0.830 (95% CI [0.774-0.877], P < 0.001) for HbA1c-SD, 0.791 (95% CI [0.655-0.808], P < 0.001) for FPG-SD, and 0.698 (95% CI [0.633-0.757], P < 0.001) for eGFR. The optimal diagnostic values were 0.91, 1.32, and 74.81 ml/min/1.73 m(2) for HbA1c-SD, FPG-SD, and eGFR, respectively. CONCLUSIONS: Cognitive function in middle-aged and elderly T2DM patients is influenced by long-term blood glucose variability, with poorer cognitive function observed in individuals with higher blood glucose variability. The impact of HbA1c-SD on MCI exhibited a greater magnitude compared to that of PFG-SD and smoking. Additionally, renal function, GLP-1RA and SGLT-2i usage exert positive effects on cognitive function. CI - (c)2023 Ding et al. FAU - Ding, JingCheng AU - Ding J AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. FAU - Shi, Qian AU - Shi Q AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. FAU - Tao, Qian AU - Tao Q AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. FAU - Su, Hong AU - Su H AD - Department of Epidemiology and Health Statistics, Anhui Medical University, Hefei, Anhui Province, China. FAU - Du, Yijun AU - Du Y AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. FAU - Pan, Tianrong AU - Pan T AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. FAU - Zhong, Xing AU - Zhong X AD - Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231220 PL - United States TA - PeerJ JT - PeerJ JID - 101603425 RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin) SB - IM MH - Aged MH - Middle Aged MH - Humans MH - *Diabetes Mellitus, Type 2/complications MH - Blood Glucose/analysis MH - Retrospective Studies MH - Glycated Hemoglobin MH - Cognition PMC - PMC10748480 OTO - NOTNLM OT - Type 2 Diabetes mellitus OT - Blood glucose variability OT - Cognitive function COIS- The authors report no conflicts of interest in this work. EDAT- 2023/12/25 06:42 MHDA- 2023/12/26 06:41 PMCR- 2023/12/20 CRDT- 2023/12/25 04:28 PHST- 2023/08/23 00:00 [received] PHST- 2023/11/29 00:00 [accepted] PHST- 2023/12/26 06:41 [medline] PHST- 2023/12/25 06:42 [pubmed] PHST- 2023/12/25 04:28 [entrez] PHST- 2023/12/20 00:00 [pmc-release] AID - 16698 [pii] AID - 10.7717/peerj.16698 [doi] PST - epublish SO - PeerJ. 2023 Dec 20;11:e16698. doi: 10.7717/peerj.16698. eCollection 2023. PMID- 37950798 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240418 IS - 1869-6953 (Print) IS - 1869-6961 (Electronic) IS - 1869-6961 (Linking) VI - 15 IP - 1 DP - 2024 Jan TI - Potential New Therapeutic Implications of Semaglutide: New Colours of the Rainbow? PG - 13-18 LID - 10.1007/s13300-023-01506-1 [doi] AB - Semaglutide is a potent glucagon-like peptide 1 receptor agonist for the management of type 2 diabetes mellitus. In addition to this, it has emerging potential clinical implications. First, there is accumulating preliminary data on its potential role in type 1 diabetes mellitus. In this setting, we need to know which patient subgroups may benefit more. Furthermore, its role in non-alcoholic fatty liver and in non-alcoholic steatohepatitis is emerging. Other potential therapeutic implications of semaglutide include kidney disease, Alzheimer disease and pulmonary diseases. Nonetheless, we still need much more information on its long-term efficacy, safety and utility in these new implications before any definitive conclusions may be drawn for everyday practice. CI - (c) 2023. The Author(s). FAU - Gouveri, Evanthia AU - Gouveri E AD - Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, 68100, Alexandroupolis, Greece. FAU - Popovic, Djordje S AU - Popovic DS AD - Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia. AD - Medical Faculty, University of Novi Sad, Novi Sad, Serbia. FAU - Papanas, Nikolaos AU - Papanas N AUID- ORCID: 0000-0002-7320-785X AD - Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, 68100, Alexandroupolis, Greece. papanasnikos@yahoo.gr. LA - eng PT - Journal Article DEP - 20231111 PL - United States TA - Diabetes Ther JT - Diabetes therapy : research, treatment and education of diabetes and related disorders JID - 101539025 PMC - PMC10786794 OTO - NOTNLM OT - Diabetes mellitus OT - Non-alcoholic fatty liver OT - Pleiotropic actions OT - Semaglutide OT - Therapy OT - Type 1 diabetes EDAT- 2023/11/11 20:48 MHDA- 2023/11/11 20:49 PMCR- 2023/11/11 CRDT- 2023/11/11 11:06 PHST- 2023/09/25 00:00 [received] PHST- 2023/10/26 00:00 [accepted] PHST- 2023/11/11 20:49 [medline] PHST- 2023/11/11 20:48 [pubmed] PHST- 2023/11/11 11:06 [entrez] PHST- 2023/11/11 00:00 [pmc-release] AID - 10.1007/s13300-023-01506-1 [pii] AID - 1506 [pii] AID - 10.1007/s13300-023-01506-1 [doi] PST - ppublish SO - Diabetes Ther. 2024 Jan;15(1):13-18. doi: 10.1007/s13300-023-01506-1. Epub 2023 Nov 11. PMID- 37907134 OWN - NLM STAT- MEDLINE DCOM- 20231216 LR - 20231216 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 961 DP - 2023 Dec 15 TI - Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders. PG - 176117 LID - S0014-2999(23)00631-3 [pii] LID - 10.1016/j.ejphar.2023.176117 [doi] AB - The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid beta metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Abeta deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Abeta monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Birajdar, Swapnali Vasant AU - Birajdar SV AD - Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, 226002, Uttar Pradesh, India. FAU - Mazahir, Farhan AU - Mazahir F AD - Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, 226002, Uttar Pradesh, India. FAU - Alam, Md Imtiyaz AU - Alam MI AD - Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, 226002, Uttar Pradesh, India. FAU - Kumar, Amit AU - Kumar A AD - Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, 226002, Uttar Pradesh, India. FAU - Yadav, Awesh K AU - Yadav AK AD - Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, 226002, Uttar Pradesh, India. Electronic address: awesh.yadav@niperraebareli.edu.in. LA - eng PT - Journal Article PT - Review DEP - 20231030 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Hypoglycemic Agents) RN - 0 (Amyloid beta-Peptides) RN - 0 (Insulin) RN - 9100L32L2N (Metformin) SB - IM MH - Humans MH - Mice MH - Animals MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Amyloid beta-Peptides/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy MH - Drug Repositioning MH - Neuroinflammatory Diseases MH - *Alzheimer Disease/drug therapy MH - Insulin/metabolism MH - *Metformin/pharmacology OTO - NOTNLM OT - AMPK/mTOR/BACE1 OT - Antidiabetic drugs OT - Insulin degrading enzyme (IDE) OT - Insulin resistance OT - Neurodegenerative disorders OT - Oxidative stress COIS- Declaration of competing interest All authors declare no competing interests with anyone or other organizations. EDAT- 2023/11/01 00:42 MHDA- 2023/12/17 09:43 CRDT- 2023/10/31 20:16 PHST- 2023/07/03 00:00 [received] PHST- 2023/10/03 00:00 [revised] PHST- 2023/10/12 00:00 [accepted] PHST- 2023/12/17 09:43 [medline] PHST- 2023/11/01 00:42 [pubmed] PHST- 2023/10/31 20:16 [entrez] AID - S0014-2999(23)00631-3 [pii] AID - 10.1016/j.ejphar.2023.176117 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Dec 15;961:176117. doi: 10.1016/j.ejphar.2023.176117. Epub 2023 Oct 30. PMID- 37869901 OWN - NLM STAT- MEDLINE DCOM- 20240113 LR - 20260603 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 26 IP - 2 DP - 2024 Feb TI - Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis. PG - 441-462 LID - 10.1111/dom.15331 [doi] AB - AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, alpha-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, alpha-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted. CI - (c) 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Kuate Defo, Alvin AU - Kuate Defo A AD - Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. FAU - Bakula, Veselko AU - Bakula V AD - Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, Quebec, Canada. FAU - Pisaturo, Alessandro AU - Pisaturo A AUID- ORCID: 0000-0002-4662-8499 AD - Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada. FAU - Labos, Christopher AU - Labos C AD - Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. FAU - Wing, Simon S AU - Wing SS AD - Division of Endocrinology & Metabolism, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. FAU - Daskalopoulou, Stella S AU - Daskalopoulou SS AUID- ORCID: 0000-0003-4774-2549 AD - Vascular Health Unit, Research Institute of the McGill University Health Centre, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. AD - Division of Internal Medicine, Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20231023 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases) RN - 0 (Glycoside Hydrolase Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 9100L32L2N (Metformin) RN - X4OV71U42S (Pioglitazone) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Sulfonylurea Compounds) RN - 0 (Thiazolidinediones) SB - IM MH - Humans MH - *Dementia/epidemiology/prevention & control MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects MH - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/therapeutic use MH - Glycoside Hydrolase Inhibitors MH - Hypoglycemic Agents/adverse effects MH - Insulin/therapeutic use MH - *Metformin/adverse effects MH - Pioglitazone/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Sulfonylurea Compounds/adverse effects MH - Systematic Reviews as Topic MH - *Thiazolidinediones/adverse effects OTO - NOTNLM OT - Alzheimer's dementia OT - diabetes OT - glucagon-like peptide-1 receptor agonists OT - metformin OT - pioglitazone OT - sodium-glucose cotransporter-2 inhibitors OT - thiazolidinediones OT - vascular dementia EDAT- 2023/10/23 06:46 MHDA- 2024/01/09 06:42 CRDT- 2023/10/23 05:29 PHST- 2023/09/12 00:00 [revised] PHST- 2023/05/11 00:00 [received] PHST- 2023/09/29 00:00 [accepted] PHST- 2024/01/09 06:42 [medline] PHST- 2023/10/23 06:46 [pubmed] PHST- 2023/10/23 05:29 [entrez] AID - 10.1111/dom.15331 [doi] PST - ppublish SO - Diabetes Obes Metab. 2024 Feb;26(2):441-462. doi: 10.1111/dom.15331. Epub 2023 Oct 23. PMID- 37866274 OWN - NLM STAT- MEDLINE DCOM- 20231113 LR - 20231215 IS - 1873-460X (Electronic) IS - 1056-8727 (Linking) VI - 37 IP - 11 DP - 2023 Nov TI - Insights from insulin resistance pathways: Therapeutic approaches against Alzheimer associated diabetes mellitus. PG - 108629 LID - S1056-8727(23)00227-1 [pii] LID - 10.1016/j.jdiacomp.2023.108629 [doi] AB - Alzheimer Associated Diabetes Mellitus, commonly known as Type 3 Diabetes Mellitus (T3DM) is a distinct subtype of diabetes with a pronounced association with Alzheimer's disease (AD). Insulin resistance serves as a pivotal link between these two conditions, leading to diminished insulin sensitivity, hyperglycemia, and impaired glucose uptake. The brain, a vital organ in AD context, is also significantly impacted by insulin resistance, resulting in energy deficits and neuronal damage, which are hallmark features of the neurodegenerative disorder. To pave the way for potential therapeutic interventions targeting the insulin resistance pathway, it is crucial to comprehend the intricate pathophysiology of T3DM and identify the overlapped features between diabetes and AD. This comprehensive review article aims to explore various pathway such as AMPK, PPARgamma, cAMP and P13K/Akt pathway as potential target for management of T3DM. Through the analysis of these complex mechanisms, our goal is to reveal their interdependencies and support the discovery of innovative therapeutic strategies. The review extensively discusses several promising pharmaceutical candidates that have demonstrated dual drug action mechanisms, addressing both peripheral and cerebral insulin resistance observed in T3DM. These candidates hold significant promise for restoring insulin function and mitigating the detrimental effects of insulin resistance on the brain. The exploration of these therapeutic options contributes to the development of innovative interventions that alleviate the burden of T3DM and enhance patient care. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Fauzi, Ayesha AU - Fauzi A AD - School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia. FAU - Thoe, Ewen Se AU - Thoe ES AD - School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia. FAU - Quan, Tang Yin AU - Quan TY AD - School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia. FAU - Yin, Adeline Chia Yoke AU - Yin ACY AD - School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia. Electronic address: YokeYin.Chia@taylors.edu.my. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20231018 PL - United States TA - J Diabetes Complications JT - Journal of diabetes and its complications JID - 9204583 RN - 0 (Insulin) SB - IM MH - Humans MH - *Alzheimer Disease/complications/drug therapy MH - Brain/metabolism MH - *Diabetes Mellitus/metabolism MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Hyperglycemia/complications MH - Insulin/therapeutic use/metabolism MH - *Insulin Resistance/physiology OTO - NOTNLM OT - AdipoRON OT - Alzheimer's disease OT - Biguanides OT - DPP4 OT - Diabetes OT - GLP-1 OT - Glimepiride OT - Insulin secretagogues OT - Metformin OT - Type 3 diabetes mellitus COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adeline Chia Yoke Yin reports financial support was provided by Malaysia Ministry of Higher Education. EDAT- 2023/10/23 00:42 MHDA- 2023/11/07 06:45 CRDT- 2023/10/22 18:11 PHST- 2023/07/11 00:00 [received] PHST- 2023/09/03 00:00 [revised] PHST- 2023/10/15 00:00 [accepted] PHST- 2023/11/07 06:45 [medline] PHST- 2023/10/23 00:42 [pubmed] PHST- 2023/10/22 18:11 [entrez] AID - S1056-8727(23)00227-1 [pii] AID - 10.1016/j.jdiacomp.2023.108629 [doi] PST - ppublish SO - J Diabetes Complications. 2023 Nov;37(11):108629. doi: 10.1016/j.jdiacomp.2023.108629. Epub 2023 Oct 18. PMID- 37771773 OWN - NLM STAT- MEDLINE DCOM- 20231002 LR - 20260921 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 13 IP - 14 DP - 2023 TI - Targeting redox imbalance in neurodegeneration: characterizing the role of GLP-1 receptor agonists. PG - 4872-4884 LID - 10.7150/thno.86831 [doi] AB - Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response. Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways. Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function. Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline. At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration. Only few drugs are able to quench ROS production in neurons. The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia. Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory. The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion. Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying. No study has evidenced a specific GLP-1RA pathway that quenches ROS production. Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS. CI - (c) The author(s). FAU - Ghosh, Puja AU - Ghosh P AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Fontanella, Rosaria Anna AU - Fontanella RA AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Scisciola, Lucia AU - Scisciola L AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Pesapane, Ada AU - Pesapane A AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Taktaz, Fatemeh AU - Taktaz F AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Franzese, Martina AU - Franzese M AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Puocci, Armando AU - Puocci A AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Ceriello, Antonio AU - Ceriello A AD - IRCCS MultiMedica, Milan, Italy. FAU - Prattichizzo, Francesco AU - Prattichizzo F AD - IRCCS MultiMedica, Milan, Italy. FAU - Rizzo, Maria Rosaria AU - Rizzo MR AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. FAU - Paolisso, Giuseppe AU - Paolisso G AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. AD - UniCamillus, International Medical University, Rome Italy. FAU - Barbieri, Michelangela AU - Barbieri M AD - Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20230904 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Amyloid beta-Peptides) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Reactive Oxygen Species) RN - 0 (Transcription Factors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Amyloid beta-Peptides/metabolism MH - *Dementia/drug therapy MH - *Diabetes Mellitus/drug therapy MH - *Diabetes Mellitus, Type 2/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - Hypoglycemic Agents/chemistry MH - Oxidation-Reduction MH - Reactive Oxygen Species/metabolism MH - Transcription Factors/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC10526673 OTO - NOTNLM OT - Dementia OT - Diabetes OT - GLP-1RAs OT - Oxidative stress OT - ROS COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2023/09/29 06:44 MHDA- 2023/10/02 06:42 PMCR- 2023/01/01 CRDT- 2023/09/29 03:55 PHST- 2023/06/05 00:00 [received] PHST- 2023/07/06 00:00 [accepted] PHST- 2023/10/02 06:42 [medline] PHST- 2023/09/29 06:44 [pubmed] PHST- 2023/09/29 03:55 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - thnov13p4872 [pii] AID - 10.7150/thno.86831 [doi] PST - epublish SO - Theranostics. 2023 Sep 4;13(14):4872-4884. doi: 10.7150/thno.86831. eCollection 2023. PMID- 37771725 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231003 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 14 DP - 2023 TI - Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta-analysis of preclinical studies. PG - 1205207 LID - 10.3389/fphar.2023.1205207 [doi] LID - 1205207 AB - Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Abeta deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD. CI - Copyright (c) 2023 Kong, Wu, Dai, Zhai, Cai, Zhu, Xu and Sun. FAU - Kong, Fanjing AU - Kong F AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Wu, Tianyu AU - Wu T AD - School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Dai, Jingyi AU - Dai J AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Zhai, Zhenwei AU - Zhai Z AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Cai, Jie AU - Cai J AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Zhu, Zhishan AU - Zhu Z AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Xu, Ying AU - Xu Y AD - Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Sun, Tao AU - Sun T AD - School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China. AD - State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. LA - eng PT - Journal Article PT - Systematic Review DEP - 20230913 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC10525376 OTO - NOTNLM OT - Alzheimer's disease OT - animal models OT - glucagon-like peptide 1 receptor agonists OT - meta-analysis OT - neuroprotective effects OT - systematic review COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/09/29 06:44 MHDA- 2023/09/29 06:45 PMCR- 2023/09/13 CRDT- 2023/09/29 03:54 PHST- 2023/04/13 00:00 [received] PHST- 2023/09/04 00:00 [accepted] PHST- 2023/09/29 06:45 [medline] PHST- 2023/09/29 06:44 [pubmed] PHST- 2023/09/29 03:54 [entrez] PHST- 2023/09/13 00:00 [pmc-release] AID - 1205207 [pii] AID - 10.3389/fphar.2023.1205207 [doi] PST - epublish SO - Front Pharmacol. 2023 Sep 13;14:1205207. doi: 10.3389/fphar.2023.1205207. eCollection 2023. PMID- 37730113 OWN - NLM STAT- MEDLINE DCOM- 20260310 LR - 20260506 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 240 DP - 2023 Dec 1 TI - Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway. PG - 109716 LID - S0028-3908(23)00306-4 [pii] LID - 10.1016/j.neuropharm.2023.109716 [doi] AB - Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using (18)FDG-PET-CT scans. We measured the expression of Abeta and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Abeta plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD. CI - Copyright (c) 2023 Elsevier Ltd. All rights reserved. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China; Shanxi Key Laboratory of Brain Disease Control, Shanxi Provincial People's Hospital, Taiyuan, China. Electronic address: wzhaojun1025@126.com. FAU - Li, Xin-Ru AU - Li XR AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. FAU - Chai, Shi-Fan AU - Chai SF AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. FAU - Li, Wei-Ran AU - Li WR AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. FAU - Li, Shuo AU - Li S AD - Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan, China. FAU - Hou, Meng AU - Hou M AD - Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan, China. FAU - Li, Jia-Lei AU - Li JL AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. FAU - Ye, Yu-Cai AU - Ye YC AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, School of Basic Medicine, Shanxi Medical University, Taiyuan, China. FAU - Holscher, Christian AU - Holscher C AD - Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Physiology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China. Electronic address: wmna@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230918 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - EC 3.5.1.- (Sirtuin 1) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - IY9XDZ35W2 (Glucose) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - 0 (Glucose Transporter Type 4) RN - 0 (Slc2a4 protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glp1r protein, mouse) SB - IM MH - Animals MH - *Alzheimer Disease/metabolism/drug therapy/genetics MH - *Sirtuin 1/metabolism MH - *Glucagon-Like Peptides/pharmacology/therapeutic use MH - Mice, Transgenic MH - Mice MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - Hippocampus/metabolism/drug effects MH - *Glucose/metabolism MH - *Glucose Transporter Type 4/metabolism MH - Disease Models, Animal MH - Signal Transduction/drug effects MH - Male MH - Glucagon-Like Peptide-1 Receptor Agonists MH - *Cognition/drug effects MH - Mice, Inbred C57BL OTO - NOTNLM OT - Alzheimer's disease OT - GLUT4 OT - Glucagon-like peptide-1 receptor OT - Glucose metabolism dysfunction OT - SIRT1 COIS- Declaration of competing interest CH is a named inventor on a patent that covers the use of GLP-1 analogues for the use of treating AD. The other authors declare no conflict of interest. EDAT- 2023/09/21 00:42 MHDA- 2026/03/11 01:11 CRDT- 2023/09/20 19:15 PHST- 2023/07/05 00:00 [received] PHST- 2023/09/06 00:00 [revised] PHST- 2023/09/13 00:00 [accepted] PHST- 2026/03/11 01:11 [medline] PHST- 2023/09/21 00:42 [pubmed] PHST- 2023/09/20 19:15 [entrez] AID - S0028-3908(23)00306-4 [pii] AID - 10.1016/j.neuropharm.2023.109716 [doi] PST - ppublish SO - Neuropharmacology. 2023 Dec 1;240:109716. doi: 10.1016/j.neuropharm.2023.109716. Epub 2023 Sep 18. PMID- 37693358 OWN - NLM STAT- MEDLINE DCOM- 20230912 LR - 20230914 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 14 DP - 2023 TI - Risk factors and drug discovery for cognitive impairment in type 2 diabetes mellitus using artificial intelligence interpretation and graph neural networks. PG - 1213711 LID - 10.3389/fendo.2023.1213711 [doi] LID - 1213711 AB - BACKGROUND: Among the 382 million diabetic patients worldwide, approximately 30% experience neuropathy, and one-fifth of these patients eventually develop diabetes cognitive impairment (CI). However, the mechanism underlying diabetes CI remains unknown, and early diagnostic methods or effective treatments are currently not available. OBJECTIVE: This study aimed to explore the risk factors for CI in patients with type 2 diabetes mellitus (T2DM), screen potential therapeutic drugs for T2DM-CI, and provide evidence for preventing and treating T2DM-CI. METHODS: This study focused on the T2DM population admitted to the First Affiliated Hospital of Hunan College of Traditional Chinese Medicine and the First Affiliated Hospital of Hunan University of Chinese Medicine. Sociodemographic data and clinical objective indicators of T2DM patients admitted from January 2018 to December 2022 were collected. Based on the Montreal Cognitive Assessment (MoCA) Scale scores, 719 patients were categorized into two groups, the T2DM-CI group with CI and the T2DM-N group with normal cognition. The survey content included demographic characteristics, laboratory serological indicators, complications, and medication information. Six machine learning algorithms were used to analyze the risk factors of T2DM-CI, and the Shapley method was used to enhance model interpretability. Furthermore, we developed a graph neural network (GNN) model to identify potential drugs associated with T2DM-CI. RESULTS: Our results showed that the T2DM-CI risk prediction model based on Catboost exhibited superior performance with an area under the receiver operating characteristic curve (AUC) of 0.95 (specificity of 93.17% and sensitivity of 78.58%). Diabetes duration, age, education level, aspartate aminotransferase (AST), drinking, and intestinal flora were identified as risk factors for T2DM-CI. The top 10 potential drugs related to T2DM-CI, including Metformin, Liraglutide, and Lixisenatide, were selected by the GNN model. Some herbs, such as licorice and cuscutae semen, were also included. Finally, we discovered the mechanism of herbal medicine interventions in gut microbiota. CONCLUSION: The method based on Interpreting AI and GNN can identify the risk factors and potential drugs associated with T2DM-CI. CI - Copyright (c) 2023 Zhang, Xie, You and Gong. FAU - Zhang, Xin AU - Zhang X AD - Department of Pediatric, The First Affiliated Hospital of Hunan College of Traditional Chinese Medicine, Zhuzhou, China. FAU - Xie, Jiajia AU - Xie J AD - Department of Ultrasound Imaging, The First Hospital of Hunan University of Chinese Medicine, Changsha, China. FAU - You, Xiong AU - You X AD - Center of Rehabilitation diagnosis and Treatment, Hunan Provincial Rehabilitation Hospital, Changsha, China. FAU - Gong, Houwu AU - Gong H AD - College of Computer Science and Electronic Engineering, Hunan University, Changsha, China. AD - Military Medical Research Institute, Academy of Military Sciences, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230825 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 SB - IM MH - Humans MH - Artificial Intelligence MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Neural Networks, Computer MH - Risk Factors MH - *Cognitive Dysfunction/epidemiology/etiology MH - Drug Discovery PMC - PMC10485700 OTO - NOTNLM OT - cognitive impairment OT - drug discovery OT - graph neural network (GNN) OT - risk factors OT - type 2 diabetes mellitus COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/09/11 06:42 MHDA- 2023/09/12 06:41 PMCR- 2023/01/01 CRDT- 2023/09/11 04:51 PHST- 2023/04/28 00:00 [received] PHST- 2023/08/04 00:00 [accepted] PHST- 2023/09/12 06:41 [medline] PHST- 2023/09/11 06:42 [pubmed] PHST- 2023/09/11 04:51 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2023.1213711 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2023 Aug 25;14:1213711. doi: 10.3389/fendo.2023.1213711. eCollection 2023. PMID- 37667187 OWN - NLM STAT- MEDLINE DCOM- 20230906 LR - 20260401 IS - 1528-3658 (Electronic) IS - 1076-1551 (Print) IS - 1076-1551 (Linking) VI - 29 IP - 1 DP - 2023 Sep 4 TI - Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/beta-catenin/NeuroD1 pathway. PG - 118 LID - 10.1186/s10020-023-00718-2 [doi] LID - 118 AB - BACKGROUND: Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear. METHODS: The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)-induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/beta-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed. RESULTS: Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-beta signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/beta-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4. CONCLUSIONS: Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/beta-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D. CI - (c) 2023. The Feinstein Institute for Medical Research. FAU - Kang, Xiaonan AU - Kang X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Wang, Dan AU - Wang D AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Zhang, Lu AU - Zhang L AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Huang, Teng AU - Huang T AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Liu, Siyue AU - Liu S AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Feng, Xiaohui AU - Feng X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Guo, Yaoyao AU - Guo Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Zhang, Ziyin AU - Zhang Z AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Wang, Zhongjing AU - Wang Z AD - Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. doctorwangzj@163.com. FAU - Ren, Huihui AU - Ren H AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. huizi9258@163.com. AD - Branch of National Clinical Research Center for Metabolic Disease, Hubei, People's Republic of China. huizi9258@163.com. FAU - Yuan, Gang AU - Yuan G AUID- ORCID: 0000-0002-8672-8849 AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. gangyuan@tjh.tjmu.edu.cn. AD - Branch of National Clinical Research Center for Metabolic Disease, Hubei, People's Republic of China. gangyuan@tjh.tjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230904 PL - England TA - Mol Med JT - Molecular medicine (Cambridge, Mass.) JID - 9501023 RN - 9P1872D4OL (Exenatide) RN - 0 (beta Catenin) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (Insulin) RN - hypoglycemic encephalopathy SB - IM EIN - Mol Med. 2026 Mar 30;32(1):46. doi: 10.1186/s10020-026-01448-x. PMID: 41913098 MH - *Alzheimer Disease/drug therapy MH - Insulin MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Exenatide/pharmacology MH - Brain Diseases MH - *Diabetes Mellitus, Experimental/drug therapy MH - *Cognitive Dysfunction/drug therapy/etiology MH - Hypoglycemia MH - Animals MH - Glycogen Synthase Kinase 3 MH - beta Catenin MH - Mice MH - Phosphatidylinositol 3-Kinases PMC - PMC10478475 OTO - NOTNLM OT - Cognitive impairment OT - Glucagon-like peptide-1 receptor agonist OT - NeuroD1 OT - Tau hyperphosphorylation OT - Type 2 diabetes OT - Wnt/beta-catenin pathway COIS- The authors declare that they have no conflicts of interests with the contents of this article. EDAT- 2023/09/05 00:42 MHDA- 2023/09/06 06:42 PMCR- 2023/09/04 CRDT- 2023/09/04 23:40 PHST- 2023/06/15 00:00 [received] PHST- 2023/08/21 00:00 [accepted] PHST- 2023/09/06 06:42 [medline] PHST- 2023/09/05 00:42 [pubmed] PHST- 2023/09/04 23:40 [entrez] PHST- 2023/09/04 00:00 [pmc-release] AID - 10.1186/s10020-023-00718-2 [pii] AID - 718 [pii] AID - 10.1186/s10020-023-00718-2 [doi] PST - epublish SO - Mol Med. 2023 Sep 4;29(1):118. doi: 10.1186/s10020-023-00718-2. PMID- 37657738 OWN - NLM STAT- MEDLINE DCOM- 20231002 LR - 20250103 IS - 1878-1780 (Electronic) IS - 1262-3636 (Linking) VI - 49 IP - 5 DP - 2023 Sep TI - GLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes. PG - 101470 LID - S1262-3636(23)00052-6 [pii] LID - 10.1016/j.diabet.2023.101470 [doi] AB - Glucagon-like peptide 1 (GLP-1) is a hormone of the incretin family, secreted in response to nutrient ingestion, and plays a role in metabolic homeostasis. GLP-1 receptor agonist has a peripheral and a central action, including stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. Through their mechanism, their use in the treatment of type 2 diabetes has been extended to the management of obesity, and numerous trials are being conducted to assess their cardiovascular effect. Type 2 diabetes appears to share common pathophysiological mechanisms with the development of cognitive disorders, such as Alzheimer's and Parkinson's disease, related to insulin resistance. In this review, we aim to examine the pathological features between type 2 diabetes and dementia, GLP-1 central effects, and analyze the relevant literature about the effect of GLP-1 analogs on cognitive function of patients with type 2 diabetes but also without. Results tends to show an improvement in some brain markers (e.g. hippocampal connections, cerebral glucose metabolism, hippocampal activation on functional magnetic resonance imaging), but without being able to demonstrate a strong correlation to cognitive scores. Some epidemiological studies suggest that GLP-1 receptor agonists may offer a protective effect, by delaying progression to dementia when diabetic patients are treated with GLP-1 receptor agonists. Ongoing trials are in progress and may provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients in the future. CI - Copyright (c) 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Monney, Marine AU - Monney M AD - Division of General Internal Medicine, Department of Medicine, Geneva University Hospitals, Geneva 1211, Switzerland. Electronic address: marine.monney@hcuge.ch. FAU - Jornayvaz, Francois R AU - Jornayvaz FR AD - Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva 1211, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. FAU - Gariani, Karim AU - Gariani K AD - Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva 1211, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. LA - eng PT - Journal Article PT - Review DEP - 20230830 PL - France TA - Diabetes Metab JT - Diabetes & metabolism JID - 9607599 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Insulin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism MH - *Parkinson Disease MH - Glucagon-Like Peptide 1/metabolism MH - Insulin/metabolism MH - Cognition MH - *Dementia MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Cognitive dysfunction OT - Dementia OT - Glucagon-like-peptide 1 OT - Glucagon-like-peptide 1 receptor agonist OT - Insulin resistance OT - Type 2 diabetes COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/09/02 05:42 MHDA- 2023/10/02 06:42 CRDT- 2023/09/01 19:26 PHST- 2023/07/18 00:00 [received] PHST- 2023/07/24 00:00 [accepted] PHST- 2023/10/02 06:42 [medline] PHST- 2023/09/02 05:42 [pubmed] PHST- 2023/09/01 19:26 [entrez] AID - S1262-3636(23)00052-6 [pii] AID - 10.1016/j.diabet.2023.101470 [doi] PST - ppublish SO - Diabetes Metab. 2023 Sep;49(5):101470. doi: 10.1016/j.diabet.2023.101470. Epub 2023 Aug 30. PMID- 37607641 OWN - NLM STAT- MEDLINE DCOM- 20230925 LR - 20260127 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 331 DP - 2023 Oct 15 TI - Mollugin activates GLP-1R to improve cognitive dysfunction in type 2 diabetic mice. PG - 122026 LID - S0024-3205(23)00661-6 [pii] LID - 10.1016/j.lfs.2023.122026 [doi] AB - AIMS: The incidence of diabetic cognitive dysfunction is increasing year by year, and it has gradually become a research hot spot. Studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists can improve cognitive dysfunction in diabetic patients. This study focuses on whether small molecule GLP-1R agonists from traditional Chinese medicine (TCM) can improve the diabetic cognitive dysfunction. MATERIALS AND METHODS: The small molecules from TCM were screened by cell membrane chromatography (CMC) with GLP-1R-HEK293 cell membrane column. MTT assay, flow cytometry, immunofluorescence cytochemistry and other methods were used to determine the effects of mollugin on the apoptosis rate and reactive oxygen species (ROS) level of high glucose (HG)/hydrogen peroxide (H(2)O(2)) induced PC12 cells. Real-Time PCR was used to detect mRNA expression in mouse cerebral cortex. Water maze test was further used to confirm the effect of mollugin on cognitive dysfunction in T2DM mice. KEY FINDINGS: Mollugin bound to GLP-1R, promoted Ca(2+) influx, increased insulin secretion and cAMP content in beta-TC-6 cells. Mollugin enhanced the cell viability, ameliorated apoptosis, reduced intracellular ROS levels in HG/H(2)O(2)-injured PC12 cells. Mollugin reduced the T2DM mice's escape latency, improved neuronal cell damage, decreased the expression of Pik3ca, Akt1 and Mapk1 mRNA in the cerebral cortex tissue. SIGNIFICANCE: The results suggest that mollugin could improve cognitive dysfunction in T2DM mice through activating GLP-1R/cAMP/PKA signal pathway. CI - Copyright (c) 2023. Published by Elsevier Inc. FAU - Wang, Zhuanzhuan AU - Wang Z AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Cui, Xin AU - Cui X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Yan, Wenhui AU - Yan W AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China. FAU - Liu, Na AU - Liu N AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Shang, Jia AU - Shang J AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Yi, Xinyao AU - Yi X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Guo, Tingli AU - Guo T AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Wei, Xiaotong AU - Wei X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Sun, Yuzhuo AU - Sun Y AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Hu, Hao AU - Hu H AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China. FAU - Ma, Weina AU - Ma W AD - School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: maweina2015@xjtu.edu.cn. FAU - Cui, Wei AU - Cui W AD - Department of Endocrinology and Second Department of Geriatrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; International Obesity and Metabolic Disease Research Center (IOMC), Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: wwei.mc@mail.xjtu.edu.cn. FAU - Chen, Lina AU - Chen L AD - School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China. Electronic address: chenlin@mail.xjtu.edu.cn. LA - eng PT - Journal Article DEP - 20230821 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Reactive Oxygen Species) RN - BBX060AN9V (Hydrogen Peroxide) RN - 55481-88-4 (rubimaillin) RN - 0 (Pyrans) SB - IM MH - Humans MH - Rats MH - Mice MH - Animals MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - *Diabetes Mellitus, Experimental/complications/drug therapy MH - Reactive Oxygen Species MH - HEK293 Cells MH - Hydrogen Peroxide MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Pyrans OTO - NOTNLM OT - CMC OT - Cognitive dysfunction OT - Diabetes OT - GLP-1 receptor OT - Mollugin COIS- Declaration of competing interest The authors declare that there are no conflicts of interest. EDAT- 2023/08/23 00:42 MHDA- 2023/09/25 06:42 CRDT- 2023/08/22 19:18 PHST- 2023/07/22 00:00 [received] PHST- 2023/08/11 00:00 [revised] PHST- 2023/08/14 00:00 [accepted] PHST- 2023/09/25 06:42 [medline] PHST- 2023/08/23 00:42 [pubmed] PHST- 2023/08/22 19:18 [entrez] AID - S0024-3205(23)00661-6 [pii] AID - 10.1016/j.lfs.2023.122026 [doi] PST - ppublish SO - Life Sci. 2023 Oct 15;331:122026. doi: 10.1016/j.lfs.2023.122026. Epub 2023 Aug 21. PMID- 37511061 OWN - NLM STAT- MEDLINE DCOM- 20230807 LR - 20230807 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 14 DP - 2023 Jul 11 TI - Potential Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Cognitive Decline and Dementia in Diabetes Mellitus. LID - 10.3390/ijms241411301 [doi] LID - 11301 AB - Dementia is a permanent illness characterized by mental instability, memory loss, and cognitive decline. Many studies have demonstrated an association between diabetes and cognitive dysfunction that proceeds in three steps, namely, diabetes-associated cognitive decrements, mild cognitive impairment (MCI; both non-amnesic MCI and amnesic MCI), and dementia [both vascular dementia and Alzheimer's disease (AD)]. Based on this association, this disease has been designated as type 3 diabetes mellitus. The underlying mechanisms comprise insulin resistance, inflammation, lipid abnormalities, oxidative stress, mitochondrial dysfunction, glycated end-products and autophagy. Moreover, insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated to be involved. Insulin in the brain has a neuroprotective role that alters cognitive skills and alteration of insulin signaling determines beta-amyloid (Abeta) accumulation, in turn promoting brain insulin resistance. In this complex mechanism, other triggers include hyperglycemia-induced overproduction of reactive oxygen species (ROS) and inflammatory cytokines, which result in neuroinflammation, suggesting that antidiabetic drugs may be potential treatments to protect against AD. Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the most attractive antidiabetic drugs due to their actions on synaptic plasticity, cognition and cell survival. The present review summarizes the significant data concerning the underlying pathophysiological and pharmacological mechanisms between diabetes and dementia. FAU - Pelle, Maria Chiara AU - Pelle MC AUID- ORCID: 0000-0002-0463-6650 AD - Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. FAU - Zaffina, Isabella AU - Zaffina I AD - Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. FAU - Giofre, Federica AU - Giofre F AD - Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. FAU - Pujia, Roberta AU - Pujia R AD - Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. FAU - Arturi, Franco AU - Arturi F AD - Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. AD - Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy. LA - eng PT - Journal Article PT - Review DEP - 20230711 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/complications MH - *Cognitive Dysfunction/complications/drug therapy MH - *Diabetes Mellitus, Type 2/complications MH - *Glucagon-Like Peptide-1 Receptor MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Insulin/therapeutic use MH - Insulin Resistance PMC - PMC10379573 OTO - NOTNLM OT - GLP-1 OT - cognitive decline OT - dementia OT - diabetes OT - diabetic complications OT - inflammation COIS- The authors declare no conflict of interest. EDAT- 2023/07/29 11:47 MHDA- 2023/07/31 11:42 PMCR- 2023/07/11 CRDT- 2023/07/29 01:21 PHST- 2023/06/07 00:00 [received] PHST- 2023/07/06 00:00 [revised] PHST- 2023/07/07 00:00 [accepted] PHST- 2023/07/31 11:42 [medline] PHST- 2023/07/29 11:47 [pubmed] PHST- 2023/07/29 01:21 [entrez] PHST- 2023/07/11 00:00 [pmc-release] AID - ijms241411301 [pii] AID - ijms-24-11301 [pii] AID - 10.3390/ijms241411301 [doi] PST - epublish SO - Int J Mol Sci. 2023 Jul 11;24(14):11301. doi: 10.3390/ijms241411301. PMID- 37500992 OWN - NLM STAT- MEDLINE DCOM- 20231122 LR - 20261010 IS - 1590-3478 (Electronic) IS - 1590-1874 (Linking) VI - 44 IP - 12 DP - 2023 Dec TI - Do oral antidiabetic medications alter the risk of Parkinson's disease? An updated systematic review and meta-analysis. PG - 4193-4203 LID - 10.1007/s10072-023-06965-9 [doi] AB - BACKGROUND: Diabetes mellitus is a known risk factor for Parkinson's disease (PD), but does this risk vary with antidiabetic medications is still unclear. This meta-analysis aims to compile evidence from the literature to assess the risk of idiopathic PD with various oral antidiabetic medications. METHODS: Databases PubMed, CENTRAL, Scopus, Web of Science, and Embase were searched till 5th April 2023. Adjusted outcomes were pooled to generate a hazard ratio (HR) on the risk of PD with different antidiabetic medications. RESULTS: Fifteen studies with 2,910,405 diabetic patients were eligible. Pooled analysis failed to show any significant difference in the risk of PD among users of metformin (HR: 1.05 95% CI: 0.91, 1.22 I(2) = 81%), glitazones (HR: 0.84 95% CI: 0.68, 1.05 I(2) = 91%), glucagon-like peptide-1 agonists (HR: 0.63 95% CI: 0.26, 1.55 I(2) = 33%), and sulfonylureas (HR: 1.13 95% CI: 0.96, 1.32 I(2) = 76%). However, a meta-analysis of four studies showed that dipeptidyl peptidase-4 inhibitor use was associated with reduced risk of PD in diabetics (HR: 0.69 95% CI: 0.56, 0.86 I(2) = 46%). Insufficient data was available on sodium-glucose cotransporter-2 inhibitors, alpha-glucosidase inhibitors, and glinides. CONCLUSIONS: Limited retrospective evidence indicates that DPP4i may reduce the risk of idiopathic PD in diabetics. Metformin, sulfonylureas, glucagon-like peptide-1 agonists, and glitazones were not associated with any change in the risk of PD. Further studies taking into confounding factors and using a common comparator group are needed to strengthen present evidence. CI - (c) 2023. Fondazione Societa Italiana di Neurologia. FAU - Xie, Yanna AU - Xie Y AD - Affiliated Hospital of Shaoxing University, NO. 999, Zhongxing South Road, Shaoxing City, Zhejiang Province, China. FAU - Wang, Jialiang AU - Wang J AD - Affiliated Hospital of Shaoxing University, NO. 999, Zhongxing South Road, Shaoxing City, Zhejiang Province, China. FAU - Jiang, Jie AU - Jiang J AD - Affiliated Hospital of Shaoxing University, NO. 999, Zhongxing South Road, Shaoxing City, Zhejiang Province, China. FAU - Liu, Furong AU - Liu F AD - Affiliated Hospital of Shaoxing University, NO. 999, Zhongxing South Road, Shaoxing City, Zhejiang Province, China. FAU - Zhang, Yifang AU - Zhang Y AUID- ORCID: 0009-0006-0220-3444 AD - Affiliated Hospital of Shaoxing University, NO. 999, Zhongxing South Road, Shaoxing City, Zhejiang Province, China. yifang162023@163.com. LA - eng GR - 2018C30025/Shaoxing Science and Technology Bureau/ PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20230727 PL - Italy TA - Neurol Sci JT - Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology JID - 100959175 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Sulfonylurea Compounds) RN - 0 (Thiazolidinediones) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology/complications MH - Glucagon-Like Peptide 1 MH - *Hypoglycemic Agents/adverse effects MH - Metformin/adverse effects MH - *Parkinson Disease/drug therapy/epidemiology/complications MH - Retrospective Studies MH - Sulfonylurea Compounds/adverse effects MH - Thiazolidinediones/adverse effects OTO - NOTNLM OT - Diabetes OT - Hypoglycemics OT - Metformin OT - Neurodegenerative disease EDAT- 2023/07/28 01:08 MHDA- 2023/11/14 06:43 CRDT- 2023/07/27 23:35 PHST- 2023/05/08 00:00 [received] PHST- 2023/07/14 00:00 [accepted] PHST- 2023/11/14 06:43 [medline] PHST- 2023/07/28 01:08 [pubmed] PHST- 2023/07/27 23:35 [entrez] AID - 10.1007/s10072-023-06965-9 [pii] AID - 10.1007/s10072-023-06965-9 [doi] PST - ppublish SO - Neurol Sci. 2023 Dec;44(12):4193-4203. doi: 10.1007/s10072-023-06965-9. Epub 2023 Jul 27. PMID- 37470232 OWN - NLM STAT- MEDLINE DCOM- 20230815 LR - 20230815 IS - 2042-650X (Electronic) IS - 2042-6496 (Linking) VI - 14 IP - 16 DP - 2023 Aug 14 TI - Microbiota dysbiosis caused by dietetic patterns as a promoter of Alzheimer's disease through metabolic syndrome mechanisms. PG - 7317-7334 LID - 10.1039/d3fo01257c [doi] AB - Microbiota dysbiosis and metabolic syndrome, consequences of a non-adequate diet, generate a feedback pathogenic state implicated in Alzheimer's disease development. The lower production of short chain fatty acids (SCFAs) under dysbiosis status leads to lipid homeostasis deregulation and decreases Angptl4 release and AMPK activation in the adipose tissue, promoting higher lipid storage (adipocyte hypertrophy) and cholesterol levels. Also, low SCFA generation reduces GPR41 and GPR43 receptor activation at the adipose tissue (increasing leptin release and leptin receptor resistance) and intestinal levels, reducing the release of GLP-1 and YPP. Therefore, lower satiety sensation and energy expenditure occur, promoting a weight gaining environment mediated by higher food intake and lipid storage, developing dyslipemia. In this context, higher glucose levels, together with higher free fatty acids in the bloodstream, promote glycolipotoxicity, provoking a reduction in insulin released, insulin receptor resistance, advanced glycation products (AGEs) and type 2 diabetes. Intestinal dysbiosis and low SCFAs reduce bacterial biodiversity, increasing lipopolysaccharide (LPS)-producing bacteria and intestinal barrier permeability. Higher amounts of LPS pass to the bloodstream (endotoxemia), causing a low-grade chronic inflammatory state characterized by higher levels of leptin, IL-1beta, IL-6 and TNF-alpha, together with a reduced release of adiponectin and IL-10. At the brain and neuronal levels, the generated insulin resistance, low-grade chronic inflammation, leptin resistance, AGE production and LPS increase directly impact the secretase enzymes and tau hyperphosphorylation, creating an enabling environment for beta-amyloid senile plaque and tau tangled formations and, as a consequence, Alzheimer's initiation, development and maintenance. FAU - Navalon-Monllor, Victor AU - Navalon-Monllor V AD - Vithas Aguas Vivas Hospital, Carretera Alzira-Tavernes de Valldigna CV-50, Km 12, 46740, Carcaixent, Valencia, Spain. FAU - Soriano-Romani, Laura AU - Soriano-Romani L AD - Ainia Technological Centre, Calle Benjamin Franklin 5-11, Parque Tecnologico de Valencia, E46980, 15 Paterna, Valencia, Spain. juanantonio.nieto@campusviu.es. FAU - Silva, Mariana AU - Silva M AD - Bioactivity and Nutritional Immunology Group (BIOINUT), Faculty of Health Science, Universidad Internacional de Valencia (VIU), Calle Pintor Sorolla 21, E46002, Valencia, Spain. FAU - de Las Hazas, Maria-Carmen Lopez AU - de Las Hazas ML AUID- ORCID: 0000-0001-8199-6724 AD - Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileno de Estudios Avanzados (IMDEA)-Alimentacion, CEI UAM+CSIC, 28049 Madrid, Spain. FAU - Hernando-Quintana, Natalia AU - Hernando-Quintana N AUID- ORCID: 0000-0001-6505-6097 AD - Obispo Polanco Hospital, Avenida Ruiz Jarabo s/n, 44002, Teruel, Spain. FAU - Suarez Dieguez, Teodoro AU - Suarez Dieguez T AD - Academic Area of Nutrition, Institute of Health Sciences, Autonomous University of the State of Hidalgo, Abasolo 600, Colonia Centro, Pachuca de Soto, E42000, Hidalgo, Mexico. FAU - Esteve, Pere Morell AU - Esteve PM AUID- ORCID: 0000-0001-7201-8806 AD - Bioactivity and Nutritional Immunology Group (BIOINUT), Faculty of Health Science, Universidad Internacional de Valencia (VIU), Calle Pintor Sorolla 21, E46002, Valencia, Spain. FAU - Nieto, Juan Antonio AU - Nieto JA AUID- ORCID: 0000-0002-9266-0190 AD - Ainia Technological Centre, Calle Benjamin Franklin 5-11, Parque Tecnologico de Valencia, E46980, 15 Paterna, Valencia, Spain. juanantonio.nieto@campusviu.es. AD - Bioactivity and Nutritional Immunology Group (BIOINUT), Faculty of Health Science, Universidad Internacional de Valencia (VIU), Calle Pintor Sorolla 21, E46002, Valencia, Spain. LA - eng PT - Journal Article PT - Review DEP - 20230814 PL - England TA - Food Funct JT - Food & function JID - 101549033 RN - 0 (Leptin) RN - 0 (Lipopolysaccharides) SB - IM MH - Humans MH - *Metabolic Syndrome/genetics MH - Leptin MH - *Alzheimer Disease/genetics MH - *Diabetes Mellitus, Type 2/microbiology MH - Lipopolysaccharides MH - Dysbiosis/microbiology MH - *Dietetics MH - *Microbiota MH - *Insulin Resistance EDAT- 2023/07/20 06:42 MHDA- 2023/08/15 06:42 CRDT- 2023/07/20 05:53 PHST- 2023/08/15 06:42 [medline] PHST- 2023/07/20 06:42 [pubmed] PHST- 2023/07/20 05:53 [entrez] AID - 10.1039/d3fo01257c [doi] PST - epublish SO - Food Funct. 2023 Aug 14;14(16):7317-7334. doi: 10.1039/d3fo01257c. PMID- 37336238 OWN - NLM STAT- MEDLINE DCOM- 20240322 LR - 20251001 IS - 1439-3999 (Electronic) IS - 0023-2165 (Linking) VI - 241 IP - 3 DP - 2024 Mar TI - Neuroprotective Effects of Anti-diabetic Drugs in the Treatment of Patients with Diabetes and Glaucoma or at High Risk for Glaucoma. PG - 302-307 LID - 10.1055/a-2066-3389 [doi] AB - There is an association between glaucoma and several risk factors and metabolic diseases, such as type 2 diabetes mellitus. Diabetes mellitus leads to neurodegenerative changes, both peripherally and in the brain. This might be a shared pathophysiology and etiology for both glaucoma and diabetes. It is interesting that drugs for the treatment of diabetes seem to have neuroprotective properties independent of their blood sugar reduction. Although prospective, randomized, clinical studies are still missing, particularly metformin and glucagon-like peptide receptor agonists (GLP 1 RA) seem to have neuroprotective effects. Sulphonylureas (e.g., glibenclamide, glimepiride) are still used. They frequently potently reduce blood pressure but may be less neuroprotective. In the present review, the evidence for neuroprotective effects of the different antidiabetic drugs is presented and a possible differential therapy for patients with diabetes and glaucoma, or at high risk of glaucoma, will be discussed. CI - Thieme. All rights reserved. FAU - Weisser, Burkhard AU - Weisser B AD - Sportmedizin, Institut fur Sportwissenschaft, Kiel, Deutschland. FAU - Erb, Carl AU - Erb C AUID- ORCID: 0000-0001-6041-1264 AD - Augenklinik am Wittenbergplatz, Berlin, Deutschland. LA - eng LA - ger PT - Journal Article PT - Review TT - Neuroprotektive Wirkungen von Antidiabetika in der Therapie von Patienten mit Diabetes und Glaukom oder hohem Glaukomrisiko. DEP - 20230619 PL - Germany TA - Klin Monbl Augenheilkd JT - Klinische Monatsblatter fur Augenheilkunde JID - 0014133 RN - 0 (Neuroprotective Agents) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Neuroprotective Agents/therapeutic use MH - Prospective Studies MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - *Glaucoma/drug therapy COIS- Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht./The authors declare that there is no conflict of interest EDAT- 2023/06/20 01:09 MHDA- 2024/03/22 06:44 CRDT- 2023/06/19 18:53 PHST- 2024/03/22 06:44 [medline] PHST- 2023/06/20 01:09 [pubmed] PHST- 2023/06/19 18:53 [entrez] AID - 10.1055/a-2066-3389 [doi] PST - ppublish SO - Klin Monbl Augenheilkd. 2024 Mar;241(3):302-307. doi: 10.1055/a-2066-3389. Epub 2023 Jun 19. PMID- 37335453 OWN - NLM STAT- MEDLINE DCOM- 20230717 LR - 20261010 IS - 1573-7365 (Electronic) IS - 0885-7490 (Linking) VI - 38 IP - 6 DP - 2023 Aug TI - Crosstalk between Alzheimer's disease and diabetes: a focus on anti-diabetic drugs. PG - 1769-1800 LID - 10.1007/s11011-023-01225-3 [doi] AB - Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) are two of the most common age-related diseases. There is accumulating evidence of an overlap in the pathophysiological mechanisms of these two diseases. Studies have demonstrated insulin pathway alternation may interact with amyloid-beta protein deposition and tau protein phosphorylation, two essential factors in AD. So attention to the use of anti-diabetic drugs in AD treatment has increased in recent years. In vitro, in vivo, and clinical studies have evaluated possible neuroprotective effects of anti-diabetic different medicines in AD, with some promising results. Here we review the evidence on the therapeutic potential of insulin, metformin, Glucagon-like peptide-1 receptor agonist (GLP1R), thiazolidinediones (TZDs), Dipeptidyl Peptidase IV (DPP IV) Inhibitors, Sulfonylureas, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Alpha-glucosidase inhibitors, and Amylin analog against AD. Given that many questions remain unanswered, further studies are required to confirm the positive effects of anti-diabetic drugs in AD treatment. So to date, no particular anti-diabetic drugs can be recommended to treat AD. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Goodarzi, Golnaz AU - Goodarzi G AD - Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AD - Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. AD - Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran. FAU - Tehrani, Sadra Samavarchi AU - Tehrani SS AD - Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AD - Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. FAU - Fana, Saeed Ebrahimi AU - Fana SE AD - Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AD - Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. FAU - Moradi-Sardareh, Hemen AU - Moradi-Sardareh H AD - Asadabad School of Medical Science, Hamadan, Asadabad, Iran. FAU - Panahi, Ghodratollah AU - Panahi G AD - Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. FAU - Maniati, Mahmood AU - Maniati M AD - English Department, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. FAU - Meshkani, Reza AU - Meshkani R AUID- ORCID: 0000-0003-1835-2883 AD - Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. rmeshkani@tums.ac.ir. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20230619 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 RN - 9100L32L2N (Metformin) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Insulin) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Metformin/pharmacology MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - Insulin/therapeutic use MH - Hypoglycemic Agents/pharmacology/therapeutic use OTO - NOTNLM OT - Alzheimer's disease (AD) OT - Amyloid-beta protein OT - Anti-diabetic drugs OT - Insulin resistance OT - Tau protein OT - Type 2 diabetes mellitus (T2DM) EDAT- 2023/06/19 13:08 MHDA- 2023/07/17 06:42 CRDT- 2023/06/19 11:09 PHST- 2023/01/07 00:00 [received] PHST- 2023/04/26 00:00 [accepted] PHST- 2023/07/17 06:42 [medline] PHST- 2023/06/19 13:08 [pubmed] PHST- 2023/06/19 11:09 [entrez] AID - 10.1007/s11011-023-01225-3 [pii] AID - 10.1007/s11011-023-01225-3 [doi] PST - ppublish SO - Metab Brain Dis. 2023 Aug;38(6):1769-1800. doi: 10.1007/s11011-023-01225-3. Epub 2023 Jun 19. PMID- 37328112 OWN - NLM STAT- MEDLINE DCOM- 20230710 LR - 20231124 IS - 1872-9649 (Electronic) IS - 1568-1637 (Linking) VI - 89 DP - 2023 Aug TI - Antidiabetic agents as a novel treatment for Alzheimer's and Parkinson's disease. PG - 101979 LID - S1568-1637(23)00138-1 [pii] LID - 10.1016/j.arr.2023.101979 [doi] AB - Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by several pathological features. In AD and PD, there is an abnormal accumulation of toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, increased astrocyte activation, and perhaps a state of insulin resistance. Epidemiological evidence has revealed a link between AD/PD and type 2 diabetes mellitus, with these disorders sharing some pathological commonalities. Such a link has opened up a promising avenue for repurposing antidiabetic agents in the treatment of neurodegenerative disorders. A successful therapeutic strategy for AD/PD would likely require a single or several agents which target the separate pathological processes in the disease. Targeting cerebral insulin signalling produces numerous neuroprotective effects in preclinical AD/PD brain models. Clinical trials have shown the promise of approved diabetic compounds in improving motor symptoms of PD and preventing neurodegenerative decline, with numerous further phase II trials and phase III trials underway in AD and PD populations. Alongside insulin signalling, targeting incretin receptors in the brain represents one of the most promising strategies for repurposing currently available agents for the treatment of AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists have displayed impressive clinical potential in preclinical and early clinical studies. In AD the GLP-1 receptor agonist, liraglutide, has been demonstrated to improve cerebral glucose metabolism and functional connectivity in small-scale pilot trials. Whilst in PD, the GLP-1 receptor agonist exenatide is effective in restoring motor function and cognition. Targeting brain incretin receptors reduces inflammation, inhibits apoptosis, prevents toxic protein aggregation, enhances long-term potentiation and autophagy as well as restores dysfunctional insulin signalling. Support is also increasing for the use of additional approved diabetic treatments, including intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear receptor gamma agonists, amylin analogs, and protein tyrosine phosphatase 1B inhibitors which are in the investigation for deployment in PD and AD treatment. As such, we provide a comprehensive review of several promising anti-diabetic agents for the treatment of AD and PD. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Nowell, Joseph AU - Nowell J AD - Department of Brain Sciences, Imperial College London, London, UK. FAU - Blunt, Eleanor AU - Blunt E AD - Department of Brain Sciences, Imperial College London, London, UK. FAU - Gupta, Dhruv AU - Gupta D AD - Department of Brain Sciences, Imperial College London, London, UK. FAU - Edison, Paul AU - Edison P AD - Department of Brain Sciences, Imperial College London, London, UK; School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK. Electronic address: paul.edison@imperial.ac.uk. LA - eng PT - Journal Article PT - Review DEP - 20230614 PL - England TA - Ageing Res Rev JT - Ageing research reviews JID - 101128963 RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - *Parkinson Disease/drug therapy/metabolism MH - Incretins/therapeutic use MH - *Alzheimer Disease/drug therapy/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide-1 Receptor/therapeutic use MH - *Neurodegenerative Diseases/metabolism MH - Insulin/therapeutic use MH - Inflammation/drug therapy MH - *Neuroprotective Agents/pharmacology/therapeutic use OTO - NOTNLM OT - Alzheimer's disease OT - Antidiabetic OT - Glucagon-like-peptide-1 OT - Incretin OT - Insulin OT - Parkinson's disease COIS- Declaration of Competing Interest Paul Edison was funded by the Medical Research Council and now by Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer's Research, UK, Alzheimer's Drug Discovery Foundation, Alzheimer's Society, UK, Alzheimer's association, US, Medical Research Council, UK and European Union. P.E. is a consultant to Pfizer and Novo Nordisk. He has received speaker fees from Novo Nordisk, Pfizer, Nordea, Piramal Life Science. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He is an external consultant to Novo Nordisk and a member of their Scientific Advisory Board. Joseph Nowell, Eleanor Blunt and Dhruv Gupta have no competing interests to declare. EDAT- 2023/06/17 05:11 MHDA- 2023/07/10 06:42 CRDT- 2023/06/16 19:18 PHST- 2023/01/25 00:00 [received] PHST- 2023/06/06 00:00 [revised] PHST- 2023/06/07 00:00 [accepted] PHST- 2023/07/10 06:42 [medline] PHST- 2023/06/17 05:11 [pubmed] PHST- 2023/06/16 19:18 [entrez] AID - S1568-1637(23)00138-1 [pii] AID - 10.1016/j.arr.2023.101979 [doi] PST - ppublish SO - Ageing Res Rev. 2023 Aug;89:101979. doi: 10.1016/j.arr.2023.101979. Epub 2023 Jun 14. PMID- 37323581 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230619 IS - 1662-5102 (Print) IS - 1662-5102 (Electronic) IS - 1662-5102 (Linking) VI - 17 DP - 2023 TI - Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress. PG - 1136070 LID - 10.3389/fncel.2023.1136070 [doi] LID - 1136070 AB - Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1beta, IL-18, and TNF-alpha, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment. CI - Copyright (c) 2023 An, Liu, Gao, Wang, Sun, Su, Zhang, Yu, Yang and Shi. FAU - An, Ji-Ren AU - An JR AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Liu, Jun-Tong AU - Liu JT AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Gao, Xiao-Meng AU - Gao XM AD - College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China. FAU - Wang, Qing-Feng AU - Wang QF AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Sun, Gui-Yan AU - Sun GY AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Su, Jia-Nan AU - Su JN AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Zhang, Chi AU - Zhang C AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Yu, Jia-Xiang AU - Yu JX AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Yang, Yu-Feng AU - Yang YF AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. FAU - Shi, Yan AU - Shi Y AD - Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, China. LA - eng PT - Journal Article DEP - 20230601 PL - Switzerland TA - Front Cell Neurosci JT - Frontiers in cellular neuroscience JID - 101477935 PMC - PMC10267480 OTO - NOTNLM OT - astrocyte polarization OT - diabetic cognitive impairment OT - hippocampus OT - iron overload OT - neuroinflammation OT - oxidative stress COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/06/16 06:42 MHDA- 2023/06/16 06:43 PMCR- 2023/01/01 CRDT- 2023/06/16 04:00 PHST- 2023/01/02 00:00 [received] PHST- 2023/05/03 00:00 [accepted] PHST- 2023/06/16 06:43 [medline] PHST- 2023/06/16 06:42 [pubmed] PHST- 2023/06/16 04:00 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fncel.2023.1136070 [doi] PST - epublish SO - Front Cell Neurosci. 2023 Jun 1;17:1136070. doi: 10.3389/fncel.2023.1136070. eCollection 2023. PMID- 37313236 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230615 IS - 2752-5457 (Electronic) IS - 2752-5457 (Linking) VI - 19 IP - 1 DP - 2023 May TI - Emerging Evidence for the Use of Antidiabetic Drugs, Glucagon-like Peptide 1 Receptor Agonists, for the Treatment of Alzheimer's Disease. PG - 16-24 LID - 10.17925/EE.2023.19.1.16 [doi] AB - From an epidemiological and pathophysiological point of view, Alzheimer's disease (AD) and type 2 diabetes (T2DM) should be considered 'sister' diseases. T2DM significantly increases the risk of developing AD, and the mechanisms of neuronal degeneration themselves worsen peripheral glucose metabolism in multiple ways. The pathophysiological links between the two diseases, particularly cerebral insulin resistance, which causes neuronal degeneration, are so close that AD is sometimes referred to as 'type 3 diabetes'. Although the latest news on the therapeutic front for AD is encouraging, no treatment has been shown to halt disease progression permanently. At best, the treatments slow down the progression; at worst, they are inactive, or cause worrying side effects, preventing their use on a larger scale. Therefore, it appears logical that optimizing the metabolic milieu through preventive or curative measures can also slow down the cerebral degeneration that characterizes AD. Among the different classes of hypoglycaemic drugs, glucagon-like peptide 1 receptor agonists, which are widely used in the treatment of T2DM, were shown to slow down, or even prevent, neuronal degeneration. Data from animal, preclinical, clinical phase II, cohort and large cardiovascular outcomes studies are encouraging. Of course, randomized clinical phase III studies, which are on-going, will be essential to verify this hypothesis. Thus, for once, there is hope for slowing down the neurodegenerative processes associated with diabetes, and that hope is the focus of this review. CI - (c) Touch Medical Media 2023. FAU - Colin, Ides M AU - Colin IM AD - Endocrino-Diabetology Research Unit, Department of Internal Medicine, Centre Hospitalier Regional Mons-Hainaut/Groupe Jolimont, Mons Belgium/Groupe Helora, Mons, Belgium. FAU - Szczepanski, Lidia W AU - Szczepanski LW AD - Endocrino-Diabetology Research Unit, Department of Internal Medicine, Centre Hospitalier Regional Mons-Hainaut/Groupe Jolimont, Mons Belgium/Groupe Helora, Mons, Belgium. FAU - Gerard, Anne-Catherine AU - Gerard AC AD - Endocrino-Diabetology Research Unit, Department of Internal Medicine, Centre Hospitalier Regional Mons-Hainaut/Groupe Jolimont, Mons Belgium/Groupe Helora, Mons, Belgium. AD - Group of Animal Molecular and Cellular Biology, Louvain Institute of Biomolecular Science and Technology, Universite Catholique de Louvain, Louvain-La-Neuve, Belgium. FAU - Elosegi, Jose-Antonio AU - Elosegi JA AD - Neurology Unit, Centre Hospitalier Universitaire Ambroise Pare, Mons Belgium/Groupe Helora, Mons, Belgium. LA - eng PT - Journal Article PT - Review DEP - 20230523 PL - England TA - touchREV Endocrinol JT - TouchREVIEWS in endocrinology JID - 101779126 PMC - PMC10258618 OTO - NOTNLM OT - Alzheimer's disease OT - antidiabetic drugs OT - glucagon-like peptide 1 receptor agonists OT - neuronal degeneration OT - pathophysiological links OT - type 2 diabetes COIS- Disclosures: Ides M Colin has served on advisory boards for Novo Nordisk, Boehringer Ingelheim, Sanofi, Abbott, Eli Lilly, Astra Zeneca, and Novartis and received honoraria for lectures. He acted as principal investigator in various clinical trials for Novo Nordisk and Sanofi. Jose-Antonio Elosegi has served on advisory boar ds for Sanofi and Bristol Meyer Squibb, and has received honoraria for lectures. He has acted as principal investigator in various clinical trials for Genzyme and Janssen. Lidia W Szczepanski and Anne-C atherine Gerard have no financial or non-financial relationships or activities to declare in relation to this article. EDAT- 2023/06/14 06:42 MHDA- 2023/06/14 06:43 PMCR- 2023/05/01 CRDT- 2023/06/14 03:53 PHST- 2023/02/24 00:00 [received] PHST- 2023/04/05 00:00 [accepted] PHST- 2023/06/14 06:43 [medline] PHST- 2023/06/14 06:42 [pubmed] PHST- 2023/06/14 03:53 [entrez] PHST- 2023/05/01 00:00 [pmc-release] AID - 10.17925/EE.2023.19.1.16 [doi] PST - ppublish SO - touchREV Endocrinol. 2023 May;19(1):16-24. doi: 10.17925/EE.2023.19.1.16. Epub 2023 May 23. PMID- 37302139 OWN - NLM STAT- MEDLINE DCOM- 20231011 LR - 20250626 IS - 1520-7560 (Electronic) IS - 1520-7552 (Linking) VI - 39 IP - 7 DP - 2023 Oct TI - Comparison on cognitive outcomes of antidiabetic agents for type 2 diabetes: A systematic review and network meta-analysis. PG - e3673 LID - 10.1002/dmrr.3673 [doi] AB - We aimed to summarise current evidence on different antidiabetic drugs to delay cognitive impairment, including mild cognitive impairment, dementia, Alzheimer's disease (AD) and vascular dementia, among subjects with type 2 diabetes mellitus (T2DM). Medline, Cochrane and Embase databases were searched from inception to 31 July 2022. Two investigators independently reviewed and screened trials comparing antidiabetic drugs with no antidiabetic drugs, placebo, or other active antidiabetic drugs on cognitive outcomes in T2DM. Data were analysed using meta-analysis and network meta-analysis. Twenty-seven studies met the inclusion criteria, including 3 randomised controlled trials, 19 cohort studies and 5 case-control studies. Compared with non-user, SGLT-2i (OR 0.41 [95% CI 0.22-0.76]), GLP-1RA (OR 0.34 [95% CI 0.14-0.85]), thiazolidinedione (OR 0.60 [95% CI 0.51-0.69]), and DPP-4i (OR 0.78 [95% CI 0.61-0.99]) users had a decreased risk of dementia, whereas sulfonylurea (OR 1.43 [95% CI 1.11-1.82]) increased dementia risk. Network meta-analysis showed that SGLT-2i was most likely to rank best (SUCRA = 94.4%), GLP-1 RA second best (SUCRA = 92.7%), thiazolidinedione third best (SUCRA = 74.7%) and DPP-4i fourth best (SUCRA = 54.9%), while sulfonylurea second worst (SUCRA = 20.0%) for decreasing dementia outcomes, by synthesising evidence from direct and indirect comparisons of multiple intervention. Evidence suggests the effects of SGLT-2i approximately GLP-1 RAs > thiazolidinedione > DPP-4i for delaying cognitive impairment, dementia and AD outcomes, whereas sulfonylurea was associated with the highest risk. These findings provide evidence for evaluating the optional treatment for clinical practice. PROSPERO REGISTRATION: Registration no. CRD42022347280. CI - (c) 2023 John Wiley & Sons Ltd. FAU - Tian, Sai AU - Tian S AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Jiang, Jiaxuan AU - Jiang J AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Wang, Jin AU - Wang J AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Miao, Yingwen AU - Miao Y AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Ji, Xinlu AU - Ji X AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. AD - Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. LA - eng PT - Journal Article PT - Network Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20230611 PL - England TA - Diabetes Metab Res Rev JT - Diabetes/metabolism research and reviews JID - 100883450 RN - 0 (Hypoglycemic Agents) RN - 0 (Sulfonylurea Compounds) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Thiazolidinediones) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Sulfonylurea Compounds/therapeutic use MH - Glucagon-Like Peptide 1/therapeutic use MH - *Dementia/epidemiology/complications MH - *Thiazolidinediones/therapeutic use MH - Cognition MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology MH - Glucagon-Like Peptide-1 Receptor OTO - NOTNLM OT - antidiabetic agents OT - cognitive impairment OT - network meta-analysis OT - type 2 diabetes mellitus EDAT- 2023/06/11 19:15 MHDA- 2023/10/11 06:45 CRDT- 2023/06/11 14:45 PHST- 2023/03/02 00:00 [revised] PHST- 2022/10/11 00:00 [received] PHST- 2023/04/25 00:00 [accepted] PHST- 2023/10/11 06:45 [medline] PHST- 2023/06/11 19:15 [pubmed] PHST- 2023/06/11 14:45 [entrez] AID - 10.1002/dmrr.3673 [doi] PST - ppublish SO - Diabetes Metab Res Rev. 2023 Oct;39(7):e3673. doi: 10.1002/dmrr.3673. Epub 2023 Jun 11. PMID- 37269487 OWN - NLM STAT- MEDLINE DCOM- 20230728 LR - 20230728 IS - 2299-5684 (Electronic) IS - 1734-1140 (Linking) VI - 75 IP - 4 DP - 2023 Aug TI - DPP-4 inhibitors and type 2 diabetes mellitus in Parkinson's disease: a mutual relationship. PG - 923-936 LID - 10.1007/s43440-023-00500-5 [doi] AB - Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis. CI - (c) 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences. FAU - Alrouji, Mohammed AU - Alrouji M AD - Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, 11961, Saudi Arabia. FAU - Al-Kuraishy, Hayder M AU - Al-Kuraishy HM AD - Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq. FAU - Al-Buhadily, Ali K AU - Al-Buhadily AK AD - Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq. FAU - Al-Gareeb, Ali I AU - Al-Gareeb AI AD - Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq. FAU - Elekhnawy, Engy AU - Elekhnawy E AUID- ORCID: 0000-0001-8287-1026 AD - Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt. engy.ali@pharm.tanta.edu.eg. FAU - Batiha, Gaber El-Saber AU - Batiha GE AD - Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AL Beheira, Egypt. gaberbatha@gmail.com. LA - eng PT - Journal Article PT - Review DEP - 20230603 PL - Switzerland TA - Pharmacol Rep JT - Pharmacological reports : PR JID - 101234999 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - TS63EW8X6F (Sitagliptin Phosphate) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Parkinson Disease/drug therapy MH - Sitagliptin Phosphate/pharmacology/therapeutic use MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Glucagon-Like Peptide 1 OTO - NOTNLM OT - DPP-4 inhibitor OT - Inflammation OT - Parkinson's disease OT - Sitagliptin EDAT- 2023/06/03 21:08 MHDA- 2023/07/28 06:42 CRDT- 2023/06/03 15:01 PHST- 2023/04/16 00:00 [received] PHST- 2023/05/19 00:00 [accepted] PHST- 2023/05/17 00:00 [revised] PHST- 2023/07/28 06:42 [medline] PHST- 2023/06/03 21:08 [pubmed] PHST- 2023/06/03 15:01 [entrez] AID - 10.1007/s43440-023-00500-5 [pii] AID - 10.1007/s43440-023-00500-5 [doi] PST - ppublish SO - Pharmacol Rep. 2023 Aug;75(4):923-936. doi: 10.1007/s43440-023-00500-5. Epub 2023 Jun 3. PMID- 37245533 OWN - NLM STAT- MEDLINE DCOM- 20230710 LR - 20260127 IS - 1872-6216 (Electronic) IS - 0047-6374 (Print) IS - 0047-6374 (Linking) VI - 213 DP - 2023 Jul TI - A feasibility study of the combination of intranasal insulin with dulaglutide for cognition in older adults with metabolic syndrome at high dementia risk - Study rationale and design. PG - 111825 LID - S0047-6374(23)00051-9 [pii] LID - 10.1016/j.mad.2023.111825 [doi] AB - INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with dulaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/dulaglutide injection, intranasal placebo/dulaglutide injection, INI/placebo injection, and intranasal placebo/placebo injection. Feasibility of combining INI with dulaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with dulaglutide (1.5 mg/week), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial of the cognitive benefits of the combination of INI with dulaglutide in individuals enriched for CVD and at high dementia risk. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Davidy, Tal AU - Davidy T AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Neurology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: Tal.davidy@mail.huji.ac.il. FAU - Yore, Iscka AU - Yore I AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Gertner Institute for Epidemiology and Health Policy Research, Endocrinology Institute Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. FAU - Ravona-Springer, Ramit AU - Ravona-Springer R AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Memory Clinic, Sheba Medical Center, Ramat Gan, Israel. FAU - Livny, Abigail AU - Livny A AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. FAU - Lesman-Segev, Orit H AU - Lesman-Segev OH AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. FAU - Azuri, Yossi AU - Azuri Y AD - Maccabi Healthcare Services, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. FAU - Carmichael, Owen AU - Carmichael O AD - Pennington Biomedical Research Center, Baton Rouge, LA, USA. FAU - Kapogiannis, Dimitrios AU - Kapogiannis D AD - Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging (NIA/NIH), Baltimore, MD, USA. FAU - Zetterberg, Henrik AU - Zetterberg H AD - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden. FAU - Lin, HungMo AU - Lin H AD - Department of anesthesiology and Yale Center for Analytical Sciences, USA. FAU - Sano, Mary AU - Sano M AD - James J. Peters VA Medical Research Center, New York, NY, USA. FAU - Beeri, Michal Schnaider AU - Beeri MS AD - The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY 10029, USA. LA - eng GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States GR - ZIA AG000975/ImNIH/Intramural NIH HHS/United States PT - Clinical Trial Protocol PT - Journal Article PT - Retracted Publication DEP - 20230526 PL - Ireland TA - Mech Ageing Dev JT - Mechanisms of ageing and development JID - 0347227 RN - 0 (Insulin) RN - 0 (Hypoglycemic Agents) RN - WTT295HSY5 (dulaglutide) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Recombinant Fusion Proteins) SB - IM RIN - Mech Ageing Dev. 2024 Jun;219:111937. doi: 10.1016/j.mad.2024.111937. PMID: 38702256 MH - Humans MH - Aged MH - Insulin MH - Feasibility Studies MH - *Metabolic Syndrome/drug therapy MH - Treatment Outcome MH - Cognition MH - *Dementia MH - *Cardiovascular Diseases/drug therapy MH - Double-Blind Method MH - Hypoglycemic Agents/pharmacology MH - *Diabetes Mellitus, Type 2/drug therapy MH - Randomized Controlled Trials as Topic MH - Glucagon-Like Peptides/analogs & derivatives MH - Immunoglobulin Fc Fragments MH - Recombinant Fusion Proteins PMC - PMC12120971 MID - NIHMS1911951 OTO - NOTNLM OT - Cerebral blood flow OT - Cognition OT - Dulaglutide OT - Intranasal insulin OT - Metabolic syndrome OT - Mild cognitive impairment EDAT- 2023/05/29 00:42 MHDA- 2023/07/10 06:42 PMCR- 2025/05/29 CRDT- 2023/05/28 19:22 PHST- 2023/03/19 00:00 [received] PHST- 2023/05/10 00:00 [revised] PHST- 2023/05/24 00:00 [accepted] PHST- 2023/07/10 06:42 [medline] PHST- 2023/05/29 00:42 [pubmed] PHST- 2023/05/28 19:22 [entrez] PHST- 2025/05/29 00:00 [pmc-release] AID - S0047-6374(23)00051-9 [pii] AID - 10.1016/j.mad.2023.111825 [doi] PST - ppublish SO - Mech Ageing Dev. 2023 Jul;213:111825. doi: 10.1016/j.mad.2023.111825. Epub 2023 May 26. PMID- 37231200 OWN - NLM STAT- MEDLINE DCOM- 20230808 LR - 20250626 IS - 1573-2606 (Electronic) IS - 1389-9155 (Print) IS - 1389-9155 (Linking) VI - 24 IP - 4 DP - 2023 Aug TI - Effects of GLP-1 receptor agonists on neurological complications of diabetes. PG - 655-672 LID - 10.1007/s11154-023-09807-3 [doi] AB - Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological complications such as stroke, cognitive impairment, and peripheral neuropathy. We performed a systematic review to examine the evidence concerning the effects of GLP-1 RAs on neurological complications of diabetes. The databases used were Pubmed, Scopus and Cochrane. We selected clinical trials which analysed the effect of GLP-1 RAs on stroke, cognitive impairment, and peripheral neuropathy. We found a total of 19 studies: 8 studies include stroke or major cardiovascular events, 7 involve cognitive impairment and 4 include peripheral neuropathy. Semaglutide subcutaneous and dulaglutide reduced stroke cases. Liraglutide, albiglutide, oral semaglutide and efpeglenatide, were not shown to reduce the number of strokes but did reduce major cardiovascular events. Exenatide, dulaglutide and liraglutide improved general cognition but no significant effect on diabetic peripheral neuropathy has been reported with GLP-1 RAs. GLP-1 RAs are promising drugs that seem to be useful in the reduction of some neurological complications of diabetes. However, more studies are needed. CI - (c) 2023. The Author(s). FAU - Garcia-Casares, Natalia AU - Garcia-Casares N AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. Nagcasares@uma.es. AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. Nagcasares@uma.es. AD - Centro de Investigaciones Medico-Sanitarias (C.I.M.ES), Malaga, Spain. Nagcasares@uma.es. AD - Departamento de Medicina, Facultad de Medicina, Universidad de Malaga, Centro de Investigaciones Medico Sanitarias (C.I.M.E.S), Universidad de Malaga, Instituto de Investigacion Biomedica de Malaga (IBIMA), Campus Universitario de Teatinos s/n., Malaga, 29010, Espana. Nagcasares@uma.es. FAU - Gonzalez-Gonzalez, Guillermo AU - Gonzalez-Gonzalez G AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. FAU - de la Cruz-Cosme, Carlos AU - de la Cruz-Cosme C AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. AD - Hospital Universitario Virgen de la Victoria de Malaga, Malaga, Spain. FAU - Garzon-Maldonado, Francisco J AU - Garzon-Maldonado FJ AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. AD - Hospital Universitario Virgen de la Victoria de Malaga, Malaga, Spain. FAU - de Rojas-Leal, Carmen AU - de Rojas-Leal C AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. FAU - Ariza, Maria J AU - Ariza MJ AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. AD - Centro de Investigaciones Medico-Sanitarias (C.I.M.ES), Malaga, Spain. FAU - Narvaez, Manuel AU - Narvaez M AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. FAU - Barbancho, Miguel Angel AU - Barbancho MA AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. AD - Centro de Investigaciones Medico-Sanitarias (C.I.M.ES), Malaga, Spain. FAU - Garcia-Arnes, Juan Antonio AU - Garcia-Arnes JA AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. FAU - Tinahones, Francisco J AU - Tinahones FJ AD - Facultad de Medicina, Departamento de Medicina, Universidad de Malaga, Malaga, Spain. fjtinahones@hotmail.com. AD - Instituto de Investigacion Biomedica de Malaga (I.B.I.M.A), Malaga, Spain. fjtinahones@hotmail.com. AD - Hospital Universitario Virgen de la Victoria de Malaga, Malaga, Spain. fjtinahones@hotmail.com. AD - Departamento de Medicina, Facultad de Medicina, Universidad de Malaga, Instituto de Investigacion Biomedica de Malaga (IBIMA), Campus Universitario de Teatinos s/n., Malaga, 29010, Espana. fjtinahones@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20230526 PL - Germany TA - Rev Endocr Metab Disord JT - Reviews in endocrine & metabolic disorders JID - 100940588 RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Liraglutide/pharmacology/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide-1 Receptor/therapeutic use MH - Glucagon-Like Peptide 1 MH - *Cardiovascular Diseases MH - *Stroke MH - *Diabetes Complications/drug therapy PMC - PMC10404567 OTO - NOTNLM OT - Alzheimer's disease OT - Cardiovascular disease OT - Cognitive impairment OT - Peripheral neuropathy OT - Stroke COIS- The authors have no competing interests to declare that are relevant to the content of this article. EDAT- 2023/05/26 01:05 MHDA- 2023/08/08 06:42 PMCR- 2023/05/26 CRDT- 2023/05/25 23:29 PHST- 2023/04/21 00:00 [accepted] PHST- 2023/08/08 06:42 [medline] PHST- 2023/05/26 01:05 [pubmed] PHST- 2023/05/25 23:29 [entrez] PHST- 2023/05/26 00:00 [pmc-release] AID - 10.1007/s11154-023-09807-3 [pii] AID - 9807 [pii] AID - 10.1007/s11154-023-09807-3 [doi] PST - ppublish SO - Rev Endocr Metab Disord. 2023 Aug;24(4):655-672. doi: 10.1007/s11154-023-09807-3. Epub 2023 May 26. PMID- 37191234 OWN - NLM STAT- MEDLINE DCOM- 20230517 LR - 20250103 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 22 IP - 5 DP - 2023 May TI - Glucagon-like peptide-1 receptor agonists to expand the healthy lifespan: Current and future potentials. PG - e13818 LID - 10.1111/acel.13818 [doi] LID - e13818 AB - To help ensure an expanded healthy lifespan for as many people as possible worldwide, there is a need to prevent or manage a number of prevalent chronic diseases directly and indirectly closely related to aging, including diabetes and obesity. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have proven beneficial in type 2 diabetes, are amongst the few medicines approved for weight management, and are also licensed for focused cardiovascular risk reduction. In addition, strong evidence suggests several other beneficial effects of the pleiotropic peptide hormone, including anti-inflammation. Consequently, GLP-1 RAs are now in advanced clinical development for the treatment of chronic kidney disease, broader cardiovascular risk reduction, metabolic liver disease and Alzheimer's disease. In sum, GLP-1 RAs are positioned as one of the pharmacotherapeutic options that can contribute to addressing the high unmet medical need characterising several prevalent aging-related diseases, potentially helping more people enjoy a prolonged healthy lifespan. CI - (c) 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. FAU - Kreiner, Frederik Flindt AU - Kreiner FF AUID- ORCID: 0000-0001-8296-453X AD - Global Medical Affairs, Novo Nordisk A/S, Soborg, Denmark. FAU - von Scholten, Bernt Johan AU - von Scholten BJ AD - Global Medical Affairs, Novo Nordisk A/S, Soborg, Denmark. FAU - Kurtzhals, Peter AU - Kurtzhals P AD - Global Medical Affairs, Novo Nordisk A/S, Soborg, Denmark. FAU - Gough, Stephen Charles Langford AU - Gough SCL AD - Global Medical Affairs, Novo Nordisk A/S, Soborg, Denmark. LA - eng PT - Journal Article DEP - 20230320 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - *Hypoglycemic Agents/therapeutic use MH - Longevity MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC10186594 OTO - NOTNLM OT - Alzheimer's disease OT - cardiovascular diseases OT - chronic kidney diseases OT - diabetes mellitus OT - glucagon-like peptide-1 OT - healthy aging OT - non-alcoholic steatohepatitis OT - obesity COIS- All authors are employees and shareholders of Novo Nordisk A/S. EDAT- 2023/05/16 13:09 MHDA- 2023/05/17 06:42 PMCR- 2023/03/20 CRDT- 2023/05/16 07:23 PHST- 2023/02/24 00:00 [revised] PHST- 2023/01/25 00:00 [received] PHST- 2023/02/28 00:00 [accepted] PHST- 2023/05/17 06:42 [medline] PHST- 2023/05/16 13:09 [pubmed] PHST- 2023/05/16 07:23 [entrez] PHST- 2023/03/20 00:00 [pmc-release] AID - ACEL13818 [pii] AID - 10.1111/acel.13818 [doi] PST - ppublish SO - Aging Cell. 2023 May;22(5):e13818. doi: 10.1111/acel.13818. Epub 2023 Mar 20. PMID- 37189641 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240917 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 11 IP - 4 DP - 2023 Mar 27 TI - The Effect of the Sodium-Glucose Cotransporter Inhibitor on Cognition and Metabolic Parameters in a Rat Model of Sporadic Alzheimer's Disease. LID - 10.3390/biomedicines11041025 [doi] LID - 1025 AB - Type 2 diabetes mellitus increases the risk of sporadic Alzheimer's disease (sAD), and antidiabetic drugs, including the sodium-glucose cotransporter inhibitors (SGLTI), are being studied as possible sAD therapy. We have explored whether the SGLTI phloridzin may influence metabolic and cognitive parameters in a rat model of sAD. Adult male Wistar rats were randomized to a control (CTR), an sAD-model group induced by intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg), a CTR+SGLTI, or an STZ-icv+SGLTI group. Two-month-long oral (gavage) SGLTI treatment (10 mg/kg) was initiated 1 month after STZ-icv and cognitive performance tested prior to sacrifice. SGLTI treatment significantly decreased plasma glucose levels only in the CTR group and failed to correct STZ-icv-induced cognitive deficit. In both the CTR and STZ-icv groups, SGLTI treatment diminished weight gain, decreased amyloid beta (Abeta) 1-42 in duodenum, and decreased the plasma levels of total glucagon-like peptide 1 (GLP-1), while the levels of active GLP-1, as well as both total and active glucose-dependent insulinotropic polypeptide, remained unchanged, compared to their respective controls. The increment in GLP-1 levels in the cerebrospinal fluid and its effect on Abeta 1-42 in duodenum could be one of the molecular mechanisms by which SGLTIs indirectly induce pleiotropic beneficial effects. FAU - Osmanovic Barilar, Jelena AU - Osmanovic Barilar J AUID- ORCID: 0000-0002-0470-0819 AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. FAU - Babic Perhoc, Ana AU - Babic Perhoc A AUID- ORCID: 0000-0002-7385-140X AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. FAU - Knezovic, Ana AU - Knezovic A AUID- ORCID: 0000-0001-8011-2034 AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. FAU - Homolak, Jan AU - Homolak J AUID- ORCID: 0000-0003-1508-3243 AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. FAU - Virag, Davor AU - Virag D AUID- ORCID: 0000-0003-3574-7107 AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. FAU - Salkovic-Petrisic, Melita AU - Salkovic-Petrisic M AD - Department of Pharmacology and Croatian, Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia. LA - eng GR - HRZZ-IP-2018-01-8938/Croatian Science Foundation/ GR - GA KK01.1.1.01.0007/European Union through the European Regional Development Fund)./ PT - Journal Article DEP - 20230327 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC10135566 OTO - NOTNLM OT - Alzheimer's disease OT - glucagon-like peptide 1 OT - sodium-glucose cotransporter inhibitor OT - streptozotocin COIS- The authors declare no conflict of interest. EDAT- 2023/05/16 06:42 MHDA- 2023/05/16 06:43 PMCR- 2023/03/27 CRDT- 2023/05/16 01:10 PHST- 2023/01/26 00:00 [received] PHST- 2023/03/16 00:00 [revised] PHST- 2023/03/23 00:00 [accepted] PHST- 2023/05/16 06:43 [medline] PHST- 2023/05/16 06:42 [pubmed] PHST- 2023/05/16 01:10 [entrez] PHST- 2023/03/27 00:00 [pmc-release] AID - biomedicines11041025 [pii] AID - biomedicines-11-01025 [pii] AID - 10.3390/biomedicines11041025 [doi] PST - epublish SO - Biomedicines. 2023 Mar 27;11(4):1025. doi: 10.3390/biomedicines11041025. PMID- 37181530 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230920 IS - 2666-6065 (Electronic) IS - 2666-6065 (Linking) VI - 33 DP - 2023 Apr TI - Sex differences in risk of cardiovascular events and mortality with sodium glucose co-transporter-2 inhibitors versus glucagon-like peptide 1 receptor agonists in Australians with type 2 diabetes: a population-based cohort study. PG - 100692 LID - 10.1016/j.lanwpc.2023.100692 [doi] LID - 100692 AB - BACKGROUND: Sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D). Despite known sex differences in diabetes-induced cardiovascular disease (CVD), pharmacological treatment recommendations are independent of sex. Our objective was to investigate possible sex differences in rates of MACE with SGLT2i vs. GLP-1RA use. METHODS: This population-based cohort study included men and women with T2D (>/=30 years), discharged from a Victorian hospital between 1st July 2013 and 1st July 2017, and dispensed an SGLT2i or GLP-1RA within 60 days of discharge. Using Cox proportional hazards regression with competing risks, subdistribution hazard ratios (sHR) with 95% confidence intervals (CI) were estimated for MACE in a follow-up to 30th June 2018. Analyses were conducted for men and women, and subgroups based on age, baseline heart failure (HF), and atherosclerotic CVD (ASCVD) status. FINDINGS: From a total of 8026 people (44.3% women, median follow-up time = 756 days), SGLT2i (n = 4231), compared to GLP-1RAs (n = 3795), reduced MACE rates in men (sHR 0.78; 95%CI 0.66-0.93), but not women. SGLT2i reduced MACE rates in men (sHR 0.72; 95%CI 0.54-0.98) and women (sHR 0.52; 95%CI 0.31-0.86) >/=65 years; in men with baseline HF (sHR 0.45; 95%CI 0.28-0.73); and in women with ASCVD (sHR 0.36; 95%CI 0.18-0.71). INTERPRETATIONS: SGLT2i, relative to GLP-1RAs, demonstrate favourable effects for MACE reductions among older Australian men and women with T2D. Analogous benefits were also observed in men with HF and women with ASCVD. FUNDING: Dementia Australia Yulgilbar Innovation Award. CI - (c) 2023 The Authors. FAU - Sharma, Abhipree AU - Sharma A AD - Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. FAU - Wood, Stephen AU - Wood S AD - Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. FAU - Bell, J Simon AU - Bell JS AD - Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. AD - Department of Epidemiology and Preventive Medicine, Monash University, VIC, Australia. FAU - De Blasio, Miles J AU - De Blasio MJ AD - Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. AD - Department of Pharmacology, Monash University, VIC, Australia. FAU - Ilomaki, Jenni AU - Ilomaki J AD - Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. AD - Department of Epidemiology and Preventive Medicine, Monash University, VIC, Australia. FAU - Ritchie, Rebecca H AU - Ritchie RH AD - Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia. AD - Department of Pharmacology, Monash University, VIC, Australia. AD - Department of Medicine, Monash University, VIC, Australia. LA - eng PT - Journal Article DEP - 20230131 PL - England TA - Lancet Reg Health West Pac JT - The Lancet regional health. Western Pacific JID - 101774968 PMC - PMC10166999 OTO - NOTNLM OT - Diabetes OT - Glucagon-like peptide 1 receptor agonists OT - Heart failure OT - Sex differences OT - Sodium glucose Co-Transporter 2 inhibitors COIS- JSB was supported by a 10.13039/501100000925National Health and Medical Research Council (10.13039/501100000925NHMRC) Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the 10.13039/501100000925NHMRC, Medical Research Future Fund, 10.13039/501100004752Victorian Government 10.13039/100012737Department of Health and Human Services, 10.13039/100008710Dementia Australia Research Foundation, 10.13039/501100016005Yulgilbar Foundation, Aged Care Quality and Safety Commission, 10.13039/501100022860Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, 10.13039/501100001238Society of Hospital Pharmacists of Australia, 10.13039/100004330GlaxoSmithKline Supported Studies Programme, 10.13039/100002429Amgen, and several aged care provider organisations unrelated to this work. JI reports grants from 10.13039/100004325AstraZeneca, 10.13039/100002429Amgen, 10.13039/100008710Dementia Australia Research Foundation, 10.13039/501100000925NHMRC, and 10.13039/501100001026National Breast Cancer Foundation, outside the submitted work. All grants and consulting funds were paid to the employing institution. AS, SW, MJD and RHR have no competing interests to declare. EDAT- 2023/05/14 19:13 MHDA- 2023/05/14 19:14 PMCR- 2023/01/31 CRDT- 2023/05/14 12:20 PHST- 2022/09/25 00:00 [received] PHST- 2022/12/11 00:00 [revised] PHST- 2023/01/03 00:00 [accepted] PHST- 2023/05/14 19:13 [pubmed] PHST- 2023/05/14 19:14 [medline] PHST- 2023/05/14 12:20 [entrez] PHST- 2023/01/31 00:00 [pmc-release] AID - S2666-6065(23)00010-X [pii] AID - 100692 [pii] AID - 10.1016/j.lanwpc.2023.100692 [doi] PST - epublish SO - Lancet Reg Health West Pac. 2023 Jan 31;33:100692. doi: 10.1016/j.lanwpc.2023.100692. eCollection 2023 Apr. PMID- 37173803 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230515 IS - 1758-5996 (Print) IS - 1758-5996 (Electronic) IS - 1758-5996 (Linking) VI - 15 IP - 1 DP - 2023 May 13 TI - The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer's diseases. PG - 101 LID - 10.1186/s13098-023-01082-1 [doi] LID - 101 AB - Human Islet amyloid polypeptide (hIAPP) from pancreatic beta cells in the islet of Langerhans has different physiological functions including inhibiting the release of insulin and glucagon. Type 2 diabetes mellitus (T2DM) is an endocrine disorder due to relative insulin insufficiency and insulin resistance (IR) is associated with increased circulating hIAPP. Remarkably, hIAPP has structural similarity with amyloid beta (Abeta) and can engage in the pathogenesis of T2DM and Alzheimer's disease (AD). Therefore, the present review aimed to elucidate how hIAPP acts as a link between T2DM and AD. IR, aging and low beta cell mass increase expression of hIAPP which binds cell membrane leading to the aberrant release of Ca(2+) and activation of the proteolytic enzymes leading to a series of events causing loss of beta cells. Peripheral hIAPP plays a major role in the pathogenesis of AD, and high circulating hIAPP level increase AD risk in T2DM patients. However, there is no hard evidence for the role of brain-derived hIAPP in the pathogenesis of AD. Nevertheless, oxidative stress, mitochondrial dysfunction, chaperon-mediated autophagy, heparan sulfate proteoglycan (HSPG), immune response, and zinc homeostasis in T2DM could be the possible mechanisms for the induction of the aggregation of hIAPP which increase AD risk. In conclusion, increasing hIAPP circulating levels in T2DM patients predispose them to the development and progression of AD. Dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists attenuate AD in T2DM by inhibiting expression and deposition of hIAP. CI - (c) 2023. The Author(s). FAU - Alrouji, Mohammed AU - Alrouji M AD - Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, 11961, Saudi Arabia. FAU - Al-Kuraishy, Hayder M AU - Al-Kuraishy HM AD - Department of clinical pharmacology and therapeutic medicine, college of medicine, ALmustansiriyiah University, M.B.Ch.B, FRCP, Baghdad, Box 14132, Iraq. FAU - Al-Gareeb, Ali I AU - Al-Gareeb AI AD - Department of clinical pharmacology and therapeutic medicine, college of medicine, ALmustansiriyiah University, M.B.Ch.B, FRCP, Baghdad, Box 14132, Iraq. FAU - Alexiou, Athanasios AU - Alexiou A AD - Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia. AD - AFNP Med, Wien, 1030, Austria. FAU - Papadakis, Marios AU - Papadakis M AD - Department of Surgery II, University Hospital Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany. marios_papadakis@yahoo.gr. FAU - Saad, Hebatallah M AU - Saad HM AD - Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matrouh, 51744, Egypt. FAU - Batiha, Gaber El-Saber AU - Batiha GE AD - Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt. LA - eng PT - Journal Article PT - Review DEP - 20230513 PL - England TA - Diabetol Metab Syndr JT - Diabetology & metabolic syndrome JID - 101488958 PMC - PMC10182652 OTO - NOTNLM OT - Alzheimer's disease OT - Human islet amyloid polypeptide insulin resistance OT - Type 2 diabetes mellitus COIS- The authors declare that they have no conflict of interest. EDAT- 2023/05/13 15:12 MHDA- 2023/05/13 15:13 PMCR- 2023/05/13 CRDT- 2023/05/12 23:41 PHST- 2023/03/01 00:00 [received] PHST- 2023/05/08 00:00 [accepted] PHST- 2023/05/13 15:13 [medline] PHST- 2023/05/13 15:12 [pubmed] PHST- 2023/05/12 23:41 [entrez] PHST- 2023/05/13 00:00 [pmc-release] AID - 10.1186/s13098-023-01082-1 [pii] AID - 1082 [pii] AID - 10.1186/s13098-023-01082-1 [doi] PST - epublish SO - Diabetol Metab Syndr. 2023 May 13;15(1):101. doi: 10.1186/s13098-023-01082-1. PMID- 37154218 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231114 IS - 1744-8417 (Electronic) IS - 1744-6651 (Linking) VI - 18 IP - 4 DP - 2023 Sep-Nov TI - The current role of SGLT2 inhibitors in type 2 diabetes and beyond: a narrative review. PG - 271-282 LID - 10.1080/17446651.2023.2210673 [doi] AB - INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2is, gliflozins), the most recent oral antihyperglycaemic agents, provide a cardiorenal protection, an effect independent of their glucose-lowering potency. AREAS COVERED: The antihyperglycaemic potency of SGLT2is was compared with that of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, especially when added to metformin monotherapy. Main results of cardiovascular/renal outcome trials with SGLT2is were summarized in different populations: patients with type 2 diabetes mellitus (T2DM) with or without established cardiovascular disease, patients (with or without T2DM) with heart failure (with reduced or preserved left ventricular ejection fraction) and in patients (with or without T2DM) with chronic kidney disease (CKD, including stage 4). Original papers and meta-analyses of these different trials have consistently reported a reduction in hospitalization for heart failure (alone or combined with cardiovascular mortality) and a reduced progression of CKD, with an overall good safety profile. EXPERT OPINION: Global use of SGLT2is has increased over time but remains suboptimal despite clinically relevant cardiovascular and renal protection, particularly in patients most likely to benefit. SGLT2is has proven both positive benefit-risk balance and cost-effectiveness in at risk patients. New prospects are expected in other complications, i.e. metabolic-associated fatty liver disease and neurodegenerative disorders. FAU - Scheen, Andre J AU - Scheen AJ AD - Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liege, Liege, Belgium. AD - Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liege University, Liege, Belgium. LA - eng PT - Journal Article PT - Review DEP - 20230508 PL - England TA - Expert Rev Endocrinol Metab JT - Expert review of endocrinology & metabolism JID - 101278293 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use MH - Stroke Volume MH - Ventricular Function, Left MH - *Renal Insufficiency, Chronic/complications/drug therapy MH - *Heart Failure/drug therapy MH - Glucose OTO - NOTNLM OT - Cardiovascular disease OT - SGLT2 inhibitor OT - cardiovascular mortality OT - chronic kidney disease OT - gliflozin OT - guidelines OT - heart failure EDAT- 2023/05/08 13:41 MHDA- 2023/05/08 13:42 CRDT- 2023/05/08 06:34 PHST- 2023/05/08 13:42 [medline] PHST- 2023/05/08 13:41 [pubmed] PHST- 2023/05/08 06:34 [entrez] AID - 10.1080/17446651.2023.2210673 [doi] PST - ppublish SO - Expert Rev Endocrinol Metab. 2023 Sep-Nov;18(4):271-282. doi: 10.1080/17446651.2023.2210673. Epub 2023 May 8. PMID- 37147888 OWN - NLM STAT- MEDLINE DCOM- 20230626 LR - 20250103 IS - 2040-1124 (Electronic) IS - 2040-1116 (Print) IS - 2040-1116 (Linking) VI - 14 IP - 7 DP - 2023 Jul TI - Cognitive protection of incretin-based therapies in patients with type 2 diabetes mellitus: A systematic review and meta-analysis based on clinical studies. PG - 864-873 LID - 10.1111/jdi.14015 [doi] AB - AIMS/INTRODUCTION: Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as an important complication of type 2 diabetes mellitus. The aims of the preset study was to investigate the cognitive protection of incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: PubMed, EMBASE, Cochrane library, Web of Science and PsycINFO were searched from the inception through 17 January 2023 for randomized controlled trials and cohort studies on the association between incretin-based therapies and cognitive function. A total of 15 studies were finally included in our systematic review, and eight of which were incorporated into our meta-analysis. RESULTS: Pooled results showed that the Mini-Mental State Examination score in incretin-based therapy groups was increased by 1.20 compared with the control group (weighted mean difference 1.20, 95% confidence interval 0.39-2.01). The results of eight studies assessed by the Newcastle Ottawa Quality Assessment Scale and the Cochrane Collaboration's tool, and the quality of the eight studies were at a relatively high level. Egger's regression did not show significant publication bias. CONCLUSIONS: Current evidence shows that incretin-based therapies might be more effective, when compared with the other hypoglycemic drugs, for cognitive improvement in patients with type 2 diabetes mellitus. CI - (c) 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd. FAU - Chai, Sanbao AU - Chai S AUID- ORCID: 0000-0002-8746-518X AD - Department of Endocrinology and Metabolism, Peking University International Hospital, Beijing, China. FAU - Liu, Fengqi AU - Liu F AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China. FAU - Yu, Shuqing AU - Yu S AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China. FAU - Yang, Zhirong AU - Yang Z AD - Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. FAU - Sun, Feng AU - Sun F AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China. LA - eng GR - 72074011/National Natural Science Foundation of China/ GR - YN2020ZD05/Peking University International Hospital Research Grant/ PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20230505 PL - Japan TA - J Diabetes Investig JT - Journal of diabetes investigation JID - 101520702 RN - 0 (Incretins) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Incretins/therapeutic use MH - *Diabetes Mellitus, Type 2/complications/drug therapy/chemically induced MH - Hypoglycemic Agents/adverse effects MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects MH - Cognition MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC10286783 OTO - NOTNLM OT - Cognitive function OT - Incretin-based therapy OT - Type 2 diabetes EDAT- 2023/05/06 09:42 MHDA- 2023/06/26 06:41 PMCR- 2023/05/05 CRDT- 2023/05/06 03:41 PHST- 2023/03/23 00:00 [revised] PHST- 2022/12/09 00:00 [received] PHST- 2023/03/26 00:00 [accepted] PHST- 2023/06/26 06:41 [medline] PHST- 2023/05/06 09:42 [pubmed] PHST- 2023/05/06 03:41 [entrez] PHST- 2023/05/05 00:00 [pmc-release] AID - JDI14015 [pii] AID - 10.1111/jdi.14015 [doi] PST - ppublish SO - J Diabetes Investig. 2023 Jul;14(7):864-873. doi: 10.1111/jdi.14015. Epub 2023 May 5. PMID- 37116797 OWN - NLM STAT- MEDLINE DCOM- 20230606 LR - 20250103 IS - 1872-8227 (Electronic) IS - 0168-8227 (Linking) VI - 200 DP - 2023 Jun TI - Circulating levels of endothelial progenitor cells are associated with better cognitive function in older adults with glucagon-like peptide 1 receptor agonist-treated type 2 diabetes. PG - 110688 LID - S0168-8227(23)00449-7 [pii] LID - 10.1016/j.diabres.2023.110688 [doi] AB - AIMS: To evaluate cognitive function in subjects with type 2 diabetes (T2D) treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) plus metformin or metformin alone and its association with endothelial progenitor cells (EPCs). METHODS: Adults with T2D treated with GLP-1RA plus metformin (GLP-1RA + MET) or MET alone for at least 12 months were included. Montreal Cognitive Assessment test (MoCA), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment (MNA) and disability tests were administered. Circulating levels of seven EPCs phenotypes were measured by flow cytometry. RESULTS: A total of 154 elderly patients were included, of whom 78 in GLP-1RA + MET group and 76 in MET group. The GLP-1RA + MET group showed better cognitive function as indicated by a significant higher MoCA and MMSE scores, and higher levels of CD34(+) CD133(+), CD133(+) KDR(+), and CD34(+) CD133(+) KDR(+) as compared with MET group. The number of CD34(+) CD133(+) KDR(+) cells was an independent predictor of higher MoCA, MMSE and MNA scores. CONCLUSIONS: People with T2D on GLP-1RA + MET treatment had better cognitive function and higher circulating levels of EPCs as compared with those on MET alone warranting further studies to understand the interrelationship between EPCs, GLP-RA treatment and cognitive health. CI - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Longo, Miriam AU - Longo M AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address: miriam.longo@unicampania.it. FAU - Di Meo, Irene AU - Di Meo I AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Caruso, Paola AU - Caruso P AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Muscio, Maria Francesca AU - Muscio MF AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Scappaticcio, Lorenzo AU - Scappaticcio L AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Maio, Antonietta AU - Maio A AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Maiorino, Maria Ida AU - Maiorino MI AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Bellastella, Giuseppe AU - Bellastella G AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Signoriello, Giuseppe AU - Signoriello G AD - Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Knop, Filip K AU - Knop FK AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Rizzo, Maria Rosaria AU - Rizzo MR AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Esposito, Katherine AU - Esposito K AD - Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy. LA - eng PT - Journal Article DEP - 20230426 PL - Ireland TA - Diabetes Res Clin Pract JT - Diabetes research and clinical practice JID - 8508335 RN - 0 (Antigens, CD34) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9100L32L2N (Metformin) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Endothelial Progenitor Cells MH - Antigens, CD34 MH - Glucagon-Like Peptide 1 MH - *Metformin/therapeutic use MH - Cognition MH - Hypoglycemic Agents/therapeutic use MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Cognitive function OT - EPCs OT - Elderly patients OT - Endothelial progenitor cells OT - GLP-1RA OT - Glucagon-like peptide 1 receptor agonists OT - Metformin OT - Type 2 diabetes COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/04/29 06:04 MHDA- 2023/06/06 06:42 CRDT- 2023/04/28 19:29 PHST- 2023/01/16 00:00 [received] PHST- 2023/04/12 00:00 [revised] PHST- 2023/04/21 00:00 [accepted] PHST- 2023/06/06 06:42 [medline] PHST- 2023/04/29 06:04 [pubmed] PHST- 2023/04/28 19:29 [entrez] AID - S0168-8227(23)00449-7 [pii] AID - 10.1016/j.diabres.2023.110688 [doi] PST - ppublish SO - Diabetes Res Clin Pract. 2023 Jun;200:110688. doi: 10.1016/j.diabres.2023.110688. Epub 2023 Apr 26. PMID- 37079222 OWN - NLM STAT- MEDLINE DCOM- 20230721 LR - 20261010 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 48 IP - 9 DP - 2023 Sep TI - Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease. PG - 2714-2730 LID - 10.1007/s11064-023-03924-w [doi] AB - Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Abeta (1-42), IRS-1 (s307), GSK-3beta, TNF-alpha, IL-1beta, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Siddiqui, Nazia AU - Siddiqui N AD - Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India. naziasiddiqui004@gmail.com. FAU - Ali, Javed AU - Ali J AD - Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India. FAU - Parvez, Suhel AU - Parvez S AD - Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India. FAU - Najmi, Abul Kalam AU - Najmi AK AD - Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India. FAU - Akhtar, Mohd AU - Akhtar M AD - Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India. LA - eng PT - Journal Article DEP - 20230420 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 3X29ZEJ4R2 (Linagliptin) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 5W494URQ81 (Streptozocin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) SB - IM MH - Rats MH - Animals MH - *Alzheimer Disease/chemically induced/drug therapy/complications MH - Linagliptin/adverse effects MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects MH - Streptozocin/toxicity MH - *Insulin Resistance/physiology MH - Neuroinflammatory Diseases MH - *Diabetes Mellitus, Type 2/complications MH - Glycogen Synthase Kinase 3 beta MH - Disease Models, Animal OTO - NOTNLM OT - Alzheimer's disease OT - Insulin Receptor Substrate-1 OT - Linagliptin OT - Neuronal insulin resistance OT - Streptozotocin EDAT- 2023/04/20 13:41 MHDA- 2023/07/21 06:43 CRDT- 2023/04/20 11:22 PHST- 2022/12/30 00:00 [received] PHST- 2023/03/24 00:00 [accepted] PHST- 2023/03/09 00:00 [revised] PHST- 2023/07/21 06:43 [medline] PHST- 2023/04/20 13:41 [pubmed] PHST- 2023/04/20 11:22 [entrez] AID - 10.1007/s11064-023-03924-w [pii] AID - 10.1007/s11064-023-03924-w [doi] PST - ppublish SO - Neurochem Res. 2023 Sep;48(9):2714-2730. doi: 10.1007/s11064-023-03924-w. Epub 2023 Apr 20. PMID- 37047011 OWN - NLM STAT- MEDLINE DCOM- 20230415 LR - 20260127 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 7 DP - 2023 Mar 23 TI - Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control. LID - 10.3390/ijms24076039 [doi] LID - 6039 AB - The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, alpha-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-gamma agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline. FAU - Youssef, Mahmoud E AU - Youssef ME AD - Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. FAU - Yahya, Galal AU - Yahya G AUID- ORCID: 0000-0002-9466-7863 AD - Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, Egypt. FAU - Popoviciu, Mihaela Simona AU - Popoviciu MS AD - Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania. FAU - Cavalu, Simona AU - Cavalu S AUID- ORCID: 0000-0001-7810-8925 AD - Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania. FAU - Abd-Eldayem, Marwa A AU - Abd-Eldayem MA AD - Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt. FAU - Saber, Sameh AU - Saber S AUID- ORCID: 0000-0002-5070-7851 AD - Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. LA - eng PT - Journal Article PT - Review DEP - 20230323 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 3.1.1.7 (Acetylcholinesterase) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (SLC5A2 protein, human) RN - 0 (Sodium-Glucose Transporter 2) SB - IM MH - Humans MH - Acetylcholinesterase MH - *Diabetes Mellitus, Type 2/epidemiology MH - Glycemic Control MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use MH - Sodium-Glucose Transporter 2 PMC - PMC10094124 OTO - NOTNLM OT - SGLT2 inhibitors OT - bone minerals OT - cancer OT - cardiorenal effects OT - cardiovascular effects OT - cognitive effects OT - metabolism COIS- There is no conflict of interest. EDAT- 2023/04/14 06:00 MHDA- 2023/04/14 06:41 PMCR- 2023/03/23 CRDT- 2023/04/13 01:09 PHST- 2023/02/03 00:00 [received] PHST- 2023/03/20 00:00 [revised] PHST- 2023/03/21 00:00 [accepted] PHST- 2023/04/14 06:41 [medline] PHST- 2023/04/13 01:09 [entrez] PHST- 2023/04/14 06:00 [pubmed] PHST- 2023/03/23 00:00 [pmc-release] AID - ijms24076039 [pii] AID - ijms-24-06039 [pii] AID - 10.3390/ijms24076039 [doi] PST - epublish SO - Int J Mol Sci. 2023 Mar 23;24(7):6039. doi: 10.3390/ijms24076039. PMID- 37013752 OWN - NLM STAT- MEDLINE DCOM- 20230407 LR - 20250103 IS - 2284-0729 (Electronic) IS - 1128-3602 (Linking) VI - 27 IP - 6 DP - 2023 Mar TI - Comprehensive review of glucagon-like peptide 1 receptor agonist treatment on the risk of cardiovascular outcomes and retinopathy as diabetic complications. PG - 2332-2340 LID - 31768 [pii] LID - 10.26355/eurrev_202303_31768 [doi] AB - Cardiovascular and microvascular disorders are serious complications of diabetes. Intensive glucose control is believed to hinder the pathological progression of these complications. In this review, we focus on the risk of diabetic retinopathy (DR) under intensive treatment with recently introduced glucose-lowering drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), sodium-glucose co-transporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs are more suitable for patients with diabetes at risk for, or established, cardiovascular complications, while SGLT2 inhibitors are more appropriate for complications of heart failure and chronic renal diseases. Accumulating evidence indicates that GLP-1RAs may provide a greater reduction in the risk of DR in patients with diabetes compared to DPP-4 inhibitors, sulfonylureas, or insulin. GLP-1RAs may be ideal antihyperglycemic drugs with direct benefits for the retina, since GLP-1R can be expressed in photoreceptors. Topical administration of GLP-1RAs induces direct retinal neuroprotection against DR by multiple mechanisms, such as preventing both neurodysfunction and retinal neurodegeneration; relieving the disruption of the blood-retinal barrier and associated vascular leakage, and inhibiting oxidative stress, inflammatory action, and neuronal apoptosis. Hence, it seems reasonable to utilize this strategy to treat patients with diabetes and early-stage DR, rather than exclusively using neuroprotective agents. FAU - Liu, H AU - Liu H AD - Department of Ophthalmology, The Affiliated People's Hospital of Ningbo University, Health Science Center, Ningbo University, Ningbo, Zhejiang, China. lu_qinkang@163.com. FAU - Zhang, J-T AU - Zhang JT FAU - Xin, S-H AU - Xin SH FAU - Ren, W-N AU - Ren WN FAU - Lu, Q-K AU - Lu QK LA - eng PT - Journal Article PT - Review PL - United States TA - Eur Rev Med Pharmacol Sci JT - European review for medical and pharmacological sciences JID - 9717360 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - IY9XDZ35W2 (Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Cardiovascular Diseases/prevention & control MH - *Diabetes Complications/drug therapy MH - *Diabetes Mellitus, Type 2/complications/drug therapy/chemically induced MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Glucose MH - Hypoglycemic Agents/therapeutic use MH - *Retinal Diseases MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2023/04/05 06:00 MHDA- 2023/04/05 06:42 CRDT- 2023/04/04 04:32 PHST- 2023/04/05 06:42 [medline] PHST- 2023/04/04 04:32 [entrez] PHST- 2023/04/05 06:00 [pubmed] AID - 31768 [pii] AID - 10.26355/eurrev_202303_31768 [doi] PST - ppublish SO - Eur Rev Med Pharmacol Sci. 2023 Mar;27(6):2332-2340. doi: 10.26355/eurrev_202303_31768. PMID- 37008061 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240914 IS - 2152-5250 (Print) IS - 2152-5250 (Electronic) IS - 2152-5250 (Linking) VI - 14 IP - 2 DP - 2023 Apr 1 TI - Impact of Insulin Degludec/Liraglutide Fixed Combination on the Gut Microbiomes of Elderly Patients With Type 2 Diabetes: Results From A Subanalysis of A Small Non-Randomised Single Arm Study. PG - 319-324 LID - 10.14336/AD.2023.0118 [doi] AB - In elderly Type 2 Diabetes (T2D) patients the relationship between the destabilization of gut microbiome and reversal of dysbiosis via glucose lowering drugs has not been explored. We investigated the effect of 6 months therapy with a fixed combination of Liraglutide and Degludec on the composition of the gut microbiome and its relationship with Quality of Life, glucose metabolism, depression, cognitive function, and markers of inflammation in a group of very old T2D subjects (n=24, 5 women, 19 men, mean age=82 years). While we observed no significant differences in microbiome biodiversity or community among study participants (N = 24, 19 men, mean age 82 years) who responded with decreased HbA1c (n=13) versus those who did not (n=11), our results revealed a significant increase in Gram-negative Alistipes among the former group (p=0.013). Among the responders, changes in the Alistipes content were associated directly with cognitive improvement (r=0.545, p=0.062) and inversely with TNFalpha levels (r=-0.608, p=0.036). Our results suggest that this combination drug may have a significant impact on both gastrointestinal microbes and cognitive function in elderly T2D individuals. CI - copyright: (c) 2022 Rizza et al. FAU - Rizza, Stefano AU - Rizza S AD - 1Department of Systems Medicine and. FAU - Pietrucci, Daniele AU - Pietrucci D AD - 2Department of Biology, University of Rome Tor Vergata, Italy. FAU - Longo, Susanna AU - Longo S AD - 1Department of Systems Medicine and. FAU - Menghini, Rossella AU - Menghini R AD - 1Department of Systems Medicine and. FAU - Teofani, Adelaide AU - Teofani A AD - 2Department of Biology, University of Rome Tor Vergata, Italy. FAU - Piciucchi, Giacomo AU - Piciucchi G AD - 1Department of Systems Medicine and. FAU - Montagna, Martina AU - Montagna M AD - 1Department of Systems Medicine and. FAU - Federici, Massimo AU - Federici M AD - 1Department of Systems Medicine and. LA - eng PT - Journal Article DEP - 20230401 PL - United States TA - Aging Dis JT - Aging and disease JID - 101540533 PMC - PMC10017153 OTO - NOTNLM OT - GLP-1 RA OT - Liraglutide OT - Type 2 diabetes OT - aging OT - microbiota COIS- Conflict of interest statement All the authors declare no relevant conflicts of interest among them or with the work. EDAT- 2023/04/04 06:00 MHDA- 2023/04/04 06:01 PMCR- 2023/04/01 CRDT- 2023/04/03 04:07 PHST- 2023/01/03 00:00 [received] PHST- 2023/01/18 00:00 [accepted] PHST- 2023/04/04 06:01 [medline] PHST- 2023/04/03 04:07 [entrez] PHST- 2023/04/04 06:00 [pubmed] PHST- 2023/04/01 00:00 [pmc-release] AID - ad-14-2-319 [pii] AID - 10.14336/AD.2023.0118 [doi] PST - epublish SO - Aging Dis. 2023 Apr 1;14(2):319-324. doi: 10.14336/AD.2023.0118. eCollection 2023 Apr 1. PMID- 36989942 OWN - NLM STAT- MEDLINE DCOM- 20230501 LR - 20260127 IS - 1873-376X (Electronic) IS - 1570-0232 (Linking) VI - 1221 DP - 2023 Apr 15 TI - Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats. PG - 123688 LID - S1570-0232(23)00098-3 [pii] LID - 10.1016/j.jchromb.2023.123688 [doi] AB - Semaglutide, one of the most potent glucagon-like peptide (GLP)-1 analogs, has widely been used to treat type II diabetes mellitus and obesity. Recent studies have shown that semaglutide also works on the brain, suggesting its potential utility for various diseases, including Parkinson's disease and Alzheimer's disease. This study aimed to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of semaglutide in both plasma and brain to characterize the pharmacokinetics and brain distribution in rats. Semaglutide was extracted by simple protein precipitation with methanol from plasma and by solid phase extraction from brain tissue. Liraglutide was used as an internal standard. Gradient elution profiles with mobile phases comprising 0.1 % formic acid in water and acetonitrile were used for chromatographic separation. The lower limit of quantification (LLOQ) of the LC-MS/MS assay was 0.5 ng/mL for both rat plasma and brain. Intra- and inter-day accuracy ranged 89.20-109.50 % in the plasma and 92.00-105.00 % in the brain. Precision was within 8.92 % in the plasma and 7.94 % in the brain. Sprague-Dawley rats were given semaglutide by intravenous (IV, 0.02 mg/kg) and subcutaneous (SC, 0.1 and 0.2 mg/kg) injection. Plasma concentrations of semaglutide showed a multi-exponential decline with an average half-life of 7.22-9.26 hr in rats. The subcutaneous bioavailability of semaglutide was 76.65-82.85 %. The brain tissue to plasma partition coefficient (K(p)) value of semaglutide was estimated as <0.01. Among the different regions of the brain, semaglutide concentrations were significantly higher in the hypothalamus. The analytical method and pharmacokinetic information may be helpful toward a better understanding of the effect of semaglutide in the brain and further development of GLP-1 analogs for various brain diseases. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Lee, Tae Suk AU - Lee TS AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea. FAU - Park, Eun Ji AU - Park EJ AD - D&D Pharmatech, Seongnam, Gyeonggi 13486, Republic of Korea. FAU - Choi, Minkyu AU - Choi M AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea. FAU - Oh, Hyun Seok AU - Oh HS AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea. FAU - An, Yejin AU - An Y AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea; College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea. FAU - Kim, Taehyung AU - Kim T AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea. FAU - Kim, Tae Hwan AU - Kim TH AD - College of Pharmacy, Daegu Catholic University, Gyeongsan, Gyeongbuk 38430, Republic of Korea. FAU - Shin, Beom Soo AU - Shin BS AD - School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea. Electronic address: bsshin@skku.edu. FAU - Shin, Soyoung AU - Shin S AD - College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea. Electronic address: shins@wku.ac.kr. LA - eng PT - Journal Article DEP - 20230322 PL - Netherlands TA - J Chromatogr B Analyt Technol Biomed Life Sci JT - Journal of chromatography. B, Analytical technologies in the biomedical and life sciences JID - 101139554 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Rats MH - Animals MH - Chromatography, Liquid/methods MH - Rats, Sprague-Dawley MH - *Tandem Mass Spectrometry/methods MH - Glucagon-Like Peptide 1 MH - *Diabetes Mellitus, Type 2 MH - Brain MH - Reproducibility of Results MH - Semaglutide OTO - NOTNLM OT - Bioavailability OT - Brain distribution OT - GLP-1 analogs OT - Hypothalamus OT - LC-MS/MS OT - Pharmacokinetics OT - Semaglutide COIS- Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Beom Soo Shin reports financial support was provided by Korea Ministry of Trade Industry and Energy. Eun Ji Park reports a relationship with D&D Pharmatech that includes: employment.]. EDAT- 2023/03/30 06:00 MHDA- 2023/05/01 06:42 CRDT- 2023/03/29 18:11 PHST- 2023/02/19 00:00 [received] PHST- 2023/03/10 00:00 [revised] PHST- 2023/03/20 00:00 [accepted] PHST- 2023/05/01 06:42 [medline] PHST- 2023/03/30 06:00 [pubmed] PHST- 2023/03/29 18:11 [entrez] AID - S1570-0232(23)00098-3 [pii] AID - 10.1016/j.jchromb.2023.123688 [doi] PST - ppublish SO - J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Apr 15;1221:123688. doi: 10.1016/j.jchromb.2023.123688. Epub 2023 Mar 22. PMID- 36976349 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20261010 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 66 IP - 10 DP - 2023 Oct TI - The expanding incretin universe: from basic biology to clinical translation. PG - 1765-1779 LID - 10.1007/s00125-023-05906-7 [doi] AB - Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet beta-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification. CI - (c) 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Drucker, Daniel J AU - Drucker DJ AUID- ORCID: 0000-0001-6688-8127 AD - Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. drucker@lunenfeld.ca. FAU - Holst, Jens J AU - Holst JJ AUID- ORCID: 0000-0001-6853-3805 AD - The Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. LA - eng GR - 154321/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20230328 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) SB - IM MH - Humans MH - *Incretins/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - Gastric Inhibitory Polypeptide/metabolism MH - Biology OTO - NOTNLM OT - Alzheimer's disease OT - Diabetes OT - Heart failure OT - Incretin OT - Non-alcoholic steatosis OT - Obesity OT - Review EDAT- 2023/03/29 06:00 MHDA- 2023/09/18 12:43 CRDT- 2023/03/28 11:15 PHST- 2023/01/06 00:00 [received] PHST- 2023/02/20 00:00 [accepted] PHST- 2023/09/18 12:43 [medline] PHST- 2023/03/29 06:00 [pubmed] PHST- 2023/03/28 11:15 [entrez] AID - 10.1007/s00125-023-05906-7 [pii] AID - 10.1007/s00125-023-05906-7 [doi] PST - ppublish SO - Diabetologia. 2023 Oct;66(10):1765-1779. doi: 10.1007/s00125-023-05906-7. Epub 2023 Mar 28. PMID- 36948022 OWN - NLM STAT- MEDLINE DCOM- 20230331 LR - 20230405 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 445 DP - 2023 May 8 TI - GLP-1 agonist Liraglutide prevents MK‑801-induced schizophrenia‑like behaviors and BDNF, CREB, p-CREB, Trk-B expressions in the hippocampus and prefrontal cortex in Balb/c mice. PG - 114386 LID - S0166-4328(23)00104-3 [pii] LID - 10.1016/j.bbr.2023.114386 [doi] AB - Glucagon-like peptide 1 (GLP-1) agonists are among the agents that can be used to treat type 2 diabetes mellitus, and they have also been reported to have neuroprotective effects. This study examined the effects of GLP-1 agonist Liraglutide on CREB, BDNF, Trk-B expression and emotional/cognitive behaviors in an experimental schizophrenia-like behavior model induced by MK-801. MK-801 (0.25 mg/kg, 0.1 ml/kg body weight) and/or Liraglutide (300 mcg/kg) were injected intraperitoneally once a day for 7 weeks into 8-10 weeks old male Balb/c mice (n = 78). Mice were randomly divided into 5 groups: Saline+Saline, MK-801 +Saline, Liraglutide+Saline, MK-801 +Liraglutide co-treatment, and Liraglutide+MK-801 co-treatment. A Morris water maze test, an elevated plus maze test, and an open field test were performed after injection. Western blots were performed on mice' hippocampus and PFC for BDNF, Trk-B, CREB, and p-CREB expression. Our study found that MK-801 impaired emotional and cognitive functions in mice. MK-801 administration did not affect Liraglutide's positive effects on spatial learning and memory activity in the Liraglutide+MK-801 group. Liraglutide administration (Liraglutide+MK-801 group) improved the BDNF/Trk-B and p-CREB/CREB ratio in the hippocampus, and the p-CREB/CREB ratio in the PFC to the control group level. The negative effects of MK-801 on cognitive behavior were not reversed by Liraglutide in the MK-801 +Liraglutide group. In conclusion, Liraglutide does not affect NMDA receptor blockade-induced emotional and cognitive behaviors. However, it has a protective effect against cognitive impairment. Furthermore, it is possible that the GLP-1 receptors in the hippocampus and PFC are involved in the modulation of NMDA receptor activity through CREB activation/deactivation. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Kutlu, Meltem Donmez AU - Kutlu MD AD - Cukurova University Faculty of Medicine. Department of Physiology, Department of Neurophysiology, Adana 01330, Turkey. Electronic address: meltemdonmez@gmail.com. FAU - Kose, Seda AU - Kose S AD - Cukurova University Faculty of Medicine. Department of Physiology, Department of Neurophysiology, Adana 01330, Turkey. FAU - Akillioglu, Kubra AU - Akillioglu K AD - Cukurova University Faculty of Medicine. Department of Physiology, Department of Neurophysiology, Adana 01330, Turkey. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230320 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 839I73S42A (Liraglutide) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Male MH - Mice MH - Animals MH - Liraglutide/pharmacology MH - Dizocilpine Maleate/pharmacology/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - Brain-Derived Neurotrophic Factor/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - *Schizophrenia/metabolism MH - Mice, Inbred BALB C MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Prefrontal Cortex/metabolism MH - Hippocampus/metabolism OTO - NOTNLM OT - BDNF OT - CREB OT - Liraglutide OT - MK-801 OT - Mice OT - Schizophrenia-like behaviors OT - Trk-B COIS- Conflict of interest We certify that there is no conflict of interest, financial, or otherwise in this study. EDAT- 2023/03/23 06:00 MHDA- 2023/03/31 06:42 CRDT- 2023/03/22 19:05 PHST- 2023/01/02 00:00 [received] PHST- 2023/03/03 00:00 [revised] PHST- 2023/03/06 00:00 [accepted] PHST- 2023/03/31 06:42 [medline] PHST- 2023/03/23 06:00 [pubmed] PHST- 2023/03/22 19:05 [entrez] AID - S0166-4328(23)00104-3 [pii] AID - 10.1016/j.bbr.2023.114386 [doi] PST - ppublish SO - Behav Brain Res. 2023 May 8;445:114386. doi: 10.1016/j.bbr.2023.114386. Epub 2023 Mar 20. PMID- 36909158 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230314 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 14 DP - 2023 TI - Hypoglycemic medicines in the treatment of Alzheimer's disease: Pathophysiological links between AD and glucose metabolism. PG - 1138499 LID - 10.3389/fphar.2023.1138499 [doi] LID - 1138499 AB - Alzheimer's Disease (AD) is a global chronic disease in adults with beta-amyloid (Abeta) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3beta and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications. CI - Copyright (c) 2023 Wang, Hu, Liu and Guo. FAU - Wang, Yixuan AU - Wang Y AD - Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China. FAU - Hu, Hao AU - Hu H AD - Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China. FAU - Liu, Xinyu AU - Liu X AD - Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China. FAU - Guo, Xiangyu AU - Guo X AD - Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China. LA - eng PT - Journal Article PT - Review DEP - 20230223 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9995522 OTO - NOTNLM OT - Alzheimer's disease OT - glucose metabolism OT - herbal medicines OT - hypoglycemic medicines OT - insulin signaling OT - mitochondria dysfunction COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/03/14 06:00 MHDA- 2023/03/14 06:01 PMCR- 2023/02/23 CRDT- 2023/03/13 03:55 PHST- 2023/01/05 00:00 [received] PHST- 2023/02/13 00:00 [accepted] PHST- 2023/03/13 03:55 [entrez] PHST- 2023/03/14 06:00 [pubmed] PHST- 2023/03/14 06:01 [medline] PHST- 2023/02/23 00:00 [pmc-release] AID - 1138499 [pii] AID - 10.3389/fphar.2023.1138499 [doi] PST - epublish SO - Front Pharmacol. 2023 Feb 23;14:1138499. doi: 10.3389/fphar.2023.1138499. eCollection 2023. PMID- 36821780 OWN - NLM STAT- MEDLINE DCOM- 20230718 LR - 20240702 IS - 1532-5415 (Electronic) IS - 0002-8614 (Print) IS - 0002-8614 (Linking) VI - 71 IP - 7 DP - 2023 Jul TI - Newer glucose-lowering drugs and risk of dementia: A systematic review and meta-analysis of observational studies. PG - 2096-2106 LID - 10.1111/jgs.18306 [doi] AB - BACKGROUND: Preclinical studies have suggested potential beneficial effects of newer glucose-lowering drugs (GLDs) including dipeptidyl peptidase (DPP)-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors, in protecting humans against cognitive decline and dementia. However, population studies aiming to demonstrate such cognitive benefits from newer GLDs have produced mixed findings. This meta-analysis aimed to evaluate the association between newer GLDs and risk of dementia in adults with type 2 diabetes (T2D). METHODS: Electronic databases were searched up to March 11, 2022 to include observational studies that examined the association between DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors and risk of dementia (including all-cause dementia, Alzheimer's disease [AD], and vascular dementia [VD]) in people with T2D. We conducted a random-effects meta-analysis to calculate the relative risk (RR) with 95% confidence interval (CI) for each class of newer GLD. RESULTS: Ten studies (from nine articles) involving 819,511 individuals with T2D were included. Three studies found that SGLT2 inhibitor users had a lower risk of all-cause dementia than non-SGLT2 inhibitor users (RR, 0.62; 95% CI, 0.39-0.97). Five studies found that users versus nonusers of GLP-1RAs were associated with a significant reduction in the risk of all-cause dementia (RR, 0.72; 95% CI, 0.54-0.97). However, a meta-analysis for AD and VD was unavailable for SGLT2 inhibitors and GLP-1RAs because only one study was included for each drug. In seven studies, users vs. nonusers of DPP-4 inhibitors were significantly associated with a decreased risk of all-cause dementia (RR, 0.84; 95% CI, 0.74-0.94) and VD (RR, 0.59; 95% CI, 0.47-0.75) but not AD (RR, 0.82; 95% CI, 0.63-1.08). CONCLUSION: Newer GLDs were associated with a decreased risk of all-cause dementia in people with T2D. Because of the observational nature and significant heterogeneity between studies, the results should be interpreted with caution. Further research is warranted to confirm our findings. CI - (c) 2023 The American Geriatrics Society. FAU - Tang, Huilin AU - Tang H AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. FAU - Shao, Hui AU - Shao H AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. FAU - Shaaban, C Elizabeth AU - Shaaban CE AUID- ORCID: 0000-0002-3016-1951 AD - Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Yang, Keming AU - Yang K AD - Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. FAU - Brown, Joshua AU - Brown J AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. FAU - Anton, Stephen AU - Anton S AD - Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, Florida, USA. AD - Department of Clinical and Health Psychology, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA. FAU - Wu, Yonghui AU - Wu Y AD - Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Bress, Adam AU - Bress A AD - Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA. FAU - Donahoo, William T AU - Donahoo WT AD - Division of Endocrinology, Diabetes and Metabolism, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - DeKosky, Steven T AU - DeKosky ST AD - Department of Neurology and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA. AD - 1Florida Alzheimer's Disease Research Center (ADRC), University of Florida, Gainesville, Florida, USA. FAU - Bian, Jiang AU - Bian J AD - Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA. FAU - Guo, Jingchuan AU - Guo J AUID- ORCID: 0000-0001-9799-2592 AD - Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA. AD - Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA. LA - eng GR - R56 AG069880/AG/NIA NIH HHS/United States GR - R01 AG080991/AG/NIA NIH HHS/United States GR - R01 AG076234/AG/NIA NIH HHS/United States GR - R01 DK133465/DK/NIDDK NIH HHS/United States GR - K01 AG071849/AG/NIA NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Systematic Review DEP - 20230223 PL - United States TA - J Am Geriatr Soc JT - Journal of the American Geriatrics Society JID - 7503062 RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - IY9XDZ35W2 (Glucose) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM CIN - J Am Geriatr Soc. 2023 Jul;71(7):2041-2045. doi: 10.1111/jgs.18405. PMID: 37227136 MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - Hypoglycemic Agents/adverse effects MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects MH - Glucose MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - *Dementia/prevention & control/complications PMC - PMC10363181 MID - NIHMS1874796 OTO - NOTNLM OT - DPP-4 inhibitors OT - GLP-1RAs OT - SGLT2 inhibitors OT - dementia OT - type 2 diabetes COIS- CONFLICT OF INTEREST The authors declare that there is no conflict of interest. EDAT- 2023/02/24 06:00 MHDA- 2023/07/18 13:07 PMCR- 2024/07/01 CRDT- 2023/02/23 15:13 PHST- 2023/01/01 00:00 [revised] PHST- 2022/07/27 00:00 [received] PHST- 2023/01/28 00:00 [accepted] PHST- 2023/07/18 13:07 [medline] PHST- 2023/02/24 06:00 [pubmed] PHST- 2023/02/23 15:13 [entrez] PHST- 2024/07/01 00:00 [pmc-release] AID - 10.1111/jgs.18306 [doi] PST - ppublish SO - J Am Geriatr Soc. 2023 Jul;71(7):2096-2106. doi: 10.1111/jgs.18306. Epub 2023 Feb 23. PMID- 36740965 OWN - NLM STAT- MEDLINE DCOM- 20230310 LR - 20230315 IS - 2093-5978 (Electronic) IS - 2093-596X (Print) IS - 2093-596X (Linking) VI - 38 IP - 1 DP - 2023 Feb TI - Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond. PG - 25-33 LID - 10.3803/EnM.2022.1642 [doi] AB - The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer's disease. FAU - Viljoen, Adie AU - Viljoen A AD - Borthwick Diabetes Research Centre, Lister Hospital (East and North Hertfordshire NHS Trust), Stevenage, UK. FAU - Bain, Stephen C AU - Bain SC AD - Department of Biomedical Sciences, Swansea University Medical School, Swansea, UK. LA - eng PT - Journal Article DEP - 20230206 PL - Korea (South) TA - Endocrinol Metab (Seoul) JT - Endocrinology and metabolism (Seoul, Korea) JID - 101554139 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide 1/therapeutic use MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology MH - *Kidney Diseases PMC - PMC10008669 OTO - NOTNLM OT - Diabetes mellitus, type 2 OT - Glucagon-like peptide 1 OT - Renal insufficiency, chronic COIS- CONFLICTS OF INTEREST Adie Viljoen has received lecture honoraria and/or, advisory board honoraria and/or, travel support and/or, conducts research trials (for which he receives no remuneration) funded by Amarin, Amgen, Astra Zeneca, Boehringer Ingelheim, Lilly, Napp, Novartis, Novo Nordisk, Regeneron, Sanofi, Takeda, and Tosoh. Stephen C. Bain has received research support from Healthcare and Research Wales (Welsh Government) and honoraria from Boehringer Ingelheim, Lilly, Merck, Napp, Novo Nordisk, and Sanofi. He has ownership in Glycosmedia (Online diabetes news service). EDAT- 2023/02/07 06:00 MHDA- 2023/03/11 06:00 PMCR- 2023/02/01 CRDT- 2023/02/06 03:03 PHST- 2022/12/14 00:00 [received] PHST- 2022/12/28 00:00 [accepted] PHST- 2023/02/07 06:00 [pubmed] PHST- 2023/03/11 06:00 [medline] PHST- 2023/02/06 03:03 [entrez] PHST- 2023/02/01 00:00 [pmc-release] AID - EnM.2022.1642 [pii] AID - enm-2022-1642 [pii] AID - 10.3803/EnM.2022.1642 [doi] PST - ppublish SO - Endocrinol Metab (Seoul). 2023 Feb;38(1):25-33. doi: 10.3803/EnM.2022.1642. Epub 2023 Feb 6. PMID- 36650694 OWN - NLM STAT- MEDLINE DCOM- 20230210 LR - 20230215 IS - 1744-8417 (Electronic) IS - 1744-6651 (Linking) VI - 18 IP - 1 DP - 2023 Jan TI - Effects of hypoglycaemic therapy on frailty: a multi-dimensional perspective. PG - 53-65 LID - 10.1080/17446651.2023.2168644 [doi] AB - INTRODUCTION: The prevalence of diabetes is increasing in older people. With increasing age, frailty emerges as a new complication leading to disability. Frailty does not only include physical dysfunction but also involves negative impact on cognition and mood. Triad of impairments (TOI) is a new concept that includes physical frailty, dementia and depression to reflect the wider spectrum of frailty. AREAS COVERED: Little is known about effects of hypoglycaemic agents on frailty syndrome. A literature search was performed on studies, which reported effects of hypoglycaemic agents on the component of the TOI. EXPERT OPINION: It appears that most hypoglycaemic agents have some effects on frailty, although the results of clinical studies are inconsistent. Metformin seems to have a consistent and a positive effect on physical frailty. Its effects on cognitive function, however, are inconclusive but tend to be positive. Metformin appeared to improve depressive symptoms. Other agents such as incretins, thiazolidinediones, and sodium glucose transporter-2 inhibitors have some positive effects on cognition and depression. Sulfonylureas, glinides, or insulin have either negative or neutral effects on TOI components. The negative effects of insulin could be partially explained by the negative psychological factors and the frequent episodes of hypoglycemia associated with such therapy. FAU - Abdelhafiz, Ahmed H AU - Abdelhafiz AH AD - Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham, UK. LA - eng PT - Journal Article DEP - 20230117 PL - England TA - Expert Rev Endocrinol Metab JT - Expert review of endocrinology & metabolism JID - 101278293 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Insulin) SB - IM MH - Humans MH - Aged MH - Hypoglycemic Agents/adverse effects MH - *Frailty/complications/drug therapy MH - *Diabetes Mellitus, Type 2/complications MH - Frail Elderly MH - *Metformin/therapeutic use MH - Insulin/therapeutic use OTO - NOTNLM OT - Older people OT - dementia OT - depression OT - diabetes OT - frailty OT - hypoglycaemic agents EDAT- 2023/01/19 06:00 MHDA- 2023/02/11 06:00 CRDT- 2023/01/18 00:42 PHST- 2023/01/19 06:00 [pubmed] PHST- 2023/02/11 06:00 [medline] PHST- 2023/01/18 00:42 [entrez] AID - 10.1080/17446651.2023.2168644 [doi] PST - ppublish SO - Expert Rev Endocrinol Metab. 2023 Jan;18(1):53-65. doi: 10.1080/17446651.2023.2168644. Epub 2023 Jan 17. PMID- 36629298 OWN - NLM STAT- MEDLINE DCOM- 20230206 LR - 20230206 IS - 2245-1919 (Electronic) IS - 2245-1919 (Linking) VI - 70 IP - 1 DP - 2022 Dec 21 TI - Incretin-based therapy of metabolic disease. LID - A10220597 [pii] AB - Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of dementia and cognitive impairment is reduced. A monomolecular coagonist (tirzepatide) of receptors for both incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) produced HbA1c values below 5.7% in 50% of the treated patients and weight losses exceeding 20% in obese individuals. These new agents will radically change our approach to the treatment of T2DM and obesity alike. CI - Articles published in the DMJ are "open access". This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. FAU - Holst, Jens Juul AU - Holst JJ AD - Novo Nordisk Foundation Center of Basic Metabolic Research and Department of Biomedical Research, the Panum Institute, University of Copenhagen, Denmark. LA - eng PT - Journal Article DEP - 20221221 PL - Denmark TA - Dan Med J JT - Danish medical journal JID - 101576205 RN - 0 (Blood Glucose) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Incretins) SB - IM MH - Humans MH - Blood Glucose/metabolism MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Gastric Inhibitory Polypeptide/metabolism MH - Glucagon-Like Peptide 1 MH - *Incretins/therapeutic use MH - *Metabolic Diseases/drug therapy MH - *Obesity/complications/drug therapy MH - Weight Loss EDAT- 2023/01/12 06:00 MHDA- 2023/01/13 06:00 CRDT- 2023/01/11 07:43 PHST- 2023/01/11 07:43 [entrez] PHST- 2023/01/12 06:00 [pubmed] PHST- 2023/01/13 06:00 [medline] AID - A10220597 [pii] PST - epublish SO - Dan Med J. 2022 Dec 21;70(1):A10220597. PMID- 36619150 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230111 IS - 2008-5230 (Print) IS - 2008-5249 (Electronic) IS - 2008-5230 (Linking) VI - 14 IP - 2 DP - 2022 Apr TI - Gut Microbiota Modification via Glucagon-like Peptide-1 with Beneficial Neuroprotective Effects. PG - 235-243 LID - 10.34172/mejdd.2022.278 [doi] AB - BACKGROUND: In recent decades, it has been shown that the association between intestinal bacterial imbalance (dysbiosis) and various diseases such as type 2 diabetes can play a role in the development of Alzheimer's and Parkinson's diseases. In this study, the beneficial effects of intestinal microbiota glucagon-like peptide 1 (GLP-1) in cognitive disorders were investigated. METHODS: PubMed-Medline, Web of Science, and Scopus were searched to identify experimental studies based on the bacterial strains along with GLP-1 1 expression in preventing or reducing cognitive impairment. Of the 233 studies, six were eligible for inclusion, and the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool was used to evaluate the risk of bias in individual studies. RESULTS: The results showed that intestinal expression of GLP-1 1 could reduce the intestinal pathogenic genus such as Enterobacteriaceae and was obviously associated with a greater number of beneficial genera such as Lactobacillus and Akkermansia. Also, the neuroprotective effects of Clostridium butyricum with GLP-1 1 in a mice were approved. Therefore, the modulation of the intestinal microbiota, mediated by an increase in the intestinal GLP-1 1 level, consequently improved cognitive function. CONCLUSION: In this review, we have indicated that the gut microbiota, by stimulating the expression of the intestinal hormones like GLP-1 1, and also with a beneficial effect in inhibiting some involved genes in inflammation, can declined the development of cognitive disorders. CI - (c) 2022 Middle East Journal of Digestive Diseases. FAU - Sayehmiri, Fatemeh AU - Sayehmiri F AD - Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Samadian, Mohammad AU - Samadian M AD - Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Mohamadkhani, Ashraf AU - Mohamadkhani A AD - Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. FAU - Tafakhori, Abbas AU - Tafakhori A AD - Associate Professor of Neurology, Iranian Center of Neurological Science; Tehran University of Medical Sciences; Tehran, Iran. FAU - Haghighat, Somayeh AU - Haghighat S AD - Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran. FAU - Rahmatian, Aryoobarzan AU - Rahmatian A AD - Faculty of Medicine, Department of neurology, Ilam University of medical science, Ilam, Iran. FAU - Mohammadkhani, Mohammad Ali AU - Mohammadkhani MA AD - Technical and Vocational University, Tehran, Iran. FAU - Fazli, Hamid Reza AU - Fazli HR AD - Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. FAU - Rezaei Tavirani, Mostafa AU - Rezaei Tavirani M AD - Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. LA - eng PT - Journal Article PT - Review DEP - 20220430 PL - Iran TA - Middle East J Dig Dis JT - Middle East journal of digestive diseases JID - 101535395 PMC - PMC9489313 OTO - NOTNLM OT - Alzheimer disease OT - Neurodegenerative diseases OT - Parkinson disease COIS- CONFLICT OF INTEREST The authors declare no conflict of interest. EDAT- 2023/01/10 06:00 MHDA- 2023/01/10 06:01 PMCR- 2022/04/01 CRDT- 2023/01/09 03:46 PHST- 2021/09/06 00:00 [received] PHST- 2022/03/17 00:00 [accepted] PHST- 2023/01/09 03:46 [entrez] PHST- 2023/01/10 06:00 [pubmed] PHST- 2023/01/10 06:01 [medline] PHST- 2022/04/01 00:00 [pmc-release] AID - 10.34172/mejdd.2022.278 [doi] PST - ppublish SO - Middle East J Dig Dis. 2022 Apr;14(2):235-243. doi: 10.34172/mejdd.2022.278. Epub 2022 Apr 30. PMID- 36587502 OWN - NLM STAT- MEDLINE DCOM- 20230208 LR - 20250103 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 115 DP - 2023 Feb TI - The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4. PG - 109653 LID - S1567-5769(22)01138-9 [pii] LID - 10.1016/j.intimp.2022.109653 [doi] AB - Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1beta, IL-6 and TNF-alpha in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1beta and TNF-alpha expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Lin, Ming-Hong AU - Lin MH AD - Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: mhlin@kmu.edu.tw. FAU - Cheng, Po-Ching AU - Cheng PC AD - Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Center for International Tropical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. Electronic address: bonjovi@tmu.edu.tw. FAU - Hsiao, Pi-Jung AU - Hsiao PJ AD - Division of Endocrinology and Metabolism, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan. Electronic address: pjhsiao101@isu.edu.tw. FAU - Chen, Szu-Chia AU - Chen SC AD - Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: chensc@kmu.edu.tw. FAU - Hung, Chih-Hsing AU - Hung CH AD - Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: 1086066@kmuh.org.tw. FAU - Kuo, Chao-Hung AU - Kuo CH AD - Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: jhkao@kmu.edu.tw. FAU - Huang, Shau-Ku AU - Huang SK AD - National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County 350, Taiwan; Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: skhuang@nhri.org.tw. FAU - Clair Chiou, Hsin-Ying AU - Clair Chiou HY AD - Center of Teaching and Research, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan; Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan. Electronic address: 1086093@mail.kmuh.org.tw. LA - eng PT - Journal Article DEP - 20221230 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 9P1872D4OL (Exenatide) RN - 0 (Tumor Necrosis Factor-alpha) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Mice MH - Animals MH - Exenatide/pharmacology/therapeutic use MH - Microglia MH - Neuroinflammatory Diseases MH - Down-Regulation MH - *Diabetes Mellitus, Type 2/metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - *Neurodegenerative Diseases/metabolism MH - Gliosis MH - Obesity/metabolism MH - Diet, High-Fat/adverse effects MH - Glucagon-Like Peptide 1/metabolism MH - Locomotion MH - Anxiety/drug therapy MH - Mice, Inbred C57BL MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Exenatide OT - Neuroinflammation OT - Obesity OT - SR-A4 OT - T2DM COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/01/02 06:00 MHDA- 2023/02/09 06:00 CRDT- 2023/01/01 18:10 PHST- 2022/10/16 00:00 [received] PHST- 2022/12/16 00:00 [revised] PHST- 2022/12/26 00:00 [accepted] PHST- 2023/01/02 06:00 [pubmed] PHST- 2023/02/09 06:00 [medline] PHST- 2023/01/01 18:10 [entrez] AID - S1567-5769(22)01138-9 [pii] AID - 10.1016/j.intimp.2022.109653 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Feb;115:109653. doi: 10.1016/j.intimp.2022.109653. Epub 2022 Dec 30. PMID- 36541080 OWN - NLM STAT- MEDLINE DCOM- 20221222 LR - 20250103 IS - 1752-2978 (Electronic) IS - 1752-296X (Print) IS - 1752-296X (Linking) VI - 30 IP - 1 DP - 2023 Feb 1 TI - Utilizing type 2 diabetes medications outside glycemic parameters - where are we headed? PG - 1-6 LID - 10.1097/MED.0000000000000787 [doi] AB - PURPOSE OF REVIEW: Glucose-lowering medications have become strong choices for purposes beyond glucose control in both patients with and without type 2 diabetes. Recent studies have explored the use of specific glucose-lowering therapies in areas such as cardiovascular disease, renal disease, obesity, nonalcoholic fatty liver disease (NAFLD), and Alzheimer's disease, among others. This begs the question if glycemic parameters should be the sole criteria utilized for initiation of diabetes therapeutic agents. RECENT FINDINGS: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in particular have demonstrated significant benefits beyond glucose control, with each demonstrating improvement, to various extent, on cardiovascular and renal outcomes, disease-modifying weight loss, progression from prediabetes, and treatment of NAFLD by ameliorating inflammation. SUMMARY: Clinical practice guidelines have been updated to reflect the use of these medications to achieve cardiometabolic, renal, and weight goals in addition to glycemic control. The success of glucose-lowering medications in the aforementioned areas have informed the research pursuits in investigating these agents for their anti-inflammatory, neuroprotective, and lipotoxic reduction effects in other diseases entirely. CI - Copyright (c) 2022 Wolters Kluwer Health, Inc. All rights reserved. FAU - Malkani, Natasha Prakash AU - Malkani NP AD - Brigham and Women's Hospital Division of Diabetes, Endocrinology, and Hypertension. Boston, Massachusetts, USA. FAU - Aroda, Vanita R AU - Aroda VR LA - eng GR - T32 DK007529/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20221206 PL - England TA - Curr Opin Endocrinol Diabetes Obes JT - Current opinion in endocrinology, diabetes, and obesity JID - 101308636 RN - 0 (Hypoglycemic Agents) RN - 0 (Blood Glucose) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - IY9XDZ35W2 (Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - Hypoglycemic Agents/therapeutic use/pharmacology MH - Blood Glucose MH - *Non-alcoholic Fatty Liver Disease/drug therapy MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Glucose MH - *Cardiovascular Diseases MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC9870453 MID - NIHMS1851193 EDAT- 2022/12/22 06:00 MHDA- 2022/12/23 06:00 PMCR- 2024/02/01 CRDT- 2022/12/21 03:33 PHST- 2022/12/21 03:33 [entrez] PHST- 2022/12/22 06:00 [pubmed] PHST- 2022/12/23 06:00 [medline] PHST- 2024/02/01 00:00 [pmc-release] AID - 01266029-202302000-00002 [pii] AID - 10.1097/MED.0000000000000787 [doi] PST - ppublish SO - Curr Opin Endocrinol Diabetes Obes. 2023 Feb 1;30(1):1-6. doi: 10.1097/MED.0000000000000787. Epub 2022 Dec 6. PMID- 36470445 OWN - NLM STAT- MEDLINE DCOM- 20221219 LR - 20250103 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 938 DP - 2023 Jan 5 TI - Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases. PG - 175439 LID - S0014-2999(22)00700-2 [pii] LID - 10.1016/j.ejphar.2022.175439 [doi] AB - Aging is a crucial risk factor for common neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Limited options are available for the treatment of age-related, multiple pathogenic mechanism-contributed diseases that usually advance to irreversible conditions with severe neurological deficits and result in a heavy socioeconomic burden on patients, families, and society. A therapy that decelerates disease progression and reduces the socioeconomic burden stemming from these diseases is required. Glucagon-like peptide-1 receptor (GLP-1R) is an important class of medication for type 2 diabetes mellitus (T2DM). Through pancreatic effects, GLP-1R agonists can stimulate insulin secretion, increase beta-cell proliferation, reduce beta-cell apoptosis, and inhibit glucagon secretion in patients with T2DM. Currently, seven clinically approved GLP-1R agonists are used for T2DM: exenatide, liraglutide, lixisenatide, extended-release exenatide, albiglutide, dulaglutide, and semaglutide. Besides the pancreas, GLP-1Rs are also expressed in organs, such as the gastrointestinal tract, heart, lung, kidney, and brain, indicating their potential use in diseases other than T2DM. Emerging evidence reveals that GLP-1R agonists possess pleiotropic effects that enrich neurogenesis, diminish apoptosis, preclude neurons from oxidative stress, and reduce neuroinflammation in various neurological conditions. These favorable effects may also be employed in neurodegenerative diseases. Herein, we reviewed the recent progress, both in preclinical studies and clinical trials, regarding these clinically used GLP-1R agonists in aging-related neurodegenerative diseases, mainly AD and PD. We stress the pleiotropic characteristics of GLP-1R agonists as repurposing drugs to target multiple pathological mechanisms and for use in the future for these devastating neurodegenerative conditions. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Chen, Shang-Der AU - Chen SD AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan. Electronic address: chensd@adm.cgmh.org.tw. FAU - Chuang, Yao-Chung AU - Chuang YC AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; College of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, 80708, Taiwan. Electronic address: ycchuang@cgmh.org.tw. FAU - Lin, Tsu-Kung AU - Lin TK AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; College of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan; Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan. Electronic address: tklin@adm.cgmh.org.tw. FAU - Yang, Jenq-Lin AU - Yang JL AD - Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan. Electronic address: jyang@cgmh.org.tw. LA - eng PT - Journal Article PT - Review DEP - 20221202 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 9P1872D4OL (Exenatide) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - Exenatide/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy/chemically induced MH - Hypoglycemic Agents/pharmacology MH - *Neurodegenerative Diseases/drug therapy/chemically induced MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonist OT - Neurodegenerative diseases OT - Parkinson's disease COIS- Declaration of competing interest None. EDAT- 2022/12/06 06:00 MHDA- 2022/12/20 06:00 CRDT- 2022/12/05 19:33 PHST- 2022/07/18 00:00 [received] PHST- 2022/11/02 00:00 [revised] PHST- 2022/11/29 00:00 [accepted] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/20 06:00 [medline] PHST- 2022/12/05 19:33 [entrez] AID - S0014-2999(22)00700-2 [pii] AID - 10.1016/j.ejphar.2022.175439 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Jan 5;938:175439. doi: 10.1016/j.ejphar.2022.175439. Epub 2022 Dec 2. PMID- 36465634 OWN - NLM STAT- MEDLINE DCOM- 20221206 LR - 20221213 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 13 DP - 2022 TI - The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease. PG - 1033479 LID - 10.3389/fendo.2022.1033479 [doi] LID - 1033479 AB - Since type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) and both have the same pathogenesis (e.g., insulin resistance), drugs used to treat T2DM have been gradually found to reduce the progression of AD in AD models. Of these drugs, glucagon-like peptide 1 receptor (GLP-1R) agonists are more effective and have fewer side effects. GLP-1R agonists have reducing neuroinflammation and oxidative stress, neurotrophic effects, decreasing Abeta deposition and tau hyperphosphorylation in AD models, which may be a potential drug for the treatment of AD. However, this needs to be verified by further clinical trials. This study aims to summarize the current information on the mechanisms and effects of GLP-1R agonists in AD. CI - Copyright (c) 2022 Du, Meng, Yao and Xu. FAU - Du, Haiyang AU - Du H AD - Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Meng, Xiaoyu AU - Meng X AD - Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China. FAU - Yao, Yu AU - Yao Y AD - Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. FAU - Xu, Jun AU - Xu J AD - Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20221117 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Humans MH - *Alzheimer Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Drug-Related Side Effects and Adverse Reactions MH - *Insulin Resistance PMC - PMC9714676 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1R agonists OT - amyloid beta OT - cognitive function OT - tau phosphorylation COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/12/06 06:00 MHDA- 2022/12/07 06:00 PMCR- 2022/01/01 CRDT- 2022/12/05 03:46 PHST- 2022/08/31 00:00 [received] PHST- 2022/10/27 00:00 [accepted] PHST- 2022/12/05 03:46 [entrez] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2022.1033479 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2022 Nov 17;13:1033479. doi: 10.3389/fendo.2022.1033479. eCollection 2022. PMID- 36419765 OWN - NLM STAT- MEDLINE DCOM- 20221125 LR - 20240907 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 13 DP - 2022 TI - The importance of estradiol for body weight regulation in women. PG - 951186 LID - 10.3389/fendo.2022.951186 [doi] LID - 951186 AB - Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders. CI - Copyright (c) 2022 Vigil, Melendez, Petkovic and Del Rio. FAU - Vigil, Pilar AU - Vigil P AD - Reproductive Health Research Institute (RHRI), Santiago, Chile. FAU - Melendez, Jaime AU - Melendez J AD - Reproductive Health Research Institute (RHRI), Santiago, Chile. FAU - Petkovic, Grace AU - Petkovic G AD - Arrowe Park Hospital, Department of Paediatrics, Wirral CH49 5PE, Merseyside, United Kingdom. FAU - Del Rio, Juan Pablo AU - Del Rio JP AD - Unidad de Psiquiatria Infantil y del Adolescente, Clinica Psiquiatrica Universitaria, Universidad de Chile, Santiago, Chile. AD - Millennium Nucleus to Improve the Mental Health of Adolescents and Youths, Millennium Science Initiative, Santiago, Chile. LA - eng PT - Journal Article PT - Review DEP - 20221107 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 4TI98Z838E (Estradiol) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - Female MH - Estradiol MH - *Insulin Resistance MH - *Diabetes Mellitus, Type 2 MH - Glucagon-Like Peptide 1 MH - Obesity MH - *Drug-Related Side Effects and Adverse Reactions PMC - PMC9677105 OTO - NOTNLM OT - GLP-1 OT - body weight OT - estrogens OT - menstrual cycle OT - mental health COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/11/25 06:00 MHDA- 2022/11/26 06:00 PMCR- 2022/01/01 CRDT- 2022/11/24 02:22 PHST- 2022/05/23 00:00 [received] PHST- 2022/10/18 00:00 [accepted] PHST- 2022/11/24 02:22 [entrez] PHST- 2022/11/25 06:00 [pubmed] PHST- 2022/11/26 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2022.951186 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2022 Nov 7;13:951186. doi: 10.3389/fendo.2022.951186. eCollection 2022. PMID- 36419409 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221125 IS - 2090-8083 (Print) IS - 2042-0080 (Electronic) IS - 2042-0080 (Linking) VI - 2022 DP - 2022 TI - DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce alpha-Synuclein Levels in the 6-OHDA Parkinson's Disease Rat Model. PG - 1428817 LID - 10.1155/2022/1428817 [doi] LID - 1428817 AB - Insulin desensitization has been observed in the brains of patients with Parkinson's disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1beta and TNF-alpha levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated alpha-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1(ser312) phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB. CI - Copyright (c) 2022 Lingyu Zhang et al. FAU - Zhang, Lingyu AU - Zhang L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Li, Chun AU - Li C AD - Department of Forensic Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, China. FAU - Zhang, Zijuan AU - Zhang Z AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. FAU - Zhang, Zhenqiang AU - Zhang Z AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. FAU - Jin, Qian-Qian AU - Jin QQ AD - Department of Forensic Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. AD - Second Hospital Neurology Department, Shanxi Medical University, Taiyuan, Shanxi, China. LA - eng PT - Journal Article DEP - 20221114 PL - United States TA - Parkinsons Dis JT - Parkinson's disease JID - 101539877 PMC - PMC9678466 COIS- CH is a named inventor on patents that cover the use of GLP-1/GIP receptor agonists in treating neurodegenerative disorders. He is the CSO of the biotech company Kariya Pharmaceuticals. The authors declare that they have no conflicts of interest. EDAT- 2022/11/25 06:00 MHDA- 2022/11/25 06:01 PMCR- 2022/11/14 CRDT- 2022/11/24 02:13 PHST- 2022/08/19 00:00 [received] PHST- 2022/10/24 00:00 [revised] PHST- 2022/11/05 00:00 [accepted] PHST- 2022/11/24 02:13 [entrez] PHST- 2022/11/25 06:00 [pubmed] PHST- 2022/11/25 06:01 [medline] PHST- 2022/11/14 00:00 [pmc-release] AID - 10.1155/2022/1428817 [doi] PST - epublish SO - Parkinsons Dis. 2022 Nov 14;2022:1428817. doi: 10.1155/2022/1428817. eCollection 2022. PMID- 36387915 OWN - NLM STAT- MEDLINE DCOM- 20221121 LR - 20221121 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 13 DP - 2022 TI - Impact of glucagon-like peptide 1 analogs on cognitive function among patients with type 2 diabetes mellitus: A systematic review and meta-analysis. PG - 1047883 LID - 10.3389/fendo.2022.1047883 [doi] LID - 1047883 AB - BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. However, little is known about the neuroprotective effects of glucagon-like peptide 1 (GLP-1) analogs on type 2 diabetes mellitus (T2DM). Herein, we assessed the impact of GLP-1 analogs on the general cognitive functioning among patients with T2DM. METHODS: Relevant studies were retrieved from PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases from their inception till June 30, 2022, without any language restrictions. For continuous variables, the mean and standard deviation (SD) were extracted. Considering the heterogeneity in general cognitive functioning assessments among the pooled studies, the standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs), were calculated. RESULTS: Five studies including 7,732 individuals with T2DM were selected for the meta-analysis. The use of GLP-1 analogs exerted no significant effects on the general cognitive functioning in self-controlled studies (SMD 0.33, 95% CI -0.03 to 0.69). Subgroup analyses among the self-controlled studies based on age and history of cardio-cerebrovascular disease showed that GLP-1 analogs significantly improved the general cognitive functioning in T2DM patients younger than 65 years (SMD 0.69, 95% CI 0.31 to 1.08) or those without cardio-cerebrovascular diseases (SMD 0.69, 95% CI 0.31 to 1.08). Similarly, differences in the general cognitive functioning for GLP-1 analogs between treated and non-treated patients with T2DM were significant in subgroups with patients younger than 65 years (SMD 1.04, 95% CI 0.61 to 1.47) or those with no history of cardio-cerebrovascular diseases (SMD 1.04, 95% CI 0.61 to 1.47). CONCLUSION: Limited evidence suggests that the use of GLP-1 analogs exerts no significant effects on general cognitive functioning but may be beneficial for patients with T2DM younger than 65 years or those without a history of cardio-cerebrovascular diseases. Further prospective clinical studies with large sample sizes are needed to validate these findings. SYSTEMATIC REVIEW REGISTRATION: www.inplasy.com, identifier 202260015. CI - Copyright (c) 2022 Luan, Cheng, Wang, Gong and Zhou. FAU - Luan, Sisi AU - Luan S AD - Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. FAU - Cheng, Wenke AU - Cheng W AD - Medical Faculty, University of Leipzig, Leipzig, Germany. FAU - Wang, Chenglong AU - Wang C AD - Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Gong, Jianhong AU - Gong J AD - Beijing Tongren Hospital, Capital Medical University, Beijing, China. FAU - Zhou, Jianbo AU - Zhou J AD - Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20221028 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Humans MH - *Glucagon-Like Peptide 1/therapeutic use MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Risk Factors MH - Cognition PMC - PMC9650490 OTO - NOTNLM OT - T2DM OT - cardio-cerebrovascular disease OT - cognitive function OT - glucagon-like peptide 1 OT - meta-analysis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/11/18 06:00 MHDA- 2022/11/22 06:00 PMCR- 2022/01/01 CRDT- 2022/11/17 12:04 PHST- 2022/09/19 00:00 [received] PHST- 2022/10/17 00:00 [accepted] PHST- 2022/11/17 12:04 [entrez] PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/11/22 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2022.1047883 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2022 Oct 28;13:1047883. doi: 10.3389/fendo.2022.1047883. eCollection 2022. PMID- 36385094 OWN - NLM STAT- MEDLINE DCOM- 20221222 LR - 20250103 IS - 1752-2978 (Electronic) IS - 1752-296X (Linking) VI - 30 IP - 1 DP - 2023 Feb 1 TI - Type 2 diabetes mellitus and cognitive function: understanding the connections. PG - 7-13 LID - 10.1097/MED.0000000000000783 [doi] AB - PURPOSE OF REVIEW: To review the connection between type 2 diabetes and cognitive dysfunction, including its epidemiology, potential mechanisms of pathophysiology, risk factors, possible prevention, and treatment considerations. RECENT FINDINGS: Diabetes is a risk factor for mild cognitive decline, in addition to Alzheimer's disease and vascular dementia. Duration of diabetes, concomitant vascular or associated co-morbidities, hyper- and hypoglycemia may lead to worsening cognitive dysfunction. Unfortunately, there is a lack of evidence-based guidance on the prevention of cognitive dysfunction in the diabetes population. Studies of diabetes medications, including metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 inhibitors (SGLT2) have shown some benefit with cardiovascular morbidity and may affect cognition. In the absence of clearly defined preventive tools, diabetes practice guidelines recommend annual cognitive screening as standard of care in adults with diabetes aged 65 years or older. SUMMARY: People living with diabetes are at risk for significant decline in cognitive function. Epidemiology and risk factors are well defined. Prevention and treatment strategies are limited and require further study. CI - Copyright (c) 2022 Wolters Kluwer Health, Inc. All rights reserved. FAU - Dao, Lisa AU - Dao L AD - Division of Endocrinology, Diabetes and Metabolism, David Geffen School of Medicine UCLA. FAU - Choi, Sarah AU - Choi S AD - UCLA School of Nursing, Los Angeles, California, USA. FAU - Freeby, Matthew AU - Freeby M AD - Division of Endocrinology, Diabetes and Metabolism, David Geffen School of Medicine UCLA. LA - eng PT - Journal Article PT - Review DEP - 20221117 PL - England TA - Curr Opin Endocrinol Diabetes Obes JT - Current opinion in endocrinology, diabetes, and obesity JID - 101308636 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Adult MH - Humans MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - Hypoglycemic Agents/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Risk Factors MH - Cognition MH - Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2022/11/18 06:00 MHDA- 2022/12/23 06:00 CRDT- 2022/11/17 10:15 PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/12/23 06:00 [medline] PHST- 2022/11/17 10:15 [entrez] AID - 01266029-202302000-00003 [pii] AID - 10.1097/MED.0000000000000783 [doi] PST - ppublish SO - Curr Opin Endocrinol Diabetes Obes. 2023 Feb 1;30(1):7-13. doi: 10.1097/MED.0000000000000783. Epub 2022 Nov 17. PMID- 36372278 OWN - NLM STAT- MEDLINE DCOM- 20221129 LR - 20250530 IS - 1096-1186 (Electronic) IS - 1043-6618 (Print) IS - 1043-6618 (Linking) VI - 186 DP - 2022 Dec TI - Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. PG - 106550 LID - S1043-6618(22)00496-0 [pii] LID - 10.1016/j.phrs.2022.106550 [doi] AB - Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation. CI - Published by Elsevier Ltd. FAU - Kopp, Katherine O AU - Kopp KO AD - Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States. Electronic address: katherine.kopp@nih.gov. FAU - Glotfelty, Elliot J AU - Glotfelty EJ AD - Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Li, Yazhou AU - Li Y AD - Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States. FAU - Greig, Nigel H AU - Greig NH AD - Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States. Electronic address: Greign@grc.nia.nih.gov. LA - eng GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Review DEP - 20221111 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Neurodegenerative Diseases/drug therapy MH - Incretins/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - Neuroinflammatory Diseases MH - Glucagon-Like Peptide 1/metabolism MH - *Parkinson Disease/drug therapy MH - *Alzheimer Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC9712272 MID - NIHMS1850778 OTO - NOTNLM OT - Alzheimer's disease OT - Glucagon-like peptide-1 (GLP-1) OT - Glucose-dependent insulinotropic peptide (GIP) OT - Incretin mimetic OT - Insulin resistance OT - Neurodegeneration OT - Neuroinflammation OT - Parkinson's disease COIS- Conflicts of interest NHG is an inventor on patents related to incretin mimetics and has assigned them in entirety to the National Institute on Aging, NIH, US Government, and hence has no personal rights to these patents. The National Institute on Aging, NIH, has a Cooperative Research and Development Agreement with Peptron Inc. (S. Korea) to support the evaluation of GLP-1R agonists in neurodegenerative disorders. All other authors declare no conflict of interest. EDAT- 2022/11/14 06:00 MHDA- 2022/11/30 06:00 PMCR- 2023/12/01 CRDT- 2022/11/13 19:34 PHST- 2022/10/11 00:00 [received] PHST- 2022/11/03 00:00 [revised] PHST- 2022/11/06 00:00 [accepted] PHST- 2022/11/14 06:00 [pubmed] PHST- 2022/11/30 06:00 [medline] PHST- 2022/11/13 19:34 [entrez] PHST- 2023/12/01 00:00 [pmc-release] AID - S1043-6618(22)00496-0 [pii] AID - 10.1016/j.phrs.2022.106550 [doi] PST - ppublish SO - Pharmacol Res. 2022 Dec;186:106550. doi: 10.1016/j.phrs.2022.106550. Epub 2022 Nov 11. PMID- 36117625 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240904 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 16 DP - 2022 TI - The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth review. PG - 970925 LID - 10.3389/fnins.2022.970925 [doi] LID - 970925 AB - Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD and PD) and that includes the highly controversial approval of the Abeta-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Abeta, Tau, and alpha-synuclein), the suppression of Ca(2+) deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD. CI - Copyright (c) 2022 Reich and Holscher. FAU - Reich, Niklas AU - Reich N AD - Biomedical and Life Sciences Division, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom. FAU - Holscher, Christian AU - Holscher C AD - Neurology Department, Second Associated Hospital, Shanxi Medical University, Taiyuan, China. AD - Henan University of Chinese Medicine, Academy of Chinese Medical Science, Zhengzhou, China. LA - eng PT - Journal Article PT - Review DEP - 20220901 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC9475012 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 OT - Parkinson's disease OT - amyloid beta OT - brain glucose hypometabolism OT - insulin resistance OT - mitochondrial dysfunction OT - neuroinflammation COIS- CH was a named inventor on patents and patent applications that cover the use of GLP-1, GIP and dual GLP-1/GIP receptor agonists as treatments for neurodegenerative disorders. CH was also the CSO of the company Kariya Pharmaceuticals. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/09/20 06:00 MHDA- 2022/09/20 06:01 PMCR- 2022/01/01 CRDT- 2022/09/19 03:57 PHST- 2022/06/23 00:00 [received] PHST- 2022/08/08 00:00 [accepted] PHST- 2022/09/19 03:57 [entrez] PHST- 2022/09/20 06:00 [pubmed] PHST- 2022/09/20 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2022.970925 [doi] PST - epublish SO - Front Neurosci. 2022 Sep 1;16:970925. doi: 10.3389/fnins.2022.970925. eCollection 2022. PMID- 36074988 OWN - NLM STAT- MEDLINE DCOM- 20220913 LR - 20250728 IS - 1536-3686 (Electronic) IS - 1075-2765 (Linking) VI - 29 IP - 5 DP - 2022 Sep-Oct 01 TI - Liraglutide as First-Line Therapy for Type 2 Diabetics With Post-COVID-19 Fatigue Syndrome and Executive Function Deficits. PG - e568-e569 LID - 10.1097/MJT.0000000000001475 [doi] FAU - Manu, Peter AU - Manu P AD - Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY and Medical Services, South Oaks Hospital, Amityville, NY. LA - eng PT - Journal Article DEP - 20220228 PL - United States TA - Am J Ther JT - American journal of therapeutics JID - 9441347 RN - 839I73S42A (Liraglutide) SB - IM MH - *COVID-19/complications MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Executive Function MH - Fatigue MH - Humans MH - Liraglutide/therapeutic use MH - *COVID-19 Drug Treatment COIS- The author has no conflicts of interest to declare. EDAT- 2022/09/09 06:00 MHDA- 2022/09/14 06:00 CRDT- 2022/09/08 15:37 PHST- 2022/09/08 15:37 [entrez] PHST- 2022/09/09 06:00 [pubmed] PHST- 2022/09/14 06:00 [medline] AID - 00045391-202210000-00009 [pii] AID - 10.1097/MJT.0000000000001475 [doi] PST - ppublish SO - Am J Ther. 2022 Sep-Oct 01;29(5):e568-e569. doi: 10.1097/MJT.0000000000001475. Epub 2022 Feb 28. PMID- 36064147 OWN - NLM STAT- MEDLINE DCOM- 20221114 LR - 20221114 IS - 1879-016X (Electronic) IS - 0163-7258 (Linking) VI - 239 DP - 2022 Nov TI - Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. PG - 108277 LID - S0163-7258(22)00171-1 [pii] LID - 10.1016/j.pharmthera.2022.108277 [doi] AB - Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent neurodegenerative disorders. Despite their pathophysiological and clinical differences, they share several mechanistic similarities at cellular and sub-cellular levels. The current treatments of AD and PD are only symptomatic, since many clinically-tested drugs failed to prevent or halt their progression. There is now evidence that type 2 diabetes mellitus is among the main risk factors for AD and PD and that the insulin resistance in the brain plays a crucial role in their neuropathological processes. Therefore, insulin nasal administration was suggested for the treatment of AD and PD, both in diabetic and non-diabetic patients. However, the adverse effects of chronic insulin prompted the research of alternative strategies, such as the novel antidiabetic drugs based on the incretin hormones glucagon-like protein-1 (GLP-1) and glucose-dependent insulinotropic Peptide (GIP). The rapid inactivation of these incretins by dipeptidyl-peptidase IV (DPP-IV) suggested the development of DPP-IV-resistant GLP-1 receptor agonists (GLP-1Ras), the recent dual GLP-1/GIP receptor agonists and the DPP-IV inhibitors (DPP-IVis). This review will first describe the experimental, pathophysiological and clinical approach for AD and PD treatment with insulin. Afterwards, the main pharmacologic properties of GLP-1Ras and of DPP-IVis will be discussed, detailing their ability to cross the BBB and get access to the brain for GLP-1Ras, and the novel strategies for BBB crossing as regards DPP-IVis. Emphasis will be placed on the main findings obtained from AD and PD experimental models about the neuroprotective effects of these drugs. For AD, the improvement of learning and memory exerted by incretin-based drugs correlated with reduction of chronic inflammation, brain Abeta plaque, tau hyperphosphorylation, protection of mitochondria, enhancement of energy utilisation. For PD, both GLP-1Ras and of DPP-IVis reversed the nigrostriatal dopaminergic cell loss progression, restored dopamine synthesis, exerted anti-inflammatory activity and improved motor functions. Finally, the encouraging results of the first clinical trials on AD and PD patients and the adverse effects of GLP-1Ras and DPP-IVis will be discussed, highlighting how the above-mentioned neuroprotective effects have a great potential to be translated into clinical settings and that the incretin-based approach represents novel promising strategy for the treatment of AD and PD, although more convincing clinical pieces of evidence are required. In perspective, the new approaches that are being developed to allow GLP-1Ras and DPP-IVis rapid entering into the Central Nervous System may substantially contribute to their repurposing for neurodegenerative disease. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Ferrari, Federica AU - Ferrari F AD - Department of Brain and Behavioural Sciences, School of Neurology - University of Pavia, Via Bassi 21, 27100 Pavia, Italy; Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27010 Pavia, Italy. FAU - Moretti, Antonio AU - Moretti A AD - Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27010 Pavia, Italy. FAU - Villa, Roberto Federico AU - Villa RF AD - Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27010 Pavia, Italy. Electronic address: rfvilla@unipv.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220903 PL - England TA - Pharmacol Ther JT - Pharmacology & therapeutics JID - 7905840 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Gastric Inhibitory Polypeptide MH - Glucagon-Like Peptide 1 MH - Hypoglycemic Agents/therapeutic use MH - Incretins/therapeutic use MH - Insulin/therapeutic use MH - *Neurodegenerative Diseases/drug therapy MH - *Neuroprotective Agents/therapeutic use OTO - NOTNLM OT - Alzheimer's disease OT - DPP-IV inhibitors OT - Diabetes OT - GLP-1R agonists OT - Neuroprotection OT - Parkinson's disease COIS- Declaration of Competing Interest All authors disclose no actual or potential conflict of interest including any financial, personal or other relationships with individuals or organizations within three years of initiating the work that could inappropriately influence, or be perceived to influence, the study design or data interpretation. The disclosure of no conflict of interest is present in the manuscript as well. EDAT- 2022/09/06 06:00 MHDA- 2022/11/09 06:00 CRDT- 2022/09/05 19:27 PHST- 2022/07/22 00:00 [received] PHST- 2022/08/26 00:00 [revised] PHST- 2022/08/29 00:00 [accepted] PHST- 2022/09/06 06:00 [pubmed] PHST- 2022/11/09 06:00 [medline] PHST- 2022/09/05 19:27 [entrez] AID - S0163-7258(22)00171-1 [pii] AID - 10.1016/j.pharmthera.2022.108277 [doi] PST - ppublish SO - Pharmacol Ther. 2022 Nov;239:108277. doi: 10.1016/j.pharmthera.2022.108277. Epub 2022 Sep 3. PMID- 36002078 OWN - NLM STAT- MEDLINE DCOM- 20221108 LR - 20221109 IS - 1879-016X (Electronic) IS - 0163-7258 (Linking) VI - 239 DP - 2022 Nov TI - Emerging roles of Glucagon like peptide-1 in the management of autoimmune diseases and diabetes-associated comorbidities. PG - 108270 LID - S0163-7258(22)00164-4 [pii] LID - 10.1016/j.pharmthera.2022.108270 [doi] AB - Currently, gastrointestinal hormone glucagon like peptide-1 (GLP-1) has received significant attention in maintaining glucose homeostasis through mechanisms involving augmentation of insulin, inhibition of glucagon secretion and regulation of gut motility. Therefore, GLP-1 receptor agonist (GLP-1RA) turns to be one of the most promising hypoglycemic agents for the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, the benefits of GLP-1 and GLP-1RAs are not limited to glucose control and weight loss. Here, we provide a concise overview of the roles of GLP-1 and GLP-1RAs in autoimmune disease, cardiovascular disease (CVD), diabetic kidney disease (DKD), diabetic foot ulcer (DFU), polycystic ovary syndrome (PCOS), and Alzheimer's disease (AD) as well as future challenges in this regard. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Shao, Shiying AU - Shao S AD - Division of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan 430030, PR China; Branch of National Clinical Research Center for Metabolic Diseases, Hubei, PR China. FAU - Zhang, Xiaoling AU - Zhang X AD - Division of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan 430030, PR China; Branch of National Clinical Research Center for Metabolic Diseases, Hubei, PR China. FAU - Xu, Qinqin AU - Xu Q AD - Division of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan 430030, PR China; Branch of National Clinical Research Center for Metabolic Diseases, Hubei, PR China. FAU - Pan, Ruping AU - Pan R AD - Department of nuclear medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China. FAU - Chen, Yong AU - Chen Y AD - Division of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan 430030, PR China; Branch of National Clinical Research Center for Metabolic Diseases, Hubei, PR China.. Electronic address: tj.y.chen@vip.163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220821 PL - England TA - Pharmacol Ther JT - Pharmacology & therapeutics JID - 7905840 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) SB - IM MH - Female MH - Humans MH - Glucagon-Like Peptide 1 MH - Glucagon-Like Peptide-1 Receptor MH - *Diabetes Mellitus, Type 2/drug therapy/complications MH - Hypoglycemic Agents MH - *Autoimmune Diseases/drug therapy OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonist OT - Glucagon like peptide-1 OT - autoimmune disease OT - cardiovascular disease OT - diabetic foot ulcer OT - diabetic kidney disease OT - polycystic ovary syndrome COIS- Declaration of Competing Interest None EDAT- 2022/08/25 06:00 MHDA- 2022/11/09 06:00 CRDT- 2022/08/24 19:23 PHST- 2022/07/12 00:00 [received] PHST- 2022/08/16 00:00 [revised] PHST- 2022/08/17 00:00 [accepted] PHST- 2022/08/25 06:00 [pubmed] PHST- 2022/11/09 06:00 [medline] PHST- 2022/08/24 19:23 [entrez] AID - S0163-7258(22)00164-4 [pii] AID - 10.1016/j.pharmthera.2022.108270 [doi] PST - ppublish SO - Pharmacol Ther. 2022 Nov;239:108270. doi: 10.1016/j.pharmthera.2022.108270. Epub 2022 Aug 21. PMID- 35992601 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220823 IS - 1663-4365 (Print) IS - 1663-4365 (Electronic) IS - 1663-4365 (Linking) VI - 14 DP - 2022 TI - Exendin-4 alleviates beta-Amyloid peptide toxicity via DAF-16 in a Caenorhabditis elegans model of Alzheimer's disease. PG - 955113 LID - 10.3389/fnagi.2022.955113 [doi] LID - 955113 AB - Epidemiological analyses indicate that type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD). They share common pathophysiological mechanisms. Thus, it has been increasingly suggested that several anti-T2DM drugs may have therapeutic potential in AD. Exendin-4, as a glucagon-like peptide-1 (GLP-1) receptor agonist, is an approved drug used to treat T2DM. In this research, the neuroprotective effect of Exendin-4 was investigated for the first time using transgenic Caenorhabditis elegans. Our results demonstrated that Exendin-4 attenuated the amyloid-beta (1-42) (Abeta1-42) toxicity via multiple mechanisms, such as depressing its expression on protein and mRNA and reducing Abeta (1-42) accumulation. Exendin-4 at 0.5 mg/ml had been shown to extend life by 34.39% in CL4176 and delay the onset of paralysis in CL4176 and CL2006 which were increased by 8.18 and 8.02%, respectively. With the treatment of Exendin-4, the nuclear translocation of DAF-16 in the transgenic nematode TJ356 was enhanced. Superoxide dismutase-3 (SOD-3), as a downstream target gene regulated by DAF-16, was upregulated on mRNA level and activity. The reactive oxygen species (ROS) level was decreased. In contrast, we observed that the ability of Exendin-4 to regulate SOD was decreased in CL4176 worms with the DAF-16 gene silenced. The activity of SOD and the mRNA level of sod-3 were downregulated by 30.45 and 43.13%, respectively. Taken together, Exendin-4 attenuated Abeta (1-42) toxicity in the C. elegans model of AD via decreasing the expression and the accumulation of Abeta (1-42). Exendin-4 exhibited the ability of antioxidant stress through DAF-16. With continuous research, Exendin-4 would become a potential therapeutic strategy for treating AD. CI - Copyright (c) 2022 Song, Sun, Wang, Su, Wang and Wang. FAU - Song, Xiangwei AU - Song X AD - School of Life Sciences, Changchun Normal University, Changchun, China. FAU - Sun, Yingqi AU - Sun Y AD - School of Life Sciences, Changchun Normal University, Changchun, China. FAU - Wang, Zhun AU - Wang Z AD - Plant Inspection and Quarantine Laboratory, Changchun Customs Technical Center, Changchun, China. FAU - Su, Yingying AU - Su Y AD - School of Life Sciences, Changchun Normal University, Changchun, China. FAU - Wang, Yangkun AU - Wang Y AD - School of Life Sciences, Changchun Normal University, Changchun, China. FAU - Wang, Xueli AU - Wang X AD - School of Grain, Jilin Business and Technology College, Changchun, China. LA - eng PT - Journal Article DEP - 20220805 PL - Switzerland TA - Front Aging Neurosci JT - Frontiers in aging neuroscience JID - 101525824 PMC - PMC9389237 OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid-beta peptide OT - Caenorhabditis elegans OT - DAF-16 OT - Exendin-4 OT - neuroprotection COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/08/23 06:00 MHDA- 2022/08/23 06:01 PMCR- 2022/01/01 CRDT- 2022/08/22 04:30 PHST- 2022/05/28 00:00 [received] PHST- 2022/07/11 00:00 [accepted] PHST- 2022/08/22 04:30 [entrez] PHST- 2022/08/23 06:00 [pubmed] PHST- 2022/08/23 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fnagi.2022.955113 [doi] PST - epublish SO - Front Aging Neurosci. 2022 Aug 5;14:955113. doi: 10.3389/fnagi.2022.955113. eCollection 2022. PMID- 35970890 OWN - NLM STAT- MEDLINE DCOM- 20220817 LR - 20251031 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 12 IP - 1 DP - 2022 Aug 15 TI - A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease. PG - 13825 LID - 10.1038/s41598-022-17338-1 [doi] LID - 13825 AB - Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study. CI - (c) 2022. The Author(s). FAU - Poupon-Bejuit, L AU - Poupon-Bejuit L AD - UCL School of Pharmacy, University College London, London, UK. FAU - Hughes, M P AU - Hughes MP AD - UCL School of Pharmacy, University College London, London, UK. FAU - Liu, W AU - Liu W AD - UCL School of Pharmacy, University College London, London, UK. FAU - Geard, A AU - Geard A AD - UCL School of Pharmacy, University College London, London, UK. FAU - Faour-Slika, N AU - Faour-Slika N AD - UCL School of Pharmacy, University College London, London, UK. FAU - Whaler, S AU - Whaler S AD - UCL School of Pharmacy, University College London, London, UK. FAU - Massaro, G AU - Massaro G AD - UCL School of Pharmacy, University College London, London, UK. giulia.massaro.13@ucl.ac.uk. FAU - Rahim, A A AU - Rahim AA AD - UCL School of Pharmacy, University College London, London, UK. a.rahim@ucl.ac.uk. LA - eng GR - MR/N026101/1/MRC_/Medical Research Council/United Kingdom GR - MR/T044853/1/MRC_/Medical Research Council/United Kingdom GR - 562646/WT_/Wellcome Trust/United Kingdom GR - MR/S036784/1/MRC_/Medical Research Council/United Kingdom GR - MR/R025134/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 204841/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - MR/R015325/1/MRC_/Medical Research Council/United Kingdom GR - 562868/DH_/Department of Health/United Kingdom GR - MR/S009434/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220815 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - EC 3.1.1.4 (Group VI Phospholipases A2) RN - EC 3.1.1.4 (Pla2g6 protein, mouse) RN - Dystonia-Parkinsonism, Adult-Onset SB - IM MH - Animals MH - *Diabetes Mellitus, Type 2 MH - Disease Models, Animal MH - Dystonic Disorders MH - Group VI Phospholipases A2/deficiency MH - Mice MH - *Neuroaxonal Dystrophies/genetics MH - *Parkinsonian Disorders/genetics PMC - PMC9378686 COIS- The authors declare no competing interests. EDAT- 2022/08/16 06:00 MHDA- 2022/08/18 06:00 PMCR- 2022/08/15 CRDT- 2022/08/15 23:19 PHST- 2021/10/28 00:00 [received] PHST- 2022/07/25 00:00 [accepted] PHST- 2022/08/15 23:19 [entrez] PHST- 2022/08/16 06:00 [pubmed] PHST- 2022/08/18 06:00 [medline] PHST- 2022/08/15 00:00 [pmc-release] AID - 10.1038/s41598-022-17338-1 [pii] AID - 17338 [pii] AID - 10.1038/s41598-022-17338-1 [doi] PST - epublish SO - Sci Rep. 2022 Aug 15;12(1):13825. doi: 10.1038/s41598-022-17338-1. PMID- 35909294 OWN - NLM STAT- MEDLINE DCOM- 20230608 LR - 20250801 IS - 1875-533X (Electronic) IS - 0929-8673 (Print) IS - 0929-8673 (Linking) VI - 30 IP - 35 DP - 2023 TI - Repurposing Metformin for Vascular Disease. PG - 3955-3978 LID - 10.2174/0929867329666220729154615 [doi] AB - Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS), metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have been linked to effects in the liver, where it acts to inhibit gluconeogenesis and lipogenesis, as well as reduce insulin resistance and enhance peripheral glucose utilization. However, direct protective effects on the endothelium and effects in the gut prior to metformin absorption are now recognized as important. In the gut, metformin modulates the glucagon-like peptide- 1 (GLP-1) - gut-brain axis and impacts the intestinal microbiota. As the apparent number of putative tissue and cellular targets for metformin has increased, so has the interest in re-purposing metformin to treat other diseases that include polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19. Metformin is also being investigated as an anti-ageing drug. Of particular interest is whether metformin provides the same level of vascular protection in individuals other than those with T2D, including obese individuals with metabolic syndrome, or in the setting of vascular thromboinflammation caused by SARS-CoV-2. In this review, we critically evaluate the literature to highlight clinical settings in which metformin might be therapeutically repurposed for the prevention and treatment of vascular disease. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Triggle, Chris R AU - Triggle CR AD - Department of Pharmacology & Medical Education, Weill Cornell Medicine in Qatar, PO Box 24144, Education City, Doha, Qatar. FAU - Marei, Isra AU - Marei I AD - Department of Pharmacology & Medical Education, Weill Cornell Medicine in Qatar, PO Box 24144, Education City, Doha, Qatar. FAU - Ye, Kevin AU - Ye K AD - Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada, V5A 1S6. FAU - Ding, Hong AU - Ding H AD - Department of Pharmacology & Medical Education, Weill Cornell Medicine in Qatar, PO Box 24144, Education City, Doha, Qatar. FAU - Anderson, Todd J AU - Anderson TJ AD - Department of Cardiac Sciences and Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada, T2N 4N1. FAU - Hollenberg, Morley D AU - Hollenberg MD AD - Department of Physiology & Pharmacology, and Department of Medicine, Cumming School of Medicine, University of Calgary, Canada, T2N 4N1. FAU - Hill, Michael A AU - Hill MA AD - Dalton Cardiovascular Research Center & Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia 65211, Missouri, USA. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Med Chem JT - Current medicinal chemistry JID - 9440157 RN - 9100L32L2N (Metformin) SB - IM MH - *Drug Repositioning MH - *Vascular Diseases/drug therapy MH - Metformin/therapeutic use MH - Humans MH - Animals MH - Endothelial Cells/drug effects MH - Exercise MH - Aging MH - COVID-19 PMC - PMC10286558 OTO - NOTNLM OT - COVID-19 OT - Metformin OT - SARS-CoV-2 OT - endothelium OT - inflammation OT - obesity OT - type 2 diabetes OT - vascular disease COIS- The authors declare no conflict of interest, financial or otherwise. EDAT- 2022/08/02 06:00 MHDA- 2023/06/06 06:42 PMCR- 2023/06/22 CRDT- 2022/08/01 01:23 PHST- 2022/02/18 00:00 [received] PHST- 2022/04/08 00:00 [revised] PHST- 2022/04/27 00:00 [accepted] PHST- 2023/06/06 06:42 [medline] PHST- 2022/08/02 06:00 [pubmed] PHST- 2022/08/01 01:23 [entrez] PHST- 2023/06/22 00:00 [pmc-release] AID - CMC-EPUB-125238 [pii] AID - CMC-30-3955 [pii] AID - 10.2174/0929867329666220729154615 [doi] PST - ppublish SO - Curr Med Chem. 2023;30(35):3955-3978. doi: 10.2174/0929867329666220729154615. PMID- 35902330 OWN - NLM STAT- MEDLINE DCOM- 20220812 LR - 20250103 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) VI - 33 IP - 9 DP - 2022 Sep TI - GLP-1 agonists: superior for mind and body in antipsychotic-treated patients? PG - 628-638 LID - S1043-2760(22)00122-9 [pii] LID - 10.1016/j.tem.2022.06.005 [doi] AB - Antipsychotics (APDs) represent a core treatment for severe mental disorders (SMEs). Providing symptomatic relief, APDs do not exert therapeutic effects on another clinically significant domain of serious mental disorders, cognitive impairment. Moreover, adverse metabolic effects (diabetes, weight gain, dyslipidemia, and increased cardiovascular risk) are common during treatment with APDs. Among pharmacological candidates reversing APD-induced metabolic adverse effects, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), approved for both diabetes and recently for obesity treatment, stand out due to their favorable effects on peripheral metabolic parameters. Interestingly, GLP-1 RAs are also proposed to have pro-cognitive effects. Particularly in terms of dual therapeutic mechanisms potentially improving both central nervous system (CNS) deficits and metabolic burden, GLP-1 RAs open a new perspective and assume a clinically advantageous position. CI - Copyright (c) 2022 Elsevier Ltd. All rights reserved. FAU - Horska, Katerina AU - Horska K AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic; Department of Clinical Pharmacy, Hospital Pharmacy, University Hospital Brno, Brno, Czech Republic. FAU - Ruda-Kucerova, Jana AU - Ruda-Kucerova J AD - Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. FAU - Skrede, Silje AU - Skrede S AD - Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway; Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Section of Clinical Pharmacology, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway. Electronic address: silje.skrede@uib.no. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220725 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 RN - 0 (Antipsychotic Agents) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Antipsychotic Agents/adverse effects MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide 1/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Obesity/chemically induced/drug therapy MH - Weight Gain MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - GLP-1 receptor agonist OT - antipsychotic OT - metabolic adverse effects OT - pro-cognitive OT - schizophrenia COIS- Declaration of interests The authors declare no interests. EDAT- 2022/07/29 06:00 MHDA- 2022/08/13 06:00 CRDT- 2022/07/28 22:05 PHST- 2022/05/03 00:00 [received] PHST- 2022/06/28 00:00 [accepted] PHST- 2022/07/29 06:00 [pubmed] PHST- 2022/08/13 06:00 [medline] PHST- 2022/07/28 22:05 [entrez] AID - S1043-2760(22)00122-9 [pii] AID - 10.1016/j.tem.2022.06.005 [doi] PST - ppublish SO - Trends Endocrinol Metab. 2022 Sep;33(9):628-638. doi: 10.1016/j.tem.2022.06.005. Epub 2022 Jul 25. PMID- 35873704 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240901 IS - 2090-8083 (Print) IS - 2042-0080 (Electronic) IS - 2042-0080 (Linking) VI - 2022 DP - 2022 TI - Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress. PG - 6813017 LID - 10.1155/2022/6813017 [doi] LID - 6813017 AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder for which no effective treatment is available. Studies have demonstrated that improving insulin resistance in type 2 diabetes mellitus (T2DM) can benefit patients with PD. In addition, a neuroprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists was demonstrated in experimental models of PD. In addition, there are some clinical trials to study the neuroprotective effect of GLP-1 analog on PD patients. Semaglutide is a long-acting, once-a-week injection treatment and the only available oral form of GLP-1 analog. In the present study, we treated the human neuroblastoma SH-SY5Y cell line with 6-hydroxydopamine (6-OHDA) as a PD in vitro model to explore the neuroprotective effects and potential mechanisms of semaglutide to protect against PD. Moreover, we compared the effect of semaglutide with liraglutide given at the same dose. We demonstrated that both semaglutide and liraglutide protect against 6-OHDA cytotoxicity by increasing autophagy flux and decreasing oxidative stress as well as mitochondrial dysfunction in SH-SY5Y cells. Moreover, by comparing the neuroprotective effects of semaglutide and liraglutide on PD cell models at the same dose, we found that semaglutide was superior to liraglutide for most parameters measured. Our results indicate that semaglutide, the new long-acting and only oral GLP-1 analog, may be represent a promising treatment for PD. CI - Copyright (c) 2022 Dong-xing Liu et al. FAU - Liu, Dong-Xing AU - Liu DX AUID- ORCID: 0000-0002-7269-8888 AD - Department of Neurology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China. FAU - Zhao, Chen-Sheng AU - Zhao CS AUID- ORCID: 0000-0003-3113-4987 AD - Department of Neurology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China. FAU - Wei, Xiao-Na AU - Wei XN AUID- ORCID: 0000-0003-1954-4246 AD - Department of Neurology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China. FAU - Ma, Yi-Peng AU - Ma YP AUID- ORCID: 0000-0001-8997-6015 AD - Department of Neurology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China. FAU - Wu, Jian-Kun AU - Wu JK AUID- ORCID: 0000-0003-1112-559X AD - Department of Neurology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China. LA - eng PT - Journal Article DEP - 20220713 PL - United States TA - Parkinsons Dis JT - Parkinson's disease JID - 101539877 PMC - PMC9300292 COIS- The authors declare that they have no conflicts of interest. EDAT- 2022/07/26 06:00 MHDA- 2022/07/26 06:01 PMCR- 2022/07/13 CRDT- 2022/07/25 03:39 PHST- 2022/03/10 00:00 [received] PHST- 2022/06/07 00:00 [revised] PHST- 2022/06/22 00:00 [accepted] PHST- 2022/07/25 03:39 [entrez] PHST- 2022/07/26 06:00 [pubmed] PHST- 2022/07/26 06:01 [medline] PHST- 2022/07/13 00:00 [pmc-release] AID - 10.1155/2022/6813017 [doi] PST - epublish SO - Parkinsons Dis. 2022 Jul 13;2022:6813017. doi: 10.1155/2022/6813017. eCollection 2022. PMID- 35771831 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230303 IS - 2191-0200 (Electronic) IS - 0334-1763 (Linking) VI - 34 IP - 1 DP - 2023 Jan 27 TI - The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS - a critical overview. PG - 1-24 LID - 10.1515/revneuro-2022-0026 [doi] AB - Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of "brain" DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of "peripheral" DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier. CI - (c) 2022 Walter de Gruyter GmbH, Berlin/Boston. FAU - Bernstein, Hans-Gert AU - Bernstein HG AD - Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. FAU - Keilhoff, Gerburg AU - Keilhoff G AD - Institute of Biochemistry and Cell Biology, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. FAU - Dobrowolny, Henrik AU - Dobrowolny H AD - Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. FAU - Steiner, Johann AU - Steiner J AD - Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. LA - eng PT - Journal Article PT - Review DEP - 20220701 PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - 9007-92-5 (Glucagon) SB - IM MH - Humans MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - Dipeptidyl Peptidase 4/metabolism MH - *Diabetes Mellitus, Type 2 MH - Glucagon MH - *COVID-19 MH - *Alzheimer Disease OTO - NOTNLM OT - CD26 OT - SARS-CoV-2 and MERS-CoV infection OT - cancer OT - central nervous system OT - enzyme inhibition OT - neurological and psychiatric disorders EDAT- 2022/07/01 06:00 MHDA- 2023/01/11 06:00 CRDT- 2022/06/30 13:44 PHST- 2022/03/10 00:00 [received] PHST- 2022/05/10 00:00 [accepted] PHST- 2022/07/01 06:00 [pubmed] PHST- 2023/01/11 06:00 [medline] PHST- 2022/06/30 13:44 [entrez] AID - revneuro-2022-0026 [pii] AID - 10.1515/revneuro-2022-0026 [doi] PST - epublish SO - Rev Neurosci. 2022 Jul 1;34(1):1-24. doi: 10.1515/revneuro-2022-0026. Print 2023 Jan 27. PMID- 35765655 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2001-0370 (Print) IS - 2001-0370 (Electronic) IS - 2001-0370 (Linking) VI - 20 DP - 2022 TI - Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents. PG - 2839-2847 LID - 10.1016/j.csbj.2022.05.057 [doi] AB - Repositioning or repurposing drugs account for a substantial part of entering approval pipeline drugs, which indicates that drug repositioning has huge market potential and value. Computational technologies such as machine learning methods have accelerated the process of drug repositioning in the last few decades years. The repositioning potential of type 2 diabetes mellitus (T2DM) drugs for various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases have been widely studied. Hence, the related summary about repurposing antidiabetic drugs is of great significance. In this review, we focus on the machine learning methods for the development of new T2DM drugs and give an overview of the repurposing potential of the existing antidiabetic agents. CI - (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. FAU - Zhu, Sha AU - Zhu S AD - Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China. FAU - Bai, Qifeng AU - Bai Q AD - Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China. FAU - Li, Lanqing AU - Li L AD - Tencent AI Lab, Shenzhen, PR China. FAU - Xu, Tingyang AU - Xu T AD - Tencent AI Lab, Shenzhen, PR China. LA - eng PT - Journal Article PT - Review DEP - 20220601 PL - United States TA - Comput Struct Biotechnol J JT - Computational and structural biotechnology journal JID - 101585369 PMC - PMC9189996 OTO - NOTNLM OT - AD, Alzheimer's Disease OT - AEs, autoencoders OT - ASCVD, atherosclerotic cardiovascular disease OT - Antidiabetic drugs OT - CNNs, convolutional neural networks OT - CV, cardiovascular OT - CVD, cardiovascular diseases OT - DBNs, deep brief networks OT - DDA, drug-disease association OT - DDI, drug-drug interaction OT - DL, deep learning OT - DM, diabetes mellitus OT - DNNs, deep neural networks OT - DPP-4, dipeptidyl peptidase 4 OT - DTI, drug-target interaction OT - Deep learning OT - Drug repositioning OT - Drug repurposing OT - GLP-1, glucagon-like peptide 1 OT - GNNs, graph neural networks OT - ML, machine learning OT - Machine learning OT - PD, Parkinson's Disease OT - PI3K/AKT, phosphatidylinositol 3-kinase/AKT OT - RNNs, recurrent neural networks OT - SGLT-2, sodium-glucose cotransporter 2 OT - T2DM OT - T2DM, type 2 diabetes mellitus OT - TZD, thiazolidinedione OT - cAMP/PKA, cyclic adenosine monophosphate/protein kinase A COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/06/30 06:00 MHDA- 2022/06/30 06:01 PMCR- 2022/06/01 CRDT- 2022/06/29 02:05 PHST- 2022/03/14 00:00 [received] PHST- 2022/05/30 00:00 [revised] PHST- 2022/05/30 00:00 [accepted] PHST- 2022/06/29 02:05 [entrez] PHST- 2022/06/30 06:00 [pubmed] PHST- 2022/06/30 06:01 [medline] PHST- 2022/06/01 00:00 [pmc-release] AID - S2001-0370(22)00213-6 [pii] AID - 10.1016/j.csbj.2022.05.057 [doi] PST - epublish SO - Comput Struct Biotechnol J. 2022 Jun 1;20:2839-2847. doi: 10.1016/j.csbj.2022.05.057. eCollection 2022. PMID- 35687178 OWN - NLM STAT- MEDLINE DCOM- 20220804 LR - 20251031 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 65 IP - 9 DP - 2022 Sep TI - GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes. PG - 1541-1554 LID - 10.1007/s00125-022-05730-5 [doi] AB - AIMS/HYPOTHESIS: We have previously shown that diabetes causes pericyte dysfunction, leading to loss of vascular integrity and vascular cognitive impairment and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), used in managing type 2 diabetes mellitus, improve the cognitive function of diabetic individuals beyond glycaemic control, yet the mechanism is not fully understood. In the present study, we hypothesise that GLP-1 RAs improve VCID by preventing diabetes-induced pericyte dysfunction. METHODS: Mice with streptozotocin-induced diabetes and non-diabetic control mice received either saline (NaCl 154 mmol/l) or exendin-4, a GLP-1 RA, through an osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularisation indices (vascular density, tortuosity and branching density). Cognitive function was evaluated with Barnes maze and Morris water maze. Human brain microvascular pericytes (HBMPCs), were grown in high glucose (25 mmol/l) and sodium palmitate (200 mumol/l) to mimic diabetic conditions. HBMPCs were treated with/without exendin-4 and assessed for nitrative and oxidative stress, and angiogenic and blood-brain barrier functions. RESULTS: Diabetic mice treated with exendin-4 showed a significant reduction in all cerebral pathological neovascularisation indices and an improved blood-brain barrier (p<0.05). The vascular protective effects were accompanied by significant improvement in the learning and memory functions of diabetic mice compared with control mice (p<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Diabetes increased GLP-1 receptor expression and receptor nitration in HBMPCs. Stimulation of HBMPCs with exendin-4 under diabetic conditions decreased diabetes-induced vascular inflammation and oxidative stress, and restored pericyte function (p<0.05). CONCLUSIONS/INTERPRETATION: This study provides novel evidence that brain pericytes express the GLP-1 receptor, which is nitrated under diabetic conditions. GLP-1 receptor activation improves brain pericyte function resulting in restoration of vascular integrity and BBB functions in diabetes. Furthermore, the GLP-1 RA exendin-4 alleviates diabetes-induced cognitive impairment in mice. Restoration of pericyte function in diabetes represents a novel therapeutic target for diabetes-induced cerebrovascular microangiopathy and VCID. CI - (c) 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. FAU - Bailey, Joseph AU - Bailey J AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. FAU - Coucha, Maha AU - Coucha M AD - Department of Pharmaceutical Sciences, School of Pharmacy, South University, Savannah, GA, USA. FAU - Bolduc, Deanna R AU - Bolduc DR AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. FAU - Burnett, Faith N AU - Burnett FN AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. FAU - Barrett, Amy C AU - Barrett AC AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. FAU - Ghaly, Mark AU - Ghaly M AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. FAU - Abdelsaid, Mohammed AU - Abdelsaid M AUID- ORCID: 0000-0001-9846-6623 AD - Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. Abdelsaid_ma@mercer.edu. LA - eng GR - 16SDG30270013/AHA/American Heart Association-American Stroke Association/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220610 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Brain/metabolism MH - *Diabetes Mellitus, Experimental/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - Disease Models, Animal MH - Exenatide/therapeutic use MH - Glucagon-Like Peptide 1/metabolism MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Mice MH - *Pericytes/metabolism PMC - PMC11973880 MID - NIHMS2065537 OTO - NOTNLM OT - Cognitive function OT - Diabetes OT - GLP-1 receptor OT - Nitration OT - Pericytes OT - Vascular cognitive impairment and dementia EDAT- 2022/06/11 06:00 MHDA- 2022/08/05 06:00 PMCR- 2025/04/07 CRDT- 2022/06/10 11:16 PHST- 2021/11/16 00:00 [received] PHST- 2022/03/17 00:00 [accepted] PHST- 2022/06/11 06:00 [pubmed] PHST- 2022/08/05 06:00 [medline] PHST- 2022/06/10 11:16 [entrez] PHST- 2025/04/07 00:00 [pmc-release] AID - 10.1007/s00125-022-05730-5 [pii] AID - 10.1007/s00125-022-05730-5 [doi] PST - ppublish SO - Diabetologia. 2022 Sep;65(9):1541-1554. doi: 10.1007/s00125-022-05730-5. Epub 2022 Jun 10. PMID- 35654594 OWN - NLM STAT- MEDLINE DCOM- 20220817 LR - 20260728 IS - 1526-632X (Electronic) IS - 0028-3878 (Print) IS - 0028-3878 (Linking) VI - 99 IP - 7 DP - 2022 Aug 16 TI - Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study. PG - e650-e659 LID - 10.1212/WNL.0000000000200771 [doi] AB - BACKGROUND AND OBJECTIVES: Previous studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear. METHODS: A 2-sample mendelian randomization study design was applied to examine the association between genetic variation in the targets of 4 antidiabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, whereas summary statistics for AD were retrieved from previous genome-wide association studies comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes mellitus (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables. RESULTS: In the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (odds ratio [OR] = 0.38 per 1 mmol/L decrement in blood glucose, 95% CI 0.19-0.72, p = 0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR = 0.35 per 1 mmol/L decrement in blood glucose, 95% CI 0.15-0.82, p = 0.016). An association between genetic variations in the glucagon-like peptide 1 (GLP-1) analogue target and a lower risk of AD was also observed (OR = 0.32 per 1 mmol/L decrement in blood glucose, 95% CI 0.13-0.79, p = 0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive. DISCUSSION: Genetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD. CI - Copyright (c) 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. FAU - Tang, Bowen AU - Tang B AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Wang, Yunzhang AU - Wang Y AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Jiang, Xia AU - Jiang X AUID- ORCID: 0000-0001-5878-8986 AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Thambisetty, Madhav AU - Thambisetty M AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Ferrucci, Luigi AU - Ferrucci L AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Johnell, Kristina AU - Johnell K AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Hagg, Sara AU - Hagg S AUID- ORCID: 0000-0002-2452-1500 AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. sara.hagg@ki.se. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - R01 AG067996/AG/NIA NIH HHS/United States GR - RF1 AG067996/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220602 PL - United States TA - Neurology JT - Neurology JID - 0401060 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM CIN - Neurology. 2022 Aug 16;99(7):267-268. doi: 10.1212/WNL.0000000000200803. PMID: 35654591 MH - *Alzheimer Disease/complications/drug therapy/genetics MH - Blood Glucose/metabolism MH - *Diabetes Mellitus, Type 2/blood/drug therapy/genetics MH - Drug Repositioning MH - Genome-Wide Association Study MH - Glucagon-Like Peptide 1/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Mendelian Randomization Analysis MH - Polymorphism, Single Nucleotide/genetics PMC - PMC9484609 EDAT- 2022/06/03 06:00 MHDA- 2022/08/18 06:00 PMCR- 2022/08/28 CRDT- 2022/06/02 21:43 PHST- 2021/10/11 00:00 [received] PHST- 2022/04/08 00:00 [accepted] PHST- 2022/06/03 06:00 [pubmed] PHST- 2022/08/18 06:00 [medline] PHST- 2022/06/02 21:43 [entrez] PHST- 2022/08/28 00:00 [pmc-release] AID - WNL.0000000000200771 [pii] AID - WNL-2022-200755 [pii] AID - 10.1212/WNL.0000000000200771 [doi] PST - ppublish SO - Neurology. 2022 Aug 16;99(7):e650-e659. doi: 10.1212/WNL.0000000000200771. Epub 2022 Jun 2. PMID- 35650449 OWN - NLM STAT- MEDLINE DCOM- 20220616 LR - 20260127 IS - 1573-904X (Electronic) IS - 0724-8741 (Print) IS - 0724-8741 (Linking) VI - 39 IP - 6 DP - 2022 Jun TI - Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. PG - 1233-1248 LID - 10.1007/s11095-022-03302-1 [doi] AB - INTRODUCTION: Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions. BACKGROUND: Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease. DISCUSSION: Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease. CONCLUSION: Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Mahapatra, Manoj K AU - Mahapatra MK AD - Department of Pharmaceutical Chemistry, Kanak Manjari Institute of Pharmaceutical Sciences, Chhend, Rourkela, 769015, Odisha, India. manojbit07@gmail.com. FAU - Karuppasamy, Muthukumar AU - Karuppasamy M AD - YaAn Pharmaceutical and Medical Communications, 1798, Balaji Nagar, Sithurajapuram, Sivakasi, 626189, Tamilnadu, India. FAU - Sahoo, Biswa M AU - Sahoo BM AD - Roland Institute of Pharmaceutical Sciences, Berhampur, 760010, Odisha, India. LA - eng PT - Journal Article PT - Review DEP - 20220601 PL - United States TA - Pharm Res JT - Pharmaceutical research JID - 8406521 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - *Alzheimer Disease/drug therapy MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide-1 Receptor/therapeutic use MH - Glucagon-Like Peptides MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - *Insulin Resistance MH - *Neurodegenerative Diseases/drug therapy MH - *Non-alcoholic Fatty Liver Disease/drug therapy MH - Obesity/drug therapy MH - *Parkinson Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Semaglutide PMC - PMC9159769 OTO - NOTNLM OT - GLP-1 receptor agonist OT - metabolic diseases OT - neurodegenerative diseases OT - obesity OT - semaglutide COIS- The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. EDAT- 2022/06/02 06:00 MHDA- 2022/06/18 06:00 PMCR- 2022/06/01 CRDT- 2022/06/01 23:30 PHST- 2022/03/21 00:00 [received] PHST- 2022/05/23 00:00 [accepted] PHST- 2022/06/02 06:00 [pubmed] PHST- 2022/06/18 06:00 [medline] PHST- 2022/06/01 23:30 [entrez] PHST- 2022/06/01 00:00 [pmc-release] AID - 10.1007/s11095-022-03302-1 [pii] AID - 3302 [pii] AID - 10.1007/s11095-022-03302-1 [doi] PST - ppublish SO - Pharm Res. 2022 Jun;39(6):1233-1248. doi: 10.1007/s11095-022-03302-1. Epub 2022 Jun 1. PMID- 35563031 OWN - NLM STAT- MEDLINE DCOM- 20220517 LR - 20230916 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 9 DP - 2022 Apr 22 TI - Antidiabetic Drugs in the Treatment of Alzheimer's Disease. LID - 10.3390/ijms23094641 [doi] LID - 4641 AB - The public health burden of type 2 diabetes mellitus and Alzheimer's disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer's disease. Human studies in patients with mild cognitive impairment and Alzheimer's disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer's disease. FAU - Michailidis, Michalis AU - Michailidis M AD - Laboratory of Psychology, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Tata, Despina A AU - Tata DA AUID- ORCID: 0000-0001-5563-4017 AD - Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Moraitou, Despina AU - Moraitou D AUID- ORCID: 0000-0002-0527-7143 AD - Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Kavvadas, Dimitrios AU - Kavvadas D AUID- ORCID: 0000-0002-3325-2752 AD - Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Karachrysafi, Sofia AU - Karachrysafi S AUID- ORCID: 0000-0001-6309-8410 AD - Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Papamitsou, Theodora AU - Papamitsou T AD - Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Vareltzis, Patroklos AU - Vareltzis P AUID- ORCID: 0000-0003-4796-183X AD - Department of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. FAU - Papaliagkas, Vasileios AU - Papaliagkas V AUID- ORCID: 0000-0003-1064-0290 AD - Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece. LA - eng PT - Journal Article PT - Review DEP - 20220422 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 9100L32L2N (Metformin) SB - IM MH - Aged MH - *Alzheimer Disease MH - *Diabetes Mellitus, Type 2/drug therapy MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin/therapeutic use MH - *Metformin/therapeutic use PMC - PMC9102472 OTO - NOTNLM OT - Alzheimer type 3 diabetes mellitus OT - PPARgamma agonists OT - amyloid beta OT - incretins OT - intranasal insulin OT - metformin OT - thiazolidinediones OT - type 2 diabetes mellitus COIS- The authors declare no conflict of interest. EDAT- 2022/05/15 06:00 MHDA- 2022/05/18 06:00 PMCR- 2022/04/22 CRDT- 2022/05/14 01:03 PHST- 2022/04/04 00:00 [received] PHST- 2022/04/18 00:00 [revised] PHST- 2022/04/19 00:00 [accepted] PHST- 2022/05/14 01:03 [entrez] PHST- 2022/05/15 06:00 [pubmed] PHST- 2022/05/18 06:00 [medline] PHST- 2022/04/22 00:00 [pmc-release] AID - ijms23094641 [pii] AID - ijms-23-04641 [pii] AID - 10.3390/ijms23094641 [doi] PST - epublish SO - Int J Mol Sci. 2022 Apr 22;23(9):4641. doi: 10.3390/ijms23094641. PMID- 35446415 OWN - NLM STAT- MEDLINE DCOM- 20220718 LR - 20220728 IS - 1945-7197 (Electronic) IS - 0021-972X (Linking) VI - 107 IP - 8 DP - 2022 Jul 14 TI - Novel Indices of Cognitive Impairment and Incident Cardiovascular Outcomes in the REWIND Trial. PG - e3448-e3454 LID - 10.1210/clinem/dgac200 [doi] AB - CONTEXT: Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown. METHODS: Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST >/= 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was >/= 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed. RESULTS: Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors. CONCLUSION: Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Endocrinology Institute, Sheba Medical Center, Ramat-Gan, and Epidemiology Department, Sackler School of Medicine, Herceg Institute of Aging, Tel Aviv University, Tel Aviv, Israel. FAU - Gerstein, Hertzel C AU - Gerstein HC AUID- ORCID: 0000-0001-8072-2836 AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. FAU - Basile, Jan AU - Basile J AD - Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC, USA. FAU - Bethel, M Angelyn AU - Bethel MA AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Cardona-Munoz, Ernesto G AU - Cardona-Munoz EG AD - CUCS-Universidad de Guadalajara, Mexico. FAU - Conget, Ignacio AU - Conget I AUID- ORCID: 0000-0002-5532-5449 AD - Endocrinology and Nutrition Dpt. Hospital Clinic i Universitari, Barcelona, Spain. FAU - Dagenais, Gilles AU - Dagenais G AD - Quebec Heart and Lung Institute, Laval University, Quebec City, Canada. FAU - Franek, Edward AU - Franek E AD - Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital MSWiA, Warsaw, Poland. FAU - Hall, Stephanie AU - Hall S AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. FAU - Hancu, Nicolae AU - Hancu N AD - Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania. FAU - Jansky, Petr AU - Jansky P AD - University Hospital Motol, Prague. FAU - Lakshmanan, Mark AU - Lakshmanan M AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Lanas, Fernando AU - Lanas F AUID- ORCID: 0000-0003-3595-9759 AD - Universidad de La Frontera, Temuco, Chile. FAU - Leiter, Lawrence A AU - Leiter LA AUID- ORCID: 0000-0002-1040-6229 AD - Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada. FAU - Lopez-Jaramillo, Patricio AU - Lopez-Jaramillo P AUID- ORCID: 0000-0002-9122-8742 AD - Masira Research Institute, Medical School, Universidad de Santander UDES, Bucaramanga, Colombia. FAU - Pirags, Valdis AU - Pirags V AD - University of Latvia, Pauls Stradins Clinical University Hospital, Riga, Latvia. FAU - Pogosova, Nana AU - Pogosova N AD - National Medical Research Center of Cardiology, Moscow, Russia. FAU - Probstfield, Jeffrey AU - Probstfield J AUID- ORCID: 0000-0002-4899-9971 AD - Department of Medicine, University of Washington, Seattle, WA,USA. FAU - Rao-Melacini, Purnima AU - Rao-Melacini P AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. FAU - Ramasundarahettige, Chinthanie AU - Ramasundarahettige C AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. FAU - Raubenheimer, Peter J AU - Raubenheimer PJ AD - Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Riddle, Matthew C AU - Riddle MC AD - Department of Medicine, Oregon Health & Science University Portland, OR, USA. FAU - Ryden, Lars AU - Ryden L AD - Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. FAU - Shaw, Jonathan E AU - Shaw JE AD - Baker Heart and Diabetes Institute, Melbourne, Australia. FAU - Sheu, Wayne H-H AU - Sheu WH AD - Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Temelkova-Kurktschiev, Theodora AU - Temelkova-Kurktschiev T AD - Robert Koch Medical Center, Sofia, Bulgaria. LA - eng SI - ClinicalTrials.gov/NCT01394952 GR - Eli Lilly and Company/ PT - Clinical Trial PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) SB - IM MH - *Cardiovascular Diseases/chemically induced/etiology MH - *Cognitive Dysfunction/epidemiology/etiology MH - *Diabetes Mellitus, Type 2/epidemiology MH - Humans MH - Hypoglycemic Agents/adverse effects MH - Incretins MH - Risk Factors MH - *Stroke/chemically induced/etiology OTO - NOTNLM OT - Cardiovascular events OT - Cognitive impairment OT - Composite outcome OT - Death OT - Geometric mean OT - MACE OT - Risk factor OT - Stroke EDAT- 2022/04/22 06:00 MHDA- 2022/07/19 06:00 CRDT- 2022/04/21 12:15 PHST- 2021/11/11 00:00 [received] PHST- 2022/04/22 06:00 [pubmed] PHST- 2022/07/19 06:00 [medline] PHST- 2022/04/21 12:15 [entrez] AID - 6569991 [pii] AID - 10.1210/clinem/dgac200 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3448-e3454. doi: 10.1210/clinem/dgac200. PMID- 35398114 OWN - NLM STAT- MEDLINE DCOM- 20220523 LR - 20220622 IS - 1873-7528 (Electronic) IS - 0149-7634 (Linking) VI - 137 DP - 2022 Jun TI - Glucose-lowering drugs, cognition, and dementia: The clinical evidence. PG - 104654 LID - S0149-7634(22)00143-9 [pii] LID - 10.1016/j.neubiorev.2022.104654 [doi] AB - Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs. CI - Copyright (c) 2022 Elsevier Ltd. All rights reserved. FAU - Wu, Che-Yuan AU - Wu CY AD - Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada. FAU - Shapiro, Lila AU - Shapiro L AD - Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada. FAU - Ouk, Michael AU - Ouk M AD - Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada. FAU - MacIntosh, Bradley J AU - MacIntosh BJ AD - Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada. FAU - Black, Sandra E AU - Black SE AD - Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Toronto Dementia Research Alliance, Toronto, Ontario, Canada. FAU - Shah, Baiju R AU - Shah BR AD - ICES, Toronto, Ontario, Canada; Divisions of Endocrinology and Obstetric Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. FAU - Swardfager, Walter AU - Swardfager W AD - Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; KITE UHN Toronto Rehabilitation Institute, Toronto, Ontario, Canada. LA - eng GR - PJT-159711/CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220406 PL - United States TA - Neurosci Biobehav Rev JT - Neuroscience and biobehavioral reviews JID - 7806090 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Cognition MH - *Dementia/drug therapy MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Glucose MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - *Metformin/therapeutic use OTO - NOTNLM OT - Cognition OT - Dementia OT - Diabetes mellitus OT - Dipeptidyl peptidase-4 inhibitors OT - Epidemiology OT - Glucagon-like peptide-1 analogues OT - Insulin OT - Metformin OT - Sodium-glucose cotransporter-2 inhibitors OT - Sulfonylureas OT - Thiazolidinediones EDAT- 2022/04/11 06:00 MHDA- 2022/05/24 06:00 CRDT- 2022/04/10 20:23 PHST- 2022/02/01 00:00 [received] PHST- 2022/04/01 00:00 [revised] PHST- 2022/04/03 00:00 [accepted] PHST- 2022/04/11 06:00 [pubmed] PHST- 2022/05/24 06:00 [medline] PHST- 2022/04/10 20:23 [entrez] AID - S0149-7634(22)00143-9 [pii] AID - 10.1016/j.neubiorev.2022.104654 [doi] PST - ppublish SO - Neurosci Biobehav Rev. 2022 Jun;137:104654. doi: 10.1016/j.neubiorev.2022.104654. Epub 2022 Apr 6. PMID- 35370875 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220405 IS - 1664-2295 (Print) IS - 1664-2295 (Electronic) IS - 1664-2295 (Linking) VI - 13 DP - 2022 TI - Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research. PG - 844697 LID - 10.3389/fneur.2022.844697 [doi] LID - 844697 AB - The public and social health burdens of ischemic stroke have been increasing worldwide. Hyperglycemia leads to a greater risk of stroke. This increased risk is commonly seen among patients with diabetes and is in connection with worsened clinical conditions and higher mortality in patients with acute ischemic stroke (AIS). Therapy for stroke focuses mainly on restoring cerebral blood flow (CBF) and ameliorating neurological impairment caused by stroke. Although choices of stroke treatment remain limited, much advance have been achieved in assisting patients in recovering from ischemic stroke, along with progress of recanalization therapy through pharmacological and mechanical thrombolysis. However, it is still necessary to develop neuroprotective therapies for AIS to protect the brain against injury before and during reperfusion, prolong the time window for intervention, and consequently improve neurological prognosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are broadly regarded as effective drugs in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data on GLP-1 and GLP-1 RAs have displayed an impressive neuroprotective efficacy in stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Based on the preclinical studies in the past decade, we review recent progress in the biological roles of GLP-1 and GLP-1 RAs in ischemic stroke. Emphasis will be placed on their neuroprotective effects in experimental models of cerebral ischemia stroke at cellular and molecular levels. CI - Copyright (c) 2022 Yang, Qiang, Li, Feng, Wei and Holscher. FAU - Yang, Xiaoyan AU - Yang X AD - Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. FAU - Qiang, Qiang AU - Qiang Q AD - Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. FAU - Li, Nan AU - Li N AD - Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. FAU - Feng, Peng AU - Feng P AD - Department of Neurology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, China. FAU - Wei, Wenshi AU - Wei W AD - Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. FAU - Holscher, Christian AU - Holscher C AD - Department of Neurology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, China. AD - Henan University of Chinese Medicine, Academy of Chinese Medical Science, Zhengzhou, China. LA - eng PT - Journal Article PT - Review DEP - 20220315 PL - Switzerland TA - Front Neurol JT - Frontiers in neurology JID - 101546899 PMC - PMC8964641 OTO - NOTNLM OT - GLP-1 OT - GLP-1R agonists OT - diabetes OT - neuroprotection OT - stroke COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/04/05 06:00 MHDA- 2022/04/05 06:01 PMCR- 2022/03/15 CRDT- 2022/04/04 05:28 PHST- 2022/01/05 00:00 [received] PHST- 2022/02/16 00:00 [accepted] PHST- 2022/04/04 05:28 [entrez] PHST- 2022/04/05 06:00 [pubmed] PHST- 2022/04/05 06:01 [medline] PHST- 2022/03/15 00:00 [pmc-release] AID - 10.3389/fneur.2022.844697 [doi] PST - epublish SO - Front Neurol. 2022 Mar 15;13:844697. doi: 10.3389/fneur.2022.844697. eCollection 2022. PMID- 35368248 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220405 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 16 DP - 2022 TI - Neuroprotective Effects of a Cholecystokinin Analogue in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Parkinson's Disease Mouse Model. PG - 814430 LID - 10.3389/fnins.2022.814430 [doi] LID - 814430 AB - Parkinson's disease (PD) is a chronic neurodegenerative disease. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for PD. Drugs originally developed for T2DM treatment such as liraglutide have shown neuroprotective effects in mouse models of PD. Cholecystokinin (CCK) is a peptide hormone with growth factor properties. Here, we demonstrate the neuroprotective effects of the (pGLu)-(Gln)-CCK8 analogue in an acute PD mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of CCK analogue (50 nmol/kg ip.) for 14 days treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. The CCK analogue administration also restored tyrosine hydroxylase (TH) positive dopaminergic neurons number and synapse number (synaptophysin levels) in the substantia nigra pars compacta (SNpc). The CCK analogue decreased glia activation and neuroinflammation in the SNpc, and regulated autophagy dysfunction induced by MPTP. CCK analogue protected against mitochondrial damage and ER stress, and also decreased the ratio of apoptosis signaling molecules Bax/Bcl-2. Importantly, the CCK analogue improved the decrease of p-CREBS(133) growth factor signaling in the SNpc. Therefore, the CCK analogue promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB pathway that also inhibits apoptosis and regulates autophagy impairment. The present results indicate that CCK analogue shows a promising potential for the treatment of PD. CI - Copyright (c) 2022 Zhang, Li, Su, Ma, Yuan, Yu, Shi, Shao, Zhang and Holscher. FAU - Zhang, Zijuan AU - Zhang Z AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. AD - School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Li, Hai AU - Li H AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. AD - School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Su, Yunfang AU - Su Y AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Ma, Jinlian AU - Ma J AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Yuan, Ye AU - Yuan Y AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Yu, Ziyang AU - Yu Z AD - School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Shi, Ming AU - Shi M AD - School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Shao, Simai AU - Shao S AD - School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Zhang, Zhenqiang AU - Zhang Z AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. FAU - Holscher, Christian AU - Holscher C AD - Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China. AD - Neurology Department of the Second Associated Hospital of Shanxi Medical University, Taiyuan, China. LA - eng PT - Journal Article DEP - 20220315 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC8964967 OTO - NOTNLM OT - CCK OT - MPTP OT - Parkinson's disease OT - apoptosis OT - autophagy OT - insulin OT - neuroinflammation COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/04/05 06:00 MHDA- 2022/04/05 06:01 PMCR- 2022/01/01 CRDT- 2022/04/04 05:05 PHST- 2021/11/13 00:00 [received] PHST- 2022/02/11 00:00 [accepted] PHST- 2022/04/04 05:05 [entrez] PHST- 2022/04/05 06:00 [pubmed] PHST- 2022/04/05 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2022.814430 [doi] PST - epublish SO - Front Neurosci. 2022 Mar 15;16:814430. doi: 10.3389/fnins.2022.814430. eCollection 2022. PMID- 35340338 OWN - NLM STAT- MEDLINE DCOM- 20220404 LR - 20220531 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 16 DP - 2022 TI - The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases. PG - 665-684 LID - 10.2147/DDDT.S348055 [doi] AB - Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes, however, there is still a lack of understanding about the drug therapy. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used in the treatment of type 2 diabetes and potential applications may include the treatment of obesity as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin. Growing evidence suggests that GLP-1 RA has the potential to treat neurodegenerative diseases, particularly in diabetes-related Alzheimer's disease (AD) and Parkinson's disease (PD). Here, we review the molecular mechanisms of the neuroprotective effects of GLP-1 RA in diabetes-related degenerative diseases, including AD and PD, and their potential effects. CI - (c) 2022 Cheng et al. FAU - Cheng, Dihe AU - Cheng D AD - Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China. FAU - Yang, Shuo AU - Yang S AD - Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China. FAU - Zhao, Xue AU - Zhao X AD - Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China. FAU - Wang, Guixia AU - Wang G AD - Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China. LA - eng PT - Journal Article PT - Review DEP - 20220314 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Aged MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide 1/agonists/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Insulin MH - *Neurodegenerative Diseases/drug therapy PMC - PMC8943601 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - cognition OT - diabetes mellitus OT - glucagon-like peptide-1 COIS- The authors report no conflicts of interest in this work. EDAT- 2022/03/29 06:00 MHDA- 2022/04/05 06:00 PMCR- 2022/03/14 CRDT- 2022/03/28 05:07 PHST- 2021/11/05 00:00 [received] PHST- 2022/02/18 00:00 [accepted] PHST- 2022/03/28 05:07 [entrez] PHST- 2022/03/29 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2022/03/14 00:00 [pmc-release] AID - 348055 [pii] AID - 10.2147/DDDT.S348055 [doi] PST - epublish SO - Drug Des Devel Ther. 2022 Mar 14;16:665-684. doi: 10.2147/DDDT.S348055. eCollection 2022. PMID- 35263425 OWN - NLM STAT- MEDLINE DCOM- 20220517 LR - 20260127 IS - 1935-5548 (Electronic) IS - 0149-5992 (Linking) VI - 45 IP - 5 DP - 2022 May 1 TI - Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but Not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study. PG - 1201-1210 LID - 10.2337/dc21-2064 [doi] AB - OBJECTIVE: The comparative neuroprotective effects of different antidiabetes drugs have not been characterized in randomized controlled trials. Here, we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty-six patients with type 2 diabetes inadequately controlled with metformin monotherapy were randomized to receive liraglutide, dapagliflozin, or acarbose treatment for 16 weeks. Brain functional MRI (fMRI) scan and a battery of cognitive assessments were evaluated pre- and postintervention in all subjects. RESULTS: The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with Gaussian random field correction and improved cognitive subdomains of delayed memory, attention, and executive function (all P < 0.05), whereas dapagliflozin or acarbose did not. Structural equation modeling analysis demonstrated that such improvements of brain health and cognitive function could be partly ascribed to a direct effect of liraglutide on left hippocampal activation (beta = 0.330, P = 0.022) and delayed memory (beta = 0.410, P = 0.004) as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all P < 0.05). CONCLUSIONS: Our head-to-head study demonstrated that liraglutide enhanced impaired brain activation and restored impaired cognitive domains in patients with type 2 diabetes, whereas dapagliflozin and acarbose did not. The results expand the clinical application of liraglutide and provide a novel treatment strategy for individuals with diabetes and a high risk of cognitive decline. CI - (c) 2022 by the American Diabetes Association. FAU - Cheng, Haiyan AU - Cheng H AD - Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Zhang, Bing AU - Zhang B AD - Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Zhang, Wen AU - Zhang W AD - Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Wang, Jin AU - Wang J AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Ni, Wenyu AU - Ni W AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Miao, Yingwen AU - Miao Y AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Liu, Jiani AU - Liu J AD - Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China. AD - Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. LA - eng SI - ClinicalTrials.gov/NCT03961659 SI - figshare/10.2337/figshare.19182023 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - T58MSI464G (Acarbose) RN - 0 (Benzhydryl Compounds) RN - 0 (Blood Glucose) RN - 0 (Glucosides) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 9100L32L2N (Metformin) RN - 1ULL0QJ8UC (dapagliflozin) SB - IM MH - Acarbose/therapeutic use MH - Benzhydryl Compounds MH - Blood Glucose/metabolism MH - Cognition MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucosides MH - Glycated Hemoglobin/metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Liraglutide/pharmacology/therapeutic use MH - *Metformin/therapeutic use EDAT- 2022/03/10 06:00 MHDA- 2022/05/18 06:00 CRDT- 2022/03/09 17:12 PHST- 2021/10/02 00:00 [received] PHST- 2022/02/11 00:00 [accepted] PHST- 2022/03/10 06:00 [pubmed] PHST- 2022/05/18 06:00 [medline] PHST- 2022/03/09 17:12 [entrez] AID - 144697 [pii] AID - 10.2337/dc21-2064 [doi] PST - ppublish SO - Diabetes Care. 2022 May 1;45(5):1201-1210. doi: 10.2337/dc21-2064. PMID- 35256932 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240824 IS - 2211-3835 (Print) IS - 2211-3843 (Electronic) IS - 2211-3835 (Linking) VI - 12 IP - 2 DP - 2022 Feb TI - Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease. PG - 511-531 LID - 10.1016/j.apsb.2021.06.014 [doi] AB - Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts. CI - (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. FAU - Austad, Steven N AU - Austad SN AD - Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Ballinger, Scott AU - Ballinger S AD - Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Buford, Thomas W AU - Buford TW AD - Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Carter, Christy S AU - Carter CS AD - Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Smith, Daniel L Jr AU - Smith DL Jr AD - Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Darley-Usmar, Victor AU - Darley-Usmar V AD - Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. FAU - Zhang, Jianhua AU - Zhang J AD - Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. LA - eng GR - I01 BX004251/BX/BLRD VA/United States GR - K02 AG062498/AG/NIA NIH HHS/United States GR - R56 AG060959/AG/NIA NIH HHS/United States GR - P30 AG050886/AG/NIA NIH HHS/United States GR - F32 AG005886/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20210630 PL - Netherlands TA - Acta Pharm Sin B JT - Acta pharmaceutica Sinica. B JID - 101600560 PMC - PMC8897048 OTO - NOTNLM OT - ACE2, angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 OT - AD, Alzheimer's disease OT - ADP, adenosine diphosphate OT - ADRD, AD-related dementias OT - Abeta, amyloid beta OT - CSF, cerebrospinal fluid OT - Circadian regulation OT - DAMPs OT - DAMPs, damage-associated molecular patterns OT - Diabetes OT - ER, estrogen receptor OT - ETC, electron transport chain OT - FCCP, trifluoromethoxy carbonylcyanide phenylhydrazone OT - FPR-1, formyl peptide receptor 1 OT - GIP, glucose-dependent insulinotropic polypeptide OT - GLP-1, glucagon-like peptide-1 OT - HBP, hexoamine biosynthesis pathway OT - HTRA, high temperature requirement A OT - Hexokinase biosynthesis pathway OT - I3A, indole-3-carboxaldehyde OT - IRF-3, interferon regulatory factor 3 OT - LC3, microtubule associated protein light chain 3 OT - LPS, lipopolysaccharide OT - LRR, leucine-rich repeat OT - MAVS, mitochondrial anti-viral signaling OT - MCI, mild cognitive impairment OT - MRI, magnetic resonance imaging OT - MRS, magnetic resonance spectroscopy OT - Mdivi-1, mitochondrial division inhibitor 1 OT - Microbiome OT - Mitochondrial DNA OT - Mitochondrial electron transport chain OT - Mitochondrial quality control OT - NLRP3, leucine-rich repeat (LRR)-containing protein (NLR)-like receptor family pyrin domain containing 3 OT - NOD, nucleotide-binding oligomerization domain OT - NeuN, neuronal nuclear protein OT - PET, fluorodeoxyglucose (FDG)-positron emission tomography OT - PKA, protein kinase A OT - POLbeta, the base-excision repair enzyme DNA polymerase beta OT - ROS, reactive oxygen species OT - Reactive species OT - SAMP8, senescence-accelerated mice OT - SCFAs, short-chain fatty acids OT - SIRT3, NAD-dependent deacetylase sirtuin-3 OT - STING, stimulator of interferon genes OT - STZ, streptozotocin OT - SkQ1, plastoquinonyldecyltriphenylphosphonium OT - T2D, type 2 diabetes OT - TCA, Tricarboxylic acid OT - TLR9, toll-like receptor 9 OT - TMAO, trimethylamine N-oxide OT - TP, tricyclic pyrone OT - TRF, time-restricted feeding OT - cAMP, cyclic adenosine monophosphate OT - cGAS, cyclic GMP/AMP synthase OT - hAPP, human amyloid precursor protein OT - hPREP, human presequence protease OT - i.p., intraperitoneal OT - mTOR, mechanistic target of rapamycin OT - mtDNA, mitochondrial DNA OT - alphakG, alpha-ketoglutarate EDAT- 2022/03/09 06:00 MHDA- 2022/03/09 06:01 PMCR- 2021/06/30 CRDT- 2022/03/08 05:39 PHST- 2021/03/31 00:00 [received] PHST- 2021/05/26 00:00 [revised] PHST- 2021/06/16 00:00 [accepted] PHST- 2022/03/08 05:39 [entrez] PHST- 2022/03/09 06:00 [pubmed] PHST- 2022/03/09 06:01 [medline] PHST- 2021/06/30 00:00 [pmc-release] AID - S2211-3835(21)00246-X [pii] AID - 10.1016/j.apsb.2021.06.014 [doi] PST - ppublish SO - Acta Pharm Sin B. 2022 Feb;12(2):511-531. doi: 10.1016/j.apsb.2021.06.014. Epub 2021 Jun 30. PMID- 35229024 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240824 IS - 2352-8737 (Electronic) IS - 2352-8737 (Linking) VI - 8 IP - 1 DP - 2022 TI - Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. PG - e12268 LID - 10.1002/trc2.12268 [doi] LID - e12268 AB - INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP-1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long-term follow-up: pooled data from three randomized double-blind placebo-controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry-based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP-1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25-0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86-0.93 with yearly increased exposure to GLP-1 RAs). DISCUSSION: Treatment with GLP-1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes. CI - (c) 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association. FAU - Norgaard, Caroline Holm AU - Norgaard CH AD - Department of Cardiology and Clinical Research Nordsjaellands University Hospital Hillerod Denmark. AD - Department of Medicine University of California Irvine Irvine California USA. FAU - Friedrich, Sarah AU - Friedrich S AD - Department of Medical Statistics University Medical Center Gottingen Gottingen Germany. FAU - Hansen, Charlotte Thim AU - Hansen CT AD - Novo Nordisk Soborg Denmark. FAU - Gerds, Thomas AU - Gerds T AD - Section of Biostatistics Copenhagen University Osterbro Denmark. FAU - Ballard, Clive AU - Ballard C AD - St Luke's Campus University of Exeter College of Medicine and Health Exeter UK. FAU - Moller, Daniel Vega AU - Moller DV AD - Novo Nordisk Soborg Denmark. FAU - Knudsen, Lotte Bjerre AU - Knudsen LB AD - Novo Nordisk Malov Denmark. FAU - Kvist, Kajsa AU - Kvist K AD - Novo Nordisk Soborg Denmark. FAU - Zinman, Bernard AU - Zinman B AD - Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada. FAU - Holm, Ellen AU - Holm E AD - Department of Medicine Nykobing Falster Hospital Hospitalsvej Nykobing Falster Denmark. FAU - Torp-Pedersen, Christian AU - Torp-Pedersen C AUID- ORCID: 0000-0003-2892-6131 AD - Department of Cardiology and Clinical Research Nordsjaellands University Hospital Hillerod Denmark. AD - Department of Cardiology Aalborg University Hospital Aalborg Denmark. FAU - Morch, Lina Steinrud AU - Morch LS AD - Novo Nordisk Soborg Denmark. LA - eng PT - Journal Article DEP - 20220223 PL - United States TA - Alzheimers Dement (N Y) JT - Alzheimer's & dementia (New York, N. Y.) JID - 101650118 PMC - PMC8864443 OTO - NOTNLM OT - dementia OT - glucagon-like peptide-1 receptor agonists OT - randomized controlled trial OT - real-world evidence OT - type 2 diabetes COIS- CHN, TG, EH, and CTP report no conflicts of interests. SF reports grants from Novo Nordisk related to the manufacture of GLP-1 RAs during the conduct of the study and support for attending meetings and/or travel from the German Research Foundation (payments made to institution); she has also been secretary of the German Consortium in Statistics (DAGStat). CTMH, DVM, KK are Novo Nordisk employees and report personal fees from Novo Nordisk A/S related to the manufacture of GLP-1 RAs (salary and shareholder), during the conduct of the study. KK also reports Novo Nordisk stock in pension funds. CTMH is also inventor on a patent application related to GLP-1 compounds and indications (patent is owned by Novo Nordisk and she receives no financial or other benefits from it) and is a minor stockholder of Novo Nordisk A/S. CB reports grants and personal fees from Acadia, Addex, Exciva, Janssen, Suven, and Lundbeck; personal fees from Roche, Otsuka, Biogen, Eli Lilly, Sunovion, Novo Nordisk, and AARP; grants and personal fees from Synexus, outside the submitted work; he also reports the following grants to his institution (UoE) from: 2021 ADDF, 2020 UKRI, 2019 IMI2, NIH, Charles Wolfson Foundation, Novo Nordisk, 2018 MRC, Synexus, Capital, award from Dennis and Mireille Gillings Foundation, Novartis, and Oryzon; honoraria from Harvard University (to institution, UoE), GE Healthcare, Acadia, AARP, and Addex. LBK is a Novo Nordisk employee and an inventor on numerous patents and applications related to GLP-1 compounds and indications; all patents are owned by Novo Nordisk, which markets liraglutide and semaglutide, and she receives no financial or other benefits from them. BZ reports grants and personal fees from Novo Nordisk during the conduct of the study, and personal fees from Eli Lilly, Merck, Boehringer Ingelheim, and Janssen, outside the submitted work. LSM is a Novo Nordisk employee and reports personal fees from Novo Nordisk A/S related to the manufacture of GLP-1 RA (salary) during the conduct of the study; she is also vice chair of the Danish Society for Pharmacoepidemiology and is on the executive committee for the Nordic PharmacoEpidemiological Network. EDAT- 2022/03/02 06:00 MHDA- 2022/03/02 06:01 PMCR- 2022/02/23 CRDT- 2022/03/01 05:58 PHST- 2021/06/28 00:00 [received] PHST- 2022/01/20 00:00 [accepted] PHST- 2022/03/01 05:58 [entrez] PHST- 2022/03/02 06:00 [pubmed] PHST- 2022/03/02 06:01 [medline] PHST- 2022/02/23 00:00 [pmc-release] AID - TRC212268 [pii] AID - 10.1002/trc2.12268 [doi] PST - epublish SO - Alzheimers Dement (N Y). 2022 Feb 23;8(1):e12268. doi: 10.1002/trc2.12268. eCollection 2022. PMID- 35180937 OWN - NLM STAT- MEDLINE DCOM- 20220311 LR - 20250103 IS - 0083-6729 (Print) IS - 0083-6729 (Linking) VI - 118 DP - 2022 TI - Effects of Glucagon-like peptide 1 (GLP-1) analogs in the hippocampus. PG - 457-478 LID - S0083-6729(21)00082-0 [pii] LID - 10.1016/bs.vh.2021.12.005 [doi] AB - The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone very well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain, and it displays critical roles in neuroprotection by activating the GLP-1 receptor signaling pathways. GLP-1 enhances learning and memory in the hippocampus, promotes neurogenesis, decreases inflammation and apoptosis, modulates reward behavior, and reduces food intake. Its pharmacokinetics have been improved to enhance the peptide's half-life, enhancing exposure and time of action. The GLP-1 agonists are successfully in clinical use for the treatment of type-2 diabetes, obesity, and clinical evaluation for the treatment of neurodegenerative diseases. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Diz-Chaves, Yolanda AU - Diz-Chaves Y AD - Laboratory of Endocrinology, Biomedical Research Center (CINBIO), University of Vigo, Vigo, Spain. Electronic address: yolandadiz@uvigo.es. FAU - Herrera-Perez, Salvador AU - Herrera-Perez S AD - Laboratory of Neuroscience, Biomedical Research Center (CINBIO), University of Vigo, Vigo, Spain. FAU - Gonzalez-Matias, Lucas C AU - Gonzalez-Matias LC AD - Laboratory of Endocrinology, Biomedical Research Center (CINBIO), University of Vigo, Vigo, Spain. FAU - Mallo, Federico AU - Mallo F AD - Laboratory of Endocrinology, Biomedical Research Center (CINBIO), University of Vigo, Vigo, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220204 PL - United States TA - Vitam Horm JT - Vitamins and hormones JID - 0413601 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) RN - 0 (Peptide Fragments) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Glucagon-Like Peptide 1/analogs & derivatives/pharmacology MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Hippocampus/metabolism MH - Humans MH - Incretins/pharmacology MH - Peptide Fragments/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - Food reward OT - Glucagon-like peptide 1 OT - Glucagon-like peptide 1 receptor OT - Hippocampus OT - Inflammation OT - Learning OT - Memory OT - Neuroprotection EDAT- 2022/02/20 06:00 MHDA- 2022/03/12 06:00 CRDT- 2022/02/19 05:24 PHST- 2022/02/19 05:24 [entrez] PHST- 2022/02/20 06:00 [pubmed] PHST- 2022/03/12 06:00 [medline] AID - S0083-6729(21)00082-0 [pii] AID - 10.1016/bs.vh.2021.12.005 [doi] PST - ppublish SO - Vitam Horm. 2022;118:457-478. doi: 10.1016/bs.vh.2021.12.005. Epub 2022 Feb 4. PMID- 35157237 OWN - NLM STAT- MEDLINE DCOM- 20220504 LR - 20261028 IS - 1539-0829 (Electronic) IS - 1534-4827 (Linking) VI - 22 IP - 1 DP - 2022 Jan TI - The Diabetes-Cardiovascular Connection in Women: Understanding the Known Risks, Outcomes, and Implications for Care. PG - 11-25 LID - 10.1007/s11892-021-01444-x [doi] AB - PURPOSE OF REVIEW: Cardiovascular disease (CVD) complications constitute about 50-70% of mortality in people with diabetes. However, there remains a persistently greater relative increase in CVD morbidity and mortality in women with diabetes than in their male counterparts. This review presents recent evidence for the risks, outcomes, and management implications for women with diabetes. RECENT FINDINGS: Compared to men, women have higher BMI and more adverse cardiovascular risk profile at time of diabetes diagnosis with greater risk for coronary heart disease, stroke, vascular dementia, and heart failure. Pregnancy-specific risk factors of gestational diabetes and pre-eclampsia are associated with future type 2 diabetes (T2D) and CVD. Women with T2D may experience greater benefits than men from GLP-1 receptor agonists. Women with diabetes are at greater relative risk for CVD complications than men, with poorer outcomes, superimposed on preexisting gender disparities in social determinants of health, lower likelihood of being offered cardioprotective interventions, and enrollment in trials. Further research and the utilization of SGLT-2 inhibitors, GLP-1 receptor agonists, and other CVD prevention strategies will help reduce morbidity and mortality. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Broni, Eric K AU - Broni EK AD - Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Ndumele, Chiadi E AU - Ndumele CE AD - Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Echouffo-Tcheugui, Justin B AU - Echouffo-Tcheugui JB AD - Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Kalyani, Rita R AU - Kalyani RR AD - Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Bennett, Wendy L AU - Bennett WL AD - Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Michos, Erin D AU - Michos ED AD - Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. edonnell@jhmi.edu. AD - Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Blalock 524-B, 600 N. Wolfe Street, Baltimore, MD, 21287, USA. edonnell@jhmi.edu. LA - eng GR - 20SFRN35120152/American Heart Association/ GR - 874772/American Heart Association/ GR - K23 HL153774/HL/NHLBI NIH HHS/United States GR - R01 DK127222/DK/NIDDK NIH HHS/United States GR - K23 HL153774/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20220214 PL - United States TA - Curr Diab Rep JT - Current diabetes reports JID - 101093791 RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Cardiovascular Diseases/etiology MH - *Diabetes Mellitus, Type 2/complications/epidemiology MH - Female MH - Humans MH - Male MH - Pregnancy MH - Risk Assessment MH - Risk Factors MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Cardiovascular diseases OT - Diabetes OT - Gestational diabetes OT - Menopause OT - Obesity OT - Polycystic ovary syndrome EDAT- 2022/02/15 06:00 MHDA- 2022/05/06 06:00 CRDT- 2022/02/14 12:17 PHST- 2021/10/18 00:00 [accepted] PHST- 2022/02/15 06:00 [pubmed] PHST- 2022/05/06 06:00 [medline] PHST- 2022/02/14 12:17 [entrez] AID - 10.1007/s11892-021-01444-x [pii] AID - 10.1007/s11892-021-01444-x [doi] PST - ppublish SO - Curr Diab Rep. 2022 Jan;22(1):11-25. doi: 10.1007/s11892-021-01444-x. Epub 2022 Feb 14. PMID- 35128745 OWN - NLM STAT- MEDLINE DCOM- 20221115 LR - 20230411 IS - 1460-9568 (Electronic) IS - 0953-816X (Print) IS - 0953-816X (Linking) VI - 56 IP - 9 DP - 2022 Nov TI - Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease. PG - 5727-5757 LID - 10.1111/ejn.15619 [doi] AB - Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly co-occur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low-grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti-diabetic agents have a decreased risk for the occurrence of AD and all-cause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon-like peptide 1 (GLP-1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non-insulin anti-diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have T2DM. Many of the trials were conducted prior to the use of diagnostic biomarkers for AD. Trials have had a wide range of durations and population sizes. Many of the agents used to treat T2DM do not cross the blood brain barrier, and the effects are posited to occur via lowering of peripheral hyperglycaemia and reduction of peripheral and central inflammation. Clinical trials of anti-diabetic agents to treat AD are ongoing and will provide insight into the therapeutic utility of these agents. CI - (c) 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. FAU - Cummings, Jeffrey AU - Cummings J AUID- ORCID: 0000-0001-8944-4158 AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA. FAU - Ortiz, Andrew AU - Ortiz A AUID- ORCID: 0000-0002-5432-046X AD - Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA. FAU - Castellino, Janelle AU - Castellino J AD - School of Medicine, University of Nevada Las Vegas, Las Vegas, Nevada, USA. FAU - Kinney, Jefferson AU - Kinney J AD - Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA. AD - Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA. LA - eng GR - P20 AG068053/AG/NIA NIH HHS/United States GR - R35 AG071476/AG/NIA NIH HHS/United States GR - U01 NS093334/NS/NINDS NIH HHS/United States GR - P30 AG072980/AG/NIA NIH HHS/United States GR - P20 GM109025/GM/NIGMS NIH HHS/United States GR - R01 AG053798/AG/NIA NIH HHS/United States GR - R56 AG062762/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220223 PL - France TA - Eur J Neurosci JT - The European journal of neuroscience JID - 8918110 RN - 0 (Hypoglycemic Agents) SB - IM MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Alzheimer Disease/drug therapy MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Risk Factors MH - *Hyperglycemia/chemically induced/complications/drug therapy MH - Inflammation/complications PMC - PMC9393901 MID - NIHMS1778165 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 agonist OT - dapagliflozin OT - diabetes OT - empagliflozin OT - insulin OT - liraglutide OT - metformin OT - mouse model OT - pioglitazone OT - rosiglitazone OT - semaglutide COIS- JC has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPath, Annovis, AriBio, Artery, Avanir, Biogen, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro, Zai Laboratories pharmaceutical, assessment and investment companies. AO, JC and JK have no conflicts of interest. EDAT- 2022/02/08 06:00 MHDA- 2022/11/16 06:00 PMCR- 2022/12/25 CRDT- 2022/02/07 05:40 PHST- 2022/01/25 00:00 [revised] PHST- 2021/10/25 00:00 [received] PHST- 2022/01/27 00:00 [accepted] PHST- 2022/02/08 06:00 [pubmed] PHST- 2022/11/16 06:00 [medline] PHST- 2022/02/07 05:40 [entrez] PHST- 2022/12/25 00:00 [pmc-release] AID - EJN15619 [pii] AID - 10.1111/ejn.15619 [doi] PST - ppublish SO - Eur J Neurosci. 2022 Nov;56(9):5727-5757. doi: 10.1111/ejn.15619. Epub 2022 Feb 23. PMID- 35128376 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231105 IS - 2590-1125 (Electronic) IS - 2590-1125 (Linking) VI - 6 DP - 2022 TI - The effect of GLP-1 receptor agonists in pre-clinical rodent models of Parkinson's disease: A systematic review and meta-analysis. PG - 100133 LID - 10.1016/j.prdoa.2022.100133 [doi] LID - 100133 AB - BACKGROUND: Parkinson's Disease (PD) is a progressive neurodegenerative condition associated with significant morbidity. Currently, there are limited pharmacological options and none of the therapies available are disease-modifying. This systematic review and meta-analysis considers a novel drug class through the research question - in pre-clinical rodent models of PD, is GLP-1 receptor agonist therapy neuroprotective when compared to vehicle controls? METHODS: A literature search was conducted to locate relevant pre-clinical studies. Two separate outcomes were considered. The primary outcome was indicators of dopaminergic neurotransmission. The secondary outcome was indicators of motor symptoms. Untreated PD models were compared to PD-models treated with GLP-1 receptor agonists. The final meta-analysis was conducted using the Cochrane RevMan software and represented continuous data using the inverse variance statistical method and random effects analysis model. The final study statistic was represented as an SMD value with a p-value < 0.05 considered statistically significant. Study heterogeneity and publication bias was assessed using I(2) values and funnel plots respectively. RESULTS: Eleven studies fit the inclusion criteria and were included in the final analysis. For the primary outcome (n = 128), there was a statistically significant relative improvement of dopaminergic neurotransmission (SMD 1.71, 95% CI = 0.74-2.68, p = 0.0005, I(2) = 76%). For the secondary outcome (n = 280), there was a statistically significant improvement in motor outcomes (SMD 2.11, 95% CI = 1.14-3.09, p < 0.0001, I(2) = 89%). CONCLUSIONS: GLP-1 receptor agonist therapy is neuroprotective in pre-clinical models of PD. This study provides the clinical foundation and research support for the design of rigorous clinical trials to further investigate these results in human PD populations. CI - (c) 2022 The Authors. FAU - Dahiya, Simran AU - Dahiya S AD - St Vincent's Clinical School, UNSW, Sydney, NSW, Australia. AD - Level 5 DeLacy Building, St Vincent's Hospital, Victoria St, Darlinghurst, NSW, Australia. FAU - Tisch, Stephen AU - Tisch S AD - St Vincent's Clinical School, UNSW, Sydney, NSW, Australia. AD - Level 5 DeLacy Building, St Vincent's Hospital, Victoria St, Darlinghurst, NSW, Australia. FAU - Greenfield, Jerry AU - Greenfield J AD - St Vincent's Clinical School, UNSW, Sydney, NSW, Australia. AD - Level 5 DeLacy Building, St Vincent's Hospital, Victoria St, Darlinghurst, NSW, Australia. LA - eng PT - Journal Article DEP - 20220119 PL - England TA - Clin Park Relat Disord JT - Clinical parkinsonism & related disorders JID - 101761473 EIN - Clin Park Relat Disord. 2023 Mar 23;8:100193. doi: 10.1016/j.prdoa.2023.100193. PMID: 37223396 PMC - PMC8804263 OTO - NOTNLM OT - GLP-1 receptor agonist OT - Parkinson's Disease OT - Type 2 Diabetes Mellitus EDAT- 2022/02/08 06:00 MHDA- 2022/02/08 06:01 PMCR- 2022/01/19 CRDT- 2022/02/07 05:37 PHST- 2021/07/23 00:00 [received] PHST- 2021/12/16 00:00 [revised] PHST- 2022/01/16 00:00 [accepted] PHST- 2022/02/07 05:37 [entrez] PHST- 2022/02/08 06:00 [pubmed] PHST- 2022/02/08 06:01 [medline] PHST- 2022/01/19 00:00 [pmc-release] AID - S2590-1125(22)00004-4 [pii] AID - 100133 [pii] AID - 10.1016/j.prdoa.2022.100133 [doi] PST - epublish SO - Clin Park Relat Disord. 2022 Jan 19;6:100133. doi: 10.1016/j.prdoa.2022.100133. eCollection 2022. PMID- 35054924 OWN - NLM STAT- MEDLINE DCOM- 20220207 LR - 20261002 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 2 DP - 2022 Jan 10 TI - GLP-1a: Going beyond Traditional Use. LID - 10.3390/ijms23020739 [doi] LID - 739 AB - Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses. FAU - Laurindo, Lucas Fornari AU - Laurindo LF AUID- ORCID: 0000-0003-3159-0982 AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. FAU - Barbalho, Sandra Maria AU - Barbalho SM AUID- ORCID: 0000-0002-5035-876X AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. AD - Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia, Marilia 17525-902, SP, Brazil. AD - Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia 17500-000, SP, Brazil. FAU - Guiguer, Elen Landgraf AU - Guiguer EL AUID- ORCID: 0000-0002-9930-9694 AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. AD - Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia, Marilia 17525-902, SP, Brazil. AD - Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia 17500-000, SP, Brazil. FAU - da Silva Soares de Souza, Maricelma AU - da Silva Soares de Souza M AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. FAU - de Souza, Gabriela Achete AU - de Souza GA AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. FAU - Fidalgo, Thiago Marques AU - Fidalgo TM AD - Department of Psychiatry, Federal University of Sao Paulo, R. Sena Madureira 04021-001, SP, Brazil. FAU - Araujo, Adriano Cressoni AU - Araujo AC AUID- ORCID: 0000-0002-5716-2444 AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. AD - Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia, Marilia 17525-902, SP, Brazil. FAU - de Souza Gonzaga, Heron F AU - de Souza Gonzaga HF AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. AD - Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia, Marilia 17525-902, SP, Brazil. FAU - de Bortoli Teixeira, Daniel AU - de Bortoli Teixeira D AD - Postgraduate Program in Animal Health, Production and Environment, University of Marilia, Marilia 17525-902, SP, Brazil. FAU - de Oliveira Silva Ullmann, Thais AU - de Oliveira Silva Ullmann T AD - Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia, Avenida Higino Muzzi Filho, Marilia 17525-902, SP, Brazil. FAU - Sloan, Katia Portero AU - Sloan KP AD - Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA. FAU - Sloan, Lance Alan AU - Sloan LA AD - Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA. AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. LA - eng PT - Journal Article PT - Systematic Review DEP - 20220110 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Peptide Fragments) RN - 119637-73-9 (glucagon-like peptide 1 (7-36)amide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Clinical Trials as Topic MH - Diabetes Mellitus, Type 2/drug therapy MH - Disease Management MH - Glucagon-Like Peptide 1/metabolism/*pharmacology/*therapeutic use MH - Humans MH - Neurodegenerative Diseases/drug therapy MH - Obesity/drug therapy MH - Peptide Fragments/metabolism/*pharmacology/*therapeutic use MH - Treatment Outcome MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8775408 OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - depression OT - diabetes OT - glucagon-like peptide-1 OT - non-alcoholic fatty liver disease OT - obesity OT - visceral insulin resistance adiposity syndrome COIS- The authors declare no conflict of interest. EDAT- 2022/01/22 06:00 MHDA- 2022/02/08 06:00 PMCR- 2022/01/10 CRDT- 2022/01/21 01:09 PHST- 2021/12/16 00:00 [received] PHST- 2021/12/28 00:00 [revised] PHST- 2021/12/30 00:00 [accepted] PHST- 2022/01/21 01:09 [entrez] PHST- 2022/01/22 06:00 [pubmed] PHST- 2022/02/08 06:00 [medline] PHST- 2022/01/10 00:00 [pmc-release] AID - ijms23020739 [pii] AID - ijms-23-00739 [pii] AID - 10.3390/ijms23020739 [doi] PST - epublish SO - Int J Mol Sci. 2022 Jan 10;23(2):739. doi: 10.3390/ijms23020739. PMID- 35034902 OWN - NLM STAT- MEDLINE DCOM- 20220411 LR - 20240826 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 86 IP - 1 DP - 2022 TI - Glucose-Lowering Medications and Post-Dementia Survival in Patients with Diabetes and Dementia. PG - 245-257 LID - 10.3233/JAD-215337 [doi] AB - BACKGROUND: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. OBJECTIVE: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. METHODS: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia - dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. RESULTS: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24-1.45]) as well as in dementia-free subjects (1.54 [1.10-1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01-1.42]). GLP-1a (0.44 [0.25-0.78]) and SGLT-2i users with dementia (0.43 [0.23-0.80]) experienced lower mortality compared to non-users. CONCLUSION: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients. FAU - Secnik, Juraj AU - Secnik J AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Department of Neurology, Charles University, Second Faculty of Medicine, Motol University Hospital, Prague, Czech Republic. FAU - Xu, Hong AU - Xu H AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Schwertner, Emilia AU - Schwertner E AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. FAU - Hammar, Niklas AU - Hammar N AD - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Alvarsson, Michael AU - Alvarsson M AD - Growth and Metabolism, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Winblad, Bengt AU - Winblad B AD - Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Eriksdotter, Maria AU - Eriksdotter M AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Garcia-Ptacek, Sara AU - Garcia-Ptacek S AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Religa, Dorota AU - Religa D AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Sulfonylurea Compounds) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - IY9XDZ35W2 (Glucose) SB - IM MH - *Dementia/complications MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - Glucagon-Like Peptide 1 MH - Glucose MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Sulfonylurea Compounds/therapeutic use PMC - PMC9028644 OTO - NOTNLM OT - Antidiabetics OT - dementia OT - diabetes OT - hyperglycemia OT - mortality OT - propensity-score COIS- Authors' disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-5337r1). EDAT- 2022/01/18 06:00 MHDA- 2022/04/12 06:00 PMCR- 2022/04/22 CRDT- 2022/01/17 05:43 PHST- 2022/01/18 06:00 [pubmed] PHST- 2022/04/12 06:00 [medline] PHST- 2022/01/17 05:43 [entrez] PHST- 2022/04/22 00:00 [pmc-release] AID - JAD215337 [pii] AID - 10.3233/JAD-215337 [doi] PST - ppublish SO - J Alzheimers Dis. 2022;86(1):245-257. doi: 10.3233/JAD-215337. PMID- 34975451 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220104 IS - 1663-4365 (Print) IS - 1663-4365 (Electronic) IS - 1663-4365 (Linking) VI - 13 DP - 2021 TI - Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer's Disease and Type 2 Diabetes. PG - 741923 LID - 10.3389/fnagi.2021.741923 [doi] LID - 741923 AB - Alzheimer's disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer's disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer's Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 mug/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-beta and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as Abeta aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena. CI - Copyright (c) 2021 Carranza-Naval, del Marco, Hierro-Bujalance, Alves-Martinez, Infante-Garcia, Vargas-Soria, Herrera, Barba-Cordoba, Atienza-Navarro, Lubian-Lopez and Garcia-Alloza. FAU - Carranza-Naval, Maria Jose AU - Carranza-Naval MJ AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. AD - Salus Infirmorum-Universidad de Cadiz, Cadiz, Spain. FAU - Del Marco, Angel AU - Del Marco A AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Hierro-Bujalance, Carmen AU - Hierro-Bujalance C AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Alves-Martinez, Pilar AU - Alves-Martinez P AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Infante-Garcia, Carmen AU - Infante-Garcia C AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Vargas-Soria, Maria AU - Vargas-Soria M AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Herrera, Marta AU - Herrera M AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. FAU - Barba-Cordoba, Belen AU - Barba-Cordoba B AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. FAU - Atienza-Navarro, Isabel AU - Atienza-Navarro I AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Lubian-Lopez, Simon AU - Lubian-Lopez S AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. AD - Section of Neonatology, Division of Pediatrics, Hospital Universitario Puerta del Mar, Cadiz, Spain. FAU - Garcia-Alloza, Monica AU - Garcia-Alloza M AD - Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. LA - eng PT - Journal Article DEP - 20211216 PL - Switzerland TA - Front Aging Neurosci JT - Frontiers in aging neuroscience JID - 101525824 PMC - PMC8716860 OTO - NOTNLM OT - Alzheimer's disease OT - hemorrhage OT - inflammation OT - liraglutide OT - neuronal loss OT - type 2 diabetes COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/01/04 06:00 MHDA- 2022/01/04 06:01 PMCR- 2021/01/01 CRDT- 2022/01/03 05:35 PHST- 2021/07/15 00:00 [received] PHST- 2021/10/20 00:00 [accepted] PHST- 2022/01/03 05:35 [entrez] PHST- 2022/01/04 06:00 [pubmed] PHST- 2022/01/04 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fnagi.2021.741923 [doi] PST - epublish SO - Front Aging Neurosci. 2021 Dec 16;13:741923. doi: 10.3389/fnagi.2021.741923. eCollection 2021. PMID- 34943038 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220113 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 12 DP - 2021 Dec 2 TI - Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease-Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors. LID - 10.3390/antiox10121935 [doi] LID - 1935 AB - Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic-lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors. FAU - Lin, Kai-Jung AU - Lin KJ AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Family Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan. FAU - Wang, Tzu-Jou AU - Wang TJ AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Pediatric, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Chen, Shang-Der AU - Chen SD AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Lin, Kai-Lieh AU - Lin KL AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Liou, Chia-Wei AU - Liou CW AUID- ORCID: 0000-0002-9003-4065 AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Lan, Min-Yu AU - Lan MY AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Chuang, Yao-Chung AU - Chuang YC AUID- ORCID: 0000-0001-9131-7385 AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Chuang, Jiin-Haur AU - Chuang JH AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Wang, Pei-Wen AU - Wang PW AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Lee, Jong-Jer AU - Lee JJ AUID- ORCID: 0000-0002-9213-0288 AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. FAU - Wang, Feng-Sheng AU - Wang FS AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan. FAU - Lin, Hung-Yu AU - Lin HY AUID- ORCID: 0000-0002-9035-5408 AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan. FAU - Lin, Tsu-Kung AU - Lin TK AUID- ORCID: 0000-0001-6656-1319 AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. LA - eng GR - MOST 109-2314-B-182A-076-MY3/Ministry of Science and Technology in Taiwan/ GR - CRRPG8K0031/Chang Gung Memorial Hospital, Medical Research Projects/ PT - Journal Article PT - Review DEP - 20211202 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC8750793 OTO - NOTNLM OT - Parkinson's disease OT - SGLT2 OT - antioxidative effects OT - diabetes OT - metabolic syndrome OT - mitochondrial dysfunction OT - oxidative stress COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/12/25 06:00 MHDA- 2021/12/25 06:01 PMCR- 2021/12/02 CRDT- 2021/12/24 01:01 PHST- 2021/10/23 00:00 [received] PHST- 2021/11/25 00:00 [revised] PHST- 2021/11/29 00:00 [accepted] PHST- 2021/12/24 01:01 [entrez] PHST- 2021/12/25 06:00 [pubmed] PHST- 2021/12/25 06:01 [medline] PHST- 2021/12/02 00:00 [pmc-release] AID - antiox10121935 [pii] AID - antioxidants-10-01935 [pii] AID - 10.3390/antiox10121935 [doi] PST - epublish SO - Antioxidants (Basel). 2021 Dec 2;10(12):1935. doi: 10.3390/antiox10121935. PMID- 34942949 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211229 IS - 2076-3425 (Print) IS - 2076-3425 (Electronic) IS - 2076-3425 (Linking) VI - 11 IP - 12 DP - 2021 Dec 15 TI - Brain Imaging of the GLP-1 Receptor in Obesity Using (68)Ga-NODAGA-Exendin-4 PET. LID - 10.3390/brainsci11121647 [doi] LID - 1647 AB - Stimulation of glucagon-like peptide-1 (GLP-1) receptors increases the insulin release in the pancreas during high glucose levels, and also stimulates a feeling of satiety. Likewise, synthetic GLP-1 receptor agonists derived from exendin are used successfully in the treatment of type-2 diabetes mellitus and obesity. Interestingly, preclinical and clinical studies further suggest that GLP-1 receptor agonists may decrease motor, behavioral, and cognitive symptoms in (animal models) Parkinson's disease and Alzheimer's disease and may slow down neurodegeneration. These observations suggest stimulation of GLP-1 receptors in the brain. The GLP-1 positron emission tomography (PET) tracer (68)Ga-NODAGA-exendin-4 has been developed and successfully used for imaging in humans. In an ongoing study on the effects of bariatric surgery on GLP-1 receptor expression, we performed (68)Ga-NODAGA-exendin-4 PET in obese subjects. Here we evaluated whether GLP-1 receptor binding could be visualized in the central nervous system in 10 obese subjects (seven woman; body mass index: mean +/- SD: 39 +/- 4.4 kg/m(2)) before bariatric surgery. Although we observed clear uptake in the pituitary area (mean SUV(max) 4.3 +/- 2.3), we found no significant uptake in other parts of the brain. We conclude that (68)Ga-NODAGA-exendin-4 PET cannot be used to analyze GLP-1 receptors in the brain of obese subjects. FAU - Deden, Laura N AU - Deden LN AUID- ORCID: 0000-0002-1243-5111 AD - Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. AD - Department of Surgery, Vitalys Clinic, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands. FAU - Booij, Jan AU - Booij J AD - Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. AD - Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands. FAU - Grandjean, Joanes AU - Grandjean J AD - Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. AD - Center for Medical Neuroscience, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands. FAU - Homberg, Judith R AU - Homberg JR AUID- ORCID: 0000-0002-7621-1010 AD - Center for Medical Neuroscience, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands. FAU - Hazebroek, Eric J AU - Hazebroek EJ AD - Department of Surgery, Vitalys Clinic, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands. AD - Division of Human Nutrition and Health, Wageningen University, 6708 PB Wageningen, The Netherlands. FAU - Gotthardt, Martin AU - Gotthardt M AD - Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. FAU - Boss, Marti AU - Boss M AD - Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. LA - eng PT - Journal Article DEP - 20211215 PL - Switzerland TA - Brain Sci JT - Brain sciences JID - 101598646 PMC - PMC8699257 OTO - NOTNLM OT - 68Ga-NODAGA-exendin-4 OT - GLP-1 receptor OT - PET OT - brain OT - obesity COIS- All authors declare no conflict of interest. EDAT- 2021/12/25 06:00 MHDA- 2021/12/25 06:01 PMCR- 2021/12/15 CRDT- 2021/12/24 01:01 PHST- 2021/11/17 00:00 [received] PHST- 2021/12/10 00:00 [revised] PHST- 2021/12/10 00:00 [accepted] PHST- 2021/12/24 01:01 [entrez] PHST- 2021/12/25 06:00 [pubmed] PHST- 2021/12/25 06:01 [medline] PHST- 2021/12/15 00:00 [pmc-release] AID - brainsci11121647 [pii] AID - brainsci-11-01647 [pii] AID - 10.3390/brainsci11121647 [doi] PST - epublish SO - Brain Sci. 2021 Dec 15;11(12):1647. doi: 10.3390/brainsci11121647. PMID- 34942358 OWN - NLM STAT- MEDLINE DCOM- 20220125 LR - 20220531 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 170 DP - 2022 Mar 1 TI - Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1. PG - 106105 LID - S0928-0987(21)00406-1 [pii] LID - 10.1016/j.ejps.2021.106105 [doi] AB - INTRODUCTION: Obesity is associated with elevated endocannabinoid tone, gut dysbiosis, and inflammation predisposing to diabetes. The endocannabinoid system mediates the effects of gut microbiota and regulates the gut barrier integrity. We examined the effects of vitamin D (VD) on colonic cannabinoid receptor 1(CB1R), tight junction proteins, gut dysbiosis, metabolic and cognitive dysfunction in a model of type 2 diabetes compared with metformin. METHODS: Rats received high-fat, high-sucrose diet (HFSD) and either VD (500 IU/kg/day; p.o.), or metformin (200 mg/kg/day; p.o.) for 8 weeks. After 6 weeks, streptozotocin (STZ) (40 mg/kg; i.p) was injected. Behavioral, cognitive, and metabolic assessments were carried out. Finally, fecal, blood, and tissue samples were collected to examine Bacteroidetes/Firmicutes ratio, colonic CB1R, zonula occludens-1 (ZO-1), occludin, and Toll-like receptor 4 (TLR4); serum lipopolysaccharides (LPS), peptidoglycan (PGN), tumor necrosis factor-alpha (TNF-a), glucagon-like peptide-1 (GLP-1), lipids, and VD; hippocampal brain-derived neurotrophic factor (BDNF) and inflammatory markers. RESULTS: VD ameliorated HFSD/STZ-induced dysbiosis/gut barrier dysfunction as indicated by lower circulating LPS, PGN and TNF-a levels, likely by downregulating colonic CB1R and upregulating ZO-1 and occludin expressions. Additionally, VD suppressed HFSD/STZ-induced hyperglycemia, hyperinsulinemia, dyslipidemia, and hippocampal neuroinflammation. These changes culminated in improved glycemic control and cognitive function. VD was more effective than metformin in decreasing serum LPS and TNF-a levels; whereas metformin resulted in better glycemic control. CONCLUSION: Targeting gut microbiota by VD could be a successful strategy in the treatment of diabetes and associated cognitive deficit. The crosstalk between VD axis and the endocannabinoid system needs further exploration. CI - Copyright (c) 2021. Published by Elsevier B.V. FAU - Hussein, Hebatallah M AU - Hussein HM AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini street, Cairo 11562, Egypt. FAU - Elyamany, Mohammed F AU - Elyamany MF AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini street, Cairo 11562, Egypt. FAU - Rashed, Laila A AU - Rashed LA AD - Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Egypt. FAU - Sallam, Nada A AU - Sallam NA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini street, Cairo 11562, Egypt. Electronic address: nada.sallam@pharma.cu.edu.eg. LA - eng PT - Journal Article DEP - 20211220 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 0 (Receptor, Cannabinoid, CB1) RN - 0 (Receptors, Cannabinoid) RN - 1406-16-2 (Vitamin D) SB - IM MH - Animals MH - *Cognitive Dysfunction MH - *Diabetes Mellitus, Type 2 MH - Diet, High-Fat MH - *Gastrointestinal Microbiome MH - Mice MH - Mice, Inbred C57BL MH - Neuroinflammatory Diseases MH - Rats MH - *Receptor, Cannabinoid, CB1 MH - Receptors, Cannabinoid MH - Vitamin D OTO - NOTNLM OT - CB1R OT - Cognitive function OT - Diabetes OT - Gut microbiota OT - Obesity OT - Vitamin D EDAT- 2021/12/24 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/12/23 20:15 PHST- 2021/07/19 00:00 [received] PHST- 2021/11/14 00:00 [revised] PHST- 2021/12/17 00:00 [accepted] PHST- 2021/12/24 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/12/23 20:15 [entrez] AID - S0928-0987(21)00406-1 [pii] AID - 10.1016/j.ejps.2021.106105 [doi] PST - ppublish SO - Eur J Pharm Sci. 2022 Mar 1;170:106105. doi: 10.1016/j.ejps.2021.106105. Epub 2021 Dec 20. PMID- 34941464 OWN - NLM STAT- MEDLINE DCOM- 20220225 LR - 20250103 IS - 1744-7658 (Electronic) IS - 1354-3784 (Linking) VI - 31 IP - 1 DP - 2022 Jan TI - New treatment approaches for Alzheimer's disease: preclinical studies and clinical trials centered on antidiabetic drugs. PG - 105-123 LID - 10.1080/13543784.2022.2022122 [doi] AB - INTRODUCTION: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD. AREAS COVERED: This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment. EXPERT OPINION: Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS. FAU - Katsenos, Andreas P AU - Katsenos AP AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. AD - Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece. FAU - Davri, Athena S AU - Davri AS AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. FAU - Simos, Yannis V AU - Simos YV AUID- ORCID: 0000-0003-1764-8906 AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. AD - Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece. FAU - Nikas, Ilias P AU - Nikas IP AD - School of Medicine, European University Cyprus, Nicosia, Cyprus. FAU - Bekiari, Chryssa AU - Bekiari C AD - Laboratory of Anatomy and Histology, school of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. FAU - Paschou, Stavroula A AU - Paschou SA AD - Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Peschos, Dimitrios AU - Peschos D AUID- ORCID: 0000-0002-5490-0755 AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. AD - Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece. FAU - Konitsiotis, Spyridon AU - Konitsiotis S AD - Department of Neurology, University Hospital of Ioannina, Ioannina, Greece. FAU - Vezyraki, Patra AU - Vezyraki P AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. FAU - Tsamis, Konstantinos I AU - Tsamis KI AUID- ORCID: 0000-0002-7032-1630 AD - Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. AD - Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece. AD - Department of Neurology, University Hospital of Ioannina, Ioannina, Greece. LA - eng PT - Journal Article PT - Review DEP - 20220102 PL - England TA - Expert Opin Investig Drugs JT - Expert opinion on investigational drugs JID - 9434197 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Alzheimer Disease/drug therapy MH - *Diabetes Mellitus, Type 2/drug therapy/epidemiology MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Randomized Controlled Trials as Topic MH - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer disease OT - GLP-1 receptor agonists OT - SGLT2 inhibitors OT - T2DM OT - antidiabetics OT - b-amyloid OT - hippocampus OT - insulin OT - metformin OT - neuroprotection EDAT- 2021/12/24 06:00 MHDA- 2022/02/26 06:00 CRDT- 2021/12/23 17:16 PHST- 2021/12/24 06:00 [pubmed] PHST- 2022/02/26 06:00 [medline] PHST- 2021/12/23 17:16 [entrez] AID - 10.1080/13543784.2022.2022122 [doi] PST - ppublish SO - Expert Opin Investig Drugs. 2022 Jan;31(1):105-123. doi: 10.1080/13543784.2022.2022122. Epub 2022 Jan 2. PMID- 34857046 OWN - NLM STAT- MEDLINE DCOM- 20220309 LR - 20220309 IS - 1758-9193 (Electronic) VI - 13 IP - 1 DP - 2021 Dec 2 TI - The association of antidiabetic medications and Mini-Mental State Examination scores in patients with diabetes and dementia. PG - 197 LID - 10.1186/s13195-021-00934-0 [doi] LID - 197 AB - BACKGROUND: The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia. METHODS: Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer's disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout. RESULTS: Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (-1.00, -1.95; -0.04) and sulfonylureas (-1.19; -2.33; -0.04) was associated with larger point-wise decrements in MMSE with annual intervals. CONCLUSIONS: In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted. CI - (c) 2021. The Author(s). FAU - Secnik, Juraj AU - Secnik J AUID- ORCID: 0000-0002-1532-3967 AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. juraj.secnik@ki.se. AD - Department of Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic. juraj.secnik@ki.se. FAU - Xu, Hong AU - Xu H AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Schwertner, Emilia AU - Schwertner E AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. FAU - Hammar, Niklas AU - Hammar N AD - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Alvarsson, Michael AU - Alvarsson M AD - Growth and Metabolism, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Winblad, Bengt AU - Winblad B AD - Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Eriksdotter, Maria AU - Eriksdotter M AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Garcia-Ptacek, Sara AU - Garcia-Ptacek S AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Religa, Dorota AU - Religa D AD - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagangen 16, 14152, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211202 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Sulfonylurea Compounds) SB - IM MH - *Dementia/complications/drug therapy/epidemiology MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Sulfonylurea Compounds/therapeutic use PMC - PMC8641148 OTO - NOTNLM OT - Antidiabetics OT - DPP-4i OT - Dementia OT - Diabetes OT - MMSE OT - Metformin COIS- The authors declare that they have no competing interests. EDAT- 2021/12/04 06:00 MHDA- 2022/03/11 06:00 PMCR- 2021/12/02 CRDT- 2021/12/03 05:44 PHST- 2021/09/13 00:00 [received] PHST- 2021/11/09 00:00 [accepted] PHST- 2021/12/03 05:44 [entrez] PHST- 2021/12/04 06:00 [pubmed] PHST- 2022/03/11 06:00 [medline] PHST- 2021/12/02 00:00 [pmc-release] AID - 10.1186/s13195-021-00934-0 [pii] AID - 934 [pii] AID - 10.1186/s13195-021-00934-0 [doi] PST - epublish SO - Alzheimers Res Ther. 2021 Dec 2;13(1):197. doi: 10.1186/s13195-021-00934-0. PMID- 34842187 OWN - NLM STAT- MEDLINE DCOM- 20220228 LR - 20220228 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 85 IP - 2 DP - 2022 TI - A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease. PG - 485-501 LID - 10.3233/JAD-210612 [doi] AB - Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3beta, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities. FAU - Lynn, Jessica AU - Lynn J AD - Massachusetts College of Pharmacy & Health Sciences (MCPHS University)/Takeda Pharmaceuticals Biopharmaceutical Industry Fellowship Program, Boston, MA, USA. FAU - Park, Mingi AU - Park M AD - Massachusetts College of Pharmacy & Health Sciences (MCPHS University)/Takeda Pharmaceuticals Biopharmaceutical Industry Fellowship Program, Boston, MA, USA. FAU - Ogunwale, Christiana AU - Ogunwale C AD - Walgreen Company, Houston, TX, USA. FAU - Acquaah-Mensah, George K AU - Acquaah-Mensah GK AD - Massachusetts College of Pharmacy & Health Sciences (MCPHS University)/Takeda Pharmaceuticals Biopharmaceutical Industry Fellowship Program, Boston, MA, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Biomarkers) RN - 0 (Glycation End Products, Advanced) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Alzheimer Disease/*chemically induced/*metabolism/therapy MH - Animals MH - Biomarkers/metabolism MH - Brain Chemistry/*physiology MH - Cognitive Dysfunction/metabolism MH - Diabetes Mellitus, Type 2/*complications MH - Glucose/*metabolism MH - Glycation End Products, Advanced/metabolism MH - Humans MH - Inflammation/metabolism MH - Insulin Resistance MH - Oxidative Stress/physiology MH - Randomized Controlled Trials as Topic OTO - NOTNLM OT - Alzheimer's disease OT - amyloid OT - blood-brain barrier OT - glucagon-like peptide 1 OT - insulin resistance OT - microbiota OT - mitochondria OT - oxidative stress OT - therapeutics OT - type 2 diabetes mellitus EDAT- 2021/11/30 06:00 MHDA- 2022/03/01 06:00 CRDT- 2021/11/29 09:00 PHST- 2021/11/30 06:00 [pubmed] PHST- 2022/03/01 06:00 [medline] PHST- 2021/11/29 09:00 [entrez] AID - JAD210612 [pii] AID - 10.3233/JAD-210612 [doi] PST - ppublish SO - J Alzheimers Dis. 2022;85(2):485-501. doi: 10.3233/JAD-210612. PMID- 34817756 OWN - NLM STAT- MEDLINE DCOM- 20220407 LR - 20261012 IS - 1573-7365 (Electronic) IS - 0885-7490 (Linking) VI - 37 IP - 2 DP - 2022 Feb TI - Neuroprotective effects of liraglutide against inflammation through the AMPK/NF-kappaB pathway in a mouse model of Parkinson's disease. PG - 451-462 LID - 10.1007/s11011-021-00879-1 [doi] AB - Parkinson's disease (PD) is a neurodegenerative disease with increasing incidence in aged populations, second only to Alzheimer's disease. Increasing evidence has shown that inflammation plays an important role in the occurrence and development of Parkinson's disease. Growing evidence has shown that AMP-activated protein kinase (AMPK) and NF-kappaB are closely related to inflammation. Glucagon-like peptide 1 (GLP-1) is a hormone that is primarily secreted by intestinal endocrine L cells, and it has a variety of physiology through binding to GLP-1 receptor. GLP-1can be used for treatment of type 2 diabetes. In addition, GLP-1 also has anti-neuroinflammation activity. However, the exact mechanism behind how GLP-1 regulates neuroinflammation remains unclear. This study was designed to examine the effect of liraglutide on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced injury in mice and its potential mechanism of action. Results showed that liraglutide dose-dependently ameliorated mouse behavior including swimming time and locomotor activity, increased the number of tyrosine hydroxylase (TH)-positive neurons and protein level, and reduced Iba1 and GFAP expression in the substantia nigra (SN). Liraglutide treatment also increased p-AMPK expression and reduced NF-kappaB protein level. Applying the AMPK inhibitor Dorsomorphin (Compound C) reversed the effect of liraglutide-reducing p-AMPK and increasing NF-kappaB expression. Finally, GFAP protein level increased, along with a decrease in TH expression. In conclusion, these results suggest that liraglutide can suppress neuroinflammation. Moreover, this effect is mediated through the AMPK/NF-kappaB signaling pathway. CI - (c) 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Cao, Bing AU - Cao B AD - Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China. FAU - Zhang, Yanqiu AU - Zhang Y AD - Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China. FAU - Chen, Jinhu AU - Chen J AD - Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People's Republic of China. FAU - Wu, Pengyue AU - Wu P AD - Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China. FAU - Dong, Yuxuan AU - Dong Y AD - Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China. FAU - Wang, Yanqin AU - Wang Y AUID- ORCID: 0000-0001-5056-1963 AD - Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China. yqw1016@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211124 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 RN - 0 (NF-kappa B) RN - 0 (Neuroprotective Agents) RN - 839I73S42A (Liraglutide) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - Disease Models, Animal MH - Inflammation/drug therapy MH - Liraglutide/pharmacology/therapeutic use MH - Mice MH - NF-kappa B MH - *Neurodegenerative Diseases MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - *Parkinson Disease/drug therapy/metabolism OTO - NOTNLM OT - AMPK OT - Liraglutide OT - NF-kappaB OT - Neuroinflammation OT - Parkinson's disease EDAT- 2021/11/25 06:00 MHDA- 2022/04/08 06:00 CRDT- 2021/11/24 12:28 PHST- 2021/08/30 00:00 [received] PHST- 2021/11/15 00:00 [accepted] PHST- 2021/11/25 06:00 [pubmed] PHST- 2022/04/08 06:00 [medline] PHST- 2021/11/24 12:28 [entrez] AID - 10.1007/s11011-021-00879-1 [pii] AID - 10.1007/s11011-021-00879-1 [doi] PST - ppublish SO - Metab Brain Dis. 2022 Feb;37(2):451-462. doi: 10.1007/s11011-021-00879-1. Epub 2021 Nov 24. PMID- 34717786 OWN - NLM STAT- MEDLINE DCOM- 20211102 LR - 20240610 IS - 2639-9636 (Print) IS - 2639-9644 (Electronic) IS - 2639-9636 (Linking) VI - 36 IP - 11 DP - 2021 Nov 1 TI - Applying the Social-Ecological Approach to Evaluate Diabetes Medication Management in Older People. PG - 548-555 LID - 10.4140/TCP.n.2021.548 [doi] AB - Glucagonlike peptide-1 receptor agonist is a common antidiabetic medication class to lower HbA1c, weight, and cardiovascular risk. This case study describes the challenges a patient with uncontrolled diabetes faced after receiving a prescription for liraglutide because of multiple levels of influence, including individual, family, institutional, and policy level barriers. The case highlights the importance of utilizing a person-centered care approach by evaluating patient's preferences, visual and motor coordination, cognitive function, psychological stress, and medication cost before prescribing injectable products for elderly patients. FAU - Poon, Ivy O AU - Poon IO AD - Texas Southern University, College of Pharmacy and Health Sciences, Houston, Texas. FAU - Ogboe, Christopher W AU - Ogboe CW AD - Texas Southern University, College of Pharmacy and Health Sciences, Houston, Texas. LA - eng GR - G12 MD007605/MD/NIMHD NIH HHS/United States GR - U54 MD007605/MD/NIMHD NIH HHS/United States PT - Journal Article PL - United States TA - Sr Care Pharm JT - The Senior care pharmacist JID - 101737969 RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) SB - IM MH - Aged MH - *Diabetes Mellitus, Type 2/drug therapy MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Liraglutide/therapeutic use MH - *Medication Therapy Management PMC - PMC8663919 MID - NIHMS1756466 COIS- The authors have no financial conflict to disclose. EDAT- 2021/11/01 06:00 MHDA- 2021/11/03 06:00 PMCR- 2021/12/10 CRDT- 2021/10/31 20:40 PHST- 2021/10/31 20:40 [entrez] PHST- 2021/11/01 06:00 [pubmed] PHST- 2021/11/03 06:00 [medline] PHST- 2021/12/10 00:00 [pmc-release] AID - 10.4140/TCP.n.2021.548 [doi] PST - ppublish SO - Sr Care Pharm. 2021 Nov 1;36(11):548-555. doi: 10.4140/TCP.n.2021.548. PMID- 34678725 OWN - NLM STAT- MEDLINE DCOM- 20220125 LR - 20260127 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 144 DP - 2021 Dec TI - Effect of deprescribing in elderly patients with type 2 diabetes: iDegLira might improve quality of life. PG - 112341 LID - S0753-3322(21)01125-2 [pii] LID - 10.1016/j.biopha.2021.112341 [doi] AB - Older people with type 2 diabetes (T2D) often have several comorbidities and take multiple drugs. This study tested a deprescribing strategy in older T2D patients, replacing a hypoglycemic therapeutic scheme with a single drug combination (iDegLira). In this 6-month, real-world, single-arm, open interventional study, we enrolled patients >/= 75 years with T2D taking >/= 2 medications for diabetes. Patients on a basal-bolus insulin regimen (n = 13), on a basal-insulin regimen plus oral glucose-lowering drugs (n = 9), and those on oral glucose-lowering drugs (n = 18) were switched to daily iDegLira. The primary clinical endpoint of the study was an improvement in CASP-19 and/or DTSQ score after 6 months. We also evaluated changes in glucose metabolism, depression, cognitive function, level of independence, and markers of inflammation. Thirty-five patients (12 women, mean age=81.4 y) completed the protocol. Results shown here are given as estimated mean difference (95%CI). DTSQ score improved [11.08 (7.13/15.02); p = 0.0001], whereas CASP-19 did not after 6 months of iDegLira treatment. We observed reductions in BMI [- 0.81 (- 1.27/0.35); p < 0.001], fasting glucose [- 52.07 (- 77.26/26.88); p < 0.001], HbA1c [- 0.58 (- 1.08/0.08); p < 0.05], and TNF-alpha [- 1.83 (- 3.12/- 0.54); p = 0.007]. Activities of daily living and cognitive function score increased [p = 0.006 and p = 0.02], whereas depression score significantly decreased [p = 0.02]. Notably, no patient reported episodes of severe hypoglycemia after initiation of iDegLira treatment. Among older patients with T2D, deprescribing using a single dose of iDegLira resulted in a greater likelihood of improving health and quality of life. Although our data indicate the effectiveness and safety of this approach, it must be confirmed in larger studies. CI - Copyright (c) 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Rizza, Stefano AU - Rizza S AD - Department of System Medicine, University of Rome Tor Vergata, Italy. Electronic address: stefano.rizza@uniroma2.it. FAU - Piciucchi, Giacomo AU - Piciucchi G AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Mavilio, Maria AU - Mavilio M AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Longo, Susanna AU - Longo S AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Montagna, Martina AU - Montagna M AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Tatonetti, Riccardo AU - Tatonetti R AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Nucera, Alessandro AU - Nucera A AD - Department of System Medicine, University of Rome Tor Vergata, Italy. FAU - Federici, Massimo AU - Federici M AD - Department of System Medicine, University of Rome Tor Vergata, Italy. LA - eng PT - Journal Article DEP - 20211019 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Drug Combinations) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin, Long-Acting) RN - 839I73S42A (Liraglutide) RN - 0 (IDegLira) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Biomarkers/blood MH - Blood Glucose/*drug effects/metabolism MH - Comorbidity MH - *Deprescriptions MH - Diabetes Mellitus, Type 2/blood/diagnosis/*drug therapy/epidemiology MH - Drug Combinations MH - Female MH - Glycated Hemoglobin/metabolism MH - Health Status MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Insulin, Long-Acting/adverse effects/*therapeutic use MH - Italy/epidemiology MH - Liraglutide/adverse effects/*therapeutic use MH - Male MH - Pilot Projects MH - Polypharmacy MH - *Quality of Life MH - Time Factors MH - Treatment Outcome OTO - NOTNLM OT - Deprescribing OT - Diabetes OT - Elderly OT - IDegLira OT - Quality of life EDAT- 2021/10/23 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/10/22 20:50 PHST- 2021/09/22 00:00 [received] PHST- 2021/10/11 00:00 [revised] PHST- 2021/10/13 00:00 [accepted] PHST- 2021/10/23 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/10/22 20:50 [entrez] AID - S0753-3322(21)01125-2 [pii] AID - 10.1016/j.biopha.2021.112341 [doi] PST - ppublish SO - Biomed Pharmacother. 2021 Dec;144:112341. doi: 10.1016/j.biopha.2021.112341. Epub 2021 Oct 19. PMID- 34676939 OWN - NLM STAT- MEDLINE DCOM- 20211124 LR - 20220531 IS - 1460-9568 (Electronic) IS - 0953-816X (Linking) VI - 54 IP - 10 DP - 2021 Nov TI - Potential new therapeutic target for Alzheimer's disease: Glucagon-like peptide-1. PG - 7749-7769 LID - 10.1111/ejn.15502 [doi] AB - Increasing evidence shows a close relationship between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Recently, glucagon-like peptide-1 (GLP-1), a gut incretin hormone, has become a well-established treatment for T2DM and is likely to be involved in treating cognitive impairment. In this mini review, the similarities between AD and T2DM are summarised with the main focus on GLP-1-based therapeutics in AD. CI - (c) 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd. FAU - Liu, Xiao-Yu AU - Liu XY AUID- ORCID: 0000-0001-5028-5436 AD - Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China. FAU - Zhang, Ni AU - Zhang N AD - Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China. FAU - Zhang, Sheng-Xiao AU - Zhang SX AD - Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China. AD - Key laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Shanxi, China. FAU - Xu, Ping AU - Xu P AD - Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20211107 PL - France TA - Eur J Neurosci JT - The European journal of neuroscience JID - 8918110 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Alzheimer Disease/drug therapy MH - *Cognitive Dysfunction MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide 1 MH - Humans OTO - NOTNLM OT - Alzheimer's disease OT - glucagon-like peptide-1 OT - learning and memory OT - neuroprotection OT - type 2 diabetes mellitus EDAT- 2021/10/23 06:00 MHDA- 2021/11/25 06:00 CRDT- 2021/10/22 08:50 PHST- 2021/10/06 00:00 [revised] PHST- 2021/03/24 00:00 [received] PHST- 2021/10/07 00:00 [accepted] PHST- 2021/10/23 06:00 [pubmed] PHST- 2021/11/25 06:00 [medline] PHST- 2021/10/22 08:50 [entrez] AID - 10.1111/ejn.15502 [doi] PST - ppublish SO - Eur J Neurosci. 2021 Nov;54(10):7749-7769. doi: 10.1111/ejn.15502. Epub 2021 Nov 7. PMID- 34676876 OWN - NLM STAT- MEDLINE DCOM- 20220209 LR - 20260127 IS - 1791-244X (Electronic) IS - 1107-3756 (Print) IS - 1107-3756 (Linking) VI - 48 IP - 6 DP - 2021 Dec TI - Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole‑kindled mice. LID - 219 [pii] LID - 10.3892/ijmm.2021.5052 [doi] AB - Epilepsy comorbidities and anti‑epileptic drugs (AEDs) are currently the main limitations of epilepsy treatment. Semaglutide is a glucagon like peptide‑1 analogue that has entered the market as a new once‑weekly drug for type II diabetes. The aim of the present study was to investigate the functions of semaglutide in epilepsy and inflammation models, in order to investigate its potential mechanism. In vitro, an inflammation model was established using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. In vivo, chronic epilepsy model mice were generated using a pentylenetetrazole (PTZ) kindling method. BV2 cell proliferation was assessed using the Cell Counting Kit‑8. The effects of semaglutide on NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and inflammatory cytokine secretion were determined using western blotting (WB) and ELISA. A lactate dehydrogenase (LDH) assay kit was used to detect the effect of semaglutide on LDH release. Electrocorticography and the modified Racine scale were used to assess seizure severity. Cognitive function was evaluated with behavioral assessment. Morphological changes in the hippocampus were observed with Nissl staining. Double immunofluorescence staining for NeuN and Iba‑1, WB and immunofluorescence analysis of apoptosis‑related proteins were used to evaluate neuronal apoptosis. The NLRP3 inflammasome was assessed by reverse transcription‑quantitative PCR, WB and immunofluorescence staining, and inflammatory cytokine release was evaluated by WB analysis in the hippocampus of C57/BL6J model mouse. Semaglutide attenuated the LPS‑ and nigericin‑induced inflammatory response and LDH release by blocking NLRP3 inflammasome activation in BV2 cells. Moreover, semaglutide decreased seizure severity, alleviated hippocampal neuronal apoptosis, ameliorated cognitive dysfunction, blocked NLRP3 inflammasome activation and decreased inflammatory cytokine secretion in PTZ‑kindled mice. These results indicated that semaglutide reduced seizure severity, exerted neuroprotective effects and ameliorated cognitive dysfunction, possibly via inhibition of NLRP3 inflammasome activation and inflammatory cytokine secretion. Semaglutide may therefore be a novel, promising adjuvant therapeutic for epilepsy and its associated comorbidities. FAU - Wang, Lei AU - Wang L AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Ding, Jiangwei AU - Ding J AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Zhu, Changliang AU - Zhu C AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Guo, Baorui AU - Guo B AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Yang, Wu AU - Yang W AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - He, Wenxin AU - He W AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Li, Xinxiao AU - Li X AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Wang, Yangyang AU - Wang Y AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Li, Wenchao AU - Li W AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. FAU - Wang, Feng AU - Wang F AD - Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, P.R. China. FAU - Sun, Tao AU - Sun T AD - Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China. LA - eng PT - Journal Article DEP - 20211022 PL - Greece TA - Int J Mol Med JT - International journal of molecular medicine JID - 9810955 RN - 0 (Cytokines) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Neuroprotective Agents) RN - WM5Z385K7T (Pentylenetetrazole) RN - 53AXN4NNHX (Semaglutide) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Cell Line MH - Cognitive Dysfunction/*drug therapy/metabolism MH - Cytokines/metabolism MH - Disease Models, Animal MH - Epilepsy/drug therapy/metabolism MH - Glucagon-Like Peptides/*pharmacology MH - Hippocampus/drug effects/metabolism MH - Inflammasomes/*drug effects/metabolism MH - Inflammation/drug therapy/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microglia/drug effects/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Neuroprotective Agents/pharmacology MH - Pentylenetetrazole/*pharmacology MH - Seizures/*drug therapy/metabolism MH - Semaglutide PMC - PMC8547541 OTO - NOTNLM OT - NLR family pyrin domain containing 3 inflammasome OT - cognitive dysfunction OT - epilepsy OT - glucagon like peptide‑1 OT - neuroprotection OT - semaglutide COIS- The authors declare that they have no competing interests. EDAT- 2021/10/23 06:00 MHDA- 2022/02/10 06:00 PMCR- 2021/10/20 CRDT- 2021/10/22 08:45 PHST- 2021/08/05 00:00 [received] PHST- 2021/10/05 00:00 [accepted] PHST- 2021/10/22 08:45 [entrez] PHST- 2021/10/23 06:00 [pubmed] PHST- 2022/02/10 06:00 [medline] PHST- 2021/10/20 00:00 [pmc-release] AID - 219 [pii] AID - ijmm-48-06-05052 [pii] AID - 10.3892/ijmm.2021.5052 [doi] PST - ppublish SO - Int J Mol Med. 2021 Dec;48(6):219. doi: 10.3892/ijmm.2021.5052. Epub 2021 Oct 22. PMID- 34647685 OWN - NLM STAT- MEDLINE DCOM- 20220425 LR - 20250103 IS - 1552-5279 (Electronic) IS - 1552-5260 (Print) IS - 1552-5260 (Linking) VI - 18 IP - 3 DP - 2022 Mar TI - Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon-like peptide-1 receptor agonists. PG - 478-497 LID - 10.1002/alz.12474 [doi] AB - Medications for type 2 diabetes (T2DM) offer a promising path for discovery and development of effective interventions for dementia syndromes. A common feature of dementia syndromes is an energy failure due to reduced energy supply to neurons and is associated with synaptic loss and results in cognitive decline and behavioral changes. Among diabetes medications, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) promote protective effects on vascular, microglial, and neuronal functions. In this review, we present evidence from animal models, imaging studies, and clinical trials that support developing GLP-1 RAs for dementia syndromes. The review examines how changes in brain energy metabolism differ in conditions of insulin resistance and T2DM from dementia and underscores the challenges that arise from the heterogeneity of dementia syndromes. The development of GLP-1 RAs as dementia therapies requires a deeper understanding of the regional changes in brain energy homeostasis guided by novel imaging biomarkers. CI - (c) 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Yassine, Hussein N AU - Yassine HN AD - Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. AD - Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Solomon, Victoria AU - Solomon V AD - Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Thakral, Angad AU - Thakral A AD - Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Sheikh-Bahaei, Nasim AU - Sheikh-Bahaei N AD - Department of Radiology, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Chui, Helena C AU - Chui HC AD - Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Braskie, Meredith N AU - Braskie MN AD - Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, USC, Los Angeles, California, USA. FAU - Schneider, Lon S AU - Schneider LS AD - Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA. AD - Department of Psychiatry and Behavioral Sciences, Keck School of Medicine USC, Los Angeles, California, USA. FAU - Talbot, Konrad AU - Talbot K AD - Departments of Neurosurgery, Pathology and Human Anatomy, and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA. LA - eng GR - R01 AG057684/AG/NIA NIH HHS/United States GR - P50 AG005142/AG/NIA NIH HHS/United States GR - R01 AG062687/AG/NIA NIH HHS/United States GR - R01 AG067063/AG/NIA NIH HHS/United States GR - R01 AG055770/AG/NIA NIH HHS/United States GR - R01 AG062007/AG/NIA NIH HHS/United States GR - U01 AG051218/AG/NIA NIH HHS/United States GR - R01 AG057658/AG/NIA NIH HHS/United States GR - RF1 MH123223/MH/NIMH NIH HHS/United States GR - P01 AG012435/AG/NIA NIH HHS/United States GR - P30 AG066530/AG/NIA NIH HHS/United States GR - R01 AG054434/AG/NIA NIH HHS/United States GR - R01 AG051346/AG/NIA NIH HHS/United States GR - R21 AG056518/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20211014 PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Brain/metabolism MH - *Dementia/drug therapy/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy MH - Glucagon-Like Peptide 1/metabolism/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Syndrome MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8940606 MID - NIHMS1734469 OTO - NOTNLM OT - Alzheimer's disease OT - glucagon-like peptide-1 OT - insulin resistance OT - type 2 diabetes COIS- Hussein N. Yassine is the co-chair of the Nutrition, Metabolism and Dementia Professional Interest Area (PIA), ISTAART. HCC sits on advisory panel of the Alzheimer's Association Los Angeles-no payments received. MNB is the director of the Masters in Neuroimaging and Informatics program at USC. Lon S. Schneider receives consulting fees from Abbott, AC Immune, Avraham, Ltd, Boehringer Ingelheim, Cognition Therapeutics, Cortexyme, Eisai, Fujifilm, Immunobrain Checkpoint Ltd, Neurally Inc, Neurim Ltd, Neuronix Ltd, Samus, Takeda, and vTv. All other authors report no other disclosures. EDAT- 2021/10/15 06:00 MHDA- 2022/04/26 06:00 PMCR- 2022/10/07 CRDT- 2021/10/14 08:47 PHST- 2021/06/11 00:00 [revised] PHST- 2021/01/19 00:00 [received] PHST- 2021/08/11 00:00 [accepted] PHST- 2021/10/15 06:00 [pubmed] PHST- 2022/04/26 06:00 [medline] PHST- 2021/10/14 08:47 [entrez] PHST- 2022/10/07 00:00 [pmc-release] AID - ALZ12474 [pii] AID - 10.1002/alz.12474 [doi] PST - ppublish SO - Alzheimers Dement. 2022 Mar;18(3):478-497. doi: 10.1002/alz.12474. Epub 2021 Oct 14. PMID- 34622228 OWN - NLM STAT- MEDLINE DCOM- 20220303 LR - 20260127 IS - 2666-3791 (Electronic) IS - 2666-3791 (Linking) VI - 2 IP - 9 DP - 2021 Sep 21 TI - Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes. PG - 100387 LID - 10.1016/j.xcrm.2021.100387 [doi] LID - 100387 AB - Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA(1c), body weight, biomarkers of cardiovascular risk, and AEs such as nausea and vomiting. At typical exposure levels for oral semaglutide, the estimated response is 1.58% (oral) versus -1.62% (subcutaneous) for HbA(1c) and 3.77% (oral) versus 3.48% (subcutaneous) reduction in body weight relative to baseline after 6 months. Increased body weight is the most important variable associated with reduced semaglutide exposure for both formulations. Hence, interindividual variation in GLP-1R responsivity or route of administration are not major determinants of GLP-1RA effectiveness in the clinic. CI - (c) 2021 The Author(s). FAU - Overgaard, Rune V AU - Overgaard RV AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Hertz, Christin L AU - Hertz CL AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Ingwersen, Steen H AU - Ingwersen SH AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Navarria, Andrea AU - Navarria A AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Drucker, Daniel J AU - Drucker DJ AD - Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada. LA - eng GR - 154321/CIHR/Canada PT - Clinical Trial, Phase III PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210903 PL - United States TA - Cell Rep Med JT - Cell reports. Medicine JID - 101766894 RN - 9007-41-4 (C-Reactive Protein) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Glycated Hemoglobin) RN - 0 (Triglycerides) RN - 53AXN4NNHX (Semaglutide) MH - Administration, Oral MH - Blood Pressure MH - *Body Weight MH - C-Reactive Protein/metabolism MH - Diabetes Mellitus, Type 2/*blood/physiopathology MH - Female MH - Glucagon-Like Peptides/administration & dosage/*blood MH - Glycated Hemoglobin/*analysis MH - Humans MH - Injections MH - Injections, Subcutaneous MH - Male MH - Middle Aged MH - Triglycerides/blood MH - Semaglutide PMC - PMC8484505 OTO - NOTNLM OT - Alzheimer's disease OT - G protein coupled receptor OT - GLP-1 OT - diabetes OT - glucagon-like peptide OT - non-alcoholic hepatosteatosis OT - obesity OT - peptide OT - weight loss COIS- R.V.O., C.L.H., S.H.I., and A.N. are full-time employees of and own stock in Novo Nordisk A/S. D.J.D. has served as an advisor or consultant or speaker within the past 12 months to Eli Lilly, Forkhead Biotherapeutics, Intarcia Therapeutics, Kallyope, Merck Research Laboratories, and Novo Nordisk, and holds non-exercised options in Kallyope. EDAT- 2021/10/09 06:00 MHDA- 2021/10/09 06:01 PMCR- 2021/09/03 CRDT- 2021/10/08 07:17 PHST- 2021/04/20 00:00 [received] PHST- 2021/06/30 00:00 [revised] PHST- 2021/08/11 00:00 [accepted] PHST- 2021/10/08 07:17 [entrez] PHST- 2021/10/09 06:00 [pubmed] PHST- 2021/10/09 06:01 [medline] PHST- 2021/09/03 00:00 [pmc-release] AID - S2666-3791(21)00245-7 [pii] AID - 100387 [pii] AID - 10.1016/j.xcrm.2021.100387 [doi] PST - epublish SO - Cell Rep Med. 2021 Sep 3;2(9):100387. doi: 10.1016/j.xcrm.2021.100387. eCollection 2021 Sep 21. PMID- 34587885 OWN - NLM STAT- MEDLINE DCOM- 20220401 LR - 20220401 IS - 1875-5828 (Electronic) IS - 1567-2050 (Linking) VI - 18 IP - 7 DP - 2021 TI - Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis. PG - 546-557 LID - 10.2174/1567205018666210929150004 [doi] AB - BACKGROUND AND OBJECTIVE: Type 2 Diabetes (T2D) patients are more prone to develop Alzheimer's Disease (AD). We have previously shown that Glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating insulin signaling, and peripheral injected Ex-4 increases insulin levels in the T2D brain. This study aims to further clarify whether the elevated insulin in the brain is produced by nerve cells under the action of Ex-4. METHODS: The neuronal cell line-HT22 was treated with Ex-4 under high glucose or normal cultivation, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-related genes were examined. The db/db mice were treated with the peripheral injection of Ex-4 and/or IntraCerebroVentricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis- related genes and the behavior tests were carried on. Finally, plasma glucose, Cerebrospinal Fluid (CSF) glucose, CSF insulin, phosphorylation of tau, phosphorylation of AKT and GSK-3beta of db/db mice were detected. RESULTS: We found that Ex-4 promoted the expression of insulin synthesis-related genes and induced an obvious increase of insulin-positive HT-22 neuronal cells in a high glucose environment. Peripheral injection of Ex-4 improved the cognitive function of db/db mice and increased brain insulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphorylation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive function of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain insulin levels dropped to an extremely low level, and the phosphorylation level of tau increased significantly. CONCLUSION: This study demonstrated that Ex-4 improved cognition function by promoting brain insulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyperphosphorylation. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Peng, Xuemin AU - Peng X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Shi, Xiaoli AU - Shi X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Huang, Jiaojiao AU - Huang J AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Zhang, Shujun AU - Zhang S AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yan, Yongli AU - Yan Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Ma, Delin AU - Ma D AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xu, Weijie AU - Xu W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xu, Weijie AU - Xu W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Dong, Kun AU - Dong K AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Tao, Jing AU - Tao J AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Mengni AU - Li M AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yang, Yan AU - Yang Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. LA - eng GR - 81670754 , 81974114, 81800686, 81600661/National Natural Science Foundation of China/ GR - 2018076/China International Medical Foundation/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United Arab Emirates TA - Curr Alzheimer Res JT - Current Alzheimer research JID - 101208441 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (tau Proteins) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) SB - IM MH - Animals MH - Brain/metabolism MH - Cognition MH - *Diabetes Mellitus, Experimental/drug therapy MH - *Diabetes Mellitus, Type 2/metabolism MH - Exenatide/pharmacology MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Hippocampus/metabolism MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Insulin MH - Mice MH - Phosphorylation MH - tau Proteins/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Type 2 diabetes OT - db/db. OT - exendin-4 OT - glucagon-like peptide-1 OT - insulin EDAT- 2021/10/01 06:00 MHDA- 2022/04/02 06:00 CRDT- 2021/09/30 05:34 PHST- 2021/01/20 00:00 [received] PHST- 2021/06/16 00:00 [revised] PHST- 2021/08/24 00:00 [accepted] PHST- 2021/10/01 06:00 [pubmed] PHST- 2022/04/02 06:00 [medline] PHST- 2021/09/30 05:34 [entrez] AID - CAR-EPUB-118240 [pii] AID - 10.2174/1567205018666210929150004 [doi] PST - ppublish SO - Curr Alzheimer Res. 2021;18(7):546-557. doi: 10.2174/1567205018666210929150004. PMID- 34577590 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211001 IS - 1424-8247 (Print) IS - 1424-8247 (Electronic) IS - 1424-8247 (Linking) VI - 14 IP - 9 DP - 2021 Sep 1 TI - Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment. LID - 10.3390/ph14090890 [doi] LID - 890 AB - Alzheimer's disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to "type 3 diabetes" and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models. FAU - Poor, Saghar Rabiei AU - Poor SR AD - Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Institute for Brain and Cognition, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. FAU - Ettcheto, Miren AU - Ettcheto M AUID- ORCID: 0000-0002-4301-7297 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. FAU - Cano, Amanda AU - Cano A AUID- ORCID: 0000-0001-9567-4283 AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028 Barcelona, Spain. AD - Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain. FAU - Sanchez-Lopez, Elena AU - Sanchez-Lopez E AUID- ORCID: 0000-0003-2571-108X AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain. FAU - Manzine, Patricia Regina AU - Manzine PR AUID- ORCID: 0000-0003-3460-9300 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Department of Gerontology, Federal University of Sao Carlos (UFSCar), Sao Carlos 13565-905, Brazil. FAU - Olloquequi, Jordi AU - Olloquequi J AD - Laboratory of Cellular and Molecular Pathology, Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autonoma de Chile, Talca 3467987, Chile. FAU - Camins, Antoni AU - Camins A AUID- ORCID: 0000-0002-1229-5956 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028 Barcelona, Spain. AD - Laboratory of Cellular and Molecular Pathology, Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autonoma de Chile, Talca 3467987, Chile. FAU - Javan, Mohammad AU - Javan M AUID- ORCID: 0000-0003-2045-6171 AD - Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Institute for Brain and Cognition, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14117-13116, Iran. LA - eng PT - Journal Article PT - Review DEP - 20210901 PL - Switzerland TA - Pharmaceuticals (Basel) JT - Pharmaceuticals (Basel, Switzerland) JID - 101238453 PMC - PMC8465337 OTO - NOTNLM OT - AMP activated protein kinase (AMPK) OT - Alzheimer's disease OT - beta amyloid OT - diabetes mellitus OT - insulin resistance OT - metformin OT - tau protein hyperphosphorylation COIS- The authors declare no conflict of interest. EDAT- 2021/09/29 06:00 MHDA- 2021/09/29 06:01 PMCR- 2021/09/01 CRDT- 2021/09/28 01:23 PHST- 2021/07/12 00:00 [received] PHST- 2021/08/23 00:00 [revised] PHST- 2021/08/28 00:00 [accepted] PHST- 2021/09/28 01:23 [entrez] PHST- 2021/09/29 06:00 [pubmed] PHST- 2021/09/29 06:01 [medline] PHST- 2021/09/01 00:00 [pmc-release] AID - ph14090890 [pii] AID - pharmaceuticals-14-00890 [pii] AID - 10.3390/ph14090890 [doi] PST - epublish SO - Pharmaceuticals (Basel). 2021 Sep 1;14(9):890. doi: 10.3390/ph14090890. PMID- 34507632 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20240226 IS - 1347-8648 (Electronic) IS - 1347-8613 (Linking) VI - 147 IP - 3 DP - 2021 Nov TI - Liraglutide ameliorates diabetes-associated cognitive dysfunction via rescuing autophagic flux. PG - 234-244 LID - S1347-8613(21)00071-2 [pii] LID - 10.1016/j.jphs.2021.07.004 [doi] AB - The incidence of diabetes-associated cognitive dysfunction is increasing. However, few clinical interventions are available to prevent the disorder. Several researches have shown that liraglutide, as a glucagon-like peptide-1 analog, has protective effects on various neurodegenerative diseases, but its roles in diabetic cognitive dysfunction are rarely reported. This study aims to investigate the protective effects of liraglutide on diabetic cognitive dysfunction and its underlying mechanisms. In vivo, the effects of liraglutide treatment were investigated in a mouse model of type 2 diabetes mellitus (T2DM). In vitro, we investigated the effects of liraglutide on the high-glucose-induced rat primary neurons. The results showed that liraglutide reduced the escape latency and increased the time in effective area in the Morris water maze test, improved the damage of hippocampal and synaptic ultrastructure, and decreased the accumulation of amyloid beta protein in hippocampus of T2DM mice. Furthermore, liraglutide increased the ratio of microtubule-associated protein light 1 chain Ⅱ/Ⅰ, the expression of Beclin1 protein and Lysosome-associated membrane protein 2 in vivo and vitro. Additionally, Bafilomycin A1 which can inhibit the fusion of autophagosome and lysosome partially abolished the effects of liraglutide. These findings indicate liraglutide ameliorates diabetes-associated cognitive dysfunction by rescuing autophagic flux. CI - Copyright (c) 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved. FAU - Zhang, Meng AU - Zhang M AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Yan, Wenhui AU - Yan W AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Yu, Ye AU - Yu Y AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Cheng, Jie AU - Cheng J AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Yi, Xinyao AU - Yi X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Guo, Tingli AU - Guo T AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Liu, Na AU - Liu N AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Shang, Jia AU - Shang J AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Wang, Zhuanzhuan AU - Wang Z AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Hu, Hao AU - Hu H AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. FAU - Chen, Lina AU - Chen L AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China. Electronic address: chenlin@xjtu.edu.cn. LA - eng PT - Journal Article DEP - 20210724 PL - Japan TA - J Pharmacol Sci JT - Journal of pharmacological sciences JID - 101167001 RN - 0 (Amyloid beta-Peptides) RN - 0 (Beclin-1) RN - 0 (Becn1 protein, mouse) RN - 0 (Lysosomal Membrane Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 839I73S42A (Liraglutide) SB - IM MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Autophagy/*drug effects MH - Beclin-1/metabolism MH - Cognitive Dysfunction/*etiology/pathology/*prevention & control MH - Diabetes Mellitus, Type 2/*complications MH - Disease Models, Animal MH - Hippocampus/metabolism/pathology/ultrastructure MH - Liraglutide/*pharmacology/*therapeutic use MH - Lysosomal Membrane Proteins/metabolism MH - Male MH - Mice, Inbred C57BL MH - Microtubule-Associated Proteins/metabolism MH - Morris Water Maze Test/drug effects MH - Rats MH - Synapses/pathology/ultrastructure MH - Mice OTO - NOTNLM OT - Amyloid beta OT - Autophagic flux OT - Diabetes-associated cognitive dysfunction OT - Liraglutide COIS- Declaration of competing interest The authors declare that there are no conflicts of interest. EDAT- 2021/09/12 06:00 MHDA- 2022/01/11 06:00 CRDT- 2021/09/11 05:25 PHST- 2021/04/05 00:00 [received] PHST- 2021/06/28 00:00 [revised] PHST- 2021/07/15 00:00 [accepted] PHST- 2021/09/11 05:25 [entrez] PHST- 2021/09/12 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] AID - S1347-8613(21)00071-2 [pii] AID - 10.1016/j.jphs.2021.07.004 [doi] PST - ppublish SO - J Pharmacol Sci. 2021 Nov;147(3):234-244. doi: 10.1016/j.jphs.2021.07.004. Epub 2021 Jul 24. PMID- 34489627 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210908 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 15 DP - 2021 TI - Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus. PG - 708547 LID - 10.3389/fnins.2021.708547 [doi] LID - 708547 AB - Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid beta hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors. CI - Copyright (c) 2021 Sim, Barua, Kim, Lee and Lee. FAU - Sim, A Young AU - Sim AY AD - Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea. AD - Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Barua, Sumit AU - Barua S AD - Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea. FAU - Kim, Jong Youl AU - Kim JY AD - Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea. FAU - Lee, Yong-Ho AU - Lee YH AD - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. FAU - Lee, Jong Eun AU - Lee JE AD - Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea. AD - Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea. AD - Brain Research Institute, Yonsei University College of Medicine, Seoul, South Korea. LA - eng PT - Journal Article PT - Review DEP - 20210811 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC8417940 OTO - NOTNLM OT - Alzheimer's disease OT - DPP-4 inhibitor OT - SGLT2 inhibitor OT - insulin resistance OT - insulin signaling OT - type 2 diabetes mellitus COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/09/08 06:00 MHDA- 2021/09/08 06:01 PMCR- 2021/01/01 CRDT- 2021/09/07 07:41 PHST- 2021/05/12 00:00 [received] PHST- 2021/07/12 00:00 [accepted] PHST- 2021/09/07 07:41 [entrez] PHST- 2021/09/08 06:00 [pubmed] PHST- 2021/09/08 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2021.708547 [doi] PST - epublish SO - Front Neurosci. 2021 Aug 11;15:708547. doi: 10.3389/fnins.2021.708547. eCollection 2021. PMID- 34480710 OWN - NLM STAT- MEDLINE DCOM- 20220331 LR - 20261010 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 47 IP - 2 DP - 2022 Feb TI - Liraglutide Alleviates Cognitive Deficit in db/db Mice: Involvement in Oxidative Stress, Iron Overload, and Ferroptosis. PG - 279-294 LID - 10.1007/s11064-021-03442-7 [doi] AB - Studies have shown that diabetes is associated with the occurrence of neurodegenerative diseases and cognitive decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The superior efficacy of liraglutide (LIRA) for cognitive impairment and numerous neurodegenerative diseases has been widely demonstrated. This study determined the effects of LIRA on diabetic cognitive impairment and on the levels of oxidative stress, lipid peroxidation, iron metabolism and ferroptosis in the hippocampus. Mice were injected daily with liraglutide (200 mug/kg/d) for 5 weeks. LIRA could repair damaged neurons and synapses, and it increased the protein expression levels of PSD 95, SYN, and BDNF. Furthermore, LIRA significantly decreased oxidative stress and lipid peroxidation levels by downregulating the production of ROS and MDA and upregulating SOD and GSH-Px in the serum and hippocampus, and the upregulation of SOD2 expression was also proven. The decreased levels of TfR1 and the upregulation of FPN1 and FTH proteins observed in the LIRA-treated db/db group were shown to reduce iron overload in the hippocampus, whereas the increased expression of Mtft and decreased expression of Mfrn in the mitochondria indicated that mitochondrial iron overload was ameliorated. Finally, LIRA was shown to prevent ferroptosis in the hippocampus by elevating the expression of GPX4 and SLC7A11 and suppressing the excessive amount of ACSL4; simultaneously, the damage to the mitochondria observed by TEM was also repaired. For the first time, we proved in the T2DM model that ferroptosis occurs in the hippocampus, which may play a role in diabetic cognitive impairment. LIRA can reduce oxidative stress, lipid peroxidation and iron overload in diabetic cognitive disorders and further inhibit ferroptosis, thereby weakening the damage to hippocampal neurons and synaptic plasticity and ultimately restoring cognitive function. CI - (c) 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - An, Ji-Ren AU - An JR AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. FAU - Su, Jia-Nan AU - Su JN AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. FAU - Sun, Gui-Yan AU - Sun GY AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. FAU - Wang, Qing-Feng AU - Wang QF AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. FAU - Fan, Ya-Dong AU - Fan YD AD - Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. FAU - Jiang, Nan AU - Jiang N AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. FAU - Yang, Yu-Feng AU - Yang YF AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. lntcmyyf@126.com. FAU - Shi, Yan AU - Shi Y AD - Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China. lntcmshiyan@163.com. LA - eng GR - [2018]12/national leading talents support program of chinese medicine- qihuang scholar/ GR - XLYC1807145/liaoning xingliao talent plan project/ GR - 21601A2015/Liaoning University of Traditional Chinese Medicine Postdoctoral Research Fund/ PT - Journal Article DEP - 20210904 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 839I73S42A (Liraglutide) SB - IM MH - Animals MH - Cognition MH - *Cognitive Dysfunction/drug therapy MH - *Ferroptosis MH - *Iron Overload/drug therapy MH - Liraglutide/pharmacology/therapeutic use MH - Mice MH - Mice, Inbred Strains MH - Oxidative Stress/physiology OTO - NOTNLM OT - Diabetic cognitive impairment OT - Ferroptosis OT - Iron overload OT - Liraglutide OT - Oxidative stress EDAT- 2021/09/05 06:00 MHDA- 2022/04/01 06:00 CRDT- 2021/09/04 12:12 PHST- 2021/06/09 00:00 [received] PHST- 2021/08/30 00:00 [accepted] PHST- 2021/08/28 00:00 [revised] PHST- 2021/09/05 06:00 [pubmed] PHST- 2022/04/01 06:00 [medline] PHST- 2021/09/04 12:12 [entrez] AID - 10.1007/s11064-021-03442-7 [pii] AID - 10.1007/s11064-021-03442-7 [doi] PST - ppublish SO - Neurochem Res. 2022 Feb;47(2):279-294. doi: 10.1007/s11064-021-03442-7. Epub 2021 Sep 4. PMID- 34479819 OWN - NLM STAT- MEDLINE DCOM- 20211005 LR - 20211005 IS - 1444-2892 (Electronic) IS - 1443-9506 (Linking) VI - 30 IP - 11 DP - 2021 Nov TI - Glucagon-Like Peptide-1 Receptor Agonists and Brain Vascular Function. PG - 1675-1680 LID - S1443-9506(21)01201-4 [pii] LID - 10.1016/j.hlc.2021.07.024 [doi] AB - Prevention of cardiovascular events and regression of atherosclerotic changes are the primary aims of preventive cardiovascular medicine. Arterial thrombosis is caused by endothelial dysfunction, which disrupts vascular haemostasis. Glucagon-like peptide 1 (GLP-1) receptor agonists have been initially used as glucose lowering agents, but over time have been used for other indications due to their cardiorenal benefit, as well as their benefit in the regression of atherosclerosis process. The aim of this paper is to present the benefits of GLP-1 receptor agonists in the prevention of atherosclerotic changes, in the preservation of brain vascular function, and to show the possible role in the treatment of neurodegenerative diseases. CI - Copyright (c) 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved. FAU - Begic, Edin AU - Begic E AD - Department of Cardiology, General Hospital "Prim.Dr. Abdulah Nakas", Sarajevo, Bosnia and Herzegovina; Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina. Electronic address: begic.edin@ssst.edu.ba. FAU - Causevic, Mirsada AU - Causevic M AD - Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina. LA - eng PT - Journal Article PT - Review DEP - 20210831 PL - Australia TA - Heart Lung Circ JT - Heart, lung & circulation JID - 100963739 RN - 0 (Cardiovascular Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - *Atherosclerosis/drug therapy/prevention & control MH - Brain MH - *Cardiovascular Agents MH - *Cardiovascular Diseases MH - *Diabetes Mellitus, Type 2 MH - Glucagon-Like Peptide-1 Receptor MH - Humans OTO - NOTNLM OT - Alzheimer's disease OT - Atherosclerosis OT - Glucagon-like peptide 1 OT - Neurodegenerative diseases OT - Therapeutics EDAT- 2021/09/05 06:00 MHDA- 2021/10/06 06:00 CRDT- 2021/09/04 05:40 PHST- 2021/05/03 00:00 [received] PHST- 2021/07/14 00:00 [revised] PHST- 2021/07/21 00:00 [accepted] PHST- 2021/09/05 06:00 [pubmed] PHST- 2021/10/06 06:00 [medline] PHST- 2021/09/04 05:40 [entrez] AID - S1443-9506(21)01201-4 [pii] AID - 10.1016/j.hlc.2021.07.024 [doi] PST - ppublish SO - Heart Lung Circ. 2021 Nov;30(11):1675-1680. doi: 10.1016/j.hlc.2021.07.024. Epub 2021 Aug 31. PMID- 34383800 OWN - NLM STAT- MEDLINE DCOM- 20211201 LR - 20250103 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 16 IP - 8 DP - 2021 TI - GLP-1 and GIP receptor agonists in the treatment of Parkinson's disease: Translational systematic review and meta-analysis protocol of clinical and preclinical studies. PG - e0255726 LID - 10.1371/journal.pone.0255726 [doi] LID - e0255726 AB - BACKGROUND: Parkinson's disease (PD) is a progressive multifactorial neurodegenerative condition. Epidemiological studies have shown that patients with type 2 diabetes mellitus (T2DM2) are at increased risk for developing PD, indicating a possible insulin-modulating role in this latter condition. We hypothesized that drugs similar to glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), used in the treatment of T2DM2, may play a role in PD. OBJECTIVES: The purpose of this study is to systematically review and meta-analyze data of preclinical and clinical studies evaluating the efficacy and safety of GLP-1 and GIP drugs in the treatment of PD. METHODS: Two reviewers will independently evaluate the studies available in the Ovid Medline, Ovid Embase, Web of Science, Cochrane Central Register of Controlled Trials, Cinahl, and Lilacs databases. Preclinical rodent or non-human primate studies and randomized controlled human clinical trials will be included, without language or publication period restrictions. Outcomes of interest in preclinical studies will be primarily locomotor improvements and adverse effects in animal models of PD. For clinical trials, we will evaluate clinical improvements rated by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-parts I, II, III, and IV, and adverse effects. The risk of bias of preclinical studies will be assessed by the SYRCLE tool and CAMARADES checklist and the clinical studies by the Cochrane tool; the certainty of the evidence will be rated by GRADE. DISCUSSION AND CONCLUSION: There is an urge for new PD treatments that may slow the progression of the disease rather than just restoring dopamine levels. This study will comprehensively review and update the state of the art of what is known about incretin hormones and PD and highlight the strengths and limitations of translating preclinical data to the clinic whenever possible. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42020223435. FAU - Vaccari, Carolina AU - Vaccari C AUID- ORCID: 0000-0002-7670-734X AD - Department of Pathology, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil. FAU - Grotto, Denise AU - Grotto D AD - Graduate Course of Pharmaceutical Sciences, University of Sorocaba (UNISO), Sorocaba, Sao Paulo, Brazil. FAU - Pereira, Tiago da V AU - Pereira TDV AD - Applied Health Research Centre, St. Michael's Hospital, University of Toronto, Toronto, Canada. AD - Department of Health Sciences, University of Leicester, Leicester, United Kingdom. FAU - de Camargo, Joao Lauro V AU - de Camargo JLV AD - Department of Pathology, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil. FAU - Lopes, Luciane C AU - Lopes LC AD - Graduate Course of Pharmaceutical Sciences, University of Sorocaba (UNISO), Sorocaba, Sao Paulo, Brazil. LA - eng PT - Journal Article DEP - 20210812 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - VTD58H1Z2X (Dopamine) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/drug therapy/genetics MH - Disease Progression MH - Dopamine/metabolism MH - *Glucagon-Like Peptide 1/agonists/genetics MH - *Glucagon-Like Peptide-1 Receptor/genetics MH - Insulin/metabolism MH - *Parkinson Disease/drug therapy/genetics/pathology MH - Meta-Analysis as Topic MH - Systematic Reviews as Topic MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8360366 COIS- The authors have declared that no competing interests exist. EDAT- 2021/08/13 06:00 MHDA- 2021/12/01 06:00 PMCR- 2021/08/12 CRDT- 2021/08/12 17:25 PHST- 2020/11/30 00:00 [received] PHST- 2021/07/20 00:00 [accepted] PHST- 2021/08/12 17:25 [entrez] PHST- 2021/08/13 06:00 [pubmed] PHST- 2021/12/01 06:00 [medline] PHST- 2021/08/12 00:00 [pmc-release] AID - PONE-D-20-37532 [pii] AID - 10.1371/journal.pone.0255726 [doi] PST - epublish SO - PLoS One. 2021 Aug 12;16(8):e0255726. doi: 10.1371/journal.pone.0255726. eCollection 2021. PMID- 34380882 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240403 IS - 1673-5374 (Print) IS - 1876-7958 (Electronic) IS - 1673-5374 (Linking) VI - 17 IP - 3 DP - 2022 Mar TI - Diabetes mellitus and Parkinson's disease: dangerous liaisons between insulin and dopamine. PG - 523-533 LID - 10.4103/1673-5374.320965 [doi] AB - The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease. FAU - De Iuliis, Angela AU - De Iuliis A AD - Department of Medicine-DiMED, University of Padova, Italy. FAU - Montinaro, Ennio AU - Montinaro E AD - Department of Neurology, Santa Maria University Hospital, Terni, Italy. FAU - Fatati, Giuseppe AU - Fatati G AD - Italian Obesity Network, Terni, Italy. FAU - Plebani, Mario AU - Plebani M AD - Department of Medicine-DiMED; Department of Medicine-DiMED, University of Padova; Department of Laboratory Medicine-Hospital of Padova, Padova, Italy. FAU - Colosimo, Carlo AU - Colosimo C AD - Department of Neurology, Santa Maria University Hospital, Terni, Italy. LA - eng PT - Journal Article PT - Review PL - India TA - Neural Regen Res JT - Neural regeneration research JID - 101316351 PMC - PMC8504381 OTO - NOTNLM OT - GLP-1 OT - Parkinson's disease OT - dopamine OT - insulin OT - type 2 diabetes mellitus COIS- None EDAT- 2021/08/13 06:00 MHDA- 2021/08/13 06:01 PMCR- 2021/08/04 CRDT- 2021/08/12 05:44 PHST- 2021/08/12 05:44 [entrez] PHST- 2021/08/13 06:00 [pubmed] PHST- 2021/08/13 06:01 [medline] PHST- 2021/08/04 00:00 [pmc-release] AID - NeuralRegenRes_2022_17_3_523_320965 [pii] AID - NRR-17-523 [pii] AID - 10.4103/1673-5374.320965 [doi] PST - ppublish SO - Neural Regen Res. 2022 Mar;17(3):523-533. doi: 10.4103/1673-5374.320965. PMID- 34366339 OWN - NLM STAT- MEDLINE DCOM- 20211203 LR - 20230807 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 83 IP - 2 DP - 2021 TI - A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer's Disease. PG - 799-818 LID - 10.3233/JAD-210256 [doi] AB - BACKGROUND: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. OBJECTIVE: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. METHODS: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. RESULTS: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. CONCLUSION: DA4-JC is a promising drug for the treatment of AD. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China. AD - Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China. AD - Key Laboratory of Cellular Physiology, Shanxi Province, China. FAU - Yang, Dan AU - Yang D AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China. FAU - Qiao, Jing AU - Qiao J AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China. FAU - Yang, Jun-Ting AU - Yang JT AD - Department of Physiology, Shanxi Medical University, Taiyuan, China. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China. AD - Key Laboratory of Cellular Physiology, Shanxi Province, China. AD - Department of Physiology, Shanxi Medical University, Taiyuan, China. FAU - Wu, Mei-Na AU - Wu MN AD - Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China. AD - Key Laboratory of Cellular Physiology, Shanxi Province, China. AD - Department of Physiology, Shanxi Medical University, Taiyuan, China. FAU - Qi, Jin-Shun AU - Qi JS AD - Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China. AD - Key Laboratory of Cellular Physiology, Shanxi Province, China. AD - Department of Physiology, Shanxi Medical University, Taiyuan, China. FAU - Holscher, Christian AU - Holscher C AD - Neuroscience Research Group, Henan University of Chinese Medicine, Zhengzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, mouse) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM EIN - J Alzheimers Dis. 2023;94(4):1617-1618. doi: 10.3233/JAD-239006. PMID: 37545245 MH - Alzheimer Disease/*pathology MH - Animals MH - Cognitive Dysfunction/*prevention & control MH - Diabetes Mellitus, Type 2/*complications MH - Disease Models, Animal MH - Disks Large Homolog 4 Protein/*genetics MH - Female MH - Glucagon-Like Peptide 1/*agonists MH - Hippocampus/pathology MH - Humans MH - Long-Term Potentiation/*drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neuroprotective Agents/*pharmacology MH - Synapses/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - cognitive impairment OT - glucagon-like peptide-1 OT - glucose-dependent insulinotropic polypeptide OT - type 2 diabetes mellitus EDAT- 2021/08/10 06:00 MHDA- 2021/12/15 06:00 CRDT- 2021/08/09 06:18 PHST- 2021/08/10 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/08/09 06:18 [entrez] AID - JAD210256 [pii] AID - 10.3233/JAD-210256 [doi] PST - ppublish SO - J Alzheimers Dis. 2021;83(2):799-818. doi: 10.3233/JAD-210256. PMID- 34310013 OWN - NLM STAT- MEDLINE DCOM- 20211018 LR - 20220531 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 23 Suppl 3 DP - 2021 Sep TI - The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. PG - 5-29 LID - 10.1111/dom.14496 [doi] AB - The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet alpha-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH(2) ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs. CI - (c) 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Nauck, Michael A AU - Nauck MA AUID- ORCID: 0000-0002-5749-6954 AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. FAU - Quast, Daniel R AU - Quast DR AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. FAU - Wefers, Jakob AU - Wefers J AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. FAU - Pfeiffer, Andreas F H AU - Pfeiffer AFH AD - Charite - Universitatsmedizin Berlin, Klinik fur Endokrinologie, Stoffwechsel- und Ernahrungsmedizin, Berlin, Germany. LA - eng PT - Journal Article PT - Review PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Blood Glucose) RN - 0 (Incretins) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) SB - IM MH - Animals MH - Blood Glucose MH - *Cardiovascular Diseases MH - *Diabetes Mellitus, Type 2/drug therapy MH - Gastric Inhibitory Polypeptide MH - Glucagon-Like Peptide 1 MH - Humans MH - Incretins MH - Receptors, Gastrointestinal Hormone OTO - NOTNLM OT - GIP OT - GLP-1 OT - GLP-1 analogue OT - drug mechanism OT - incretin physiology OT - incretin therapy EDAT- 2021/07/27 06:00 MHDA- 2021/10/21 06:00 CRDT- 2021/07/26 12:44 PHST- 2021/07/13 00:00 [revised] PHST- 2021/05/31 00:00 [received] PHST- 2021/07/13 00:00 [accepted] PHST- 2021/07/27 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2021/07/26 12:44 [entrez] AID - 10.1111/dom.14496 [doi] PST - ppublish SO - Diabetes Obes Metab. 2021 Sep;23 Suppl 3:5-29. doi: 10.1111/dom.14496. PMID- 34305527 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210727 IS - 1662-5099 (Print) IS - 1662-5099 (Electronic) IS - 1662-5099 (Linking) VI - 14 DP - 2021 TI - Glucagon-Like Peptide-1 Receptor Agonist Ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Neurotoxicity Through Enhancing Mitophagy Flux and Reducing alpha-Synuclein and Oxidative Stress. PG - 697440 LID - 10.3389/fnmol.2021.697440 [doi] LID - 697440 AB - Parkinson disease (PD) is the second most common neurodegenerative disease without known disease modification therapy to slow down disease progression. This disease has pathological features of Lewy bodies with alpha-synuclein aggregation being the major component and selective dopaminergic neuronal loss over the substantia nigra. Although the exact etiology is still unknown, mitochondrial dysfunction has been shown to be central in PD pathophysiology. Type 2 diabetes mellitus has recently been connected to PD, and anti-diabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to possess neuroprotective effects in PD animal models. The GLP-1RA liraglutide is currently under a phase 2 clinical trial to measure its effect on motor and non-motor symptoms in PD patients. In this study, we used an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to test the possible mechanism of the GLP-1RA liraglutide in the pathogenesis of PD. We show that the neurobehavioral and motor dysfunction caused by the mitochondrial complex I inhibitor, MPTP, can be partially reversed by liraglutide. The GLP-1RA can protect mice from apoptosis of substantia nigra neurons induced by MPTP. MPTP treatment led to imbalanced mitochondrial fusion and fission dynamics, altered mitochondrial morphology, impeded autophagy flux, increased alpha-synuclein accumulation, and elevated oxidative stress. Specifically, the normalizing of mitochondrial fusion-fission dynamic-related proteins and enhancement of autophagy flux after administration of liraglutide is associated with improving neuronal survival. This suggests that GLP-1RAs may provide potential beneficial effects for PD caused by mitochondrial dysfunction through improvement of mitochondrial morphology balance and enhancing damaged organelle degradation. CI - Copyright (c) 2021 Lin, Lin, Lin, Lin, Lan, Wang, Wang, Wang, Tsai, Liou and Chuang. FAU - Lin, Tsu-Kung AU - Lin TK AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Lin, Kai-Jung AU - Lin KJ AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Lin, Hung-Yu AU - Lin HY AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Research Assistant Center, Show Chwan Memorial Hospital, Changhua, Taiwan. FAU - Lin, Kai-Lieh AU - Lin KL AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Lan, Min-Yu AU - Lan MY AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Wang, Pei-Wen AU - Wang PW AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Wang, Tzu-Jou AU - Wang TJ AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Pediatric, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Wang, Feng-Sheng AU - Wang FS AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Tsai, Po-Chin AU - Tsai PC AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Liou, Chia-Wei AU - Liou CW AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Chuang, Jiin-Haur AU - Chuang JH AD - Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. AD - Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. LA - eng PT - Journal Article DEP - 20210707 PL - Switzerland TA - Front Mol Neurosci JT - Frontiers in molecular neuroscience JID - 101477914 PMC - PMC8292641 OTO - NOTNLM OT - GLP-1 OT - Parkinson disease OT - autophagy flux OT - diabetes mellitus OT - mega-mitochondria OT - mitochondrial dynamics OT - mitochondrial morphology OT - alpha-synuclein COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/07/27 06:00 MHDA- 2021/07/27 06:01 PMCR- 2021/01/01 CRDT- 2021/07/26 06:21 PHST- 2021/04/19 00:00 [received] PHST- 2021/05/14 00:00 [accepted] PHST- 2021/07/26 06:21 [entrez] PHST- 2021/07/27 06:00 [pubmed] PHST- 2021/07/27 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fnmol.2021.697440 [doi] PST - epublish SO - Front Mol Neurosci. 2021 Jul 7;14:697440. doi: 10.3389/fnmol.2021.697440. eCollection 2021. PMID- 34250817 OWN - NLM STAT- MEDLINE DCOM- 20211028 LR - 20250103 IS - 2047-9980 (Electronic) IS - 2047-9980 (Linking) VI - 10 IP - 14 DP - 2021 Jul 20 TI - Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway. PG - e020734 LID - 10.1161/JAHA.120.020734 [doi] LID - e020734 AB - Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon-like peptide-1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near-infrared spectroscopy. At 12 weeks, patients in the glucagon-like peptide-1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention (P=0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions (P=0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions (P<0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03707171. FAU - Li, Qiang AU - Li Q AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Jia, Mengxiao AU - Jia M AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Yan, Zhencheng AU - Yan Z AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Li, Qiang AU - Li Q AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Sun, Fang AU - Sun F AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - He, Chengkang AU - He C AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Li, Yingsha AU - Li Y AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Zhou, Xunmei AU - Zhou X AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Zhang, Hexuan AU - Zhang H AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Liu, Xiaoli AU - Liu X AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Bu, Xiaona AU - Bu X AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Gao, Peng AU - Gao P AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - He, Hongbo AU - He H AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Zhao, Zhigang AU - Zhao Z AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. FAU - Zhu, Zhiming AU - Zhu Z AD - Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China. LA - eng SI - ClinicalTrials.gov/NCT03707171 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210710 PL - England TA - J Am Heart Assoc JT - Journal of the American Heart Association JID - 101580524 RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 9100L32L2N (Metformin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Biomarkers/metabolism MH - Blood Glucose/metabolism MH - Cognition/*physiology MH - Cognitive Dysfunction/etiology/metabolism/*prevention & control MH - Diabetes Mellitus, Type 2/complications/*drug therapy/metabolism MH - Female MH - Follow-Up Studies MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Liraglutide/*pharmacology MH - Male MH - Metformin/*therapeutic use MH - Middle Aged MH - Prefrontal Cortex/*drug effects/metabolism/physiopathology MH - Prognosis MH - Prospective Studies MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8483500 OTO - NOTNLM OT - cognitive function OT - functional near-infrared spectroscopy OT - liraglutide OT - metabolic changes OT - type 2 diabetes mellitus COIS- None. EDAT- 2021/07/13 06:00 MHDA- 2021/10/29 06:00 PMCR- 2021/07/20 CRDT- 2021/07/12 08:41 PHST- 2021/07/13 06:00 [pubmed] PHST- 2021/10/29 06:00 [medline] PHST- 2021/07/12 08:41 [entrez] PHST- 2021/07/20 00:00 [pmc-release] AID - JAH36435 [pii] AID - 10.1161/JAHA.120.020734 [doi] PST - ppublish SO - J Am Heart Assoc. 2021 Jul 20;10(14):e020734. doi: 10.1161/JAHA.120.020734. Epub 2021 Jul 10. PMID- 34168725 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210626 IS - 1948-9358 (Print) IS - 1948-9358 (Electronic) IS - 1948-9358 (Linking) VI - 12 IP - 6 DP - 2021 Jun 15 TI - Alzheimer's disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. PG - 745-766 LID - 10.4239/wjd.v12.i6.745 [doi] AB - At present, Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD. CI - (c)The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Rojas, Milagros AU - Rojas M AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. FAU - Chavez-Castillo, Mervin AU - Chavez-Castillo M AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. FAU - Bautista, Jordan AU - Bautista J AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. FAU - Ortega, Angel AU - Ortega A AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. FAU - Nava, Manuel AU - Nava M AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. FAU - Salazar, Juan AU - Salazar J AD - Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela. juanjsv18@hotmail.com. FAU - Diaz-Camargo, Edgar AU - Diaz-Camargo E AD - Universidad Simon Bolivar, Facultad de Ciencias Juridicas y Sociales, Cucuta 540006, Colombia. FAU - Medina, Oscar AU - Medina O AD - Universidad Simon Bolivar, Facultad de Ciencias Juridicas y Sociales, Cucuta 540006, Colombia. FAU - Rojas-Quintero, Joselyn AU - Rojas-Quintero J AD - Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States. FAU - Bermudez, Valmore AU - Bermudez V AD - Universidad Simon Bolivar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia. LA - eng PT - Journal Article PT - Review PL - United States TA - World J Diabetes JT - World journal of diabetes JID - 101547524 PMC - PMC8192246 OTO - NOTNLM OT - Alzheimer's disease OT - Cognitive dysfunction OT - Glucagon-like peptide 1 OT - Hypoglycemic agents OT - Islet amyloid polypeptide OT - Oxidative stress OT - Type 2 diabetes mellitus COIS- Conflict-of-interest statement: Authors declare no conflict of interests for this article. EDAT- 2021/06/26 06:00 MHDA- 2021/06/26 06:01 PMCR- 2021/06/15 CRDT- 2021/06/25 06:51 PHST- 2021/02/13 00:00 [received] PHST- 2021/03/20 00:00 [revised] PHST- 2021/05/21 00:00 [accepted] PHST- 2021/06/25 06:51 [entrez] PHST- 2021/06/26 06:00 [pubmed] PHST- 2021/06/26 06:01 [medline] PHST- 2021/06/15 00:00 [pmc-release] AID - 10.4239/wjd.v12.i6.745 [doi] PST - ppublish SO - World J Diabetes. 2021 Jun 15;12(6):745-766. doi: 10.4239/wjd.v12.i6.745. PMID- 34154020 OWN - NLM STAT- MEDLINE DCOM- 20220719 LR - 20220719 IS - 1439-3646 (Electronic) IS - 0947-7349 (Linking) VI - 130 IP - 7 DP - 2022 Jul TI - Prevalence of Atherosclerotic Cardiovascular Disease, Heart Failure, and Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus: A Primary Care Research Network-based Study. PG - 447-453 LID - 10.1055/a-1508-3912 [doi] AB - AIMS: This study aims to assess the prevalence of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), chronic kidney disease (CKD), and their combined presence in type 2 diabetes (T2D) patients in primary care for whom the 2019 ADA/EASD consensus update "Management of Hyperglycemia in Type 2 Diabetes" recommends GLP-1 receptor agonists (GLP-1RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-I) as first-line medications after metformin. METHODS: Data were obtained in 2015 from Intego, a morbidity registration network of 111 general practitioners (GPs) working in 48 practices and including 123 261 registered patients. RESULTS: Of 123 261 patients, 9616 had T2D. Of these patients, 4200 (43.7%) presented with ASCVD and/or CKD and/or HF. Specifically, 3348 (34.8%) patients had ASCVD, 388 (4.0%) had heart failure, and 1402 (14.6%) had CKD. Compared to patients without any of these comorbidities, patients with at least 1 of these conditions were older (69.7 +/-12.6 vs. 63.1+/-12.5 years), had higher LDL-C values (104.2+/-35.8 mg/dl vs. 97.2+/-37.7) and less frequently achieved the systolic blood pressure target of 140 mm Hg (53 vs. 61%) (all p<0.001). Comorbid patients also had significantly more other comorbidities, such as dementia or cancer; received more recommended medications, such as statins; and received less metformin. Most patients with HF (325; 3.4%) had ASCVD (114; 1.2%), CKD (76; 0.8%), or both (135; 1.4%). In total, 478 patients with CKD (5.0%) also had ASCVD. CONCLUSIONS: At the primary care level, 44% of T2D patients suffer from ASCVD, CKD, and/or HF, and thus qualify for GLP-1RA or SGLT2-I therapy. CI - Thieme. All rights reserved. FAU - Goderis, Geert AU - Goderis G AD - Academic Center for General Practice, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium. FAU - Vaes, Bert AU - Vaes B AD - Academic Center for General Practice, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium. FAU - Mamouris, Pavlos AU - Mamouris P AD - Academic Center for General Practice, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium. FAU - van Craeyveld, Eline AU - van Craeyveld E AD - Medical Department, Novo Nordisk Pharma Belux, Brussels, Belgium. FAU - Mathieu, Chantal AU - Mathieu C AD - Clinical and Experimental Endocrinology, UZ Gasthuisberg, KU Leuven, Leuven, Belgium. LA - eng PT - Journal Article DEP - 20210621 PL - Germany TA - Exp Clin Endocrinol Diabetes JT - Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association JID - 9505926 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 9100L32L2N (Metformin) SB - IM MH - *Cardiovascular Diseases/drug therapy MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - *Heart Failure/epidemiology MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - *Metformin/therapeutic use MH - Prevalence MH - Primary Health Care MH - *Renal Insufficiency, Chronic MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use COIS- GG has received unrestricted research grants from Novo Nordisk, Astra Zeneca, and Sanofi Aventis. PM has no conflict of interest to declare. BV has no conflict of interest to declare. EVC is a medical advisor at Novo Nordisk Pharma Belux, Brussels, Belgium. CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp, and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Hanmi Pharmaceuticals, Roche, Medtronic, ActoBio Therapeutics, Pfizer, and UCB; financial compensation for these activities has been received by KU Leuven. KU Leuven has received research support for CM from Medtronic, Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Roche, Abbott, ActoBio Therapeutics, and Novartis. CM serves or has served on the speakers' bureau for Novo Nordisk, Sanofi, Merck Sharp, and Dohme, Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca, and Novartis; financial compensation for these activities has been received by KU Leuven. EDAT- 2021/06/22 06:00 MHDA- 2022/07/20 06:00 CRDT- 2021/06/21 20:36 PHST- 2021/06/22 06:00 [pubmed] PHST- 2022/07/20 06:00 [medline] PHST- 2021/06/21 20:36 [entrez] AID - 10.1055/a-1508-3912 [doi] PST - ppublish SO - Exp Clin Endocrinol Diabetes. 2022 Jul;130(7):447-453. doi: 10.1055/a-1508-3912. Epub 2021 Jun 21. PMID- 34137731 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240403 IS - 2049-3614 (Print) IS - 2049-3614 (Electronic) IS - 2049-3614 (Linking) VI - 10 IP - 7 DP - 2021 Jul 17 TI - How glucagon-like peptide 1 receptor agonists work. PG - R200-R212 LID - 10.1530/EC-21-0130 [doi] AB - In recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of action, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists. FAU - Andreasen, Christine Rode AU - Andreasen CR AD - Steno Diabetes Center Copenhagen, Gentofte, Denmark. AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. FAU - Andersen, Andreas AU - Andersen A AD - Steno Diabetes Center Copenhagen, Gentofte, Denmark. AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. FAU - Knop, Filip Krag AU - Knop FK AD - Steno Diabetes Center Copenhagen, Gentofte, Denmark. AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. AD - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Vilsboll, Tina AU - Vilsboll T AD - Steno Diabetes Center Copenhagen, Gentofte, Denmark. AD - Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. LA - eng PT - Journal Article PT - Review DEP - 20210717 PL - England TA - Endocr Connect JT - Endocrine connections JID - 101598413 PMC - PMC8346189 OTO - NOTNLM OT - cardiovascular OT - diabetes OT - inflammation OT - metabolism OT - obesity EDAT- 2021/06/18 06:00 MHDA- 2021/06/18 06:01 PMCR- 2021/06/16 CRDT- 2021/06/17 12:23 PHST- 2021/05/26 00:00 [received] PHST- 2021/06/16 00:00 [accepted] PHST- 2021/06/18 06:00 [pubmed] PHST- 2021/06/18 06:01 [medline] PHST- 2021/06/17 12:23 [entrez] PHST- 2021/06/16 00:00 [pmc-release] AID - EC-21-0130.R1 [pii] AID - EC-21-0130 [pii] AID - 10.1530/EC-21-0130 [doi] PST - epublish SO - Endocr Connect. 2021 Jul 17;10(7):R200-R212. doi: 10.1530/EC-21-0130. PMID- 34118986 OWN - NLM STAT- MEDLINE DCOM- 20210625 LR - 20210625 IS - 1758-9193 (Electronic) VI - 13 IP - 1 DP - 2021 Jun 12 TI - Role of liraglutide in Alzheimer's disease pathology. PG - 112 LID - 10.1186/s13195-021-00853-0 [doi] LID - 112 AB - BACKGROUND: The described relationship between Alzheimer's disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology. MAIN BODY: Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve beta cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer's Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date. CONCLUSION: The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients. FAU - Vargas-Soria, Maria AU - Vargas-Soria M AD - Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Edificio Andres Segovia, C/Dr. Maranon 3, 3er piso, Cadiz, Spain. FAU - Carranza-Naval, Maria Jose AU - Carranza-Naval MJ AD - Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Edificio Andres Segovia, C/Dr. Maranon 3, 3er piso, Cadiz, Spain. AD - Salus Infirmorum-Universidad de Cadiz, Cadiz, Spain. FAU - Del Marco, Angel AU - Del Marco A AD - Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Edificio Andres Segovia, C/Dr. Maranon 3, 3er piso, Cadiz, Spain. angeljose.delmarco@uca.es. FAU - Garcia-Alloza, Monica AU - Garcia-Alloza M AUID- ORCID: 0000-0003-1610-4114 AD - Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Edificio Andres Segovia, C/Dr. Maranon 3, 3er piso, Cadiz, Spain. monica.garcia@uca.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20210612 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) SB - IM MH - *Alzheimer Disease/drug therapy MH - Amyloid beta-Peptides MH - Animals MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Disease Models, Animal MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Liraglutide/therapeutic use MH - tau Proteins PMC - PMC8199799 OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid OT - Cognition OT - Inflammation OT - Liraglutide OT - Tau COIS- The authors declare that they have no competing interests. EDAT- 2021/06/14 06:00 MHDA- 2021/06/29 06:00 PMCR- 2021/06/12 CRDT- 2021/06/13 20:25 PHST- 2021/05/21 00:00 [received] PHST- 2021/05/31 00:00 [accepted] PHST- 2021/06/13 20:25 [entrez] PHST- 2021/06/14 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2021/06/12 00:00 [pmc-release] AID - 10.1186/s13195-021-00853-0 [pii] AID - 853 [pii] AID - 10.1186/s13195-021-00853-0 [doi] PST - epublish SO - Alzheimers Res Ther. 2021 Jun 12;13(1):112. doi: 10.1186/s13195-021-00853-0. PMID- 34093449 OWN - NLM STAT- MEDLINE DCOM- 20211223 LR - 20240811 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 12 DP - 2021 TI - Proglucagon-Derived Peptides as Therapeutics. PG - 689678 LID - 10.3389/fendo.2021.689678 [doi] LID - 689678 AB - Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development. CI - Copyright (c) 2021 Lafferty, O'Harte, Irwin, Gault and Flatt. FAU - Lafferty, Ryan A AU - Lafferty RA AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - O'Harte, Finbarr P M AU - O'Harte FPM AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Irwin, Nigel AU - Irwin N AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Gault, Victor A AU - Gault VA AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Flatt, Peter R AU - Flatt PR AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20210518 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Glucagon-Like Peptide 2) RN - 55963-74-1 (Proglucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9007-92-5 (Glucagon) SB - IM MH - Diabetes Mellitus, Type 2/*drug therapy MH - Glucagon/metabolism/*therapeutic use MH - Glucagon-Like Peptide 1/*therapeutic use MH - Glucagon-Like Peptide 2/*therapeutic use MH - Humans MH - Proglucagon/metabolism/*therapeutic use PMC - PMC8171296 OTO - NOTNLM OT - GLP-1 OT - GLP-2 OT - diabetes OT - glucagon OT - multi-agonist OT - obesity OT - oxyntomodulin OT - proglucagon COIS- PF, VG, NI,and FO'H are named on patents filed by Ulster University for the exploitation of incretin-based drugs and other peptide therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/06/08 06:00 MHDA- 2021/12/24 06:00 PMCR- 2021/01/01 CRDT- 2021/06/07 05:50 PHST- 2021/04/01 00:00 [received] PHST- 2021/05/05 00:00 [accepted] PHST- 2021/06/07 05:50 [entrez] PHST- 2021/06/08 06:00 [pubmed] PHST- 2021/12/24 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2021.689678 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2021 May 18;12:689678. doi: 10.3389/fendo.2021.689678. eCollection 2021. PMID- 34016830 OWN - NLM STAT- MEDLINE DCOM- 20211209 LR - 20250103 IS - 1533-712X (Electronic) IS - 0271-0749 (Linking) VI - 41 IP - 4 DP - 2021 Jul-Aug 01 TI - Effect of Exenatide Use on Cognitive and Affective Functioning in Obese Patients With Type 2 Diabetes Mellitus: Exenatide Use Mediates Depressive Scores Through Increased Perceived Stress Levels. PG - 428-435 LID - 10.1097/JCP.0000000000001409 [doi] AB - PURPOSE/BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a molecule used to treat type 2 diabetes mellitus (T2DM). Given their widespread expression in the nervous system, GLP-1 receptors also play a role in regulating mood and cognitive function. Here, we aimed to compare obese patients with T2DM, with or without exenatide (a GLP-1R agonist) use on cognitive and affective functioning. METHODS/PROCEDURES: A total of 43 patients with T2DM (23 on exenatide and 20 without exenatide) were evaluated with the Snaith-Hamilton Pleasure Scale, Cognitive Failures Questionnaire, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7, Childhood Trauma Questionnaire, Perceived Stress Scale (PSS), and Chronic Stress Scale, in addition to laboratory-based measures of reward learning (the probabilistic reward task) and working memory (Letter-N-Back task). FINDINGS/RESULTS: Patients on exenatide had higher body mass index (BMI) (37.88 +/- 5.44 vs 35.29 +/- 6.30; P = 0.015), PHQ-9 (9.70 +/- 4.92 vs 6.70 +/- 4.66; P = 0.026), and PSS (29.39 +/- 6.70 vs 23.35 +/- 7.69; P = 0.015) scores. Other stress scales (Childhood Trauma Questionnaire and Chronic Stress Scale), Generalized Anxiety Disorder-7 scores, response bias, or discriminability as assessed by probabilistic reward task and self-report (Cognitive Failures Questionnaire) and laboratory-based (Letter-N-Back) cognitive measures were not significantly different between groups (both Ps > 0.05). Multivariate linear regression analyses adding BMI and PSS as covariates revealed that although BMI had no effect (P = 0.5), PSS significantly predicted PHQ-9 scores (P = 0.004). Mediation analysis showed that exenatide users reported higher PSS, with greater PSS associated with higher PHQ-9 levels (b = 0.236). There was no evidence on exenatide directly influencing PHQ-9 independent of PSS (c' = 1.573; P = 0.305; 95% bootstrap confidence interval, -1.487 to 4.634). IMPLICATIONS/CONCLUSIONS: Based on previous research and our findings, exenatide use might be mediating depression scores through disrupting stress responses. CI - Copyright (c) 2021 Wolters Kluwer Health, Inc. All rights reserved. FAU - Eren-Yazicioglu, Candan Yasemin AU - Eren-Yazicioglu CY AD - From the Research Center for Translational Medicine, and Graduate School of Health Sciences, Neuroscience Ph.D. Program, Koc University, Istanbul, Turkey. FAU - Kara, Buket AU - Kara B AD - Centre of Resilience for Social Justice, School of Health Sciences, University of Brighton, Brighton, UK. FAU - Sancak, Seda AU - Sancak S AD - Department of Internal Medicine, Endocrinology and Metabolism Disorders, University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital. FAU - Uysal, Sanem Pinar AU - Uysal SP AD - School of Medicine. FAU - Yazici, Dilek AU - Yazici D AD - Department of Endocrinology and Metabolism, School of Medicine, Koc University. FAU - Okuroglu, Nalan AU - Okuroglu N AD - Department of Internal Medicine, University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey. FAU - Whitton, Alexis E AU - Whitton AE AD - Black Dog Institute, University of New South Wales, Sydney, NSW, Australia. FAU - Rutherford, Ashleigh V AU - Rutherford AV AD - Department of Psychology, Yale University, New Haven, CT. FAU - Yapici-Eser, Hale AU - Yapici-Eser H LA - eng PT - Journal Article PL - United States TA - J Clin Psychopharmacol JT - Journal of clinical psychopharmacology JID - 8109496 RN - 0 (Anti-Obesity Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Affective Symptoms/diagnosis/drug therapy/physiopathology MH - Anti-Obesity Agents/administration & dosage/adverse effects MH - *Cognition/drug effects/physiology MH - *Depression/diagnosis/drug therapy/physiopathology MH - *Diabetes Mellitus, Type 2/drug therapy/psychology MH - *Exenatide/administration & dosage/adverse effects MH - Female MH - *Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Hypoglycemic Agents/administration & dosage/adverse effects MH - Male MH - Middle Aged MH - *Obesity/drug therapy/psychology MH - Psychological Techniques MH - Self Concept MH - Stress, Psychological/diagnosis/physiopathology MH - Treatment Outcome MH - *Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2021/05/22 06:00 MHDA- 2021/12/15 06:00 CRDT- 2021/05/21 06:02 PHST- 2021/05/22 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/05/21 06:02 [entrez] AID - 00004714-900000000-98301 [pii] AID - 10.1097/JCP.0000000000001409 [doi] PST - ppublish SO - J Clin Psychopharmacol. 2021 Jul-Aug 01;41(4):428-435. doi: 10.1097/JCP.0000000000001409. PMID- 33984196 OWN - NLM STAT- MEDLINE DCOM- 20210601 LR - 20210601 IS - 1899-5276 (Print) IS - 1899-5276 (Linking) VI - 30 IP - 5 DP - 2021 May TI - Exenatide regulates inflammation and the production of reactive oxygen species via inhibition of S1PR2 synthesis. PG - 555-561 LID - 10.17219/acem/133483 [doi] AB - BACKGROUND: Microvascular dysfunction is one of the most serious complications of diabetic retinopathy (DR). As a novel treatment drug for type 2 diabetes, exenatide possesses protective properties against retinal neurodegeneration. Sphingosine-1-phosphate receptor 2 (S1PR2) could regulate blood glucose in diabetes, and inhibition of S1PR2 is involved in the treatment of diabetes. However, the mechanism of exenatide in human retinal vascular endothelial cells (hRVECs) has not been fully defined. OBJECTIVES: We tested the hypothesis that S1PR2 plays a vital role in high glucose (HG)-induced hRVECs, and that exenatide could ameliorate HG-induced hRVEC injury by regulating S1PR2 production. MATERIAL AND METHODS: The hRVECs underwent HG-stimulation. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot were performed to examine the expression of S1PR2. Oxidative stress levels, inflammatory markers and cell apoptosis were detected using reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay (ELISA) kits and TUNEL staining. RESULTS: High glucose increased the level of S1PR2 in hRVECs and reduced the expression of glucagon-like peptide-1 receptor (GLP1R) compared to the control group. Exenatide decreased the level of S1PR2 induced by HG. Sphingosine-1 blocked the effects of exenatide, alleviating the ROS and cell apoptosis induced by HG. JTE-013 treatment protected hRVECs from injury by HG. The inhibitory effects of exenatide on S1PR2 expression lessened HG-induced hRVEC injury. CONCLUSIONS: The results demonstrate a possible mechanism of exenatide mediated inhibition of S1PR2 synthesis, and support S1PR2 as a novel target for treating DR. FAU - Yang, Yunyun AU - Yang Y AD - Department of Ophthalmology, Zhangjiagang TCM Hospital (affiliated to Nanjing University of Chinese Medicine), China. FAU - Zhao, Qingyi AU - Zhao Q AD - Department of Ophthalmology, Zhangjiagang TCM Hospital (affiliated to Nanjing University of Chinese Medicine), China. LA - eng PT - Journal Article PL - Poland TA - Adv Clin Exp Med JT - Advances in clinical and experimental medicine : official organ Wroclaw Medical University JID - 101138582 RN - 0 (Reactive Oxygen Species) RN - 0 (S1PR2 protein, human) RN - 0 (Sphingosine-1-Phosphate Receptors) RN - 9P1872D4OL (Exenatide) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Apoptosis MH - *Diabetes Mellitus, Type 2 MH - *Endothelial Cells MH - Exenatide/pharmacology MH - Glucose MH - Humans MH - Inflammation MH - Oxidative Stress MH - Reactive Oxygen Species MH - Sphingosine-1-Phosphate Receptors OTO - NOTNLM OT - SIPR2 OT - diabetic retinopathy OT - exenatide OT - high glucose EDAT- 2021/05/14 06:00 MHDA- 2021/06/02 06:00 CRDT- 2021/05/13 17:36 PHST- 2021/05/14 06:00 [pubmed] PHST- 2021/06/02 06:00 [medline] PHST- 2021/05/13 17:36 [entrez] AID - 10.17219/acem/133483 [doi] PST - ppublish SO - Adv Clin Exp Med. 2021 May;30(5):555-561. doi: 10.17219/acem/133483. PMID- 33941038 OWN - NLM STAT- MEDLINE DCOM- 20230405 LR - 20230405 IS - 1563-5279 (Electronic) IS - 0020-7454 (Linking) VI - 133 IP - 5 DP - 2023 May TI - The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. PG - 473-491 LID - 10.1080/00207454.2021.1924707 [doi] AB - Glucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases. FAU - Zhang, LongQing AU - Zhang L AD - Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Zhang, Wen AU - Zhang W AD - Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Tian, XueBi AU - Tian X AUID- ORCID: 0000-0002-0624-6816 AD - Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. LA - eng PT - Journal Article PT - Review DEP - 20230214 PL - England TA - Int J Neurosci JT - The International journal of neuroscience JID - 0270707 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Transcription Factors) SB - IM MH - Humans MH - Glucagon-Like Peptide 1 MH - Glucagon-Like Peptide-1 Receptor MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Islets of Langerhans MH - *Spinal Cord Injuries/drug therapy MH - Transcription Factors OTO - NOTNLM OT - CNS diseases OT - GLP-1 OT - GLP-1R OT - neuroprotection EDAT- 2021/05/05 06:00 MHDA- 2023/04/05 06:42 CRDT- 2021/05/04 05:46 PHST- 2023/04/05 06:42 [medline] PHST- 2021/05/05 06:00 [pubmed] PHST- 2021/05/04 05:46 [entrez] AID - 10.1080/00207454.2021.1924707 [doi] PST - ppublish SO - Int J Neurosci. 2023 May;133(5):473-491. doi: 10.1080/00207454.2021.1924707. Epub 2023 Feb 14. PMID- 33900631 OWN - NLM STAT- MEDLINE DCOM- 20220413 LR - 20250103 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 179 IP - 4 DP - 2022 Feb TI - Protective properties of GLP-1 and associated peptide hormones in neurodegenerative disorders. PG - 695-714 LID - 10.1111/bph.15508 [doi] AB - Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. Glucagon-like peptide 1 (GLP-1) is a hormone that has growth factor-like and neuroprotective properties. Several clinical trials have been conducted, testing GLP-1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes-induced memory impairments. The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP-1. GIP analogues have shown neuroprotective effects in animal models of disease and can improve on the effects of GLP-1. Novel dual GLP-1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. The improved neuroprotective effects of these drugs suggest that they are superior to single GLP-1 receptor agonists and could provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc. CI - (c) 2021 The British Pharmacological Society. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - The Second Associated Hospital, Neurology Department, Shanxi Medical University, Taiyuan, China. AD - Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, China. LA - eng PT - Journal Article PT - Review DEP - 20210529 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - *Alzheimer Disease/drug therapy MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - Gastric Inhibitory Polypeptide/pharmacology/therapeutic use MH - Glucagon-Like Peptide 1 MH - Humans MH - Insulin MH - *Neuroprotective Agents/pharmacology/therapeutic use MH - *Parkinson Disease/drug therapy MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8820183 OTO - NOTNLM OT - Alzheimer OT - Parkinson OT - brain OT - epilepsy OT - incretins OT - inflammation OT - stroke COIS- The author is a named inventor on patents and patent application that cover the use of GLP-1, GIP and dual GLP-1/GIP receptor agonists as treatments for neurodegenerative disorders. The patents are owned by Ulster University and Lancaster University, UK. He is the CSO of the company Kariya Pharmaceuticals. EDAT- 2021/04/27 06:00 MHDA- 2022/04/14 06:00 PMCR- 2022/02/07 CRDT- 2021/04/26 12:31 PHST- 2021/04/21 00:00 [revised] PHST- 2021/01/31 00:00 [received] PHST- 2021/04/22 00:00 [accepted] PHST- 2021/04/27 06:00 [pubmed] PHST- 2022/04/14 06:00 [medline] PHST- 2021/04/26 12:31 [entrez] PHST- 2022/02/07 00:00 [pmc-release] AID - BPH15508 [pii] AID - 10.1111/bph.15508 [doi] PST - ppublish SO - Br J Pharmacol. 2022 Feb;179(4):695-714. doi: 10.1111/bph.15508. Epub 2021 May 29. PMID- 33864929 OWN - NLM STAT- MEDLINE DCOM- 20220131 LR - 20240226 IS - 1872-9738 (Electronic) IS - 0892-0362 (Print) IS - 0892-0362 (Linking) VI - 87 DP - 2021 Sep-Oct TI - Long-term functional alterations following prenatal GLP-1R activation. PG - 106984 LID - S0892-0362(21)00038-6 [pii] LID - 10.1016/j.ntt.2021.106984 [doi] AB - Evidence supporting the use of glucagon-like peptide-1 (GLP-1) analogues to pharmacologically treat disorders beyond type 2 diabetes and obesity is increasing. However, little is known about how activation of the GLP-1 receptor (GLP-1R) during pregnancy affects maternal and offspring outcomes. We treated female C57Bl/6 J mice prior to conception and throughout gestation with a long-lasting GLP-1R agonist, Exendin-4. While GLP-1R activation has significant effects on food and drug reward, depression, locomotor activity, and cognition in adults, we found few changes in these domains in exendin-4-exposed offspring. Repeated injections of Exendin-4 had minimal effects on the dams and may have enhanced maternal care. Offspring exposed to the drug weighed significantly more than their control counterparts during the preweaning period and demonstrated alterations in anxiety-like outcomes, which indicate a developmental role for GLP-1R modulation in the stress response that may be sex-specific. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Graham, Devon L AU - Graham DL AD - Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, FL 32306, United States of America. FAU - Madkour, Haley S AU - Madkour HS AD - Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, FL 32306, United States of America. FAU - Noble, Brenda L AU - Noble BL AD - Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, FL 32306, United States of America. FAU - Schatschneider, Chris AU - Schatschneider C AD - Department of Psychology, Florida State University, Tallahassee, FL 32306, United States of America. FAU - Stanwood, Gregg D AU - Stanwood GD AD - Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, FL 32306, United States of America. Electronic address: gregg.stanwood@med.fsu.edu. LA - eng GR - R03 MH110749/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210420 PL - United States TA - Neurotoxicol Teratol JT - Neurotoxicology and teratology JID - 8709538 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Brain/metabolism MH - Cognition/drug effects MH - Exenatide/drug effects/*metabolism MH - Female MH - Glucagon-Like Peptide 1/metabolism/*pharmacology MH - Glucagon-Like Peptide-1 Receptor/*drug effects/*metabolism MH - Mice, Inbred C57BL MH - *Time MH - Mice PMC - PMC8555578 MID - NIHMS1693923 OTO - NOTNLM OT - Anxiety OT - Brain OT - Development OT - Developmental programming OT - GLP-1 OT - Pregnancy EDAT- 2021/04/18 06:00 MHDA- 2022/02/01 06:00 PMCR- 2022/09/01 CRDT- 2021/04/17 20:09 PHST- 2020/12/14 00:00 [received] PHST- 2021/03/29 00:00 [revised] PHST- 2021/04/09 00:00 [accepted] PHST- 2021/04/18 06:00 [pubmed] PHST- 2022/02/01 06:00 [medline] PHST- 2021/04/17 20:09 [entrez] PHST- 2022/09/01 00:00 [pmc-release] AID - S0892-0362(21)00038-6 [pii] AID - 10.1016/j.ntt.2021.106984 [doi] PST - ppublish SO - Neurotoxicol Teratol. 2021 Sep-Oct;87:106984. doi: 10.1016/j.ntt.2021.106984. Epub 2021 Apr 20. PMID- 33859286 OWN - NLM STAT- MEDLINE DCOM- 20211118 LR - 20250103 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 Apr 15 TI - Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition. PG - 8326 LID - 10.1038/s41598-021-87809-4 [doi] LID - 8326 AB - Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome. FAU - Wang, Ming AU - Wang M AD - BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea. FAU - Yoon, Gwangho AU - Yoon G AD - BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea. AD - Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, 58128, Republic of Korea. FAU - Song, Juhyun AU - Song J AD - BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea. juhyunsong@chonnam.ac.kr. AD - Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, 58128, Republic of Korea. juhyunsong@chonnam.ac.kr. FAU - Jo, Jihoon AU - Jo J AD - BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea. Jihoon.Jo@chonnam.ac.kr. AD - NeuroMedical Convergence Lab, Biomedical Research Institute, Chonnam National University Hospital, Jebong-ro, Gwangju, 501-757, Republic of Korea. Jihoon.Jo@chonnam.ac.kr. AD - Department of Neurology, Chonnam National University Medical School, Gwangju, 501-757, Republic of Korea. Jihoon.Jo@chonnam.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210415 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Cells, Cultured MH - Cerebral Cortex/cytology MH - Cognition/drug effects MH - Dendrites/*pathology MH - Diet, High-Fat/adverse effects MH - Exenatide/*pharmacology MH - Glucagon-Like Peptide-1 Receptor/physiology MH - Hippocampus/cytology MH - Insulin Resistance MH - Long-Term Potentiation/*drug effects MH - Mice MH - Neuronal Plasticity/drug effects MH - Neurons/*cytology MH - Obesity/etiology/*pathology/*physiopathology/psychology MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC8050263 COIS- The authors declare no competing interests. EDAT- 2021/04/17 06:00 MHDA- 2021/11/19 06:00 PMCR- 2021/04/15 CRDT- 2021/04/16 06:17 PHST- 2020/11/16 00:00 [received] PHST- 2021/03/30 00:00 [accepted] PHST- 2021/04/16 06:17 [entrez] PHST- 2021/04/17 06:00 [pubmed] PHST- 2021/11/19 06:00 [medline] PHST- 2021/04/15 00:00 [pmc-release] AID - 10.1038/s41598-021-87809-4 [pii] AID - 87809 [pii] AID - 10.1038/s41598-021-87809-4 [doi] PST - epublish SO - Sci Rep. 2021 Apr 15;11(1):8326. doi: 10.1038/s41598-021-87809-4. PMID- 33845041 OWN - NLM STAT- MEDLINE DCOM- 20211025 LR - 20211025 IS - 1095-6808 (Electronic) IS - 0091-3022 (Linking) VI - 62 DP - 2021 Jul TI - Diabetes, insulin and new therapeutic strategies for Parkinson's disease: Focus on glucagon-like peptide-1 receptor agonists. PG - 100914 LID - S0091-3022(21)00016-9 [pii] LID - 10.1016/j.yfrne.2021.100914 [doi] AB - Parkinson's disease and diabetes mellitus are two chronic disorders associated with aging that are becoming increasingly prevalent worldwide. Parkinson is a multifactorial progressive condition with no available disease modifying treatments at the moment. Over the last few years there is growing interest in the relationship between diabetes (and impaired insulin signaling) and neurodegenerative diseases, as well as the possible benefit of antidiabetic treatments as neuroprotectors, even in non-diabetic patients. Insulin regulates essential functions in the brain such as neuronal survival, autophagy of toxic proteins, synaptic plasticity, neurogenesis, oxidative stress and neuroinflammation. We review the existing epidemiological, experimental and clinical evidence that supports the interplay between insulin and neurodegeneration in Parkinson's disease, as well as the role of antidiabetic treatments in this disease. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Labandeira, Carmen M AU - Labandeira CM AD - Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain; Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: Carmen.Maria.Labandeira.Guerra@sergas.es. FAU - Fraga-Bau, Arturo AU - Fraga-Bau A AD - Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain. FAU - Arias Ron, David AU - Arias Ron D AD - Department of Clinical Oncology, University Hospital Complex, Ourense, Spain. FAU - Munoz, Ana AU - Munoz A AD - Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Spain. FAU - Alonso-Losada, Gema AU - Alonso-Losada G AD - Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain. FAU - Koukoulis, Antonio AU - Koukoulis A AD - Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain. FAU - Romero-Lopez, Jesus AU - Romero-Lopez J AD - Department of Clinical Neurology, Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain. FAU - Rodriguez-Perez, Ana I AU - Rodriguez-Perez AI AD - Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Spain. LA - eng PT - Journal Article PT - Review DEP - 20210415 PL - United States TA - Front Neuroendocrinol JT - Frontiers in neuroendocrinology JID - 7513292 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - *Diabetes Mellitus MH - *Diabetes Mellitus, Type 2 MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Insulin MH - *Parkinson Disease/drug therapy OTO - NOTNLM OT - Diabetes OT - Exenatide, antidiabetic OT - GLP OT - Glucagon-like peptide OT - Insulin OT - Neuroinflammation OT - Neuroprotection OT - Parkinson OT - Repurposing EDAT- 2021/04/13 06:00 MHDA- 2021/10/26 06:00 CRDT- 2021/04/12 20:12 PHST- 2020/05/03 00:00 [received] PHST- 2021/03/20 00:00 [revised] PHST- 2021/04/06 00:00 [accepted] PHST- 2021/04/13 06:00 [pubmed] PHST- 2021/10/26 06:00 [medline] PHST- 2021/04/12 20:12 [entrez] AID - S0091-3022(21)00016-9 [pii] AID - 10.1016/j.yfrne.2021.100914 [doi] PST - ppublish SO - Front Neuroendocrinol. 2021 Jul;62:100914. doi: 10.1016/j.yfrne.2021.100914. Epub 2021 Apr 15. PMID- 33811589 OWN - NLM STAT- MEDLINE DCOM- 20220630 LR - 20220716 IS - 1573-6830 (Electronic) IS - 0272-4340 (Print) IS - 0272-4340 (Linking) VI - 42 IP - 6 DP - 2022 Aug TI - A High-Fat Diet Increases Activation of the Glucagon-Like Peptide-1-Producing Neurons in the Nucleus Tractus Solitarii: an Effect that is Partially Reversed by Drugs Normalizing Glycemia. PG - 1995-2002 LID - 10.1007/s10571-021-01079-2 [doi] AB - Glucagon-like peptide-1 (GLP-1) is a peripheral incretin and centrally active peptide produced in the intestine and nucleus tractus solitarii (NTS), respectively. GLP-1 not only regulates metabolism but also improves cognition and is neuroprotective. While intestinal GLP-1-producing cells have been well characterized, less is known about GLP-1-producing neurons in NTS. We hypothesized that obesity-induced type 2 diabetes (T2D) impairs the function of NTS GLP-1-producing neurons and glycemia normalization counteracts this effect. We used immunohistochemistry/quantitative microscopy to investigate the number, potential atrophy, and activation (cFos-expression based) of NTS GLP-1-producing neurons, in non-diabetic versus obese/T2D mice (after 12 months of high-fat diet). NTS neuroinflammation was also assessed. The same parameters were quantified in obese/T2D mice treated from month 9 to 12 with two unrelated anti-hyperglycemic drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride. We show no effect of T2D on the number and volume but increased activation of NTS GLP-1-producing neurons. This effect was partially normalized by both anti-diabetic treatments, concurrent with decreased neuroinflammation. Increased activation of NTS GLP-1-producing neurons could represent an aberrant metabolic demand in T2D/obesity, attenuated by glycemia normalization. Whether this effect represents a pathophysiological process preceding GLP-1 signaling impairment in the CNS, remains to be investigated. CI - (c) 2021. The Author(s). FAU - Lietzau, Grazyna AU - Lietzau G AUID- ORCID: 0000-0001-5119-3082 AD - Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset Internal Medicine, 118 83, Stockholm, Sweden. grazyna.lietzau@gumed.edu.pl. AD - Faculty of Medicine, Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland. grazyna.lietzau@gumed.edu.pl. FAU - Ntika, Stelia AU - Ntika S AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. AD - Department of Research, Sodertalje Hospital, Sodertalje, Sweden. FAU - Pintana, Hiranya AU - Pintana H AD - Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset Internal Medicine, 118 83, Stockholm, Sweden. FAU - Tracy, Linda AU - Tracy L AD - Department of Research, Sodertalje Hospital, Sodertalje, Sweden. FAU - Klein, Thomas AU - Klein T AD - Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. FAU - Nystrom, Thomas AU - Nystrom T AD - Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset Internal Medicine, 118 83, Stockholm, Sweden. FAU - Darsalia, Vladimer AU - Darsalia V AD - Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset Internal Medicine, 118 83, Stockholm, Sweden. FAU - Patrone, Cesare AU - Patrone C AD - Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset Internal Medicine, 118 83, Stockholm, Sweden. FAU - Krizhanovskii, Camilla AU - Krizhanovskii C AUID- ORCID: 0000-0003-2195-165X AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. camilla.krizhanovskii@ki.se. AD - Department of Research, Sodertalje Hospital, Sodertalje, Sweden. camilla.krizhanovskii@ki.se. LA - eng GR - 20160511/Hjart-Lungfonden/ PT - Journal Article DEP - 20210403 PL - Netherlands TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (Blood Glucose) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Blood Glucose/metabolism MH - *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism MH - Diet, High-Fat MH - *Glucagon-Like Peptide 1/metabolism MH - Mice MH - Neurons/metabolism MH - Obesity/drug therapy MH - Solitary Nucleus/metabolism PMC - PMC9239971 OTO - NOTNLM OT - Diabetes OT - Dipeptidyl peptidase-4 inhibitors OT - GLP-1 OT - Nucleus tractus solitarii OT - Obesity OT - Sulfonylurea COIS- Work in the Patrone/Nystrom's NeuroCardioMetabol group (http://ki.se/en/kisos/the-neurocardiometabol-group) is supported by Boehringer Ingelheim Pharma GmbH & Co. TK is employed at Boehringer Ingelheim Pharma GmbH & Co. KG. TN has received unrestricted grants from AstraZeneca and consultancy fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Merck, and Sanofi-Aventis. The other authors declare that they have no conflicts of interest. EDAT- 2021/04/04 06:00 MHDA- 2022/07/01 06:00 PMCR- 2021/04/03 CRDT- 2021/04/03 12:09 PHST- 2020/12/03 00:00 [received] PHST- 2021/03/12 00:00 [accepted] PHST- 2021/04/04 06:00 [pubmed] PHST- 2022/07/01 06:00 [medline] PHST- 2021/04/03 12:09 [entrez] PHST- 2021/04/03 00:00 [pmc-release] AID - 10.1007/s10571-021-01079-2 [pii] AID - 1079 [pii] AID - 10.1007/s10571-021-01079-2 [doi] PST - ppublish SO - Cell Mol Neurobiol. 2022 Aug;42(6):1995-2002. doi: 10.1007/s10571-021-01079-2. Epub 2021 Apr 3. PMID- 33614900 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240330 IS - 2352-8737 (Electronic) IS - 2352-8737 (Linking) VI - 7 IP - 1 DP - 2021 TI - Association between exenatide use and incidence of Alzheimer's disease. PG - e12139 LID - 10.1002/trc2.12139 [doi] LID - e12139 AB - INTRODUCTION: Recent developments suggest that insulin-sensitizing agents used to treat type II diabetes (T2DM) may also prove useful in reducing the risk of Alzheimer's disease (AD). The objective of this study is to analyze the association between exenatide use among Medicare beneficiaries with T2DM and the incidence of AD. METHODS: We performed a retrospective cohort analysis on claims data from a 20% random sample of Medicare beneficiaries with T2DM from 2007 to 2013 (n = 342,608). We compared rates of incident AD between 2009 and 2013 according to exenatide use in 2007-2008, measured by the number of 30-day-equivalent fills. We adjusted for demographics, comorbidities, and use of other drugs. Unmeasured confounding was assessed with an instrumental variables approach. RESULTS: The sample was mostly female (65%), White (76%), and 74 years old on average. Exenatide users were more likely to be male (38% vs. 35%), White (87% vs. 76%), and younger (by 4.2 years) than non-users. Each additional 30-day-equivalent claim was associated with a 2.4% relative reduction in incidence (odds ratio 0.976; 95% confidence interval 0.963-0.989; P < .001). There was no evidence of unmeasured confounding. DISCUSSION: Exenatide use is associated with a reduced incidence of AD among Medicare beneficiaries aged 65 years or older with T2DM. The association shown in this study warrants consideration by clinicians prescribing insulin sensitizing agents to patients. CI - (c) 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. FAU - Zhou, Bo AU - Zhou B AD - USC Schaeffer Center for Health Policy and Economics Los Angeles California USA. AD - USC School of Pharmacy Los Angeles California USA. FAU - Zissimopoulos, Julie AU - Zissimopoulos J AD - USC Schaeffer Center for Health Policy and Economics Los Angeles California USA. AD - USC Price School of Public Policy Los Angeles California USA. FAU - Nadeem, Hasan AU - Nadeem H AD - University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA. FAU - Crane, Matthew A AU - Crane MA AD - Johns Hopkins University School of Medicine Baltimore Maryland USA. FAU - Goldman, Dana AU - Goldman D AD - USC Schaeffer Center for Health Policy and Economics Los Angeles California USA. AD - USC School of Pharmacy Los Angeles California USA. AD - USC Price School of Public Policy Los Angeles California USA. FAU - Romley, John A AU - Romley JA AD - USC Schaeffer Center for Health Policy and Economics Los Angeles California USA. AD - USC School of Pharmacy Los Angeles California USA. AD - USC Price School of Public Policy Los Angeles California USA. LA - eng GR - P30 AG043073/AG/NIA NIH HHS/United States GR - R01 AG055401/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20210214 PL - United States TA - Alzheimers Dement (N Y) JT - Alzheimer's & dementia (New York, N. Y.) JID - 101650118 PMC - PMC7882542 OTO - NOTNLM OT - Alzheimer's disease incidence OT - diabetes OT - exenatide OT - prevention EDAT- 2021/02/23 06:00 MHDA- 2021/02/23 06:01 PMCR- 2021/02/14 CRDT- 2021/02/22 05:58 PHST- 2020/10/20 00:00 [received] PHST- 2020/11/25 00:00 [accepted] PHST- 2021/02/22 05:58 [entrez] PHST- 2021/02/23 06:00 [pubmed] PHST- 2021/02/23 06:01 [medline] PHST- 2021/02/14 00:00 [pmc-release] AID - TRC212139 [pii] AID - 10.1002/trc2.12139 [doi] PST - epublish SO - Alzheimers Dement (N Y). 2021 Feb 14;7(1):e12139. doi: 10.1002/trc2.12139. eCollection 2021. PMID- 33435277 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210218 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 1 DP - 2021 Jan 9 TI - Role of Exendin-4 in Brain Insulin Resistance, Mitochondrial Function, and Neurite Outgrowth in Neurons under Palmitic Acid-Induced Oxidative Stress. LID - 10.3390/antiox10010078 [doi] LID - 78 AB - Glucagon like peptide 1 (GLP-1) is an incretin hormone produced by the gut and brain, and is currently being used as a therapeutic drug for type 2 diabetes and obesity, suggesting that it regulates abnormal appetite patterns, and ameliorates impaired glucose metabolism. Many researchers have demonstrated that GLP-1 agonists and GLP-1 receptor agonists exert neuroprotective effects against brain damage. Palmitic acid (PA) is a saturated fatty acid, and increases the risk of neuroinflammation, lipotoxicity, impaired glucose metabolism, and cognitive decline. In this study, we investigated whether or not Exentin-4 (Ex-4; GLP-1 agonist) inhibits higher production of reactive oxygen species (ROS) in an SH-SY5Y neuronal cell line under PA-induced apoptosis conditions. Moreover, pre-treatment with Ex-4 in SH-SY5Y neuronal cells prevents neural apoptosis and mitochondrial dysfunction through several cellular signal pathways. In addition, insulin sensitivity in neurons is improved by Ex-4 treatment under PA-induced insulin resistance. Additionally, our imaging data showed that neuronal morphology is improved by EX-4 treatment, in spite of PA-induced neuronal damage. Furthermore, we identified that Ex-4 inhibits neuronal damage and enhanced neural complexity, such as neurite length, secondary branches, and number of neurites from soma in PA-treated SH-SY5Y. We observed that Ex-4 significantly increases neural complexity, dendritic spine morphogenesis, and development in PA treated primary cortical neurons. Hence, we suggest that GLP-1 administration may be a crucial therapeutic solution for improving neuropathology in the obese brain. FAU - Jo, Danbi AU - Jo D AD - Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea. AD - BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, Korea. FAU - Yoon, Gwangho AU - Yoon G AD - Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea. AD - BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, Korea. FAU - Song, Juhyun AU - Song J AUID- ORCID: 0000-0002-9165-8507 AD - Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea. AD - BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, Korea. LA - eng GR - NRF-2019R1F1A1054111/National Research Foundation of Korea/ GR - NRF-2019R1A6A3A01090326/National Research Foundation of Korea/ PT - Journal Article DEP - 20210109 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC7827489 OTO - NOTNLM OT - exendin-4 (Ex-4) OT - glucagon like petide-1 (GLP-1) OT - neuronal structure OT - obesity OT - palmitic acid (PA) COIS- The authors have no conflicts of interest to declare. EDAT- 2021/01/14 06:00 MHDA- 2021/01/14 06:01 PMCR- 2021/01/09 CRDT- 2021/01/13 01:01 PHST- 2020/12/18 00:00 [received] PHST- 2021/01/06 00:00 [revised] PHST- 2021/01/07 00:00 [accepted] PHST- 2021/01/13 01:01 [entrez] PHST- 2021/01/14 06:00 [pubmed] PHST- 2021/01/14 06:01 [medline] PHST- 2021/01/09 00:00 [pmc-release] AID - antiox10010078 [pii] AID - antioxidants-10-00078 [pii] AID - 10.3390/antiox10010078 [doi] PST - epublish SO - Antioxidants (Basel). 2021 Jan 9;10(1):78. doi: 10.3390/antiox10010078. PMID- 33409802 OWN - NLM STAT- MEDLINE DCOM- 20211028 LR - 20261010 IS - 1179-1993 (Electronic) IS - 1178-2595 (Linking) VI - 35 IP - 1 DP - 2021 Jan TI - Repurposing GLP-1 Receptor Agonists for Parkinson's Disease: Current Evidence and Future Opportunities. PG - 11-19 LID - 10.1007/s40290-020-00374-5 [doi] AB - The global burden of chronic disorders such as Parkinson's disease (PD) has rapidly increased over recent decades. Despite an increasing understanding of PD pathophysiology, there are no effective therapies capable of stopping or slowing the progression of this neurological condition. It has been suggested that type 2 diabetes mellitus (T2DM) may be a risk factor for PD and comorbid T2DM may worsen PD symptoms, as well as accelerate neurodegeneration. In fact, the similar pathological mechanisms shared by PD and T2DM have inspired several studies on the therapeutic potential of T2DM drugs against PD, among which glucagon-like peptide-1 receptor (GLP-1R) agonists are promising candidates. Here, we highlight the mechanisms linking T2DM and PD, as well as the links between insulin resistance (IR) and PD patients' risk of developing cognitive deficits. We also briefly review the effects of GLP-1R agonists on PD and discuss how the successful use of these substances in preclinical models of PD has paved the way for PD clinical trials. We further discuss how recent evidence on the beneficial effects of dulaglutide on cognitive function of T2DM patients may have important implications for PD drug repurposing. FAU - Victorino, Daniella Balduino AU - Victorino DB AUID- ORCID: 0000-0002-2518-3902 AD - Discipline of Neuroscience, Department of Neurology and Neurosurgery, Paulista Medical School, Federal University of Sao Paulo, Pedro de Toledo 669, 1st Floor, Sao Paulo, SP, 04039-032, Brazil. dani_balduino@hotmail.com. FAU - Nejm, Mariana AU - Nejm M AD - Discipline of Neuroscience, Department of Neurology and Neurosurgery, Paulista Medical School, Federal University of Sao Paulo, Pedro de Toledo 669, 1st Floor, Sao Paulo, SP, 04039-032, Brazil. FAU - Guimaraes-Marques, Marcia AU - Guimaraes-Marques M AD - Discipline of Neuroscience, Department of Neurology and Neurosurgery, Paulista Medical School, Federal University of Sao Paulo, Pedro de Toledo 669, 1st Floor, Sao Paulo, SP, 04039-032, Brazil. FAU - Scorza, Fulvio Alexandre AU - Scorza FA AD - Discipline of Neuroscience, Department of Neurology and Neurosurgery, Paulista Medical School, Federal University of Sao Paulo, Pedro de Toledo 669, 1st Floor, Sao Paulo, SP, 04039-032, Brazil. FAU - Scorza, Carla Alessandra AU - Scorza CA AD - Discipline of Neuroscience, Department of Neurology and Neurosurgery, Paulista Medical School, Federal University of Sao Paulo, Pedro de Toledo 669, 1st Floor, Sao Paulo, SP, 04039-032, Brazil. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210107 PL - New Zealand TA - Pharmaceut Med JT - Pharmaceutical medicine JID - 101471195 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Pharmaceutical Preparations) SB - IM MH - *Diabetes Mellitus, Type 2/complications/drug therapy/epidemiology MH - Drug Repositioning MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - *Parkinson Disease/complications/drug therapy/epidemiology MH - *Pharmaceutical Preparations EDAT- 2021/01/08 06:00 MHDA- 2021/10/29 06:00 CRDT- 2021/01/07 06:12 PHST- 2020/12/15 00:00 [accepted] PHST- 2021/01/08 06:00 [pubmed] PHST- 2021/10/29 06:00 [medline] PHST- 2021/01/07 06:12 [entrez] AID - 10.1007/s40290-020-00374-5 [pii] AID - 10.1007/s40290-020-00374-5 [doi] PST - ppublish SO - Pharmaceut Med. 2021 Jan;35(1):11-19. doi: 10.1007/s40290-020-00374-5. Epub 2021 Jan 7. PMID- 33153424 OWN - NLM STAT- MEDLINE DCOM- 20211025 LR - 20211025 IS - 2212-3911 (Electronic) IS - 1574-8863 (Linking) VI - 16 IP - 2 DP - 2021 TI - A Review of the Efficacy and Cardiovascular Safety of Amylin Analogues. PG - 129-141 LID - 10.2174/1574886315999201105153852 [doi] AB - A large proportion of persons with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) do not reach the glycosylated haemoglobin (HbA1c) target of < 7% (53 mmol/- mol), with an increasing proportion of them being overweight or obese. In both T1DM and T2DM, there is accelerated gastric emptying and postprandial hyperglucagonemia. Furthermore, insulin therapy itself is associated with risk of hypoglycemia and weight-gain both of which are barriers to achieving good control. Medications which can achieve significant HbA1c and weight reduction associated with an ability to delay gastric emptying and suppress the glucagon secretion with minimal/ no hypoglycemia are of particular interest as an adjuvant to insulin. A synthetic amylin analogue, pramlintide is a drug with above mentioned properties. Other medications with similar properties are glucagon-like peptide-1 receptor agonists (GLP-1 RAs). In this article, we will review the efficacy of pramlintide when given with insulin in improving HbA1c, weight, and cognition with- /without GLP-1 RAs as well as its cardiovascular (CV) safety. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Koshy, Rithika Mary AU - Koshy RM AD - Department of Medicine, Kings College Hospital NHS Foundation Trust, London, BR6 8ND, United Kingdom. FAU - Fernandez, Cornelius James AU - Fernandez CJ AD - Department of Endocrinology & Metabolism, Pilgrim Hospital, Boston, PE21 9QS, United Kingdom. FAU - Jacob, Koshy AU - Jacob K AD - Department of Endocrinology & Metabolism, Eastbourne Hospital, Eastbourne, BN21 2UD, United Kingdom. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Drug Saf JT - Current drug safety JID - 101270895 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Islet Amyloid Polypeptide) RN - 0 (Pharmaceutical Preparations) SB - IM MH - *Diabetes Mellitus, Type 1 MH - *Diabetes Mellitus, Type 2/diagnosis/drug therapy MH - Humans MH - Hypoglycemic Agents/adverse effects MH - Insulin/adverse effects MH - Islet Amyloid Polypeptide/adverse effects MH - *Pharmaceutical Preparations OTO - NOTNLM OT - Amylin analogues OT - cardiovascular safety OT - diabetes mellitus OT - glycosylated haemoglobin OT - postprandial hyperglucagonemia OT - pramlintide EDAT- 2020/11/07 06:00 MHDA- 2021/10/26 06:00 CRDT- 2020/11/06 05:35 PHST- 2020/05/13 00:00 [received] PHST- 2020/07/30 00:00 [revised] PHST- 2020/08/12 00:00 [accepted] PHST- 2020/11/07 06:00 [pubmed] PHST- 2021/10/26 06:00 [medline] PHST- 2020/11/06 05:35 [entrez] AID - CDS-EPUB-111219 [pii] AID - 10.2174/1574886315999201105153852 [doi] PST - ppublish SO - Curr Drug Saf. 2021;16(2):129-141. doi: 10.2174/1574886315999201105153852. PMID- 33068776 OWN - NLM STAT- MEDLINE DCOM- 20211119 LR - 20260127 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 46 DP - 2021 Apr TI - GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. PG - 101102 LID - S2212-8778(20)30176-9 [pii] LID - 10.1016/j.molmet.2020.101102 [doi] LID - 101102 AB - BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW: To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA(1c), both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA(1c) reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases. CI - Copyright (c) 2020 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Nauck, Michael A AU - Nauck MA AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. Electronic address: michael.nauck@rub.de. FAU - Quast, Daniel R AU - Quast DR AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. FAU - Wefers, Jakob AU - Wefers J AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. FAU - Meier, Juris J AU - Meier JJ AD - Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. LA - eng PT - Journal Article PT - Review DEP - 20201014 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (Blood Glucose) RN - 9P1872D4OL (Exenatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Insulin) RN - 839I73S42A (Liraglutide) RN - 0 (Peptides) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 53AXN4NNHX (Semaglutide) RN - 5E7U48495E (rGLP-1 protein) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) RN - WTT295HSY5 (dulaglutide) SB - IM MH - Animals MH - Blood Glucose MH - Body Weight MH - Cardiovascular System/drug effects MH - Diabetes Mellitus, Type 2/*drug therapy MH - Exenatide/pharmacology MH - Glucagon-Like Peptide 1/analogs & derivatives MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Glucagon-Like Peptides/analogs & derivatives/pharmacology MH - Humans MH - Hypoglycemia MH - Immunoglobulin Fc Fragments MH - Insulin/pharmacology MH - Liraglutide/pharmacology MH - Neurodegenerative Diseases MH - Peptides/pharmacology MH - Psoriasis MH - Recombinant Fusion Proteins MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Semaglutide MH - Glucagon-Like Peptide-2 Receptor PMC - PMC8085572 OTO - NOTNLM OT - Albiglutide OT - Body weight OT - Cardiovascular disease OT - Dulaglutide OT - Exenatide OT - Glucagon-like peptide-1 receptor agonists OT - Liraglutide OT - Lixisenatide OT - Semaglutide OT - Type 2 diabetes EDAT- 2020/10/18 06:00 MHDA- 2021/11/20 06:00 PMCR- 2020/10/14 CRDT- 2020/10/17 20:08 PHST- 2020/08/25 00:00 [received] PHST- 2020/10/09 00:00 [revised] PHST- 2020/10/12 00:00 [accepted] PHST- 2020/10/18 06:00 [pubmed] PHST- 2021/11/20 06:00 [medline] PHST- 2020/10/17 20:08 [entrez] PHST- 2020/10/14 00:00 [pmc-release] AID - S2212-8778(20)30176-9 [pii] AID - 101102 [pii] AID - 10.1016/j.molmet.2020.101102 [doi] PST - ppublish SO - Mol Metab. 2021 Apr;46:101102. doi: 10.1016/j.molmet.2020.101102. Epub 2020 Oct 14. PMID- 32954901 OWN - NLM STAT- MEDLINE DCOM- 20210719 LR - 20250130 IS - 1559-7016 (Electronic) IS - 0271-678X (Print) IS - 0271-678X (Linking) VI - 41 IP - 1 DP - 2021 Jan TI - Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review. PG - 14-30 LID - 10.1177/0271678X20952011 [doi] AB - Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness. FAU - Maskery, Mark P AU - Maskery MP AUID- ORCID: 0000-0001-5661-6267 AD - Lancaster Medical School, Lancaster University, Lancaster, UK. AD - Department of Neurology, Royal Preston Hospital, Preston, UK. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China. FAU - Jones, Stephanie P AU - Jones SP AD - Faculty of Health and Wellbeing, University of Central Lancashire, Preston, UK. FAU - Price, Christopher I AU - Price CI AD - Institute of Neuroscience, Stroke Research Group, Newcastle University, Newcastle, UK. FAU - Strain, W David AU - Strain WD AD - NIHR Exeter Clinical Research Facility and Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK. FAU - Watkins, Caroline L AU - Watkins CL AD - Faculty of Health and Wellbeing, University of Central Lancashire, Preston, UK. FAU - Werring, David J AU - Werring DJ AD - Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK. FAU - Emsley, Hedley Ca AU - Emsley HC AD - Lancaster Medical School, Lancaster University, Lancaster, UK. AD - Department of Neurology, Royal Preston Hospital, Preston, UK. LA - eng PT - Journal Article PT - Scoping Review DEP - 20200920 PL - United States TA - J Cereb Blood Flow Metab JT - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JID - 8112566 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) SB - IM MH - Animals MH - Disease Models, Animal MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Humans MH - Ischemic Stroke/*drug therapy MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Prospective Studies MH - Retrospective Studies PMC - PMC7747170 OTO - NOTNLM OT - Acute stroke OT - animal models OT - clinical trials OT - neuroprotection OT - reperfusion COIS- Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CH is a named inventor on several patent applications that cover the use of GLP-1RAs for the treatment of neurodegenerative disorders. WDS has received speaker honoraria, conference sponsorship by Astra-Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Colgate Palmolive, Eli Lilly, GlaxoSmithKline, Lundbeck, Menarini, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, and Takeda. He holds research grants from Astra-Zeneca, Novo Nordisk and Novartis. EDAT- 2020/09/22 06:00 MHDA- 2021/07/20 06:00 PMCR- 2021/09/20 CRDT- 2020/09/21 08:40 PHST- 2020/09/22 06:00 [pubmed] PHST- 2021/07/20 06:00 [medline] PHST- 2020/09/21 08:40 [entrez] PHST- 2021/09/20 00:00 [pmc-release] AID - 10.1177_0271678X20952011 [pii] AID - 10.1177/0271678X20952011 [doi] PST - ppublish SO - J Cereb Blood Flow Metab. 2021 Jan;41(1):14-30. doi: 10.1177/0271678X20952011. Epub 2020 Sep 20. PMID- 32854859 OWN - NLM STAT- MEDLINE DCOM- 20211011 LR - 20211011 IS - 2162-5514 (Electronic) IS - 0074-7742 (Linking) VI - 155 DP - 2020 TI - Evidence for pathophysiological commonalities between metabolic and neurodegenerative diseases. PG - 65-89 LID - S0074-7742(20)30007-6 [pii] LID - 10.1016/bs.irn.2020.01.007 [doi] AB - Diabetes mellitus is a risk factor for developing neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This relationship seems counter-intuitive as these pathological syndromes appear to be very different. However, they share underlying mechanisms such as desensitization of insulin signaling. Insulin not only regulates blood glucose levels, but also acts as a growth factor that is important for neuronal activity and repair. Insulin signaling desensitization has been found in the brains of people with progressive neurodegenerative diseases, which is most likely driven by chronic inflammation. Based on this, insulin has been tested in patients with Alzheimer's disease, and it was found that memory formation was improved and brain pathology reduced. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, and numerous drugs that mimic this peptide are on the market to treat type 2 diabetes mellitus. Preclinical studies have provided robust evidence that some of these drugs, such as liraglutide or lixisenatide can enter the brain and improve key pathological parameters, such as memory loss, impairment of motor activity, synapse loss, reduced energy utilization by neurons and chronic inflammation in the brain. First clinical trials with a GLP-1 mimetic show good effects in patients with Parkinson's disease, improving motor control and insulin signaling in the brain. This is a proof of concept that this approach is viable and that drug treatment affects the main drivers of the disease and does not just modify the symptoms. It demonstrates that this new research area is a promising and fertile space for the development of novel treatments for neurodegenerative diseases. CI - (c) 2020 Elsevier Inc. All rights reserved. FAU - Holscher, Christian AU - Holscher C AD - Neurology Department of the Second Associated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China; Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China. Electronic address: c.holscher@hactcm.edu.cn. LA - eng PT - Journal Article PT - Review DEP - 20200811 PL - United States TA - Int Rev Neurobiol JT - International review of neurobiology JID - 0374740 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Diabetes Mellitus, Type 2/complications MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Insulin/physiology MH - Metabolic Diseases/complications/drug therapy/*physiopathology MH - Neurodegenerative Diseases/complications/drug therapy/*physiopathology OTO - NOTNLM OT - Alzheimer's disease OT - Diabetes OT - Glucagon-like peptide-1 OT - Inflammation OT - Insulin OT - Neurodegeneration OT - Parkinson's disease EDAT- 2020/08/29 06:00 MHDA- 2021/10/12 06:00 CRDT- 2020/08/29 06:00 PHST- 2020/08/29 06:00 [entrez] PHST- 2020/08/29 06:00 [pubmed] PHST- 2021/10/12 06:00 [medline] AID - S0074-7742(20)30007-6 [pii] AID - 10.1016/bs.irn.2020.01.007 [doi] PST - ppublish SO - Int Rev Neurobiol. 2020;155:65-89. doi: 10.1016/bs.irn.2020.01.007. Epub 2020 Aug 11. PMID- 32832719 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2451-0629 (Print) IS - 2451-0629 (Electronic) IS - 2451-0629 (Linking) VI - 5 DP - 2020 TI - Diabetes and dementia - the two faces of Janus. PG - e186-e197 LID - 10.5114/amsad.2020.97433 [doi] AB - Patients with type 2 diabetes are at high risk for cognitive decline and dementia. Despite the limited data on the possible pathogenetic mechanisms, evidence suggests that cognitive decline, and thus dementia and Alzheimer's disease, might arise from a complex interplay between type 2 diabetes and the aging brain, including decreased insulin signalling and glucose metabolism, mitochondrial dysfunction, neuroinflammation, and vascular disease. Furthermore, there is increasing interest on the effects of antidiabetic agents on cognitive decline. There are many studies showing that antidiabetic agents might have beneficial effects on the brain, mainly through inhibition of oxidative stress, inflammation, and apoptosis. In addition, experimental studies on patients with diabetes and Alzheimer's disease have shown beneficial effects on synaptic plasticity, metabolism of amyloid-beta, and microtubule-associated protein tau. Therefore, in the present review, we discuss the effects of antidiabetic agents in relation to cognitive decline, and in particular dementia and Alzheimer's disease, in patients with type 2 diabetes. CI - Copyright: (c) 2020 Termedia & Banach. FAU - Papazafiropoulou, Athanasia K AU - Papazafiropoulou AK AD - 1 Department of Internal Medicine and Diabetes Centre, Tzaneio General Hospital, Piraeus, Greece. FAU - Koros, Chris AU - Koros C AD - 1 Department of Neurology, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece. FAU - Melidonis, Andreas AU - Melidonis A AD - Diabetes and Cardiometabolic Centre, Metropolitan Hospital, Piraeus, Greece. FAU - Antonopoulos, Stavros AU - Antonopoulos S AD - 1 Department of Internal Medicine and Diabetes Centre, Tzaneio General Hospital, Piraeus, Greece. LA - eng PT - Journal Article DEP - 20200721 PL - Poland TA - Arch Med Sci Atheroscler Dis JT - Archives of medical sciences. Atherosclerotic diseases JID - 101701205 PMC - PMC7433787 OTO - NOTNLM OT - Alzheimer's disease OT - dementia OT - glucagon-like peptide-1 receptor agonists OT - neurodegenerative diseases OT - sodium-glucose co-transporter-2 inhibitors OT - type 2 diabetes COIS- The authors declare no conflict of interest. EDAT- 2020/08/25 06:00 MHDA- 2020/08/25 06:01 PMCR- 2020/07/21 CRDT- 2020/08/25 06:00 PHST- 2020/02/05 00:00 [received] PHST- 2020/04/18 00:00 [accepted] PHST- 2020/08/25 06:00 [entrez] PHST- 2020/08/25 06:00 [pubmed] PHST- 2020/08/25 06:01 [medline] PHST- 2020/07/21 00:00 [pmc-release] AID - 41375 [pii] AID - 10.5114/amsad.2020.97433 [doi] PST - epublish SO - Arch Med Sci Atheroscler Dis. 2020 Jul 21;5:e186-e197. doi: 10.5114/amsad.2020.97433. eCollection 2020. PMID- 32832307 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2168-8184 (Print) IS - 2168-8184 (Electronic) IS - 2168-8184 (Linking) VI - 12 IP - 8 DP - 2020 Aug 18 TI - Diabetes Mellitus and Parkinson's Disease: Shared Pathophysiological Links and Possible Therapeutic Implications. PG - e9853 LID - 10.7759/cureus.9853 [doi] LID - e9853 AB - Diabetes mellitus (DM) is the most common chronic metabolic disease. Parkinson's disease (PD) is considered one of the most common neurodegenerative diseases. There are many similarities between both conditions. Both disorders are chronic diseases. Both diseases result from a decrease in a specific substance: dopamine in PD, and insulin in DM. Besides, both disorders arise due to the destruction of particular cells, dopaminergic cells in PD, and pancreatic beta-cell in DM. Recently, many epidemiological and experimental studies showed a connection between DM and PD. There are common underlying mechanisms in the pathophysiology of both diseases. These underlying mechanisms include mitochondrial dysfunction, oxidative stress, hyperglycemia, and inflammation. Insulin resistance is indeed the hallmark of DM, especially type 2 diabetes mellitus (T2DM), which plays a significant role in these pathophysiological and molecular mechanisms. Besides, many studies revealed that anti-diabetic drugs have a beneficial effect on PD. In this current literature review, we aim to explore the standard pathophysiological and molecular linkages between these two disorders as well as how DM could affect the incidence and progression of PD. We also review how anti-diabetic drugs impact PD. In the future, further experimental and expanded clinical studies are needed to fully understand the exact pathophysiological connections between the two disorders and the efficacy of insulin and other anti-diabetic drugs in the treatment of PD in diabetic patients. Fully understanding and targeting these pathophysiological and molecular links could result in de novo curative therapy for PD and DM. CI - Copyright (c) 2020, Hassan et al. FAU - Hassan, Abdallah AU - Hassan A AD - Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. FAU - Sharma Kandel, Rajan AU - Sharma Kandel R AD - Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. FAU - Mishra, Rohi AU - Mishra R AD - Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. FAU - Gautam, Jeevan AU - Gautam J AD - Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. FAU - Alaref, Amer AU - Alaref A AD - Diagnostic Radiology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. FAU - Jahan, Nusrat AU - Jahan N AD - Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA. LA - eng PT - Journal Article PT - Review DEP - 20200818 PL - United States TA - Cureus JT - Cureus JID - 101596737 PMC - PMC7437092 OTO - NOTNLM OT - diabetes mellitus /parkinson's disease OT - glp 1 /parkinson OT - incretins/parkinson OT - insulin resistance/parkinson COIS- The authors have declared that no competing interests exist. EDAT- 2020/08/25 06:00 MHDA- 2020/08/25 06:01 PMCR- 2020/08/18 CRDT- 2020/08/25 06:00 PHST- 2020/08/25 06:00 [entrez] PHST- 2020/08/25 06:00 [pubmed] PHST- 2020/08/25 06:01 [medline] PHST- 2020/08/18 00:00 [pmc-release] AID - 10.7759/cureus.9853 [doi] PST - epublish SO - Cureus. 2020 Aug 18;12(8):e9853. doi: 10.7759/cureus.9853. PMID- 32756077 OWN - NLM STAT- MEDLINE DCOM- 20200824 LR - 20241118 IS - 1536-5964 (Electronic) IS - 0025-7974 (Print) IS - 0025-7974 (Linking) VI - 99 IP - 31 DP - 2020 Jul 31 TI - Effect of dipeptidyl peptidase-4 inhibitors inhibitor on cognitive dysfunction in diabetes: A protocol for systematic review and meta analysis. PG - e20707 LID - 10.1097/MD.0000000000020707 [doi] LID - e20707 AB - INTRODUCTION: There is a risk of cognitive impairment in diabetic patients. Some studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4) inhibitors can play a protective role in controlling blood glucose and blocking the DPP-4 to attach antibody glucagon-like peptide -1 degradation and prolong antibody glucagon-like peptide -1, promoting the growth of neurites and the formation of synapses. The purpose of this study is to explore the effect of the DPP-4 inhibitor on cognitive impairment in diabetic patients by meta-analysis. METHODS: The system review plan will strictly follow the Systematic Review and Meta-Analysis Protocols entry for reporting. PubMed, EMBASE, Cochrane Library, Clinicaltrials(clinicaltrials.gov), Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database and Wanfang Databases will be systematically searched, and all randomized controlled trials comparing DPP-4 inhibitors with placebo or other hypoglycemic drugs to study cognitive impairment in type 2 diabetic patients will be included. The inclusion, evaluation and data extraction of the literature will be conducted by 2 persons independently, and the dispute will be resolved by a third person. All the meta-analysis of the included literature and the research progress of the existing research are analyzed as the main results. ETHICS AND DISSEMINATION: It is to evaluate and analyze the completed research, so there is no ethical problem. The research results will be published in a peer-reviewed journal. REGISTRATION: The protocol of this systematic review and meta-analysis was registered on International Platform of Registered Systematic Review and Meta-analysis Protocols (https://inplasy.com/) (number. 202040185). FAU - Liu, Shiyu AU - Liu S AUID- ORCID: 0000-0002-3410-1470 AD - School of Clinical Medicine. FAU - Wang, Xian AU - Wang X AD - School of Clinical Medicine. FAU - Deng, Huan AU - Deng H AD - School of Clinical Medicine. FAU - Xia, Yuguo AU - Xia Y AD - School of Clinical Medicine. FAU - Yang, Xiaomei AU - Yang X AD - School of Clinical Medicine. FAU - Chen, Qiu AU - Chen Q AD - Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. LA - eng PT - Journal Article PL - United States TA - Medicine (Baltimore) JT - Medicine JID - 2985248R RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Cognitive Dysfunction/*drug therapy/etiology MH - Diabetes Mellitus, Type 2/*complications/drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Meta-Analysis as Topic PMC - PMC7402785 COIS- The authors have no conflicts of interest to disclose. EDAT- 2020/08/07 06:00 MHDA- 2020/08/25 06:00 PMCR- 2020/07/31 CRDT- 2020/08/07 06:00 PHST- 2020/08/07 06:00 [entrez] PHST- 2020/08/07 06:00 [pubmed] PHST- 2020/08/25 06:00 [medline] PHST- 2020/07/31 00:00 [pmc-release] AID - 00005792-202007310-00007 [pii] AID - MD-D-20-04068 [pii] AID - 10.1097/MD.0000000000020707 [doi] PST - ppublish SO - Medicine (Baltimore). 2020 Jul 31;99(31):e20707. doi: 10.1097/MD.0000000000020707. PMID- 32741836 OWN - NLM STAT- MEDLINE DCOM- 20210603 LR - 20210603 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 76 IP - 4 DP - 2020 TI - Dementia Diagnosis Is Associated with Changes in Antidiabetic Drug Prescription: An Open-Cohort Study of approximately 130,000 Swedish Subjects over 14 Years. PG - 1581-1594 LID - 10.3233/JAD-200618 [doi] AB - BACKGROUND: Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. OBJECTIVE: Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. METHODS: We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naive subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). RESULTS: Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11-1.31] and lower probability of DPP-4i (0.72 [0.66-0.79]), GLP-1a (0.51 [0.41-0.63]), and SGLT-2i dispensation (0.44 [0.36-0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (beta difference 0.97%) and lower increase in DPP-4i (-0.58%), GLP-1a (-0.13%), and SGLT-2i (-0.21%) dispensation in dementia patients compared to dementia-free controls. CONCLUSION: Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects. FAU - Secnik, Juraj AU - Secnik J AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. FAU - Xu, Hong AU - Xu H AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. FAU - Schwertner, Emilia AU - Schwertner E AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. FAU - Hammar, Niklas AU - Hammar N AD - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Alvarsson, Michael AU - Alvarsson M AD - Department of Molecular Medicine and Surgery, Growth and Metabolism, Karolinska Institutet, Stockholm, Sweden. FAU - Winblad, Bengt AU - Winblad B AD - Department of Neurobiology, Center for Alzheimer Research, Division of Neurogeriatrics, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Eriksdotter, Maria AU - Eriksdotter M AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. FAU - Garcia-Ptacek, Sara AU - Garcia-Ptacek S AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Department of Internal Medicine, Sodersjukhuset, Section for Neurology, Stockholm, Sweden. FAU - Religa, Dorota AU - Religa D AD - Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. AD - Theme Aging, Karolinska University Hospital, Huddinge, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Sulfonylurea Compounds) RN - 9100L32L2N (Metformin) SB - IM MH - Aged MH - Aged, 80 and over MH - Cohort Studies MH - Dementia/chemically induced/*diagnosis MH - Diabetes Mellitus, Type 2/complications MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Drug Therapy, Combination/methods MH - Female MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Metformin/*therapeutic use MH - Middle Aged MH - Sodium-Glucose Transporter 2 Inhibitors/*therapeutic use MH - Sulfonylurea Compounds/*therapeutic use MH - Sweden PMC - PMC7504989 OTO - NOTNLM OT - Dementia OT - diabetes mellitus OT - hypoglycemic agents OT - pharmacoepidemiology COIS- Authors' disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-0618r1). EDAT- 2020/08/04 06:00 MHDA- 2021/06/04 06:00 PMCR- 2020/09/21 CRDT- 2020/08/04 06:00 PHST- 2020/08/04 06:00 [pubmed] PHST- 2021/06/04 06:00 [medline] PHST- 2020/08/04 06:00 [entrez] PHST- 2020/09/21 00:00 [pmc-release] AID - JAD200618 [pii] AID - 10.3233/JAD-200618 [doi] PST - ppublish SO - J Alzheimers Dis. 2020;76(4):1581-1594. doi: 10.3233/JAD-200618. PMID- 32737929 OWN - NLM STAT- MEDLINE DCOM- 20211029 LR - 20211029 IS - 1097-4547 (Electronic) IS - 0360-4012 (Linking) VI - 98 IP - 11 DP - 2020 Nov TI - Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin-4 treatment. PG - 2357-2369 LID - 10.1002/jnr.24706 [doi] AB - Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid beta and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes. CI - (c) 2020 Wiley Periodicals LLC. FAU - King, Matthew R AU - King MR AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Anderson, Nicholas J AU - Anderson NJ AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Deciu, Mihaela AU - Deciu M AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Guernsey, Lucie S AU - Guernsey LS AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Cundiff, Morgan AU - Cundiff M AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Hajizadeh, Shohreh AU - Hajizadeh S AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. FAU - Jolivalt, Corinne G AU - Jolivalt CG AUID- ORCID: 0000-0003-4391-1341 AD - Department of Pathology, University of California San Diego, La Jolla, CA, USA. LA - eng GR - AG039736/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20200801 PL - United States TA - J Neurosci Res JT - Journal of neuroscience research JID - 7600111 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (MAPT protein, human) RN - 0 (tau Proteins) RN - 9P1872D4OL (Exenatide) SB - IM MH - Amyloid beta-Protein Precursor/*genetics MH - Animals MH - Brain Chemistry/drug effects/genetics MH - Cognition Disorders/drug therapy/*genetics/psychology MH - Diabetes Mellitus, Experimental/psychology MH - Exenatide/*pharmacology MH - Female MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Insulin/*deficiency MH - *Insulin Resistance MH - Male MH - Maze Learning/drug effects MH - Memory MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred DBA MH - Mice, Transgenic MH - Obesity/metabolism/psychology MH - Psychomotor Performance MH - tau Proteins/*genetics OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 analog OT - RRID:AB_476730 OT - RRID:AB_570891 OT - RRID:AB_662807 OT - RRID:AB_94944 OT - adiponectin OT - diabetes EDAT- 2020/08/02 06:00 MHDA- 2021/10/30 06:00 CRDT- 2020/08/02 06:00 PHST- 2019/11/08 00:00 [received] PHST- 2020/06/29 00:00 [revised] PHST- 2020/07/12 00:00 [accepted] PHST- 2020/08/02 06:00 [pubmed] PHST- 2021/10/30 06:00 [medline] PHST- 2020/08/02 06:00 [entrez] AID - 10.1002/jnr.24706 [doi] PST - ppublish SO - J Neurosci Res. 2020 Nov;98(11):2357-2369. doi: 10.1002/jnr.24706. Epub 2020 Aug 1. PMID- 32700772 OWN - NLM STAT- MEDLINE DCOM- 20200925 LR - 20250103 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 7 IP - 7 DP - 2020 Jul 23 TI - GLP-1 receptor agonists for Parkinson's disease. PG - CD012990 LID - 10.1002/14651858.CD012990.pub2 [doi] LID - CD012990 AB - BACKGROUND: Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. OBJECTIVES: To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. SEARCH METHODS: We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. MAIN RESULTS: Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). AUTHORS' CONCLUSIONS: Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists. CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Mulvaney, Caroline A AU - Mulvaney CA AD - Lancaster Medical School, Lancaster University, Lancaster, UK. FAU - Duarte, Goncalo S AU - Duarte GS AD - Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina de Lisboa, Lisboa, Portugal. AD - Instituto de Medicina Molecular, Lisboa, Portugal. FAU - Handley, Joel AU - Handley J AD - Lancaster Medical School, Lancaster University, Lancaster, UK. AD - Department of Neurology, Salford Royal Hospital, Salford, UK. FAU - Evans, David Jw AU - Evans DJ AD - Lancaster Medical School, Lancaster University, Lancaster, UK. FAU - Menon, Suresh AU - Menon S AD - Department of Medicine, McMaster University, Hamilton, Canada. FAU - Wyse, Richard AU - Wyse R AD - The Cure Parkinson's Trust, London, UK. FAU - Emsley, Hedley Ca AU - Emsley HC AD - Lancaster Medical School, Lancaster University, Lancaster, UK. AD - Department of Neurology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20200723 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Hypoglycemic Agents) RN - 0 (Placebos) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM UOF - doi: 10.1002/14651858.CD012990 MH - Bias MH - Double-Blind Method MH - Exenatide/administration & dosage/adverse effects/*therapeutic use MH - Humans MH - Hypoglycemic Agents/administration & dosage/therapeutic use MH - Parkinson Disease/*drug therapy MH - Placebos/administration & dosage MH - Quality of Life MH - Randomized Controlled Trials as Topic MH - Self Administration MH - Single-Blind Method MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC7390475 COIS- CAM: none known. GSD: none known. JH: none known. DE: none known. SM: none known. RW: none known. HCAE: none known. EDAT- 2020/07/24 06:00 MHDA- 2020/09/26 06:00 PMCR- 2021/07/23 CRDT- 2020/07/24 06:00 PHST- 2020/07/24 06:00 [entrez] PHST- 2020/07/24 06:00 [pubmed] PHST- 2020/09/26 06:00 [medline] PHST- 2021/07/23 00:00 [pmc-release] AID - CD012990.pub2 [pii] AID - 10.1002/14651858.CD012990.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Jul 23;7(7):CD012990. doi: 10.1002/14651858.CD012990.pub2. PMID- 32657406 OWN - NLM STAT- MEDLINE DCOM- 20210308 LR - 20260307 IS - 1367-4811 (Electronic) IS - 1367-4803 (Print) IS - 1367-4803 (Linking) VI - 36 IP - Suppl_1 DP - 2020 Jul 1 TI - Combining phenome-driven drug-target interaction prediction with patients' electronic health records-based clinical corroboration toward drug discovery. PG - i436-i444 LID - 10.1093/bioinformatics/btaa451 [doi] AB - MOTIVATION: Predicting drug-target interactions (DTIs) using human phenotypic data have the potential in eliminating the translational gap between animal experiments and clinical outcomes in humans. One challenge in human phenome-driven DTI predictions is integrating and modeling diverse drug and disease phenotypic relationships. Leveraging large amounts of clinical observed phenotypes of drugs and diseases and electronic health records (EHRs) of 72 million patients, we developed a novel integrated computational drug discovery approach by seamlessly combining DTI prediction and clinical corroboration. RESULTS: We developed a network-based DTI prediction system (TargetPredict) by modeling 855 904 phenotypic and genetic relationships among 1430 drugs, 4251 side effects, 1059 diseases and 17 860 genes. We systematically evaluated TargetPredict in de novo cross-validation and compared it to a state-of-the-art phenome-driven DTI prediction approach. We applied TargetPredict in identifying novel repositioned candidate drugs for Alzheimer's disease (AD), a disease affecting over 5.8 million people in the United States. We evaluated the clinical efficiency of top repositioned drug candidates using EHRs of over 72 million patients. The area under the receiver operating characteristic (ROC) curve was 0.97 in the de novo cross-validation when evaluated using 910 drugs. TargetPredict outperformed a state-of-the-art phenome-driven DTI prediction system as measured by precision-recall curves [measured by average precision (MAP): 0.28 versus 0.23, P-value < 0.0001]. The EHR-based case-control studies identified that the prescriptions top-ranked repositioned drugs are significantly associated with lower odds of AD diagnosis. For example, we showed that the prescription of liraglutide, a type 2 diabetes drug, is significantly associated with decreased risk of AD diagnosis [adjusted odds ratios (AORs): 0.76; 95% confidence intervals (CI) (0.70, 0.82), P-value < 0.0001]. In summary, our integrated approach that seamlessly combines computational DTI prediction and large-scale patients' EHRs-based clinical corroboration has high potential in rapidly identifying novel drug targets and drug candidates for complex diseases. AVAILABILITY AND IMPLEMENTATION: nlp.case.edu/public/data/TargetPredict. CI - (c) The Author(s) 2020. Published by Oxford University Press. FAU - Zhou, Mengshi AU - Zhou M AD - Center for Artificial Intelligence in Drug Discovery, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. AD - Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. FAU - Zheng, Chunlei AU - Zheng C AD - Center for Artificial Intelligence in Drug Discovery, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. FAU - Xu, Rong AU - Xu R AD - Center for Artificial Intelligence in Drug Discovery, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. LA - eng GR - R01 AG057557/AG/NIA NIH HHS/United States GR - UL1 TR002548/TR/NCATS NIH HHS/United States GR - DP2 HD084068/HD/NICHD NIH HHS/United States GR - R56 AG062272/AG/NIA NIH HHS/United States GR - R01 AG061388/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Bioinformatics JT - Bioinformatics (Oxford, England) JID - 9808944 RN - 0 (Pharmaceutical Preparations) SB - IM MH - *Diabetes Mellitus, Type 2 MH - Drug Development MH - Drug Discovery MH - Electronic Health Records MH - Humans MH - *Pharmaceutical Preparations PMC - PMC7355254 EDAT- 2020/07/14 06:00 MHDA- 2021/03/09 06:00 PMCR- 2020/07/13 CRDT- 2020/07/14 06:00 PHST- 2020/07/14 06:00 [entrez] PHST- 2020/07/14 06:00 [pubmed] PHST- 2021/03/09 06:00 [medline] PHST- 2020/07/13 00:00 [pmc-release] AID - 5870514 [pii] AID - btaa451 [pii] AID - 10.1093/bioinformatics/btaa451 [doi] PST - ppublish SO - Bioinformatics. 2020 Jul 1;36(Suppl_1):i436-i444. doi: 10.1093/bioinformatics/btaa451. PMID- 32656265 OWN - NLM STAT- MEDLINE DCOM- 20210527 LR - 20210527 IS - 2314-6753 (Electronic) IS - 2314-6745 (Print) VI - 2020 DP - 2020 TI - The Mechanism of Metabolic Influences on the Endogenous GLP-1 by Oral Antidiabetic Medications in Type 2 Diabetes Mellitus. PG - 4727390 LID - 10.1155/2020/4727390 [doi] LID - 4727390 AB - Incretin-based therapy is now a prevalent treatment option for patients with type 2 diabetes mellitus (T2DM). It has been associated with considerably good results in the management of hyperglycemia with cardiac or nephron-benefits. For this reason, it is recommended for individuals with cardiovascular diseases in many clinical guidelines. As an incretin hormone, glucagon-like peptide-1 (GLP-1) possesses multiple metabolic benefits such as optimizing energy usage, maintaining body weight, beta cell preservation, and suppressing neurodegeneration. However, recent studies indicate that oral antidiabetic medications interact with endogenous or exogenous GLP-1. Since these drugs are transported to distal intestine portions, there are concerns whether these oral drugs directly stimulate intestinal L cells which release GLP-1, or whether they do so via indirect inhibition of the activity of dipeptidyl peptidase-IV (DPP-IV). In this review, we discuss the metabolic relationships between oral antihyperglycemic drugs from the aspect of gut, microbiota, hormones, beta cell function, central nervous system, and other cellular mechanisms. CI - Copyright (c) 2020 Thiquynhnga Nguyen et al. FAU - Nguyen, Thiquynhnga AU - Nguyen T AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Gong, Min AU - Gong M AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Wen, Song AU - Wen S AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Yuan, Xinlu AU - Yuan X AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Wang, Chaoxun AU - Wang C AUID- ORCID: 0000-0002-3237-3405 AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Jin, Jianlan AU - Jin J AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. FAU - Zhou, Ligang AU - Zhou L AUID- ORCID: 0000-0003-4824-0735 AD - Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China. LA - eng PT - Journal Article PT - Review DEP - 20200616 PL - United States TA - J Diabetes Res JT - Journal of diabetes research JID - 101605237 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Diabetes Mellitus, Type 2/*drug therapy/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/administration & dosage/*therapeutic use MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Hypoglycemic Agents/administration & dosage/*therapeutic use MH - Insulin-Secreting Cells/*drug effects/metabolism PMC - PMC7320283 COIS- The authors declare no conflict of interest. EDAT- 2020/07/14 06:00 MHDA- 2021/05/28 06:00 PMCR- 2020/06/16 CRDT- 2020/07/14 06:00 PHST- 2020/03/12 00:00 [received] PHST- 2020/06/05 00:00 [accepted] PHST- 2020/07/14 06:00 [entrez] PHST- 2020/07/14 06:00 [pubmed] PHST- 2021/05/28 06:00 [medline] PHST- 2020/06/16 00:00 [pmc-release] AID - 10.1155/2020/4727390 [doi] PST - epublish SO - J Diabetes Res. 2020 Jun 16;2020:4727390. doi: 10.1155/2020/4727390. eCollection 2020. PMID- 32635358 OWN - NLM STAT- MEDLINE DCOM- 20201120 LR - 20201120 IS - 1660-4601 (Electronic) IS - 1661-7827 (Print) IS - 1660-4601 (Linking) VI - 17 IP - 13 DP - 2020 Jul 3 TI - Antidiabetic Agents for Treatment of Parkinson's Disease: A Meta-Analysis. LID - 10.3390/ijerph17134805 [doi] LID - 4805 AB - Background: Clinical and epidemiological studies suggest that two of the most common geriatric diseases, type 2 diabetes and Parkinson's disease (PD), are linked. These studies notably suggest that treatment of insulin resistance in type 2 diabetes may beneficially modify the pathophysiology of PD and help to maintain motor and nonmotor function. In this meta-analysis, we evaluate the efficacy of new antidiabetic agents in the treatment of PD. Methods: We systematically searched PubMed, Medline, ProQuest, ScienceDirect, ClinicalKey, and Cochrane Library from the date of their inception until 15 March 2020. Multiple efficacy parameters were compared between treatment groups. The results are expressed as mean differences with 95% confidence intervals (CIs) in a random-effects model. Results: A meta-analysis of the data extracted from three randomized control trials revealed that treatment with exenatide yielded significant improvements in scores on the Unified Parkinson's Disease Rating Scale Part I (UPDRS-I) (-0.438, 95% CI, -0.828 to -0.048, p = 0.028), UPDRS Part IV (UPDRS-IV) (-0.421, 95% CI, -0.811 to -0.032, p = 0.034) and the Mattis Dementia Rating Scale (MDRS) (-0.595, 95% CI, -1.038 to -0.151, p = 0.009). At the 12-month follow-up, the UPDRS Part III (UPDRS-III) scores in the off-medication phase revealed significant improvements in patients using exenatide (-0.729; 95% CI, -1.233 to -0.225, p = 0.005). Treatment with pioglitazone did not yield significant improvements in UPDRS, MDRS, or Parkinson's Disease Questionnaire scores. Conclusion: This meta-analysis suggests that exenatide use is associated with the alleviation of cognitive, motor and nonmotor symptoms. However, long-term studies with a large sample size of patients with PD of varying severity are required. FAU - Wang, Shu-Yi AU - Wang SY AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500209, Taiwan. FAU - Wu, Shey-Lin AU - Wu SL AD - Department of Neurology, Changhua Christian Hospital, Changhua 500209, Taiwan. FAU - Chen, Ta-Cheng AU - Chen TC AD - Department of Neurology, Changhua Christian Hospital, Changhua 500209, Taiwan. FAU - Chuang, Chieh-Sen AU - Chuang CS AD - Department of Neurology, Changhua Christian Hospital, Changhua 500209, Taiwan. AD - College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review DEP - 20200703 PL - Switzerland TA - Int J Environ Res Public Health JT - International journal of environmental research and public health JID - 101238455 RN - 0 (Hypoglycemic Agents) RN - 9P1872D4OL (Exenatide) SB - IM MH - Aged MH - Diabetes Mellitus, Type 2 MH - Exenatide MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Parkinson Disease/*drug therapy MH - Treatment Outcome PMC - PMC7369739 OTO - NOTNLM OT - Parkinson's disease OT - Thiazolidinedione OT - antidiabetic agent OT - glucagon-like peptide 1 OT - meta-analysis COIS- The authors report no financial interests or potential conflicts of interest. EDAT- 2020/07/09 06:00 MHDA- 2020/11/21 06:00 PMCR- 2020/07/01 CRDT- 2020/07/09 06:00 PHST- 2020/04/24 00:00 [received] PHST- 2020/06/26 00:00 [revised] PHST- 2020/06/30 00:00 [accepted] PHST- 2020/07/09 06:00 [entrez] PHST- 2020/07/09 06:00 [pubmed] PHST- 2020/11/21 06:00 [medline] PHST- 2020/07/01 00:00 [pmc-release] AID - ijerph17134805 [pii] AID - ijerph-17-04805 [pii] AID - 10.3390/ijerph17134805 [doi] PST - epublish SO - Int J Environ Res Public Health. 2020 Jul 3;17(13):4805. doi: 10.3390/ijerph17134805. PMID- 32585235 OWN - NLM STAT- MEDLINE DCOM- 20210913 LR - 20210913 IS - 1872-6216 (Electronic) IS - 0047-6374 (Linking) VI - 190 DP - 2020 Sep TI - Potential roles of Glucagon-like peptide-1 and its analogues in cognitive impairment associated with type 2 diabetes mellitus. PG - 111294 LID - S0047-6374(20)30090-7 [pii] LID - 10.1016/j.mad.2020.111294 [doi] AB - Type 2 diabetes mellitus (T2DM) is a global disease that poses a significant threat to public health. The incidence of both diabetes and dementia has increased simultaneously. Researchers have found that a large proportion of dementia patients have T2DM. In recent years, increasing evidence has demonstrated a link between cognitive decline and T2DM. Although the exact pathogenesis of cognitive impairment in T2DM is still unknown, current studies suggest that hyperglycemia, cerebrovascular disease, brain insulin resistance, and changes in gamma-aminobutyric acid (GABAergic) neurons may mediate the association between T2DM and cognitive impairment. These potential mechanisms may become targets for the treatment of cognitive disorders in patients with T2DM. Glucagon-like peptide-1 (GLP-1), a widely used anti-diabetic drug, has been shown to not only effectively lower blood glucose but also improve neurological function. Previous research has confirmed that GLP-1 and its analogues are effective in the treatment of cognitive impairment in patients with T2DM. This review describes current evidence on the mechanisms underlying the association between T2DM and cognitive impairment. In particular, this review focuses on recent advances in GLP-1 and its analogues for the treatment of T2DM-related cognitive impairment. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Yu, Zi-Wei AU - Yu ZW AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Liu, Rong AU - Liu R AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Li, Xin AU - Li X AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Wang, Ying AU - Wang Y AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Fu, Yu-Hong AU - Fu YH AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Li, Hui-Yao AU - Li HY AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Yuan, Yue AU - Yuan Y AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. FAU - Gao, Xin-Yuan AU - Gao XY AD - Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: 15369337970@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20200702 PL - Ireland TA - Mech Ageing Dev JT - Mechanisms of ageing and development JID - 0347227 RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Cognitive Dysfunction/drug therapy/physiopathology MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism/psychology MH - *Glucagon-Like Peptide 1/analogs & derivatives/pharmacology MH - Humans MH - Incretins/pharmacology OTO - NOTNLM OT - Cognitive impairment OT - Glucagon-like peptide-1 OT - Glucagon-like peptide-1 analogues OT - Type 2 diabetes mellitus EDAT- 2020/06/26 06:00 MHDA- 2021/09/14 06:00 CRDT- 2020/06/26 06:00 PHST- 2020/01/14 00:00 [received] PHST- 2020/06/12 00:00 [revised] PHST- 2020/06/19 00:00 [accepted] PHST- 2020/06/26 06:00 [pubmed] PHST- 2021/09/14 06:00 [medline] PHST- 2020/06/26 06:00 [entrez] AID - S0047-6374(20)30090-7 [pii] AID - 10.1016/j.mad.2020.111294 [doi] PST - ppublish SO - Mech Ageing Dev. 2020 Sep;190:111294. doi: 10.1016/j.mad.2020.111294. Epub 2020 Jul 2. PMID- 32570036 OWN - NLM STAT- MEDLINE DCOM- 20210517 LR - 20250103 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 86 DP - 2020 Sep TI - Glucagon-like peptide-1 receptor agonist Exendin-4 improves neurological outcomes by attenuating TBI- induced inflammatory responses and MAPK activation in rats. PG - 106715 LID - S1567-5769(20)30987-5 [pii] LID - 10.1016/j.intimp.2020.106715 [doi] AB - Traumatic brain injury (TBI) can be exacerbated and prolonged for months or even years by chronic inflammatory processes with long-term consequences on neurodegeneration and neurological impairment. However, there are no clear pharmacological therapies of benefit to manage neurological dysfunctions, which, relating to the molecular mechanisms underlying the behavioral deficits after TBI, have yet to be fully identified. Recently, a glucagon-like peptide 1 (GLP-1) agonist, Exendin-4, was approved not only for the treatment of type 2 diabetes mellitus, but it also played a neurotrophic role in various CNS neurological diseases. In this study, we evaluated the neuroprotective effects of Exendin-4 on neurological outcome, cerebral blood flow, neurodegeneration, and inflammatory responses by utilizing a cortical contusion impact injury (CCI) model in rats. We found that TBI rats displayed neurological impairments, neurodegeneration, reduction of cerebral blood flow, and inflammatory responses, while Exendin-4 promoted neurological, cognitive, and cerebral blood flow recovery and attenuated neural degeneration and inflammatory cytokines after TBI. Furthermore, Exendin-4 treatment significantly diminished the TBI-induced overexpression of TNFalpha and IL-1beta, as well as phosphorylation of p38 and ERK1/2. These data suggest a strong beneficial action of the glucagon-like peptide-1 receptor agonist Exendin-4 in improving neurological outcomes by attenuating inflammatory responses induced by traumatic brain injury, which is of therapeutic potential for TBI. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Zhang, Jun AU - Zhang J AD - Graduate School of Tianjin Medical University, Tianjin 300070, China. FAU - Yi, Tailong AU - Yi T AD - Tianjin Key Laboratory of Neurotrauma Repair, Institute of Neurotrauma Repair of the Characteristic Medical Center of Chinese People's Armed Police Force (PAP), Tianjin 300162, China. FAU - Cheng, Shixiang AU - Cheng S AD - Tianjin Key Laboratory of Neurotrauma Repair, Institute of Neurotrauma Repair of the Characteristic Medical Center of Chinese People's Armed Police Force (PAP), Tianjin 300162, China. Electronic address: shixiangcheng_tj@163.com. FAU - Zhang, Sai AU - Zhang S AD - Tianjin Key Laboratory of Neurotrauma Repair, Institute of Neurotrauma Repair of the Characteristic Medical Center of Chinese People's Armed Police Force (PAP), Tianjin 300162, China. Electronic address: zhangsai718_tj@163.com. LA - eng PT - Journal Article DEP - 20200620 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Cytokines) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Neuroprotective Agents) RN - 0 (Tnf protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.11.24 (Mapk1 protein, mouse) RN - EC 2.7.11.24 (Mapk3 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Behavior, Animal/drug effects MH - Brain Injuries, Traumatic/complications/*drug therapy/pathology MH - Cerebrovascular Circulation/drug effects MH - Cognition/drug effects MH - Cytokines/metabolism MH - Disease Models, Animal MH - Enzyme Activation MH - Exenatide/*pharmacology/therapeutic use MH - Inflammation/*drug therapy/etiology MH - Interleukin-1beta/metabolism MH - Male MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Neuroglia/drug effects MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Rats, Sprague-Dawley MH - Tumor Necrosis Factor-alpha/metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Animal models OT - Exendin-4 OT - Glucagon-like peptide-1 OT - Inflammation OT - Neurological outcomes OT - Traumatic brain injury COIS- Declaration of Competing Interest There are no conflicts of interest to disclose for the authors. EDAT- 2020/06/23 06:00 MHDA- 2021/05/18 06:00 CRDT- 2020/06/23 06:00 PHST- 2020/04/02 00:00 [received] PHST- 2020/06/06 00:00 [revised] PHST- 2020/06/15 00:00 [accepted] PHST- 2020/06/23 06:00 [pubmed] PHST- 2021/05/18 06:00 [medline] PHST- 2020/06/23 06:00 [entrez] AID - S1567-5769(20)30987-5 [pii] AID - 10.1016/j.intimp.2020.106715 [doi] PST - ppublish SO - Int Immunopharmacol. 2020 Sep;86:106715. doi: 10.1016/j.intimp.2020.106715. Epub 2020 Jun 20. PMID- 32562683 OWN - NLM STAT- MEDLINE DCOM- 20200914 LR - 20200914 IS - 1474-4465 (Electronic) IS - 1474-4422 (Linking) VI - 19 IP - 7 DP - 2020 Jul TI - Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. PG - 582-590 LID - S1474-4422(20)30173-3 [pii] LID - 10.1016/S1474-4422(20)30173-3 [doi] AB - BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged >/=50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9.5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m(2). Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1.5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1.5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5.4 (IQR 5.1-5.9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4.05 per 100 patient-years in participants assigned dulaglutide and 4.35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0.93, 95% CI 0.85-1.02; p=0.11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0.86, 95% CI 0.79-0.95; p=0.0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Cukierman-Yaffe, Tali AU - Cukierman-Yaffe T AD - Endocrinology Institute, Gertner Institute, Sheba Medical Center, Ramat-Gan, Israel; Epidemiology Department, Sackler School of Medicine, Herceg Institute of Aging, Tel Aviv University, Tel Aviv, Israel. FAU - Gerstein, Hertzel C AU - Gerstein HC AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. Electronic address: gerstein@mcmaster.ca. FAU - Colhoun, Helen M AU - Colhoun HM AD - University of Edinburgh, Edinburgh, UK. FAU - Diaz, Rafael AU - Diaz R AD - Estudios Clinicos Latino America, Rosario, Argentina. FAU - Garcia-Perez, Luis-Emilio AU - Garcia-Perez LE AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Lakshmanan, Mark AU - Lakshmanan M AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Bethel, Angelyn AU - Bethel A AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Xavier, Denis AU - Xavier D AD - St John's Medical College, Bangalore, India. FAU - Probstfield, Jeffrey AU - Probstfield J AD - Department of Medicine, University of Washington, Seattle, WA, USA. FAU - Riddle, Matthew C AU - Riddle MC AD - Department of Medicine, Oregon Health and Science University Portland, OR, USA. FAU - Ryden, Lars AU - Ryden L AD - Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. FAU - Atisso, Charles Messan AU - Atisso CM AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Hall, Stephanie AU - Hall S AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. FAU - Rao-Melacini, Purnima AU - Rao-Melacini P AD - Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. FAU - Basile, Jan AU - Basile J AD - Medical University of South Carolina, Charleston, SC, USA. FAU - Cushman, William C AU - Cushman WC AD - Memphis Veterans Affairs Medical Center, Memphis, TN, USA. FAU - Franek, Edward AU - Franek E AD - Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital, Warsaw, Poland. FAU - Keltai, Matyas AU - Keltai M AD - Semmelweis University, Hungarian Institute of Cardiology, Budapest, Hungary. FAU - Lanas, Fernando AU - Lanas F AD - Universidad de La Frontera, Temuco, Chile. FAU - Leiter, Lawrence A AU - Leiter LA AD - Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. FAU - Lopez-Jaramillo, Patricio AU - Lopez-Jaramillo P AD - Masira Research Institute, Medical School, Universidad de Santander, Bucaramanga, Colombia. FAU - Pirags, Valdis AU - Pirags V AD - Latvijas Universitate, Riga, Latvia. FAU - Pogosova, Nana AU - Pogosova N AD - National Medical Research Center of Cardiology, Moscow, Russia. FAU - Raubenheimer, Peter J AU - Raubenheimer PJ AD - Department of Medicine, University of Cape Town, Cape Town, South Africa. FAU - Shaw, Jonathan E AU - Shaw JE AD - Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. FAU - Sheu, Wayne H-H AU - Sheu WH AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Temelkova-Kurktschiev, Theodora AU - Temelkova-Kurktschiev T AD - Robert Koch Medical Center, Sofia, Bulgaria. LA - eng SI - ClinicalTrials.gov/NCT01394952 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Lancet Neurol JT - The Lancet. Neurology JID - 101139309 RN - 0 (Hypoglycemic Agents) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Recombinant Fusion Proteins) RN - 62340-29-8 (Glucagon-Like Peptides) RN - WTT295HSY5 (dulaglutide) SB - IM EIN - Lancet Neurol. 2020 Oct;19(10):e9. doi: 10.1016/S1474-4422(20)30303-3. PMID: 32949548 MH - Adult MH - Aged MH - Cognitive Dysfunction/*epidemiology/etiology MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Double-Blind Method MH - Female MH - Glucagon-Like Peptides/*analogs & derivatives/therapeutic use MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Immunoglobulin Fc Fragments/*therapeutic use MH - Male MH - Middle Aged MH - Recombinant Fusion Proteins/*therapeutic use MH - Treatment Outcome EDAT- 2020/06/21 06:00 MHDA- 2020/09/15 06:00 CRDT- 2020/06/21 06:00 PHST- 2020/02/13 00:00 [received] PHST- 2020/04/10 00:00 [revised] PHST- 2020/04/23 00:00 [accepted] PHST- 2020/06/21 06:00 [entrez] PHST- 2020/06/21 06:00 [pubmed] PHST- 2020/09/15 06:00 [medline] AID - S1474-4422(20)30173-3 [pii] AID - 10.1016/S1474-4422(20)30173-3 [doi] PST - ppublish SO - Lancet Neurol. 2020 Jul;19(7):582-590. doi: 10.1016/S1474-4422(20)30173-3. PMID- 32446679 OWN - NLM STAT- MEDLINE DCOM- 20200911 LR - 20250418 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 109 DP - 2020 Aug TI - Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis. PG - 154265 LID - S0026-0495(20)30129-3 [pii] LID - 10.1016/j.metabol.2020.154265 [doi] AB - BACKGROUND: Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. OBJECTIVE: This study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. METHODS: Relevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis. RESULTS: Nine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38-0.74, HR for metformin, 0.75; 95% CI, 0.63-0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73-0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55-0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P = 0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20-0.59, HR, 0.48; 95% CI, 0.30-0.77, HR, 0.45; 95% CI, 0.29-0.73 and HR, 0.55; 95% CI, 0.34-0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25-0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74-1.00 and HR, 0.65; 95% CI, 0.55-0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13-2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46-1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47-1.15). CONCLUSION: This analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Zhou, Jian-Bo AU - Zhou JB AD - Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, China. Electronic address: jbzhou@ccmu.edu.cn. FAU - Tang, Xingyao AU - Tang X AD - Beijing Tongren Hospital, Capital Medical University, China. FAU - Han, Min AU - Han M AD - Department of Nephrology, Tongji Medical College, Huazhong University of Science and Technology, China. FAU - Yang, Jinkui AU - Yang J AD - Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, China. FAU - Simo, Rafael AU - Simo R AD - Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig de la Vall d'Hebron, 119, 08035 Barcelona, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Electronic address: rafael.simo@vhir.org. LA - eng PT - Journal Article PT - Network Meta-Analysis PT - Research Support, Non-U.S. Gov't DEP - 20200522 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Protective Agents) RN - 0 (Sulfonylurea Compounds) RN - 0 (Thiazolidinediones) RN - 9100L32L2N (Metformin) RN - AA68LXK93C (2,4-thiazolidinedione) SB - IM MH - *Bayes Theorem MH - Dementia/*etiology/prevention & control MH - Diabetes Mellitus, Type 2/complications/drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - Humans MH - Hypoglycemic Agents/*pharmacology/therapeutic use MH - Metformin/pharmacology/therapeutic use MH - Protective Agents MH - Risk MH - Sulfonylurea Compounds/pharmacology/therapeutic use MH - Thiazolidinediones/pharmacology/therapeutic use OTO - NOTNLM OT - Antidiabetic agents OT - Dementia OT - Network meta-analysis COIS- Declaration of competing interest None. EDAT- 2020/05/25 06:00 MHDA- 2020/09/12 06:00 CRDT- 2020/05/25 06:00 PHST- 2020/03/23 00:00 [received] PHST- 2020/05/13 00:00 [revised] PHST- 2020/05/19 00:00 [accepted] PHST- 2020/05/25 06:00 [pubmed] PHST- 2020/09/12 06:00 [medline] PHST- 2020/05/25 06:00 [entrez] AID - S0026-0495(20)30129-3 [pii] AID - 10.1016/j.metabol.2020.154265 [doi] PST - ppublish SO - Metabolism. 2020 Aug;109:154265. doi: 10.1016/j.metabol.2020.154265. Epub 2020 May 22. PMID- 32436545 OWN - NLM STAT- MEDLINE DCOM- 20210415 LR - 20210415 IS - 1364-5528 (Electronic) IS - 0003-2654 (Linking) VI - 145 IP - 13 DP - 2020 Jul 7 TI - Mass spectrometry imaging of free-floating brain sections detects pathological lipid distribution in a mouse model of Alzheimer's-like pathology. PG - 4595-4605 LID - 10.1039/d0an00592d [doi] AB - Mass spectrometry imaging (MSI) is a modern analytical technique capable of monitoring the spatial distribution of compounds within target tissues. Collection and storage are important steps in sample preparation. The recommended and most widely used preservation procedure for MSI is freezing samples in isopentane and storing them at temperatures below -80 degrees C. On the other hand, the most common and general method for preserving biological samples in clinical practice is fixation in paraformaldehyde. Special types of samples prepared from these fixed tissues that are used for histology and immunohistochemistry are free-floating sections. It would be very beneficial if the latter procedure could also be applicable for the samples intended for subsequent MSI analysis. In the present work, we optimized and evaluated paraformaldehyde-fixed free-floating sections for the analysis of lipids in mouse brains and used the sections for the study of lipid changes in double transgenic APP/PS1 mice, a model of Alzheimer's-like pathology. Moreover, we examined the neuroprotective properties of palm(11)-PrRP31, an anorexigenic and glucose-lowering analog of prolactin-releasing peptide, and liraglutide, a type 2 diabetes drug. From the free-floating sections, we obtained lipid images without interference or delocalization, and we demonstrated that free-floating sections can be used for the MSI of lipids. In the APP/PS1 mice, we observed a changed distribution of various lipids compared to the controls. The most significant changes in lipids in the brains of APP/PS1 mice compared to wild-type controls were related to gangliosides (GM2 36:1, GM3 36:1) and phosphatidylinositols (PI 38:4, 36:4) in regions where the accumulation of senile plaques occurred. In APP/PS1 mice peripherally treated with palm(11)-PrRP31 or liraglutide for 2 months, we found that both peptides reduced the amount and space occupied by lipids, which were linked to the senile plaques. These results indicate that palm(11)-PrRP31 as well as liraglutide might be potentially useful in the treatment of neurodegenerative diseases. FAU - Strnad, Stepan AU - Strnad S AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague, Czech Republic. vladimir.vrkoslav@uochb.cas.cz. FAU - PraZienkova, Veronika AU - PraZienkova V FAU - Holubova, Martina AU - Holubova M FAU - Sykora, David AU - Sykora D FAU - Cvacka, Josef AU - Cvacka J FAU - Maletinska, Lenka AU - Maletinska L FAU - Zelezna, Blanka AU - Zelezna B FAU - Kunes, Jaroslav AU - Kunes J FAU - Vrkoslav, Vladimir AU - Vrkoslav V LA - eng PT - Journal Article DEP - 20200521 PL - England TA - Analyst JT - The Analyst JID - 0372652 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Lipids) RN - 0 (PSEN1 protein, human) RN - 0 (Polymers) RN - 0 (Presenilin-1) RN - 0 (Prolactin-Releasing Hormone) RN - 0 (palm11-PrRP31) RN - 1HG84L3525 (Formaldehyde) RN - 839I73S42A (Liraglutide) RN - Y19UC83H8E (paraform) SB - IM MH - Alzheimer Disease/*metabolism/pathology MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Astrocytes/metabolism MH - Cerebral Cortex/drug effects/*metabolism/pathology MH - Formaldehyde/chemistry MH - Hippocampus/drug effects/*metabolism/pathology MH - *Lipid Metabolism MH - Lipids/*analysis MH - Liraglutide/pharmacology MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Plaque, Amyloid/metabolism MH - Polymers/chemistry MH - Presenilin-1/genetics MH - Prolactin-Releasing Hormone/analogs & derivatives/pharmacology MH - Specimen Handling MH - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization EDAT- 2020/05/22 06:00 MHDA- 2021/04/16 06:00 CRDT- 2020/05/22 06:00 PHST- 2020/05/22 06:00 [pubmed] PHST- 2021/04/16 06:00 [medline] PHST- 2020/05/22 06:00 [entrez] AID - 10.1039/d0an00592d [doi] PST - ppublish SO - Analyst. 2020 Jul 7;145(13):4595-4605. doi: 10.1039/d0an00592d. Epub 2020 May 21. PMID- 32380197 OWN - NLM STAT- MEDLINE DCOM- 20210607 LR - 20210607 IS - 1879-016X (Electronic) IS - 0163-7258 (Linking) VI - 212 DP - 2020 Aug TI - Can dipeptidyl peptidase-4 inhibitors treat cognitive disorders? PG - 107559 LID - S0163-7258(20)30087-5 [pii] LID - 10.1016/j.pharmthera.2020.107559 [doi] AB - The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Cheng, Qi AU - Cheng Q AD - Department of Neurology and Neurophysiology, Liverpool Hospital, Sydney, New South Wales, Australia; Stroke and Neurology Research Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia. FAU - Cheng, Jinluo AU - Cheng J AD - Department of Endocrinology, Changzhou No.2 People's Hospital, Nanjing Medical University, Changzhou, China. FAU - Cordato, Dennis AU - Cordato D AD - Department of Neurology and Neurophysiology, Liverpool Hospital, Sydney, New South Wales, Australia; Stroke and Neurology Research Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia. FAU - Gao, Jianqun AU - Gao J AD - Brain and Mind Centre, Central Clinical School, the University of Sydney, Sydney, Australia. Electronic address: drgaojqun@icloud.com. LA - eng PT - Journal Article PT - Review DEP - 20200505 PL - England TA - Pharmacol Ther JT - Pharmacology & therapeutics JID - 7905840 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Cognitive Dysfunction/*drug therapy MH - Diabetes Mellitus, Type 2/complications MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Gastric Inhibitory Polypeptide/physiology MH - Gastrointestinal Microbiome/drug effects MH - Glucagon-Like Peptide 1/physiology MH - Glucagon-Like Peptide-1 Receptor/physiology MH - Humans MH - Insulin Resistance OTO - NOTNLM OT - Alzheimer's disease OT - Cerebrovascular disease OT - Cognitive disorder OT - Dementia OT - Dipeptidyl peptidase-4 OT - Inhibitor OT - Neurodegenerative disease COIS- Declaration of Competing Interest The authors declare that there are no conflicts of interest. EDAT- 2020/05/08 06:00 MHDA- 2021/06/08 06:00 CRDT- 2020/05/08 06:00 PHST- 2020/02/02 00:00 [received] PHST- 2020/04/24 00:00 [revised] PHST- 2020/04/29 00:00 [accepted] PHST- 2020/05/08 06:00 [pubmed] PHST- 2021/06/08 06:00 [medline] PHST- 2020/05/08 06:00 [entrez] AID - S0163-7258(20)30087-5 [pii] AID - 10.1016/j.pharmthera.2020.107559 [doi] PST - ppublish SO - Pharmacol Ther. 2020 Aug;212:107559. doi: 10.1016/j.pharmthera.2020.107559. Epub 2020 May 5. PMID- 32362872 OWN - NLM STAT- MEDLINE DCOM- 20210528 LR - 20260127 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 11 DP - 2020 TI - Plasma N-Acetylaspartate Is Related to Age, Obesity, and Glucose Metabolism: Effects of Antidiabetic Treatment and Bariatric Surgery. PG - 216 LID - 10.3389/fendo.2020.00216 [doi] LID - 216 AB - Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = -0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = -0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function. CI - Copyright (c) 2020 Daniele, Campi, Saba, Codini, Ciccarone, Giusti, Del Prato, Esterline and Ferrannini. FAU - Daniele, Giuseppe AU - Daniele G AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Campi, Beatrice AU - Campi B AD - C.N.R. Institute of Clinical Physiology, Pisa, Italy. FAU - Saba, Alessandro AU - Saba A AD - Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy. AD - Laboratory of Clinical Pathology, St. Chiara University Hospital, Pisa, Italy. FAU - Codini, Simone AU - Codini S AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Ciccarone, Annamaria AU - Ciccarone A AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Giusti, Laura AU - Giusti L AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Del Prato, Stefano AU - Del Prato S AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Esterline, Russel L AU - Esterline RL AD - AstraZeneca Pharmaceutical, Gaithersburg, MD, United States. FAU - Ferrannini, Ele AU - Ferrannini E AD - C.N.R. Institute of Clinical Physiology, Pisa, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200417 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 30KYC7MIAI (Aspartic Acid) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 0 (hemoglobin A1c protein, human) RN - 997-55-7 (N-acetylaspartate) SB - IM MH - Adult MH - Aged MH - Aspartic Acid/*analogs & derivatives/blood MH - Bariatric Surgery/*methods MH - Biomarkers/*blood MH - Blood Glucose/analysis MH - Case-Control Studies MH - Cross-Sectional Studies MH - Diabetes Mellitus, Type 2/*blood/drug therapy/surgery MH - Female MH - Follow-Up Studies MH - Glucose Intolerance/*blood/drug therapy/surgery MH - Glycated Hemoglobin/analysis MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Insulin Resistance MH - Male MH - Middle Aged MH - Obesity, Morbid/*blood/drug therapy/surgery MH - Prognosis MH - Retrospective Studies MH - Young Adult PMC - PMC7181885 OTO - NOTNLM OT - N-acetylaspartate OT - bariatric surgery OT - dapagliflozin OT - exenatide OT - glucose metabolism OT - neuronal function OT - obesity OT - type 2 diabetes EDAT- 2020/05/05 06:00 MHDA- 2021/05/29 06:00 PMCR- 2020/01/01 CRDT- 2020/05/05 06:00 PHST- 2019/11/07 00:00 [received] PHST- 2020/03/25 00:00 [accepted] PHST- 2020/05/05 06:00 [entrez] PHST- 2020/05/05 06:00 [pubmed] PHST- 2021/05/29 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2020.00216 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2020 Apr 17;11:216. doi: 10.3389/fendo.2020.00216. eCollection 2020. PMID- 32300876 OWN - NLM STAT- MEDLINE DCOM- 20201119 LR - 20250103 IS - 1432-5233 (Electronic) IS - 0940-5429 (Linking) VI - 57 IP - 10 DP - 2020 Oct TI - The effects of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists on cognitive functions in adults with type 2 diabetes mellitus: a systematic review and meta-analysis. PG - 1129-1144 LID - 10.1007/s00592-020-01529-1 [doi] AB - AIMS: The effects of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors/DPP-4I) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) on cognition in patients with type 2 diabetes mellitus (T2DM) remain controversial. We aimed to explore this clinical issue through a systematic review and meta-analysis. METHODS: PubMed, EMBASE and the Cochrane Library were searched, and data were expressed as mean difference (MD) or hazard ratio (HR)/odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity was assessed using the Chi-squared test and the I(2) statistic. The study was registered with PROSPERO (ID: CRD42019138777). RESULTS: Eleven studies (n = 304,258 T2DM patients) were included in our review. In the DPP-4I group, six studies were enrolled to estimate DeltaMini-Mental State Examination (MMSE) scores from baseline to the final evaluations after DPP-4I treatment, which showed no statistical difference (MD 0.20; 95% CI - 0.75 to 1.15, p = 0.68). DeltaMMSE scores in the DPP-4I group and the other antidiabetic groups were compared, revealing no statistical difference (MD 0.57; 95% CI - 0.05 to 1.19, p = 0.07). Two cohort studies were pooled to determine the HRs for dementia, showing a lower risk of dementia after DPP-4I treatment (HR 0.52; 95% CI 0.29-0.93, p = 0.03). In the GLP-1 analogs group, two studies were included, one of which revealed a downward trend in the risk of dementia after GLP-1 analog treatment, while the other revealed no significant difference after incretins treatment. CONCLUSIONS: Currently there is not enough irrefutable evidence to support the hypothesis of positive effects of incretins on cognition. Further clinical studies need to be performed. FAU - Jin, Yuxin AU - Jin Y AUID- ORCID: 0000-0001-8611-9739 AD - Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China. AD - Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China. FAU - Zhao, Hang AU - Zhao H AD - Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China. FAU - Hou, Yilin AU - Hou Y AD - Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China. AD - Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China. FAU - Song, Guangyao AU - Song G AD - Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China. guangyaosong123@163.com. AD - Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China. guangyaosong123@163.com. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20200416 PL - Germany TA - Acta Diabetol JT - Acta diabetologica JID - 9200299 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Adult MH - Cognition/*drug effects/physiology MH - Diabetes Mellitus, Type 2/*drug therapy/psychology MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Glucagon-Like Peptide 1/analogs & derivatives/therapeutic use MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Incretins/therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Cognition OT - Dipeptidyl peptidase-4 inhibitors OT - Glucagon-like peptide 1 receptor agonists OT - Meta-analysis OT - Type 2 diabetes mellitus EDAT- 2020/04/18 06:00 MHDA- 2020/11/20 06:00 CRDT- 2020/04/18 06:00 PHST- 2020/02/02 00:00 [received] PHST- 2020/03/27 00:00 [accepted] PHST- 2020/04/18 06:00 [pubmed] PHST- 2020/11/20 06:00 [medline] PHST- 2020/04/18 06:00 [entrez] AID - 10.1007/s00592-020-01529-1 [pii] AID - 10.1007/s00592-020-01529-1 [doi] PST - ppublish SO - Acta Diabetol. 2020 Oct;57(10):1129-1144. doi: 10.1007/s00592-020-01529-1. Epub 2020 Apr 16. PMID- 32269764 OWN - NLM STAT- MEDLINE DCOM- 20200625 LR - 20230919 IS - 2046-1402 (Electronic) IS - 2046-1402 (Linking) VI - 9 DP - 2020 TI - Recent advances in understanding the role of glucagon-like peptide 1. LID - F1000 Faculty Rev-239 [pii] LID - 10.12688/f1000research.20602.1 [doi] AB - The discovery that glucagon-like peptide 1 (GLP-1) mediates a significant proportion of the incretin effect during the postprandial period and the subsequent observation that GLP-1 bioactivity is retained in type 2 diabetes (T2D) led to new therapeutic strategies being developed for T2D treatment based on GLP-1 action. Although owing to its short half-life exogenous GLP-1 has no use therapeutically, GLP-1 mimetics, which have a much longer half-life than native GLP-1, have proven to be effective for T2D treatment since they prolong the incretin effect in patients. These GLP-1 mimetics are a desirable therapeutic option for T2D since they do not provoke hypoglycaemia or weight gain and have simple modes of administration and monitoring. Additionally, over more recent years, GLP-1 action has been found to mediate systemic physiological beneficial effects and this has high clinical relevance due to the post-diagnosis complications of T2D. Indeed, recent studies have found that certain GLP-1 analogue therapies improve the cardiovascular outcomes for people with diabetes. Furthermore, GLP-1-based therapies may enable new therapeutic strategies for diseases that can also arise independently of the clinical manifestation of T2D, such as dementia and Parkinson's disease. GLP-1 functions by binding to its receptor (GLP-1R), which expresses mainly in pancreatic islet beta cells. A better understanding of the mechanisms and signalling pathways by which acute and chronic GLP-1R activation alleviates disease phenotypes and induces desirable physiological responses during healthy conditions will likely lead to the development of new therapeutic GLP-1 mimetic-based therapies, which improve prognosis to a greater extent than current therapies for an array of diseases. CI - Copyright: (c) 2020 Reed J et al. FAU - Reed, Josh AU - Reed J AD - Institute of Life Science, Medical School, Swansea University, Swansea, Wales, SA2 8PP, UK. FAU - Bain, Stephen AU - Bain S AD - Institute of Life Science, Medical School, Swansea University, Swansea, Wales, SA2 8PP, UK. FAU - Kanamarlapudi, Venkateswarlu AU - Kanamarlapudi V AUID- ORCID: 0000-0002-8739-1483 AD - Institute of Life Science, Medical School, Swansea University, Swansea, Wales, SA2 8PP, UK. LA - eng GR - BB/F017596/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20200406 PL - England TA - F1000Res JT - F1000Research JID - 101594320 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Diabetes Mellitus, Type 2 MH - Glucagon-Like Peptide 1/*physiology/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents MH - Incretins MH - *Insulin-Secreting Cells PMC - PMC7137394 OTO - NOTNLM OT - GLP-1 OT - GLP-1R OT - Type 2 diabetes OT - incretin COIS- No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed. EDAT- 2020/04/10 06:00 MHDA- 2020/06/26 06:00 PMCR- 2020/04/06 CRDT- 2020/04/10 06:00 PHST- 2020/03/23 00:00 [accepted] PHST- 2020/04/10 06:00 [entrez] PHST- 2020/04/10 06:00 [pubmed] PHST- 2020/06/26 06:00 [medline] PHST- 2020/04/06 00:00 [pmc-release] AID - F1000 Faculty Rev-239 [pii] AID - 10.12688/f1000research.20602.1 [doi] PST - epublish SO - F1000Res. 2020 Apr 6;9:F1000 Faculty Rev-239. doi: 10.12688/f1000research.20602.1. eCollection 2020. PMID- 32247373 OWN - NLM STAT- MEDLINE DCOM- 20210111 LR - 20250530 IS - 1875-7855 (Electronic) IS - 0079-6123 (Linking) VI - 252 DP - 2020 TI - Repurposing anti-diabetic drugs for the treatment of Parkinson's disease: Rationale and clinical experience. PG - 493-523 LID - S0079-6123(19)30205-5 [pii] LID - 10.1016/bs.pbr.2019.10.008 [doi] AB - The most pressing need in Parkinson's disease (PD) clinical practice is to identify agents that might slow down, stop or reverse the neurodegenerative process of Parkinson's disease and therefore avoid the onset of the most disabling, dopa-refractory symptoms of the disease. These include dementia, speech and swallowing problems, poor balance and falling. To date, there have been no agents which have yet had robust trial data to confirm positive effects at slowing down the neurodegenerative disease process of PD. In this chapter we will review the reasons why there is growing interest in drugs currently licensed for the treatment of diabetes as agents which may slow down disease progression in PD, including a review of the published trials regarding exenatide, a GLP-1 receptor agonist licensed to treat type 2 diabetes, and recently shown to be associated with reduced severity of PD in a randomized, placebo controlled washout design trial of 60 patients treated for 48 weeks. This subject is now a major area of interest for multiple pharmaceutical companies hoping to bring GLP-1 receptor agonists forward as treatment options in PD. CI - (c) 2020 Elsevier B.V. All rights reserved. FAU - Foltynie, Tom AU - Foltynie T AD - Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, United Kingdom. Electronic address: t.foltynie@ucl.ac.uk. FAU - Athauda, Dilan AU - Athauda D AD - Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, United Kingdom. LA - eng GR - 16/167/19/DH_/Department of Health/United Kingdom PT - Journal Article PT - Review DEP - 20191127 PL - Netherlands TA - Prog Brain Res JT - Progress in brain research JID - 0376441 RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - *Drug Repositioning MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Parkinson Disease/*drug therapy/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Diabetes OT - Glucagon-like peptide 1 OT - Parkinson's disease EDAT- 2020/04/06 06:00 MHDA- 2021/01/12 06:00 CRDT- 2020/04/06 06:00 PHST- 2020/04/06 06:00 [entrez] PHST- 2020/04/06 06:00 [pubmed] PHST- 2021/01/12 06:00 [medline] AID - S0079-6123(19)30205-5 [pii] AID - 10.1016/bs.pbr.2019.10.008 [doi] PST - ppublish SO - Prog Brain Res. 2020;252:493-523. doi: 10.1016/bs.pbr.2019.10.008. Epub 2019 Nov 27. PMID- 32210695 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231103 IS - 1319-562X (Print) IS - 2213-7106 (Electronic) IS - 2213-7106 (Linking) VI - 27 IP - 2 DP - 2020 Feb TI - Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators. PG - 736-750 LID - 10.1016/j.sjbs.2019.12.028 [doi] AB - The incidence of Alzheimer's disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Abeta aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed. CI - (c) 2019 Published by Elsevier B.V. on behalf of King Saud University. FAU - Jayaraj, Richard L AU - Jayaraj RL AD - Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates. FAU - Azimullah, Sheikh AU - Azimullah S AD - Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates. FAU - Beiram, Rami AU - Beiram R AD - Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates. LA - eng PT - Journal Article PT - Review DEP - 20191226 PL - Saudi Arabia TA - Saudi J Biol Sci JT - Saudi journal of biological sciences JID - 101543796 PMC - PMC6997863 OTO - NOTNLM OT - AAV, Adeno-associated virus OT - ABCA1, ATP binding cassette subfamily A member 1 OT - AD, Alzheimer's disease OT - ADAMTS9, ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 OT - AGPAT1, 1-acyl-sn-glycerol-3-phosphate acyltransferase alpha OT - Alzheimer's disease OT - Anti-diabetic drugs OT - ApoE, Apolipoprotein E OT - Arab population OT - Abeta, Amyloid-beta OT - BACE1, Beta-secretase 1 OT - BBB, Blood-Brain Barrier OT - BMI, Body mass index OT - CALR, calreticulin gene OT - CIP2A, Cancerous Inhibitor Of Protein Phosphatase 2A OT - COX-2, Cyclooxygenase 2 OT - CSF, Cerebrospinal fluid OT - DM, Diabetes mellitus OT - DUSP9, Dual Specificity Phosphatase 9 OT - Diabetes mellitus OT - ECE-1, Endotherin converting enzyme 1 OT - FDG-PET, Fluorodeoxyglucose- positron emission tomography OT - FRMD4A, FERM Domain Containing 4A OT - FTO, Fat Mass and Obesity Associated Gene OT - GLP-1, Glucagon like peptide OT - GNPDA2, Glucosamine-6-phosphate deaminase 2 OT - GSK-3beta, Glycogen synthase kinase 3 beta OT - IDE, Insulin degrading enzyme OT - IGF-1, Insulin-like growth factor 1 OT - IR, Insulin receptor OT - IR, Insulin resistance OT - Insulin signaling OT - LPA, Lipophosphatidic acid OT - MC4R, Melanocortin 4 receptor OT - MCI, Myocardial infarction OT - MENA, Middle East North African OT - MG-H1, Methylglyoxal-hydroimidazolone isomer trifluoroactic acid salt OT - MRI, Magnetic resonance imaging OT - NDUFS3, NADH:Ubiquinone Oxidoreductase Core Subunit S3 OT - NF-kappaB, nuclear factor kappa-light-chain-enhancer of activated B cells OT - NFT, Neurofibrillary tangles OT - NOTCH4, Neurogenic locus notch homolog protein 4 OT - PI3K, Phosphoinositide-3 OT - PP2A, Protein phosphatase 2 OT - PPAR-gamma2, Peroxisome proliferator-activated receptor gamma 2 OT - Pit-PET, Pittsburgh compound B- positron emission tomography OT - RAB1A, Ras-related protein 1A OT - SORT, Sortilin OT - STZ, Streptozotocin OT - T1DM, Type 1 Diabetes Mellitus OT - T2DM, Type 2 Diabetes Mellitus OT - TCF7L2, Transcription Factor 7 Like 2 OT - TFAP2B, Transcription Factor AP-2 Beta COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/03/27 06:00 MHDA- 2020/03/27 06:01 PMCR- 2019/12/26 CRDT- 2020/03/27 06:00 PHST- 2019/10/28 00:00 [received] PHST- 2019/12/14 00:00 [revised] PHST- 2019/12/18 00:00 [accepted] PHST- 2020/03/27 06:00 [entrez] PHST- 2020/03/27 06:00 [pubmed] PHST- 2020/03/27 06:01 [medline] PHST- 2019/12/26 00:00 [pmc-release] AID - S1319-562X(19)30328-6 [pii] AID - 10.1016/j.sjbs.2019.12.028 [doi] PST - ppublish SO - Saudi J Biol Sci. 2020 Feb;27(2):736-750. doi: 10.1016/j.sjbs.2019.12.028. Epub 2019 Dec 26. PMID- 32175781 OWN - NLM STAT- MEDLINE DCOM- 20210101 LR - 20250103 IS - 1744-7658 (Electronic) IS - 1354-3784 (Linking) VI - 29 IP - 4 DP - 2020 Apr TI - Brain insulin resistance: role in neurodegenerative disease and potential for targeting. PG - 333-348 LID - 10.1080/13543784.2020.1738383 [doi] AB - Introduction: This review evaluates the novel strategy of treating Alzheimer's and Parkinson's disease (AD and PD) withdrugs that initially have been developed to treat type 2 diabetes. As insulin signalling has been found to be de-sensitized in the brains of patients, drugs that can re-sensitize insulin signalling have been tested to evaluate if this strategy can alter disease progression.Areas covered: The review will give an overview of preclinical and clinical tests in AD and PD of drugs activating insulin receptors, glucagon-like peptide -1 (GLP-1) receptors, and glucose-dependent insulinotropic polypeptide (GIP) receptors.Expert opinion: Insulin, GLP-1 and GIP receptor agonists have shown good effects in preclinical studies. First clinical trials in MCI/AD patients have shown that insulin can improve on key pathological symptoms of AD such as memory impairment, brain activity, neuronal energy utilization, and inflammation markers. A GLP-1 receptor agonist has shown disease-modifying effects in PD patients, and first pilot studies have shown encouraging effects of a GLP-1 receptor agonist in AD patients. Novel dual GLP-1/GIP receptor agonists that cross the blood brain barrier show superior neuroprotective effects compared to single GLP-1 or GIP receptor agonists, and show great promise as novel treatments of AD and PD. FAU - Holscher, Christian AU - Holscher C AD - Second Hospital, Neurology Department, Shanxi Medical University, Taiyuan, Shanxi, PR China. AD - Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China. LA - eng PT - Journal Article PT - Review DEP - 20200316 PL - England TA - Expert Opin Investig Drugs JT - Expert opinion on investigational drugs JID - 9434197 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/drug therapy/*metabolism MH - Animals MH - Brain/*metabolism MH - Gastric Inhibitory Polypeptide/metabolism MH - Glucagon-Like Peptide 1/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Insulin/metabolism MH - *Insulin Resistance MH - Parkinson Disease/drug therapy/*metabolism MH - Receptors, Gastrointestinal Hormone/agonists/metabolism MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 OT - Parkinson's disease OT - growth factor OT - inflammation OT - insulin OT - mitochondria EDAT- 2020/03/17 06:00 MHDA- 2021/01/02 06:00 CRDT- 2020/03/17 06:00 PHST- 2020/03/17 06:00 [pubmed] PHST- 2021/01/02 06:00 [medline] PHST- 2020/03/17 06:00 [entrez] AID - 10.1080/13543784.2020.1738383 [doi] PST - ppublish SO - Expert Opin Investig Drugs. 2020 Apr;29(4):333-348. doi: 10.1080/13543784.2020.1738383. Epub 2020 Mar 16. PMID- 32162525 OWN - NLM STAT- MEDLINE DCOM- 20201204 LR - 20240425 IS - 1938-2731 (Electronic) IS - 1533-3175 (Print) IS - 1533-3175 (Linking) VI - 35 DP - 2020 Jan-Dec TI - Antidiabetic Drugs for the Risk of Alzheimer Disease in Patients With Type 2 DM Using FAERS. PG - 1533317519899546 LID - 10.1177/1533317519899546 [doi] LID - 1533317519899546 AB - Alzheimer disease (AD) may develop after the onset of type 2 diabetes mellitus (T2DM), and the risk of AD may depend on the antidiabetic drug administered. We compared the risk of AD among 66 085 patients (>/= 65 years) with T2DM (1250 having concomitant AD) who had been administered antidiabetic drug monotherapy for T2DM who had voluntarily reported themselves in the Food and Drug Administration Adverse Event Reporting System. The risk of AD from the use of different antidiabetic drug monotherapies compared to that of metformin monotherapy was assessed by logistic regression. Rosiglitazone (adjusted reporting odds ratio [aROR] = 0.11; 95% confidence interval [CI]: 0.07-0.17; P < .001), exenatide (aROR = 0.22; 95% CI: 0.11-0.37; P < .001), liraglutide (aROR = 0.36; 95% CI: 0.19-0.62; P < .001), dulaglutide (aROR = 0.39; 95% CI: 0.17-0.77; P = .014), and sitagliptin (aROR = 0.75; 95% CI: 0.60-0.93; P = .011) were found to have a significantly lower associated risk of AD than that of metformin. Therefore, the administration of glucagon-like peptide 1 receptor agonists and rosiglitazone may reduce the risk of AD in patients with T2DM. FAU - Akimoto, Hayato AU - Akimoto H AUID- ORCID: 0000-0002-5397-0137 AD - Faculty of Pharmacy and Pharmaceutical Sciences, Department of Analytical Pharmaceutics and Informatics, Josai University, Sakado, Saitama, Japan. FAU - Negishi, Akio AU - Negishi A AD - Faculty of Pharmacy and Pharmaceutical Sciences, Department of Analytical Pharmaceutics and Informatics, Josai University, Sakado, Saitama, Japan. FAU - Oshima, Shinji AU - Oshima S AUID- ORCID: 0000-0003-2638-0550 AD - Faculty of Pharmacy and Pharmaceutical Sciences, Department of Analytical Pharmaceutics and Informatics, Josai University, Sakado, Saitama, Japan. FAU - Wakiyama, Haruna AU - Wakiyama H AD - Faculty of Pharmacy and Pharmaceutical Sciences, Department of Analytical Pharmaceutics and Informatics, Josai University, Sakado, Saitama, Japan. FAU - Okita, Mitsuyoshi AU - Okita M AD - Josai University Pharmacy, Iruma-gun, Saitama, Japan. FAU - Horii, Norimitsu AU - Horii N AD - Josai University Pharmacy, Iruma-gun, Saitama, Japan. AD - Faculty of Pharmacy and Pharmaceutical Sciences, Laboratory of Pharmacy Management, Josai University, Sakado, Saitama, Japan. FAU - Inoue, Naoko AU - Inoue N AD - Josai University Pharmacy, Iruma-gun, Saitama, Japan. AD - Faculty of Pharmacy and Pharmaceutical Sciences, Laboratory of Pharmacy Management, Josai University, Sakado, Saitama, Japan. FAU - Ohshima, Shigeru AU - Ohshima S AD - Josai University Pharmacy, Iruma-gun, Saitama, Japan. AD - Faculty of Pharmacy and Pharmaceutical Sciences, Laboratory of Pharmacy Management, Josai University, Sakado, Saitama, Japan. FAU - Kobayashi, Daisuke AU - Kobayashi D AD - Faculty of Pharmacy and Pharmaceutical Sciences, Department of Analytical Pharmaceutics and Informatics, Josai University, Sakado, Saitama, Japan. LA - eng PT - Journal Article PL - United States TA - Am J Alzheimers Dis Other Demen JT - American journal of Alzheimer's disease and other dementias JID - 101082834 RN - 0 (Hypoglycemic Agents) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Recombinant Fusion Proteins) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 839I73S42A (Liraglutide) RN - 9100L32L2N (Metformin) RN - 9P1872D4OL (Exenatide) RN - WTT295HSY5 (dulaglutide) SB - IM MH - Aged MH - Alzheimer Disease/*diagnosis MH - Diabetes Mellitus, Type 2/*complications/drug therapy MH - Exenatide/therapeutic use MH - Female MH - Glucagon-Like Peptides/analogs & derivatives/therapeutic use MH - Humans MH - Hypoglycemic Agents/*adverse effects MH - Immunoglobulin Fc Fragments/therapeutic use MH - Liraglutide/therapeutic use MH - Male MH - Metformin/*adverse effects/*therapeutic use MH - Recombinant Fusion Proteins/therapeutic use PMC - PMC11005324 OTO - NOTNLM OT - Alzheimer disease OT - FDA adverse event reporting system OT - antidiabetics OT - dementia OT - type 2 diabetes mellitus COIS- The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2020/03/13 06:00 MHDA- 2020/12/15 06:00 PMCR- 2020/03/12 CRDT- 2020/03/13 06:00 PHST- 2020/03/13 06:00 [entrez] PHST- 2020/03/13 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/03/12 00:00 [pmc-release] AID - 10.1177_1533317519899546 [pii] AID - 10.1177/1533317519899546 [doi] PST - ppublish SO - Am J Alzheimers Dis Other Demen. 2020 Jan-Dec;35:1533317519899546. doi: 10.1177/1533317519899546. PMID- 32147454 OWN - NLM STAT- MEDLINE DCOM- 20210603 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 170 DP - 2020 Jun 15 TI - A GLP-1/GIP/Gcg receptor triagonist improves memory behavior, as well as synaptic transmission, neuronal excitability and Ca(2+) homeostasis in 3xTg-AD mice. PG - 108042 LID - S0028-3908(20)30108-8 [pii] LID - 10.1016/j.neuropharm.2020.108042 [doi] AB - Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca(2+) flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca(2+) balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Li, Tian AU - Li T AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Jiao, Juan-Juan AU - Jiao JJ AD - Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, 030009, PR China. FAU - Su, Qiang AU - Su Q AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Holscher, Christian AU - Holscher C AD - Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan province, PR China. FAU - Zhang, Jun AU - Zhang J AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Yan, Xu-Dong AU - Yan XD AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Zhao, Hui-Min AU - Zhao HM AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Immunology and Microbiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. Electronic address: jinshunqi2009@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200306 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (MAPT protein, human) RN - 0 (Presenilin-1) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (Receptors, Glucagon) RN - 0 (tau Proteins) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Calcium Signaling/*drug effects/physiology MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Female MH - Glucagon-Like Peptide-1 Receptor/physiology MH - Hippocampus/drug effects/physiology MH - Homeostasis/drug effects/physiology MH - Humans MH - Hypoglycemic Agents/administration & dosage MH - Male MH - Maze Learning/drug effects/physiology MH - Memory, Short-Term/*drug effects/physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurons/drug effects/physiology MH - Organ Culture Techniques MH - Presenilin-1/genetics MH - Receptors, Gastrointestinal Hormone/*agonists/physiology MH - Receptors, Glucagon/*agonists/physiology MH - Synaptic Transmission/*drug effects/physiology MH - tau Proteins/genetics MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - 3xTg-AD mice OT - GLP-1/GIP/Gcg triagonist OT - Miniature excitatory postsynaptic currents (mEPSCs) OT - PSD-95 OT - Synaptophysin OT - Transmembrane calcium flux OT - Whole cell calcium currents COIS- Declaration of competing interests The authors declare no actual or potential conflict of interest. EDAT- 2020/03/10 06:00 MHDA- 2021/06/04 06:00 CRDT- 2020/03/10 06:00 PHST- 2019/09/10 00:00 [received] PHST- 2020/02/13 00:00 [revised] PHST- 2020/03/04 00:00 [accepted] PHST- 2020/03/10 06:00 [pubmed] PHST- 2021/06/04 06:00 [medline] PHST- 2020/03/10 06:00 [entrez] AID - S0028-3908(20)30108-8 [pii] AID - 10.1016/j.neuropharm.2020.108042 [doi] PST - ppublish SO - Neuropharmacology. 2020 Jun 15;170:108042. doi: 10.1016/j.neuropharm.2020.108042. Epub 2020 Mar 6. PMID- 32143329 OWN - NLM STAT- MEDLINE DCOM- 20210104 LR - 20210104 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 21 IP - 5 DP - 2020 Mar 4 TI - Liraglutide Protects Against Brain Amyloid-beta(1-42) Accumulation in Female Mice with Early Alzheimer's Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation. LID - 10.3390/ijms21051746 [doi] LID - 1746 AB - Alzheimer's disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Abeta) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Abeta and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Abeta(1-42) levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females. FAU - Duarte, Ana I AU - Duarte AI AUID- ORCID: 0000-0002-0223-7867 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao-Polo II, Rua D. Francisco de Lemos, 3030-789 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Candeias, Emanuel AU - Candeias E AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao-Polo II, Rua D. Francisco de Lemos, 3030-789 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Alves, Ines N AU - Alves IN AUID- ORCID: 0000-0001-8329-3758 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Mena, Debora AU - Mena D AUID- ORCID: 0000-0001-6141-6235 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Silva, Daniela F AU - Silva DF AUID- ORCID: 0000-0001-9259-3277 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Machado, Nuno J AU - Machado NJ AUID- ORCID: 0000-0001-5097-4231 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Campos, Elisa J AU - Campos EJ AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. FAU - Santos, Maria S AU - Santos MS AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Life Sciences Department, University of Coimbra, Largo Marques de Pombal, 3004-517 Coimbra, Portugal. FAU - Oliveira, Catarina R AU - Oliveira CR AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. FAU - Moreira, Paula I AU - Moreira PI AUID- ORCID: 0000-0001-5177-6747 AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Center for Innovative Biomedicine and Biotechnology (CIBB), Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal. AD - Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. LA - eng GR - PTDC/SAU-TOX/117481/2010/Fundacao para a Ciencia e a Tecnologia/ GR - Strategic Project POCI-01-0145-FEDER-007440/Fundacao para a Ciencia e a Tecnologia/ GR - Healthy Aging CENTRO-01-0145-FEDER-000012/undefined undefined/ GR - N/A/Fundo Europeu de Desenvolvimento Estrategico Regional (FEDER)/ GR - Projectos de Desenvolvimento e Implementacao de Infraestruturas de Investigacao inseridas no RNIE/N/A/ GR - Programa Operacional Competitividade e Internacionalizacao - POCI "Programa Operacional COMPETE2020" (Fellowship SFRH/BD/90036/2012 to E. Candeias and Post-Doctoral Researcher contract DL57/2016 #SFRH/BPD/84473/2012 to A.I. Duarte)/N/A/ PT - Journal Article DEP - 20200304 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-42)) RN - 4TI98Z838E (Estradiol) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Alzheimer Disease/*metabolism MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Behavior, Animal MH - Brain/*metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Diabetes Mellitus, Type 2/metabolism MH - Estradiol/metabolism MH - Female MH - Glucagon-Like Peptide 1/metabolism MH - Glycolysis MH - Hypoglycemic Agents/*pharmacology MH - Inflammation/*metabolism MH - Liraglutide/*pharmacology MH - Maze Learning MH - Memory Disorders MH - Mice MH - Neurofibrillary Tangles/metabolism MH - Nitrosative Stress MH - Oxidative Stress MH - Peptide Fragments/*metabolism MH - Phenotype MH - Plaque, Amyloid/metabolism PMC - PMC7084254 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 mimetics OT - brain protection OT - female sex OT - liraglutide COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2020/03/08 06:00 MHDA- 2021/01/05 06:00 PMCR- 2020/03/01 CRDT- 2020/03/08 06:00 PHST- 2019/12/09 00:00 [received] PHST- 2020/02/23 00:00 [revised] PHST- 2020/02/28 00:00 [accepted] PHST- 2020/03/08 06:00 [entrez] PHST- 2020/03/08 06:00 [pubmed] PHST- 2021/01/05 06:00 [medline] PHST- 2020/03/01 00:00 [pmc-release] AID - ijms21051746 [pii] AID - ijms-21-01746 [pii] AID - 10.3390/ijms21051746 [doi] PST - epublish SO - Int J Mol Sci. 2020 Mar 4;21(5):1746. doi: 10.3390/ijms21051746. PMID- 32111301 OWN - NLM STAT- MEDLINE DCOM- 20210111 LR - 20210111 IS - 1873-7528 (Electronic) IS - 0149-7634 (Linking) VI - 110 DP - 2020 Mar TI - Glucose signaling in the brain and periphery to memory. PG - 100-113 LID - S0149-7634(18)30365-8 [pii] LID - 10.1016/j.neubiorev.2019.03.018 [doi] AB - Glucose has many diverse physiological roles such as energy metabolism, appetite control and memory consolidation. We recently reported that memory-related gene expression is epigenetically controlled in murine brain cells and that glucose can regulate gene expression in a cell-specific manner. However, the literature reviews have indicated that glucose can also regulate gut cells to release incretins which might play a role in memory processes directly or indirectly by vagus nerve stimulation. In this review, we discussed the effects of glucose on the gut and brain, aiming to understand more in-depth the role of glucose in memory function. In addition, we also discussed the alteration of glucose-signaling in type-2 diabetes mellitus (T2DM) and a possible link to Alzheimer's disease (AD) pathologies. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Hossain, Md Shamim AU - Hossain MS AD - Department of Neuroinflammation and Brain Fatigue Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Electronic address: shamim@physiol.med.kyushu-u.ac.jp. FAU - Oomura, Yutaka AU - Oomura Y AD - Department of Neuroinflammation and Brain Fatigue Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. FAU - Fujino, Takehiko AU - Fujino T AD - Institute of Rheological Functions of Food, 2241-1 Kubara, Hisayama-machi, Kasuya-gun, Fukuoka, 811-2501, Japan. FAU - Akashi, Koichi AU - Akashi K AD - Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Neurosci Biobehav Rev JT - Neuroscience and biobehavioral reviews JID - 7806090 RN - IY9XDZ35W2 (Glucose) SB - IM MH - Alzheimer Disease/metabolism/*physiopathology MH - Animals MH - Brain/*physiology/physiopathology MH - Diabetes Mellitus, Type 2/metabolism MH - Glucose/*metabolism MH - Humans MH - Memory/*physiology MH - Signal Transduction/physiology OTO - NOTNLM OT - BDNF OT - Epigenetics OT - FGF-1 OT - Glucose OT - Incretins OT - Memory OT - Vagus nerve EDAT- 2020/03/01 06:00 MHDA- 2021/01/12 06:00 CRDT- 2020/03/01 06:00 PHST- 2018/05/20 00:00 [received] PHST- 2019/01/30 00:00 [revised] PHST- 2019/03/24 00:00 [accepted] PHST- 2020/03/01 06:00 [entrez] PHST- 2020/03/01 06:00 [pubmed] PHST- 2021/01/12 06:00 [medline] AID - S0149-7634(18)30365-8 [pii] AID - 10.1016/j.neubiorev.2019.03.018 [doi] PST - ppublish SO - Neurosci Biobehav Rev. 2020 Mar;110:100-113. doi: 10.1016/j.neubiorev.2019.03.018. PMID- 32079069 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 1999-4923 (Print) IS - 1999-4923 (Electronic) IS - 1999-4923 (Linking) VI - 12 IP - 2 DP - 2020 Feb 16 TI - Long-Lasting Exendin-4 Fusion Protein Improves Memory Deficits in High-Fat Diet/Streptozotocin-Induced Diabetic Mice. LID - 10.3390/pharmaceutics12020159 [doi] LID - 159 AB - Glucagon-like peptide 1 (GLP-1) mimetics have been approved as an adjunct therapy for glycemic control in type 2 diabetic patients for the increased insulin secretion under hyperglycemic conditions. Recently, it is reported that such agents elicit neuroprotective effects against diabetes-associated cognitive decline. However, there is an issue of poor compliance by multiple daily subcutaneous injections for sufficient glycemic control due to their short duration, and neuroprotective actions were not fully studied, yet. In this study, using the prepared exendin-4 fusion protein agent, we investigated the pharmacokinetic profile and the role of this GLP-1 mimetics on memory deficits in a high-fat diet (HFD)/streptozotocin (STZ) mouse model of type 2 diabetic mellitus. After induction of diabetes, mice were administered weekly by intraperitoneal injection of GLP-1 mimetics for 6 weeks. This treatment reversed HFD/STZ-induced metabolic symptoms of increased body weight, hyperglycemia, and hepatic steatosis. Furthermore, the impaired cognitive performance of diabetic mice was significantly reversed by GLP-1 mimetics. GLP-1 mimetic treatment also reversed decreases in GLP-1/GLP-1 receptor expression levels in both the pancreas and hippocampus of diabetic mice; increases in hippocampal inflammation, mitochondrial fission, and calcium-binding protein levels were also reversed. These findings suggest that GLP-1 mimetics are promising agents for both diabetes and neurodegenerative diseases that are associated with increased GLP-1 expression in the brain. FAU - Park, Kyung-Ah AU - Park KA AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Jin, Zhen AU - Jin Z AUID- ORCID: 0000-0003-0540-5173 AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Lee, Jong Youl AU - Lee JY AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - An, Hyeong Seok AU - An HS AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Choi, Eun Bee AU - Choi EB AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Kim, Kyung Eun AU - Kim KE AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Shin, Hyun Joo AU - Shin HJ AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Jeong, Eun Ae AU - Jeong EA AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. FAU - Min, Kyoung Ah AU - Min KA AD - College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae, Gyeongnam 50834, Korea. FAU - Shin, Meong Cheol AU - Shin MC AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam 52828, Korea. FAU - Roh, Gu Seob AU - Roh GS AUID- ORCID: 0000-0003-4010-9628 AD - Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea. LA - eng GR - 2015R1A5A2008833/National Research Foundation of Korea/ PT - Journal Article DEP - 20200216 PL - Switzerland TA - Pharmaceutics JT - Pharmaceutics JID - 101534003 PMC - PMC7076426 OTO - NOTNLM OT - Glucagon-like peptide 1R (GLP-1R) OT - diabetic mice OT - exendin-4 OT - fusion protein OT - hippocampus OT - memory deficits COIS- The authors declare no conflicts of interest. EDAT- 2020/02/23 06:00 MHDA- 2020/02/23 06:01 PMCR- 2020/02/01 CRDT- 2020/02/22 06:00 PHST- 2020/01/22 00:00 [received] PHST- 2020/02/12 00:00 [revised] PHST- 2020/02/14 00:00 [accepted] PHST- 2020/02/22 06:00 [entrez] PHST- 2020/02/23 06:00 [pubmed] PHST- 2020/02/23 06:01 [medline] PHST- 2020/02/01 00:00 [pmc-release] AID - pharmaceutics12020159 [pii] AID - pharmaceutics-12-00159 [pii] AID - 10.3390/pharmaceutics12020159 [doi] PST - epublish SO - Pharmaceutics. 2020 Feb 16;12(2):159. doi: 10.3390/pharmaceutics12020159. PMID- 31998717 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240729 IS - 2296-634X (Print) IS - 2296-634X (Electronic) IS - 2296-634X (Linking) VI - 7 DP - 2019 TI - Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury. PG - 356 LID - 10.3389/fcell.2019.00356 [doi] LID - 356 AB - Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote beta-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders. CI - Copyright (c) 2020 Bader, Li, Tweedie, Shlobin, Bernstein, Rubovitch, Tovar-y-Romo, DiMarchi, Hoffer, Greig and Pick. FAU - Bader, Miaad AU - Bader M AD - Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States. FAU - Tweedie, David AU - Tweedie D AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States. FAU - Shlobin, Nathan A AU - Shlobin NA AD - Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. FAU - Bernstein, Adi AU - Bernstein A AD - Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Rubovitch, Vardit AU - Rubovitch V AD - Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Tovar-Y-Romo, Luis B AU - Tovar-Y-Romo LB AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States. AD - Division of Neuroscience, Institute of Cellular Physiology, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. FAU - DiMarchi, Richard D AU - DiMarchi RD AD - Department of Chemistry, Indiana University, Bloomington, IN, United States. FAU - Hoffer, Barry J AU - Hoffer BJ AD - Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, United States. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States. FAU - Pick, Chaim G AU - Pick CG AD - Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. AD - Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. AD - Center for the Biology of Addictive Diseases, Tel Aviv University, Tel Aviv, Israel. LA - eng GR - R56 AG057028/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20200110 PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 PMC - PMC6965031 OTO - NOTNLM OT - concussive head injury OT - glucagon-like peptide-1 OT - glucose-dependent insulinotropic polypeptide OT - incretin OT - liraglutide OT - traumatic brain injury OT - twincretin EDAT- 2020/01/31 06:00 MHDA- 2020/01/31 06:01 PMCR- 2019/01/01 CRDT- 2020/01/31 06:00 PHST- 2019/09/09 00:00 [received] PHST- 2019/12/10 00:00 [accepted] PHST- 2020/01/31 06:00 [entrez] PHST- 2020/01/31 06:00 [pubmed] PHST- 2020/01/31 06:01 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fcell.2019.00356 [doi] PST - epublish SO - Front Cell Dev Biol. 2020 Jan 10;7:356. doi: 10.3389/fcell.2019.00356. eCollection 2019. PMID- 31965072 OWN - NLM STAT- MEDLINE DCOM- 20211029 LR - 20261010 IS - 1476-5497 (Electronic) IS - 0307-0565 (Linking) VI - 44 IP - 6 DP - 2020 Jun TI - Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study. PG - 1254-1263 LID - 10.1038/s41366-020-0535-5 [doi] AB - BACKGROUND/OBJECTIVES: Diabetic subjects are at increased risk of subtle cognitive impairment since the disease early stages and of dementia later in life. In animal models, glucagon-like peptide-1 receptor agonizts (GLP1-RAs) have been shown to exert neuroprotective effects, expecially in the memory domain. We assessed whether treatment with a GLP1-RA might affect cognitive functions in type 2 diabetic subjects independently on the weight loss it might induce. SUBJECTS/METHODS: Forty metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes mellitus, received liraglutide (1.8 mg/d) (n = 20) or lifestyle counseling (dietary intervention and exercise training) (n = 20) until achieving a modest and comparable weight loss (-7% of initial body weight). INTERVENTIONS/METHODS: A detailed neuropsychological assessment before and after weight loss was completed in 16 patients per arm, who were administered a total of seven psychological tests, thus assessing three composite domain z-scores for attention, memory, and executive control. RESULTS: After comparable weight loss and superimposable glycemic control and insulin sensitivity, a significant increase in short term memory (mean Digit Span Z score from -0.06 to 0.80, p = 0.024) and memory composite z-score (mean memory z-score from -0.67 to 0.032, p = 0.0065) was observed in the liraglutide exposed subjects (between group p = 0.041 and p = 0.033, respectively). CONCLUSIONS: Liraglutide might slow down memory function decline in diabetic patients in early, and possibly preclinical stages of the disease. FAU - Vadini, Francesco AU - Vadini F AD - Psychoinfectivology Service, Pescara General Hospital, Pescara, Italy. FAU - Simeone, Paola G AU - Simeone PG AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Boccatonda, Andrea AU - Boccatonda A AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Guagnano, Maria T AU - Guagnano MT AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Liani, Rossella AU - Liani R AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Tripaldi, Romina AU - Tripaldi R AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Di Castelnuovo, Augusto AU - Di Castelnuovo A AD - Mediterranea, Cardiocentro, Napoli, Italy. FAU - Cipollone, Francesco AU - Cipollone F AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Consoli, Agostino AU - Consoli A AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. FAU - Santilli, Francesca AU - Santilli F AUID- ORCID: 0000-0002-4593-905X AD - Department of Medicine and Aging, Center of Aging Science and Translational Medicine (CESI-Met), Via Luigi Polacchi, Chieti, Italy. francesca.santilli@unich.it. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200121 PL - England TA - Int J Obes (Lond) JT - International journal of obesity (2005) JID - 101256108 RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 9100L32L2N (Metformin) SB - IM MH - Diabetes Mellitus, Type 2/*drug therapy MH - Female MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Life Style MH - Liraglutide/therapeutic use MH - Longitudinal Studies MH - Male MH - *Memory MH - Metformin/therapeutic use MH - Middle Aged MH - Neuropsychological Tests MH - Obesity/*drug therapy MH - Prediabetic State/*drug therapy MH - Psychometrics MH - Weight Loss EDAT- 2020/01/23 06:00 MHDA- 2021/10/30 06:00 CRDT- 2020/01/23 06:00 PHST- 2019/08/01 00:00 [received] PHST- 2020/01/07 00:00 [accepted] PHST- 2019/12/17 00:00 [revised] PHST- 2020/01/23 06:00 [pubmed] PHST- 2021/10/30 06:00 [medline] PHST- 2020/01/23 06:00 [entrez] AID - 10.1038/s41366-020-0535-5 [pii] AID - 10.1038/s41366-020-0535-5 [doi] PST - ppublish SO - Int J Obes (Lond). 2020 Jun;44(6):1254-1263. doi: 10.1038/s41366-020-0535-5. Epub 2020 Jan 21. PMID- 31960630 OWN - NLM STAT- MEDLINE DCOM- 20210319 LR - 20231113 IS - 2162-3279 (Electronic) VI - 10 IP - 3 DP - 2020 Mar TI - The novel GLP-1/GIP analogue DA5-CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD. PG - e01505 LID - 10.1002/brb3.1505 [doi] LID - e01505 AB - INTRODUCTION: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease for which there is no cure. Recent studies have shown a close link between type 2 diabetes and AD, which suggested that drugs for type 2 diabetes may be effective for AD. GLP-1 and GIP are incretin hormones that can ameliorate diabetes. METHODS: In the present study, we tested the novel dual GLP-1/GIP receptor agonist DA5-CH in the icv. streptozotocin (STZ)-induced insulin desensitization model of AD in rats to explore the protective effects of DA5-CH. RESULTS: The results show that DA5-CH could reverse the STZ-induced working memory impairments in a Y-maze tests, and spatial memory impairments in the water maze task, and decrease the levels of phosphorylated tau(S396) protein in the hippocampus. In EEG recordings, STZ treatment diminished the power of the theta band frequency. DA5-CH was able to increase the energy of theta band activity in the hippocampal CA1 region. The drug also increased the expression of synapse-related proteins in the hippocampus. After DA5-CH treatment, mitochondrial stress was alleviated as shown by the improved ratio of Bax/Bcl-2 in the hippocampus. Growth factor signaling was also normalized as shown by the increased level of the transcription factor P-CREB(S133) . In addition, we were able to show that DA5-CH can cross the blood-brain barrier at an increased rate compared with other dual GLP-1/GIP or single GLP-1 receptor agonists. CONCLUSION: Therefore, our results demonstrate that DA5-CH has neuroprotective effects in the STZ-induced animal model and that DA5-CH has potential to treat neurodegenerative disorders such as AD. CI - (c) 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. FAU - Li, Cheng AU - Li C AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Liu, Weizhen AU - Liu W AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Li, Xiaohui AU - Li X AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Zhang, Zijuan AU - Zhang Z AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Qi, Huaxin AU - Qi H AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Liu, Shijin AU - Liu S AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Yan, Ningning AU - Yan N AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Xing, Ying AU - Xing Y AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. FAU - Holscher, Christian AU - Holscher C AUID- ORCID: 0000-0002-8159-3260 AD - Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China. FAU - Wang, Zhiju AU - Wang Z AD - Department of Physiology and Neurobiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China. LA - eng GR - 81771193/National Natural Science Foundation of China/International GR - Scientific Research and development/International GR - Zhengzhou University/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200120 PL - United States TA - Brain Behav JT - Brain and behavior JID - 101570837 RN - 0 (DA5-CH peptide) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (tau Proteins) RN - 5W494URQ81 (Streptozocin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/chemically induced/*metabolism/physiopathology MH - Animals MH - Disease Models, Animal MH - Glucagon-Like Peptide 1/*agonists MH - Hippocampus/*drug effects/metabolism MH - Male MH - Maze Learning/drug effects MH - Memory, Short-Term/drug effects MH - Neuroprotective Agents/*pharmacology MH - Peptides/*pharmacology MH - Phosphorylation/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Streptozocin MH - Theta Rhythm/*drug effects/physiology MH - tau Proteins/*metabolism PMC - PMC7066337 OTO - NOTNLM OT - Alzheimer's disease OT - CREB OT - GLP-1/GIP dual agonist OT - apoptosis OT - growth factor OT - streptozotocin OT - theta band frequency COIS- Professor Christian Holscher is a named inventor on a patent that covers the use of dual agonist peptides as treatments for neurodegenerative disorders. The patent is owned by Lancaster University, UK. EDAT- 2020/01/22 06:00 MHDA- 2021/03/20 06:00 PMCR- 2020/01/20 CRDT- 2020/01/22 06:00 PHST- 2019/07/17 00:00 [received] PHST- 2019/10/28 00:00 [revised] PHST- 2019/11/22 00:00 [accepted] PHST- 2020/01/22 06:00 [pubmed] PHST- 2021/03/20 06:00 [medline] PHST- 2020/01/22 06:00 [entrez] PHST- 2020/01/20 00:00 [pmc-release] AID - BRB31505 [pii] AID - 10.1002/brb3.1505 [doi] PST - ppublish SO - Brain Behav. 2020 Mar;10(3):e01505. doi: 10.1002/brb3.1505. Epub 2020 Jan 20. PMID- 31767182 OWN - NLM STAT- MEDLINE DCOM- 20200623 LR - 20250530 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 30 DP - 2019 Dec TI - Glucagon-like peptide 1 (GLP-1). PG - 72-130 LID - S2212-8778(19)30913-5 [pii] LID - 10.1016/j.molmet.2019.09.010 [doi] AB - BACKGROUND: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent beta-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders. CI - Copyright (c) 2019 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Muller, T D AU - Muller TD AD - Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tubingen, Germany. Electronic address: timo.mueller@helmholtz-muenchen.de. FAU - Finan, B AU - Finan B AD - Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA. FAU - Bloom, S R AU - Bloom SR AD - Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK. FAU - D'Alessio, D AU - D'Alessio D AD - Division of Endocrinology, Duke University Medical Center, Durham, NC, USA. FAU - Drucker, D J AU - Drucker DJ AD - The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada. FAU - Flatt, P R AU - Flatt PR AD - SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK. FAU - Fritsche, A AU - Fritsche A AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tubingen, Tubingen, Germany. FAU - Gribble, F AU - Gribble F AD - Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK. FAU - Grill, H J AU - Grill HJ AD - Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA. FAU - Habener, J F AU - Habener JF AD - Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA. FAU - Holst, J J AU - Holst JJ AD - Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Langhans, W AU - Langhans W AD - Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland. FAU - Meier, J J AU - Meier JJ AD - Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany. FAU - Nauck, M A AU - Nauck MA AD - Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universitat Bochum), Bochum, Germany. FAU - Perez-Tilve, D AU - Perez-Tilve D AD - Department of Internal Medicine, University of Cincinnati-College of Medicine, Cincinnati, OH, USA. FAU - Pocai, A AU - Pocai A AD - Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, USA. FAU - Reimann, F AU - Reimann F AD - Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK. FAU - Sandoval, D A AU - Sandoval DA AD - Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Schwartz, T W AU - Schwartz TW AD - Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark. FAU - Seeley, R J AU - Seeley RJ AD - Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Stemmer, K AU - Stemmer K AD - Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. FAU - Tang-Christensen, M AU - Tang-Christensen M AD - Obesity Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark. FAU - Woods, S C AU - Woods SC AD - Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA. FAU - DiMarchi, R D AU - DiMarchi RD AD - Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA. FAU - Tschop, M H AU - Tschop MH AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universitat Munchen, Munich, Germany; Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. LA - eng GR - MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00014/5/MRC_/Medical Research Council/United Kingdom GR - MR/K02115X/1/MRC_/Medical Research Council/United Kingdom GR - R01 DK021397/DK/NIDDK NIH HHS/United States GR - P30 DK020572/DK/NIDDK NIH HHS/United States GR - MC_UU_00014/3/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20190930 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Receptors, Glucagon) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Blood Glucose/metabolism MH - Diabetes Mellitus, Type 2/metabolism MH - Gastric Inhibitory Polypeptide/metabolism MH - Glucagon-Like Peptide 1/*metabolism/*pharmacology MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Glucose/metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin/metabolism MH - Insulin Secretion MH - Insulin-Secreting Cells/metabolism MH - Obesity/metabolism MH - Receptors, Glucagon/metabolism PMC - PMC6812410 OTO - NOTNLM OT - Diabetes OT - GLP-1 OT - Glucagon OT - Incretin OT - Insulin OT - Obesity EDAT- 2019/11/27 06:00 MHDA- 2020/06/24 06:00 PMCR- 2019/09/30 CRDT- 2019/11/27 06:00 PHST- 2019/07/17 00:00 [received] PHST- 2019/09/10 00:00 [revised] PHST- 2019/09/22 00:00 [accepted] PHST- 2019/11/27 06:00 [entrez] PHST- 2019/11/27 06:00 [pubmed] PHST- 2020/06/24 06:00 [medline] PHST- 2019/09/30 00:00 [pmc-release] AID - S2212-8778(19)30913-5 [pii] AID - 10.1016/j.molmet.2019.09.010 [doi] PST - ppublish SO - Mol Metab. 2019 Dec;30:72-130. doi: 10.1016/j.molmet.2019.09.010. Epub 2019 Sep 30. PMID- 31765661 OWN - NLM STAT- MEDLINE DCOM- 20200928 LR - 20200928 IS - 1095-6867 (Electronic) IS - 0018-506X (Linking) VI - 118 DP - 2020 Feb TI - A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice. PG - 104640 LID - S0018-506X(19)30447-7 [pii] LID - 10.1016/j.yhbeh.2019.104640 [doi] AB - Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Abeta(1)(-)(42)-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Abeta plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3beta levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Abeta and normalization of PI3K/AKT/GSK3beta cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. FAU - Han, Yu-Fei AU - Han YF AD - Guangzhou Kingmed Diagnostics, Guangzhou, PR China. FAU - Zhao, Fang AU - Zhao F AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. FAU - Yang, Guang-Zhao AU - Yang GZ AD - Department of Cardiovascular Medicine, The First Hospital of Shanxi Medical University, Taiyuan, PR China. FAU - Yuan, Li AU - Yuan L AD - Department of Physiology, Changzhi Medical College, Changzhi, PR China. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, PR China. FAU - Yang, Jun-Ting AU - Yang JT AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. FAU - Holscher, Christian AU - Holscher C AD - Neuroscience research group, Henan university of Chinese medicine, Zhengzhou, PR China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. Electronic address: jinshunqi2009@163.com. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. Electronic address: wmna@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191128 PL - United States TA - Horm Behav JT - Hormones and behavior JID - 0217764 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (D-Ser2-oxyntomodulin) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 0 (Oxyntomodulin) RN - 0 (Presenilin-1) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/drug therapy/genetics/*pathology MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Disease Models, Animal MH - Glucagon-Like Peptide 1/*agonists/pharmacology MH - Hippocampus/drug effects MH - Insulin/metabolism MH - Long-Term Potentiation/drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neuronal Plasticity/*drug effects MH - Neuroprotective Agents/pharmacology MH - Oxyntomodulin/*pharmacology/therapeutic use MH - Presenilin-1/genetics MH - Receptors, Glucagon/*agonists MH - Spatial Memory/*drug effects OTO - NOTNLM OT - (D-Ser2) oxyntomodulin OT - APP/PS1 transgenic mice OT - GLP-l receptor OT - Glucagon receptor OT - Learning and memory OT - Long-term potentiation OT - PI3K/AKT/GSK3beta EDAT- 2019/11/26 06:00 MHDA- 2020/09/29 06:00 CRDT- 2019/11/26 06:00 PHST- 2019/04/20 00:00 [received] PHST- 2019/11/16 00:00 [revised] PHST- 2019/11/16 00:00 [accepted] PHST- 2019/11/26 06:00 [pubmed] PHST- 2020/09/29 06:00 [medline] PHST- 2019/11/26 06:00 [entrez] AID - S0018-506X(19)30447-7 [pii] AID - 10.1016/j.yhbeh.2019.104640 [doi] PST - ppublish SO - Horm Behav. 2020 Feb;118:104640. doi: 10.1016/j.yhbeh.2019.104640. Epub 2019 Nov 28. PMID- 31730763 OWN - NLM STAT- MEDLINE DCOM- 20200727 LR - 20260127 IS - 1090-2430 (Electronic) IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 324 DP - 2020 Feb TI - Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury. PG - 113113 LID - S0014-4886(19)30260-2 [pii] LID - 10.1016/j.expneurol.2019.113113 [doi] AB - A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy. CI - Copyright (c) 2019. Published by Elsevier Inc. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: liyaz@mail.nih.gov. FAU - Glotfelty, Elliot J AU - Glotfelty EJ AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Namdar, Inbar AU - Namdar I AD - Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel. FAU - Tweedie, David AU - Tweedie D AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Olson, Lars AU - Olson L AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Hoffer, Barry J AU - Hoffer BJ AD - Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. FAU - DiMarchi, Richard D AU - DiMarchi RD AD - Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. FAU - Pick, Chagi G AU - Pick CG AD - Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: Greign@Grc.nia.nih.gov. LA - eng GR - R56 AG057028/AG/NIA NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20191112 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - E0399OZS9N (Cyclic AMP) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 9007-92-5 (Glucagon) RN - 3KX376GY7L (Glutamic Acid) RN - 0 (Neuroprotective Agents) RN - 0 (Nootropic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Animals MH - Brain Injuries, Traumatic/*drug therapy/psychology MH - Cell Line MH - Cyclic AMP/metabolism MH - Dose-Response Relationship, Drug MH - Gastric Inhibitory Polypeptide/*agonists MH - Glucagon/*agonists MH - Glutamic Acid/toxicity MH - Humans MH - Injections, Subcutaneous MH - Male MH - Mice MH - Mice, Inbred ICR MH - Neuroprotective Agents/administration & dosage/*therapeutic use MH - Nootropic Agents/administration & dosage/*therapeutic use MH - Oxidative Stress/drug effects MH - Space Perception/drug effects MH - Visual Perception/drug effects MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-1 Receptor PMC - PMC12451672 MID - NIHMS1751138 OTO - NOTNLM OT - Exendin-4 OT - Glucagon (Gcg) OT - Glucagon-like peptide-1 (GLP-1) OT - Glucose-dependent insulinotropic polypeptide (GIP) OT - Incretin OT - Incretin mimetic OT - Mild traumatic brain injury OT - Neuroprotective OT - Neurotrophic OT - Triagonist COIS- Author disclosure statement R.D.D. is a co-inventor on patent applications owned by Indiana University that pertain to the Triagonist peptide in this paper. All other authors declare no competing interests. EDAT- 2019/11/16 06:00 MHDA- 2020/07/28 06:00 PMCR- 2025/09/22 CRDT- 2019/11/16 06:00 PHST- 2019/10/07 00:00 [received] PHST- 2019/11/08 00:00 [revised] PHST- 2019/11/11 00:00 [accepted] PHST- 2019/11/16 06:00 [pubmed] PHST- 2020/07/28 06:00 [medline] PHST- 2019/11/16 06:00 [entrez] PHST- 2025/09/22 00:00 [pmc-release] AID - S0014-4886(19)30260-2 [pii] AID - 10.1016/j.expneurol.2019.113113 [doi] PST - ppublish SO - Exp Neurol. 2020 Feb;324:113113. doi: 10.1016/j.expneurol.2019.113113. Epub 2019 Nov 12. PMID- 31714795 OWN - NLM STAT- MEDLINE DCOM- 20200729 LR - 20200729 IS - 1522-1555 (Electronic) IS - 0193-1849 (Linking) VI - 318 IP - 5 DP - 2020 May 1 TI - Mitochondrial dysfunction plays a key role in the development of neurodegenerative diseases in diabetes. PG - E750-E764 LID - 10.1152/ajpendo.00179.2019 [doi] AB - Mitochondria have an essential function in cell survival due to their role in bioenergetics, reactive oxygen species generation, calcium buffering, and other metabolic activities. Mitochondrial dysfunctions are commonly found in neurodegenerative diseases (NDs), and diabetes is a risk factor for NDs. However, the role of mitochondria in diabetic neurodegeneration is still unclear. In the present study, we review the latest evidence on the role of mitochondrial dysfunctions in the development of diabetes-related NDs and the underlying molecular mechanisms. Hypoglycemic agents, especially metformin, have been proven to have neuroprotective effects in the treatment of diabetes, in which mitochondria could act as one of the underlying mechanisms. Other hypoglycemic agents, including thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, have gained more attention because of their beneficial effects on NDs, presumably by improving mitochondrial function. Our review highlights the notion that mitochondria could be a promising therapeutic target in the treatment of NDs in patients with diabetes. FAU - Cheng, Han AU - Cheng H AUID- ORCID: 0000-0002-8096-9561 AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. FAU - Gang, Xiaokun AU - Gang X AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. FAU - Liu, Yujia AU - Liu Y AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. FAU - Wang, Gang AU - Wang G AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. FAU - Zhao, Xue AU - Zhao X AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. FAU - Wang, Guixia AU - Wang G AD - Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20191112 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) SB - IM MH - Animals MH - Brain/*metabolism/pathology MH - Diabetes Mellitus, Type 2/*complications/drug therapy/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin Secretion/*physiology MH - Mitochondria/*metabolism/pathology MH - Neurodegenerative Diseases/*metabolism/pathology/prevention & control OTO - NOTNLM OT - diabetes OT - hypoglycemic agents OT - insulin signaling OT - mitochondria OT - neurodegenerative diseases EDAT- 2019/11/13 06:00 MHDA- 2020/07/30 06:00 CRDT- 2019/11/13 06:00 PHST- 2019/11/13 06:00 [pubmed] PHST- 2020/07/30 06:00 [medline] PHST- 2019/11/13 06:00 [entrez] AID - 10.1152/ajpendo.00179.2019 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E750-E764. doi: 10.1152/ajpendo.00179.2019. Epub 2019 Nov 12. PMID- 31680842 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 13 DP - 2019 TI - Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases. PG - 1112 LID - 10.3389/fnins.2019.01112 [doi] LID - 1112 AB - Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters' alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid beta peptide aggregation in Alzheimer's disease (AD) and dopamine (DA) levels in Parkinson's disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline. CI - Copyright (c) 2019 Grieco, Giorgi, Gentile, d'Erme, Morano, Maras and Filardi. FAU - Grieco, Maddalena AU - Grieco M AD - Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy. FAU - Giorgi, Alessandra AU - Giorgi A AD - Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy. FAU - Gentile, Maria Cristina AU - Gentile MC AD - Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy. FAU - d'Erme, Maria AU - d'Erme M AD - Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy. FAU - Morano, Susanna AU - Morano S AD - Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy. FAU - Maras, Bruno AU - Maras B AD - Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy. FAU - Filardi, Tiziana AU - Filardi T AD - Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy. LA - eng PT - Journal Article PT - Review DEP - 20191018 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC6813233 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonists OT - Parkinson's disease OT - glucagon-like peptide-1 OT - neurodegenerative diseases OT - type 2 diabetes EDAT- 2019/11/05 06:00 MHDA- 2019/11/05 06:01 PMCR- 2019/01/01 CRDT- 2019/11/05 06:00 PHST- 2019/06/14 00:00 [received] PHST- 2019/10/02 00:00 [accepted] PHST- 2019/11/05 06:00 [entrez] PHST- 2019/11/05 06:00 [pubmed] PHST- 2019/11/05 06:01 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2019.01112 [doi] PST - epublish SO - Front Neurosci. 2019 Oct 18;13:1112. doi: 10.3389/fnins.2019.01112. eCollection 2019. PMID- 31646466 OWN - NLM STAT- MEDLINE DCOM- 20200630 LR - 20260127 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 36 IP - 12 DP - 2019 Dec TI - Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine. PG - 3321-3339 LID - 10.1007/s12325-019-01126-x [doi] AB - Estimates suggest that there are currently 122.8 million adults 65-99 years of age living with diabetes, of whom 90-95% are diagnosed with type 2 diabetes (T2D). Over the past two decades, a greater understanding of the complex and multifactorial pathogenesis of T2D has resulted in the development and introduction of new-generation classes of glucose-lowering therapies, which are now extensively endorsed by prevailing guidelines and are increasingly being used worldwide. These newer agents may further assist in the effective pharmacological management of T2D through the provision of patient-centered care that acknowledges multimorbidity and is respectful of and responsive to individual patient preferences and barriers. Given these considerations, the therapeutic approach in older patients with T2D is complex, particularly in those who have functional dependence, frailty, dementia, or who are at end-of-life. It is currently too early to draw conclusions on the long-term use of newer glucose-lowering agents in this population, as their efficacy and safety in older adults remains largely unknown. In this review, we will discuss considerations for the use of glucose-lowering treatments in older adults, with particular focus on the use of basal insulin and glucagon-like peptide-1 receptor agonists, and the rationale for the use of combination therapy comprising these agents. Finally, we will review clinical data from studies of the fixed-ratio combination of insulin glargine and lixisenatide in older patients with T2D. FUNDING: Sanofi US, Inc. FAU - Handelsman, Yehuda AU - Handelsman Y AUID- ORCID: 0000-0001-7830-0247 AD - Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA, 91356, USA. yhandelsman@gmail.com. FAU - Muskiet, Marcel H A AU - Muskiet MHA AD - Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Location VUMC), 1081 HV, Amsterdam, The Netherlands. FAU - Meneilly, Graydon S AU - Meneilly GS AD - Department of Medicine, The University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z1M9, Canada. LA - eng SI - figshare/10.6084/m9.figshare.9959780 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20191023 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 2ZM8CX04RZ (Insulin Glargine) RN - 0 (Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) EIN - Adv Ther. 2020 Feb;37(2):973. doi: 10.1007/s12325-019-01185-0. PMID: 31873867 MH - Activities of Daily Living MH - Aged MH - Aged, 80 and over MH - Aging MH - Diabetes Mellitus, Type 2/*drug therapy MH - Frailty/epidemiology MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Insulin/therapeutic use MH - Insulin Glargine/administration & dosage/adverse effects/*therapeutic use MH - Peptides/administration & dosage/adverse effects/*therapeutic use MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-2 Receptor PMC - PMC6860469 OTO - NOTNLM OT - Basal insulin OT - Fixed-ratio combination OT - GLP-1 OT - Glucagon-like peptide-1 receptor agonist OT - Older adults OT - Type 2 diabetes EDAT- 2019/10/28 06:00 MHDA- 2020/07/01 06:00 PMCR- 2019/10/23 CRDT- 2019/10/25 06:00 PHST- 2019/07/18 00:00 [received] PHST- 2019/10/28 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2019/10/25 06:00 [entrez] PHST- 2019/10/23 00:00 [pmc-release] AID - 10.1007/s12325-019-01126-x [pii] AID - 1126 [pii] AID - 10.1007/s12325-019-01126-x [doi] PST - ppublish SO - Adv Ther. 2019 Dec;36(12):3321-3339. doi: 10.1007/s12325-019-01126-x. Epub 2019 Oct 23. PMID- 31628935 OWN - NLM STAT- MEDLINE DCOM- 20210106 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 162 DP - 2020 Jan 1 TI - Neuroprotective and restorative properties of the GLP-1/GIP dual agonist DA-JC1 compared with a GLP-1 single agonist in Alzheimer's disease. PG - 107813 LID - S0028-3908(19)30380-6 [pii] LID - 10.1016/j.neuropharm.2019.107813 [doi] AB - The sister incretins glucagon-like peptide-1 (GLP-1) and glucagon dependent insulinotropic polypeptide (GIP) are growth factors responsible for re-sensitizing insulin signalling. Interestingly, their analogues, originally developed to treat type 2 diabetes (T2D), have demonstrated a range of neuroprotective and neurorestorative properties. Novel peptide GLP-1/GIP dual agonist (DA) shows good effects in diabetic patients, superior to the effects demonstrated by single GIP or GLP-1 mimetics. Furthermore, novel DAs have shown considerable neuroprotection in neurodegenerative models. Here, we investigated the neuroprotective and restorative involvement of the DA DA-JC1 and liraglutide (Lg), a single GLP-1 receptor analogue, in vitro using human neuroblastoma (SH-SY5Y) against oxidative stress induced by oxygen peroxide (H(2)O(2)), and in vivo, in a mouse model of Alzheimer's disease (AD), APP/PS1. First, we determined the ideal concentration of the peptides and demonstrated that DA-JC1 protects cells against oxidative stress more than Lg, improving cell viability, normalizing reactive oxygen species (ROS) and attenuating DNA damage generated by H(2)O(2). Moreover, in 10-to-12-months-old APP/PS1 animals treated for 4 weeks, both Lg and DA-JC1 were very efficient in stimulating neurogenesis and reducing some important hallmarks of AD, but DA-JC1 was better than Lg in attenuating crucial neuroinflammatory markers, especially reactive astrocyte, in both wild-type (WT) and APP/PS1 hippocampal regions. Altogether, this study suggests an interactive role of GLP-1 and GIP receptors, enhancing the efficiency of single GLP-1 analogues, especially in attenuating oxidative stress and neuroinflammation. We confirm that combining GLP-1 and GIP results in a variety of beneficial effects, providing key evidences for the development of a promising therapeutic strategy for AD. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Salles, Geisa Nogueira AU - Salles GN AD - Laboratory of Dynamics of Cellular Compartments, Instituto de Pesquisa e Desenvolvimento (IP&D), Universidade Do Vale Do Paraiba, Av. Shishima Hifumi, 2911, 12244-000, Sao Jose Dos Campos, SP, Brazil; Departament of Biochemestry, Laboratory of Neurobiology, Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 669, 04039-032, Sao Paulo, SP, Brazil. FAU - Calio, Michele Longoni AU - Calio ML AD - Departament of Biochemestry, Laboratory of Neurobiology, Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 669, 04039-032, Sao Paulo, SP, Brazil. FAU - Holscher, Christian AU - Holscher C AD - Research and Experimental Center, Henan University of Chinese Medicine, 450000, Zhengzhou City, Henan province, China. FAU - Pacheco-Soares, Cristina AU - Pacheco-Soares C AD - Laboratory of Dynamics of Cellular Compartments, Instituto de Pesquisa e Desenvolvimento (IP&D), Universidade Do Vale Do Paraiba, Av. Shishima Hifumi, 2911, 12244-000, Sao Jose Dos Campos, SP, Brazil. FAU - Porcionatto, Marimelia AU - Porcionatto M AD - Departament of Biochemestry, Laboratory of Neurobiology, Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 669, 04039-032, Sao Paulo, SP, Brazil. FAU - Lobo, Anderson Oliveira AU - Lobo AO AD - LIMAV - Interdisciplinary Laboratory for Advanced Materials, Materials Science & Engineering Graduate Program, UFPI - Federal University of Piaui, 64049-550, Teresina, PI, Brazil. Electronic address: lobo@ufpi.edu.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191016 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Presenilin-1) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 839I73S42A (Liraglutide) RN - BBX060AN9V (Hydrogen Peroxide) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/genetics/*metabolism MH - Amyloid beta-Peptides/drug effects/metabolism MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Brain/*drug effects/metabolism/pathology MH - Cell Line, Tumor MH - Cell Survival MH - DNA Damage/*drug effects MH - Hippocampus/drug effects/metabolism/pathology MH - Humans MH - Hydrogen Peroxide MH - In Vitro Techniques MH - Incretins/*pharmacology MH - Lateral Ventricles/drug effects/metabolism/pathology MH - Liraglutide/*pharmacology MH - Mice MH - Mice, Transgenic MH - Neurons/*drug effects/metabolism/pathology MH - Neuroprotective Agents/*pharmacology MH - Oxidative Stress/drug effects MH - Peptides/pharmacology MH - Presenilin-1/genetics MH - Receptors, Gastrointestinal Hormone/*agonists MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1/GIP dual agonist OT - Incretins OT - Liraglutide EDAT- 2019/10/20 06:00 MHDA- 2021/01/07 06:00 CRDT- 2019/10/20 06:00 PHST- 2019/04/22 00:00 [received] PHST- 2019/09/25 00:00 [revised] PHST- 2019/10/14 00:00 [accepted] PHST- 2019/10/20 06:00 [pubmed] PHST- 2021/01/07 06:00 [medline] PHST- 2019/10/20 06:00 [entrez] AID - S0028-3908(19)30380-6 [pii] AID - 10.1016/j.neuropharm.2019.107813 [doi] PST - ppublish SO - Neuropharmacology. 2020 Jan 1;162:107813. doi: 10.1016/j.neuropharm.2019.107813. Epub 2019 Oct 16. PMID- 31614723 OWN - NLM STAT- MEDLINE DCOM- 20200219 LR - 20200219 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 20 DP - 2019 Oct 12 TI - Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1. LID - 10.3390/ijms20205064 [doi] LID - 5064 AB - Post-translational modulation of peptidylprolyl isomerase Pin1 might link impaired glucose metabolism and neurodegeneration, being Pin1 effectors target for the glucagon-Like-Peptide1 analog liraglutide. We tested the hypotheses in Pin1 silenced cells (SH-SY5Y) treated with 2-deoxy-d-glucose (2DG) and methylglyoxal (MG), stressors causing altered glucose trafficking, glucotoxicity and protein glycation. Rescue by liraglutide was investigated. Pin1 silencing caused increased levels of reactive oxygen species, upregulated energy metabolism as suggested by raised levels of total ATP content and mRNA of SIRT1, PGC1alpha, NRF1; enhanced mitochondrial fission events as supported by raised protein expression of FIS1 and DRP1. 2DG and MG reduced significantly cell viability in all the cell lines. In Pin1 KD clones, 2DG exacerbated altered mitochondrial dynamics causing higher rate of fission events. Liraglutide influenced insulin signaling pathway (GSK3b/Akt); improved cell viability also in cells treated with 2DG; but it did not revert mitochondrial dysfunction in Pin1 KD model. In cells treated with MG, liraglutide enhanced cell viability, reduced ROS levels and cell death (AnnexinV/PI); and trended to reduce anti-apoptotic signals (BAX, BCL2, CASP3). Pin1 silencing mimics neuronal metabolic impairment of patients with impaired glucose metabolism and neurodegeneration. Liraglutide rescues to some extent cellular dysfunctions induced by Pin1 silencing. FAU - Bianchi, Marzia AU - Bianchi M AD - Research Area for Multi-factorial Diseases, Obesity and Diabetes, Bambino Gesu Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy. marzia.bianchi@opbg.net. FAU - D'Oria, Valentina AU - D'Oria V AD - Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesu' Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy. valentina.doria@opbg.net. FAU - Braghini, Maria Rita AU - Braghini MR AD - Molecular Genetics of Complex Phenotypes Research Unit, Bambino Gesu Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy. mariarita.braghini@opbg.net. FAU - Petrini, Stefania AU - Petrini S AUID- ORCID: 0000-0002-3249-0003 AD - Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesu' Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy. stefania.petrini@opbg.net. FAU - Manco, Melania AU - Manco M AUID- ORCID: 0000-0002-6581-975X AD - Research Area for Multi-factorial Diseases, Obesity and Diabetes, Bambino Gesu Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy. melania.manco@opbg.net. LA - eng GR - RC201802P004271 and RC2019.1.4_MANCO1.5./Ministero Italiano della Salute/ PT - Journal Article DEP - 20191012 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Insulin) RN - 0 (NIMA-Interacting Peptidylprolyl Isomerase) RN - 0 (NRF1 protein, human) RN - 0 (Neuroprotective Agents) RN - 0 (Nuclear Respiratory Factor 1) RN - 0 (PPARGC1A protein, human) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Reactive Oxygen Species) RN - 722KLD7415 (Pyruvaldehyde) RN - 839I73S42A (Liraglutide) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - 9G2MP84A8W (Deoxyglucose) RN - EC 3.5.1.- (SIRT1 protein, human) RN - EC 3.5.1.- (Sirtuin 1) RN - EC 5.2.1.8 (PIN1 protein, human) SB - IM MH - Adenosine Triphosphate/metabolism MH - Apoptosis MH - Cell Line, Tumor MH - Deoxyglucose/toxicity MH - Gene Silencing MH - Humans MH - Insulin/metabolism MH - Liraglutide/*pharmacology MH - NIMA-Interacting Peptidylprolyl Isomerase/*genetics/metabolism MH - Neurons/drug effects/metabolism MH - Neuroprotective Agents/*pharmacology MH - Nuclear Respiratory Factor 1/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism MH - Pyruvaldehyde/toxicity MH - Reactive Oxygen Species/metabolism MH - Sirtuin 1/genetics/metabolism PMC - PMC6829573 OTO - NOTNLM OT - 2-deoxy-d-glucose OT - Alzheimer's disease OT - Pin1 OT - brain glucotoxicity OT - brain insulin resistance OT - liraglutide OT - methylglyoxal OT - type 2 diabetes OT - type 3 diabetes COIS- The authors declare they have no conflict of interest. EDAT- 2019/10/17 06:00 MHDA- 2020/02/20 06:00 PMCR- 2019/10/01 CRDT- 2019/10/17 06:00 PHST- 2019/09/30 00:00 [received] PHST- 2019/10/11 00:00 [accepted] PHST- 2019/10/17 06:00 [entrez] PHST- 2019/10/17 06:00 [pubmed] PHST- 2020/02/20 06:00 [medline] PHST- 2019/10/01 00:00 [pmc-release] AID - ijms20205064 [pii] AID - ijms-20-05064 [pii] AID - 10.3390/ijms20205064 [doi] PST - epublish SO - Int J Mol Sci. 2019 Oct 12;20(20):5064. doi: 10.3390/ijms20205064. PMID- 31565780 OWN - NLM STAT- MEDLINE DCOM- 20200327 LR - 20201001 IS - 1179-1969 (Electronic) IS - 1170-229X (Print) IS - 1170-229X (Linking) VI - 36 IP - 12 DP - 2019 Dec TI - Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus. PG - 1083-1096 LID - 10.1007/s40266-019-00706-4 [doi] AB - The management of type 2 diabetes mellitus in older adults requires a comprehensive understanding of the relationship between the disease (medical) and the functional, psychological/cognitive, and social geriatric domains, to individualize both glycemic targets and therapeutic approaches. Prevention of hypoglycemia is a major priority that should be addressed as soon as its presence or risk is detected, adjusting the target and therapeutics accordingly. Nonetheless, treatment intensification should not be neglected when applicable, consistent with recommendations from organizations such as the American Geriatrics Society and the American Diabetes Association, to reduce not only long-term macrovascular and microvascular complications (individualization), but also short-term complications from hyperglycemia (polyuria, volume depletion, urinary incontinence). Such complications can negatively impact the physical and cognitive function of older adults, worsen their quality of life, and additionally affect their families and society. We emphasize individualization, utilizing the multiple classes of antihyperglycemic agents available. Metformin remains as first-line therapy, and additional agents offer advantages and disadvantages that ought to be considered when developing a patient-centric plan of care. For selected cases, injectable therapies such as long-acting basal insulin analogs and glucagon-like peptide-1 receptor agonists can offer advantages to counter hypoglycemia risk, patient-related barriers, and clinical inertia. Furthermore, some injectable agents could potentially simplify regimens while providing safe and effective glycemic control. In this review, we discuss the use of injectable therapies for selected community-dwelling older adults, barriers to transition to injectable therapy, and measures aimed at removing these barriers and assisting physicians and their teams to transition older patients to injectable therapies when appropriate. FAU - Valencia, Willy M AU - Valencia WM AD - Geriatrics Research, Education and Clinical Center (GRECC), Miami VA Healthcare System, 1201 NW 16th St., 11 GRC, CLC 207 A2, Miami, FL, 33125, USA. willy.valencia-rodrigo@va.gov. AD - Department of Humanities, Health and Society, Florida International University Herbert Wertheim College of Medicine, Miami, FL, 33199, USA. willy.valencia-rodrigo@va.gov. AD - Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. willy.valencia-rodrigo@va.gov. FAU - Florez, Hermes J AU - Florez HJ AD - Geriatrics Research, Education and Clinical Center (GRECC), Miami VA Healthcare System, 1201 NW 16th St., 11 GRC, CLC 207 A2, Miami, FL, 33125, USA. AD - Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. FAU - Palacio, Ana M AU - Palacio AM AD - Geriatrics Research, Education and Clinical Center (GRECC), Miami VA Healthcare System, 1201 NW 16th St., 11 GRC, CLC 207 A2, Miami, FL, 33125, USA. AD - Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. LA - eng PT - Journal Article PT - Review PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) SB - IM EIN - Drugs Aging. 2020 Oct;37(10):777. doi: 10.1007/s40266-020-00795-6. PMID: 32909196 MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Blood Glucose/metabolism MH - Diabetes Mellitus, Type 2/*blood/drug therapy MH - Humans MH - Hypoglycemia/chemically induced/*prevention & control MH - Hypoglycemic Agents/*administration & dosage/adverse effects MH - Independent Living MH - Quality of Life PMC - PMC7481154 COIS- Willy M. Valencia and Ana M. Palacio have nothing to declare. Hermes J. Florez is a consultant (in a scientific advisory capacity) for the SENIOR study. EDAT- 2019/10/01 06:00 MHDA- 2020/03/28 06:00 PMCR- 2020/09/08 CRDT- 2019/10/01 06:00 PHST- 2019/10/01 06:00 [pubmed] PHST- 2020/03/28 06:00 [medline] PHST- 2019/10/01 06:00 [entrez] PHST- 2020/09/08 00:00 [pmc-release] AID - 10.1007/s40266-019-00706-4 [pii] AID - 706 [pii] AID - 10.1007/s40266-019-00706-4 [doi] PST - ppublish SO - Drugs Aging. 2019 Dec;36(12):1083-1096. doi: 10.1007/s40266-019-00706-4. PMID- 31518224 OWN - NLM STAT- MEDLINE DCOM- 20201006 LR - 20250530 IS - 1875-5828 (Electronic) IS - 1567-2050 (Print) IS - 1567-2050 (Linking) VI - 16 IP - 8 DP - 2019 TI - A Pilot Study of Exenatide Actions in Alzheimer's Disease. PG - 741-752 LID - 10.2174/1567205016666190913155950 [doi] AB - BACKGROUND: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD). OBJECTIVE: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD. METHOD: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone. RESULTS: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Abeta42 in EVs. CONCLUSION: The positive finding of lower EV Abeta42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Abeta42 in and of itself may not improve cognitive outcomes in AD. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Mullins, Roger J AU - Mullins RJ AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Mustapic, Maja AU - Mustapic M AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Chia, Chee W AU - Chia CW AD - Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Carlson, Olga AU - Carlson O AD - Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Gulyani, Seema AU - Gulyani S AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Tran, Joyce AU - Tran J AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Mattson, Mark P AU - Mattson MP AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Resnick, Susan AU - Resnick S AD - Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Egan, Josephine M AU - Egan JM AD - Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. FAU - Kapogiannis, Dimitrios AU - Kapogiannis D AD - Laboratory of Neurosciences, National Institute on Aging/National Institutes of Health (NIA/NIH), 3001 S. Hanover St, NM531, Baltimore, MD, 21225, United States. LA - eng SI - ClinicalTrials.gov/NCT01255163 GR - P30 AG066507/AG/NIA NIH HHS/United States GR - Z01 AG000423/ImNIH/Intramural NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States GR - ZIA AG000975/ImNIH/Intramural NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't PL - United Arab Emirates TA - Curr Alzheimer Res JT - Current Alzheimer research JID - 101208441 RN - 0 (Biomarkers) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Aged MH - Alzheimer Disease/diagnostic imaging/*drug therapy/metabolism/psychology MH - Biomarkers/blood/cerebrospinal fluid MH - Brain/diagnostic imaging/drug effects MH - Cognitive Dysfunction/diagnostic imaging/drug therapy/metabolism/psychology MH - Double-Blind Method MH - Exenatide/adverse effects/*therapeutic use MH - Female MH - Glucagon-Like Peptide 1/agonists MH - Humans MH - Male MH - Neuroprotective Agents/adverse effects/*therapeutic use MH - Neuropsychological Tests MH - Pilot Projects PMC - PMC7476877 MID - NIHMS1620777 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 agonist OT - diabetes OT - exenatide OT - memory OT - placebo. COIS- CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. EDAT- 2019/09/14 06:00 MHDA- 2020/10/07 06:00 PMCR- 2020/09/08 CRDT- 2019/09/14 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2019/07/10 00:00 [revised] PHST- 2019/08/16 00:00 [accepted] PHST- 2019/09/14 06:00 [pubmed] PHST- 2020/10/07 06:00 [medline] PHST- 2019/09/14 06:00 [entrez] PHST- 2020/09/08 00:00 [pmc-release] AID - CAR-EPUB-100792 [pii] AID - 10.2174/1567205016666190913155950 [doi] PST - ppublish SO - Curr Alzheimer Res. 2019;16(8):741-752. doi: 10.2174/1567205016666190913155950. PMID- 31474827 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 13 DP - 2019 TI - The Relevance of Insulin Action in the Dopaminergic System. PG - 868 LID - 10.3389/fnins.2019.00868 [doi] LID - 868 AB - The advances in medicine, together with lifestyle modifications, led to a rising life expectancy. Unfortunately, however, aging is accompanied by an alarming boost of age-associated chronic pathologies, including neurodegenerative and metabolic diseases. Interestingly, a non-negligible interplay between alterations of glucose homeostasis and brain dysfunction has clearly emerged. In particular, epidemiological studies have pointed out a possible association between Type 2 Diabetes (T2D) and Parkinson's Disease (PD). Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. This review aims to provide an exhaustive analysis of the most recent evidences supporting the key role of insulin resistance in PD pathogenesis. It will focus on the relevance of insulin in the brain, working as pro-survival neurotrophic factor and as a master regulator of neuronal mitochondrial function and oxidative stress. Insulin action as a modulator of dopamine signaling and of alpha-synuclein degradation will be described in details, too. The intriguing idea that shared deregulated pathogenic pathways represent a link between PD and insulin resistance has clinical and therapeutic implications. Thus, ongoing studies about the promising healing potential of common antidiabetic drugs such as metformin, exenatide, DPP IV inhibitors, thiazolidinediones and bromocriptine, will be summarized and the rationale for their use to decelerate neurodegeneration will be critically assessed. FAU - Fiory, Francesca AU - Fiory F AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Perruolo, Giuseppe AU - Perruolo G AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Cimmino, Ilaria AU - Cimmino I AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Cabaro, Serena AU - Cabaro S AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Pignalosa, Francesca Chiara AU - Pignalosa FC AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Miele, Claudia AU - Miele C AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Beguinot, Francesco AU - Beguinot F AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Formisano, Pietro AU - Formisano P AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. FAU - Oriente, Francesco AU - Oriente F AD - Department of Translational Medicine, University of Naples Federico II, Naples, Italy. AD - URT "Genomic of Diabetes," Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. LA - eng PT - Journal Article PT - Review DEP - 20190816 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC6706784 OTO - NOTNLM OT - Parkinson's disease OT - dopamine OT - insulin resistance OT - neurodegeneration OT - type 2 diabetes mellitus EDAT- 2019/09/03 06:00 MHDA- 2019/09/03 06:01 PMCR- 2019/01/01 CRDT- 2019/09/03 06:00 PHST- 2019/02/27 00:00 [received] PHST- 2019/08/02 00:00 [accepted] PHST- 2019/09/03 06:00 [entrez] PHST- 2019/09/03 06:00 [pubmed] PHST- 2019/09/03 06:01 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2019.00868 [doi] PST - epublish SO - Front Neurosci. 2019 Aug 16;13:868. doi: 10.3389/fnins.2019.00868. eCollection 2019. PMID- 31437816 OWN - NLM STAT- MEDLINE DCOM- 20191129 LR - 20220411 IS - 1479-683X (Electronic) IS - 0804-4643 (Linking) VI - 181 IP - 5 DP - 2019 Nov TI - Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case-control study. PG - 499-507 LID - EJE-19-0259 [pii] LID - 10.1530/EJE-19-0259 [doi] AB - OBJECTIVE: Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia. DESIGN: We performed a nested case-control study within a cohort of all 176 250 patients registered with type 2 diabetes in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (insulin, metformin, sulfonylurea and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose). METHODS: Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders. RESULTS: Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89-0.99), 0.80 (95% CI 0.74-0.88), 0.58 (95% CI: 0.50-0.67), and 0.58 (95% CI: 0.42-0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment. CONCLUSION: Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes. FAU - Wium-Andersen, Ida Kim AU - Wium-Andersen IK AD - Psychiatric Center Copenhagen, Copenhagen O, Denmark. FAU - Osler, Merete AU - Osler M AD - Center for Clinical Research and Prevention, Frederiksberg Hospital, Frederiksberg, Denmark. AD - Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark. FAU - Jorgensen, Martin Balslev AU - Jorgensen MB AD - Psychiatric Center Copenhagen, Copenhagen O, Denmark. FAU - Rungby, Jorgen AU - Rungby J AD - Department of Endocrinology and Copenhagen Center for Translational Research, Bispebjerg Hospital, Copenhagen NV, Denmark. FAU - Wium-Andersen, Marie Kim AU - Wium-Andersen MK AD - Center for Clinical Research and Prevention, Frederiksberg Hospital, Frederiksberg, Denmark. LA - eng PT - Journal Article PL - England TA - Eur J Endocrinol JT - European journal of endocrinology JID - 9423848 RN - 0 (Hypoglycemic Agents) SB - IM MH - Aged MH - Case-Control Studies MH - Cohort Studies MH - Comorbidity MH - Dementia/*epidemiology/etiology/psychology MH - Denmark/epidemiology MH - Diabetes Complications/*epidemiology/psychology MH - Diabetes Mellitus, Type 2/*complications/drug therapy MH - Drug Therapy, Combination MH - Female MH - Follow-Up Studies MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Middle Aged MH - Socioeconomic Factors EDAT- 2019/08/23 06:00 MHDA- 2019/11/30 06:00 CRDT- 2019/08/23 06:00 PHST- 2019/04/07 00:00 [received] PHST- 2019/07/18 00:00 [accepted] PHST- 2019/08/23 06:00 [pubmed] PHST- 2019/11/30 06:00 [medline] PHST- 2019/08/23 06:00 [entrez] AID - EJE-19-0259 [pii] AID - 10.1530/EJE-19-0259 [doi] PST - ppublish SO - Eur J Endocrinol. 2019 Nov;181(5):499-507. doi: 10.1530/EJE-19-0259. PMID- 31434198 OWN - NLM STAT- MEDLINE DCOM- 20200121 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 16 DP - 2019 Aug 20 TI - Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases. LID - 10.3390/ijms20164052 [doi] LID - 4052 AB - Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin's administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-alpha, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1(bright). Significant reduction in Abeta42 level has been associated with the use of linagliptin implying potential application in Alzheimer's disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron's survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1alpha/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1alpha/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases. FAU - Wicinski, Michal AU - Wicinski M AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Gorski, Karol AU - Gorski K AUID- ORCID: 0000-0001-5732-9403 AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Walczak, Maciej AU - Walczak M AUID- ORCID: 0000-0003-4660-1330 AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. maciej.walczak5@hotmail.com. FAU - Wodkiewicz, Eryk AU - Wodkiewicz E AUID- ORCID: 0000-0002-2834-3414 AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Slupski, Maciej AU - Slupski M AD - Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Pawlak-Osinska, Katarzyna AU - Pawlak-Osinska K AD - Department of Pathophysiology of Hearing and Balance System, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Malinowski, Bartosz AU - Malinowski B AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. LA - eng PT - Journal Article PT - Review DEP - 20190820 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Neuroprotective Agents) RN - 0 (Tumor Necrosis Factor-alpha) RN - 31C4KY9ESH (Nitric Oxide) RN - 3X29ZEJ4R2 (Linagliptin) RN - EC 3.5.1.- (Sirtuin 1) SB - IM MH - Animals MH - Brain Ischemia/*drug therapy MH - Cell Proliferation/drug effects MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Linagliptin/*therapeutic use MH - Male MH - Neurodegenerative Diseases/*drug therapy MH - Neuroprotective Agents/*therapeutic use MH - Nitric Oxide/metabolism MH - Sirtuin 1/metabolism MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC6719127 OTO - NOTNLM OT - inflammation OT - linagliptin OT - neurodegeneration OT - pathways OT - pharmacology COIS- The authors declare no conflict of interest EDAT- 2019/08/23 06:00 MHDA- 2020/01/22 06:00 PMCR- 2019/08/01 CRDT- 2019/08/23 06:00 PHST- 2019/07/19 00:00 [received] PHST- 2019/08/16 00:00 [revised] PHST- 2019/08/17 00:00 [accepted] PHST- 2019/08/23 06:00 [entrez] PHST- 2019/08/23 06:00 [pubmed] PHST- 2020/01/22 06:00 [medline] PHST- 2019/08/01 00:00 [pmc-release] AID - ijms20164052 [pii] AID - ijms-20-04052 [pii] AID - 10.3390/ijms20164052 [doi] PST - epublish SO - Int J Mol Sci. 2019 Aug 20;20(16):4052. doi: 10.3390/ijms20164052. PMID- 31399442 OWN - NLM STAT- MEDLINE DCOM- 20200625 LR - 20200625 IS - 1935-5548 (Electronic) IS - 0149-5992 (Linking) VI - 42 IP - 10 DP - 2019 Oct TI - Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial. PG - 1930-1938 LID - 10.2337/dc19-0783 [doi] AB - OBJECTIVE: Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease. RESEARCH DESIGN AND METHODS: The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score /=24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed. RESULTS: Of the 6,979 participants in CARMELINA, CARMELINA-COG included 1,545 (mean +/- SD age, 68 +/- 8 years; MMSE, 28.3 +/- 1.7; estimated glomerular filtration rate, 52 +/- 23 mL/min/1.73 m(2); and HbA(1c), 7.8 +/- 0.9% [61.4 +/- 10.1 mmol/mol]). Over a median treatment duration of 2.5 years, accelerated cognitive decline occurred in 28.4% (linagliptin) vs. 29.3% (placebo) (odds ratio 0.96 [95% CI 0.77, 1.19]). Consistent effects were observed across subgroups by baseline characteristics. Absolute cognitive performance changes were also similar between treatment groups. CONCLUSIONS: In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years. CI - (c) 2019 by the American Diabetes Association. FAU - Biessels, Geert Jan AU - Biessels GJ AUID- ORCID: 0000-0001-6862-2496 AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands g.j.biessels@umcutrecht.nl. FAU - Verhagen, Chloe AU - Verhagen C AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - Janssen, Jolien AU - Janssen J AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. AD - Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - van den Berg, Esther AU - van den Berg E AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. AD - Department of Neurology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. FAU - Zinman, Bernard AU - Zinman B AUID- ORCID: 0000-0002-0041-1876 AD - Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Rosenstock, Julio AU - Rosenstock J AUID- ORCID: 0000-0001-8324-3275 AD - Dallas Diabetes Research Center, Dallas, TX. FAU - George, Jyothis T AU - George JT AD - Therapeutic Area Cardiometabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. FAU - Passera, Anna AU - Passera A AD - HMS Analytical Software GmbH, Sulzbach, Germany. FAU - Schnaidt, Sven AU - Schnaidt S AD - Biostatistics and Data Sciences, Boehringer Ingelheim, Biberach, Germany. FAU - Johansen, Odd Erik AU - Johansen OE AUID- ORCID: 0000-0003-2470-0530 CN - CARMELINA Investigators LA - eng SI - ClinicalTrials.gov/NCT01897532 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190809 PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - 0 (Blood Glucose) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Incretins) RN - 3X29ZEJ4R2 (Linagliptin) SB - IM MH - Aged MH - Blood Glucose/metabolism MH - Cardiovascular Diseases/complications/*drug therapy/psychology MH - Cognition/*drug effects MH - Cognitive Dysfunction/etiology/*prevention & control MH - Comorbidity MH - Diabetes Mellitus, Type 2/complications/*drug therapy/psychology MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Female MH - Glomerular Filtration Rate MH - Humans MH - Incretins/therapeutic use MH - Kidney/physiopathology MH - Kidney Diseases/complications/*drug therapy/psychology MH - Linagliptin/*therapeutic use MH - Male MH - Middle Aged MH - Treatment Outcome EDAT- 2019/08/11 06:00 MHDA- 2020/06/26 06:00 CRDT- 2019/08/11 06:00 PHST- 2019/04/20 00:00 [received] PHST- 2019/07/15 00:00 [accepted] PHST- 2019/08/11 06:00 [pubmed] PHST- 2020/06/26 06:00 [medline] PHST- 2019/08/11 06:00 [entrez] AID - dc19-0783 [pii] AID - 10.2337/dc19-0783 [doi] PST - ppublish SO - Diabetes Care. 2019 Oct;42(10):1930-1938. doi: 10.2337/dc19-0783. Epub 2019 Aug 9. PMID- 31396586 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20250530 IS - 2575-9108 (Electronic) IS - 2575-9108 (Linking) VI - 2 IP - 2 DP - 2019 Apr 12 TI - Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury. PG - 66-91 LID - 10.1021/acsptsci.9b00003 [doi] AB - Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI. FAU - Glotfelty, Elliot J AU - Glotfelty EJ AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Delgado, Thomas AU - Delgado T AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Tovar-Y-Romo, Luis B AU - Tovar-Y-Romo LB AD - Division of Neuroscience, Institute of Cellular Physiology, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. FAU - Luo, Yu AU - Luo Y AD - Department of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45221, USA. FAU - Hoffer, Barry AU - Hoffer B AD - Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. FAU - Olson, Lars AU - Olson L AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Karlsson, Tobias AU - Karlsson T AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Mattson, Mark P AU - Mattson MP AD - Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Harvey, Brandon AU - Harvey B AD - Molecular Mechanisms of Cellular Stress and Inflammation Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Tweedie, David AU - Tweedie D AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. LA - eng GR - R01 NS091213/NS/NINDS NIH HHS/United States GR - R01 NS094152/NS/NINDS NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States GR - Z99 DA999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article DEP - 20190211 PL - United States TA - ACS Pharmacol Transl Sci JT - ACS pharmacology & translational science JID - 101721411 PMC - PMC6687335 MID - NIHMS1015186 OTO - NOTNLM OT - GIP OT - GLP-1 OT - Gcg OT - TBI OT - brain trauma OT - exendin-4 OT - glucagon OT - incretins OT - microglia OT - neurodegeneration COIS- Conflicts of Interest: All other coauthors declare no conflicts of interest. EDAT- 2019/08/10 06:00 MHDA- 2019/08/10 06:01 CRDT- 2019/08/10 06:00 PHST- 2019/08/10 06:00 [entrez] PHST- 2019/08/10 06:00 [pubmed] PHST- 2019/08/10 06:01 [medline] AID - 10.1021/acsptsci.9b00003 [doi] PST - ppublish SO - ACS Pharmacol Transl Sci. 2019 Apr 12;2(2):66-91. doi: 10.1021/acsptsci.9b00003. Epub 2019 Feb 11. PMID- 31359797 OWN - NLM STAT- MEDLINE DCOM- 20200907 LR - 20200907 IS - 1744-8360 (Electronic) IS - 1473-7175 (Linking) VI - 19 IP - 11 DP - 2019 Nov TI - Current and future clinical utilities of Parkinson's disease and dementia biomarkers: can they help us conquer the disease? PG - 1149-1161 LID - 10.1080/14737175.2019.1649141 [doi] AB - Introduction: Biomarkers for Parkinson's disease and Alzheimer's disease are essential, not only for disease detection, but also provide insight into potential disease relationships leading to better detection and therapy. As metabolic disease is known to increase neurodegeneration risk, such mechanisms may reveal such novel targets for PD and AD. Moreover, metabolic disease, including insulin resistance, offer novel biomarker and therapeutic targets for neurodegeneration, including glucagon-like-peptide-1, dipeptidyl peptidase-4 and adiponectin. Areas covered: The authors reviewed PubMed-listed research articles, including ours, on a number of putative PD, AD and neurodegenerative disease targets of interest, focusing on the relevance of metabolic syndrome and insulin resistance mechanisms, especially type II diabetes, to PD and AD. We highlighted various issues surrounding the current state of knowledge and propose avenues for future development. Expert opinion: Biomarkers for PD and AD are indispensable for disease diagnosis, prognostication and tracking disease severity, especially for clinical therapy trials. Although no validated PD biomarkers exist, their potential utility has generated tremendous interest. Combining insulin-resistance biomarkers with other core biomarkers or using them to predict non-motor symptoms of PD may be clinically useful. Collectively, although still unclear, potential biomarkers and therapies can aid in shedding new light on novel aspects of both PD and AD. FAU - Ho, Gilbert AU - Ho G AD - PCND Neuroscience Research Institute , Poway , CA , USA. FAU - Takamatsu, Yoshiki AU - Takamatsu Y AD - Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan. FAU - Waragai, Masaaki AU - Waragai M AD - Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan. FAU - Wada, Ryoko AU - Wada R AD - Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan. FAU - Sugama, Shuei AU - Sugama S AD - Department of Physiology, Nippon Medical School , Tokyo , Japan. FAU - Takenouchi, Takato AU - Takenouchi T AD - Institute of Agrobiological Sciences, National Agriculture and Food Research Organization , Tsukuba , Japan. FAU - Fujita, Masayo AU - Fujita M AD - Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan. FAU - Ali, Alysha AU - Ali A AD - PCND Neuroscience Research Institute , Poway , CA , USA. FAU - Hsieh, Mindy Hsin-I AU - Hsieh MH AD - PCND Neuroscience Research Institute , Poway , CA , USA. FAU - Hashimoto, Makoto AU - Hashimoto M AD - Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan. LA - eng PT - Journal Article PT - Review DEP - 20190809 PL - England TA - Expert Rev Neurother JT - Expert review of neurotherapeutics JID - 101129944 RN - 0 (Biomarkers) SB - IM MH - *Biomarkers MH - Dementia/*diagnosis MH - Humans MH - Metabolic Syndrome/*diagnosis MH - Parkinson Disease/*diagnosis OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - biomarker OT - diabetes mellitus OT - dipeptidyl peptidase-4 OT - diponectin OT - glucagon-like-peptide-1 OT - leucine-rich repeat kinase 2 OT - miRNA OT - neurodegeneration OT - synuclein OT - therapy EDAT- 2019/07/31 06:00 MHDA- 2020/09/08 06:00 CRDT- 2019/07/31 06:00 PHST- 2019/07/31 06:00 [pubmed] PHST- 2020/09/08 06:00 [medline] PHST- 2019/07/31 06:00 [entrez] AID - 10.1080/14737175.2019.1649141 [doi] PST - ppublish SO - Expert Rev Neurother. 2019 Nov;19(11):1149-1161. doi: 10.1080/14737175.2019.1649141. Epub 2019 Aug 9. PMID- 31352032 OWN - NLM STAT- MEDLINE DCOM- 20200826 LR - 20260127 IS - 1878-4216 (Electronic) IS - 0278-5846 (Linking) VI - 95 DP - 2019 Dec 20 TI - Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants. PG - 109720 LID - S0278-5846(19)30213-1 [pii] LID - 10.1016/j.pnpbp.2019.109720 [doi] AB - Epidemiological and mechanistic studies support the association between Diabetes Mellitus and mood disorders, such as Major Depressive Disorder and Bipolar Disorder. This association is especially relevant in specific domains of depressive psychopathology, such as disturbances in reward systems and cognitive functions. Several anti-hyperglycemic agents have demonstrated effects on depressive symptoms and cognitive decline and this efficacy is probably the result of an action in shared brain targets between these two groups of conditions. These medications include subcutaneous insulin, intranasal insulin, metformin, and liraglutide. The study of the mechanisms involved in the relationship between Diabetes Mellitus and mood disorders offers a new avenue of investigation, and this understanding can be applied when examining whether antidiabetic agents can be repurposed as antidepressants and mood stabilizers. The objective of this narrative review is to critically appraise the literature surrounding drugs commonly used as anti-hyperglycemic agents and their effects on the brain, while discussing their potential as a new treatment for mental illnesses, and specifically, mood disorders. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Grigolon, Ruth B AU - Grigolon RB AD - Post-Graduation Program in Psychiatry and Medical Psychology, Universidade Federal de Sao Paulo (Unifesp), Sao Paulo, SP, Brazil; Research Group in Molecular and Behavioral Neuroscience of Mood Disorders, Universidade Federal de Sao Paulo (Unifesp), Sao Paulo, SP, Brazil. FAU - Brietzke, Elisa AU - Brietzke E AD - Post-Graduation Program in Psychiatry and Medical Psychology, Universidade Federal de Sao Paulo (Unifesp), Sao Paulo, SP, Brazil; Research Group in Molecular and Behavioral Neuroscience of Mood Disorders, Universidade Federal de Sao Paulo (Unifesp), Sao Paulo, SP, Brazil; Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada. Electronic address: elisa.brietzke@queensu.ca. FAU - Mansur, Rodrigo B AU - Mansur RB AD - Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network (UHN), Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. FAU - Idzikowski, Maia A AU - Idzikowski MA AD - Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada. FAU - Gerchman, Fernando AU - Gerchman F AD - Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Unit of Endocrinology and Metabolism, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil. FAU - De Felice, Fernanda G AU - De Felice FG AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Psychiatry and Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada. FAU - McIntyre, Roger S AU - McIntyre RS AD - Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network (UHN), Toronto, ON, Canada; Brain and Cognition Discovery Foundation (BCDF), Toronto, ON, Canada. LA - eng PT - Journal Article PT - Review DEP - 20190725 PL - England TA - Prog Neuropsychopharmacol Biol Psychiatry JT - Progress in neuro-psychopharmacology & biological psychiatry JID - 8211617 RN - 0 (Antidepressive Agents) RN - 0 (Antimanic Agents) RN - 0 (Hypoglycemic Agents) SB - IM MH - Antidepressive Agents/therapeutic use MH - Antimanic Agents/therapeutic use MH - Bipolar Disorder/complications/*drug therapy MH - Major Depressive Disorder/complications/*drug therapy MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Treatment Outcome OTO - NOTNLM OT - Anti-hyperglycemic agents OT - Bipolar disorder OT - Insulin OT - Major depressive disorder OT - Type 2 diabetes Mellitus EDAT- 2019/07/29 06:00 MHDA- 2020/08/28 06:00 CRDT- 2019/07/29 06:00 PHST- 2019/03/10 00:00 [received] PHST- 2019/07/08 00:00 [revised] PHST- 2019/07/25 00:00 [accepted] PHST- 2019/07/29 06:00 [pubmed] PHST- 2020/08/28 06:00 [medline] PHST- 2019/07/29 06:00 [entrez] AID - S0278-5846(19)30213-1 [pii] AID - 10.1016/j.pnpbp.2019.109720 [doi] PST - ppublish SO - Prog Neuropsychopharmacol Biol Psychiatry. 2019 Dec 20;95:109720. doi: 10.1016/j.pnpbp.2019.109720. Epub 2019 Jul 25. PMID- 31333136 OWN - NLM STAT- MEDLINE DCOM- 20200914 LR - 20200914 IS - 1873-5592 (Electronic) IS - 1389-4501 (Linking) VI - 20 IP - 16 DP - 2019 TI - Computational and Experimental Approaches to Design Inhibitors of Amylin Aggregation. PG - 1680-1694 LID - 10.2174/1389450120666190719164316 [doi] AB - Amylin is a neuroendocrine peptide hormone secreted by pancreatic ss-cells; however, amylin is toxic to ss-cells when it is aggregated in type 2 diabetes mellitus (T2DM). It is important to understand amylin's structures and aggregation mechanism for the discovery and design of effective drugs to inhibit amylin aggregation. In this review, we investigated experimental and computational studies on amylin structures and inhibitors. Our review provides some novel insights into amylin, particularly for the design of its aggregation inhibitors to treat T2DM. We detailed the potential inhibitors that have been studied hitherto and highlighted the neglected need to consider different amylin attributes that depend on the presence/absence of physiologically relevant conditions, such as membranes. These conditions and the experimental methods can greatly influence the results of studies on amylininhibitor complexes. Text-mining over 3,000 amylin-related PubMed abstracts suggests the combined therapeutic potential of amylin with leptin and glucagon-like peptide-1, which are two key hormones in obesity. The results also suggest that targeting amylin aggregation can contribute to therapeutic efforts for Alzheimer's disease (AD). Therefore, we have also reviewed the role of amylin in other conditions including obesity and AD. Finally, we provided insights for designing inhibitors of different types (small molecules, proteins, peptides/mimetics, metal ions) to inhibit amylin aggregation. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Kumar, Ammu Prasanna AU - Kumar AP AD - Department of Chemistry, College of Arts and Sciences, Khalifa University, Abu Dhabi, United Arab Emirates. AD - Research Unit in Bioinformatics, Department of Biochemistry and Microbiology, Rhodes University, South Africa. FAU - Lee, Sungmun AU - Lee S AD - Department of Biomedical Engineering and Healthcare Engineering Innovation Center, College of Engineering, Khalifa University, Abu Dhabi, United Arab Emirates. FAU - Lukman, Suryani AU - Lukman S AD - Department of Chemistry, College of Arts and Sciences, Khalifa University, Abu Dhabi, United Arab Emirates. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Drug Targets JT - Current drug targets JID - 100960531 RN - 0 (Islet Amyloid Polypeptide) RN - 0 (Peptide Hormones) RN - 0 (Protein Aggregates) SB - IM MH - Alzheimer Disease/drug therapy/metabolism MH - Diabetes Mellitus, Type 2/metabolism MH - Humans MH - Islet Amyloid Polypeptide/*metabolism MH - Peptide Hormones/metabolism MH - Protein Aggregates/*drug effects OTO - NOTNLM OT - Alzheimer's disease therapy OT - Amylin OT - IAPP OT - aggregation inhibitors OT - conformation of amylin OT - islet amyloid polypeptide OT - literature review OT - type 2 diabetes therapy. EDAT- 2019/07/25 06:00 MHDA- 2020/09/15 06:00 CRDT- 2019/07/24 06:00 PHST- 2019/04/30 00:00 [received] PHST- 2019/07/04 00:00 [revised] PHST- 2019/07/05 00:00 [accepted] PHST- 2019/07/25 06:00 [pubmed] PHST- 2020/09/15 06:00 [medline] PHST- 2019/07/24 06:00 [entrez] AID - CDT-EPUB-99790 [pii] AID - 10.2174/1389450120666190719164316 [doi] PST - ppublish SO - Curr Drug Targets. 2019;20(16):1680-1694. doi: 10.2174/1389450120666190719164316. PMID- 31330313 OWN - NLM STAT- MEDLINE DCOM- 20200430 LR - 20200430 IS - 1872-9649 (Electronic) IS - 1568-1637 (Linking) VI - 54 DP - 2019 Sep TI - Diabetes drugs in the fight against Alzheimer's disease. PG - 100936 LID - S1568-1637(19)30100-X [pii] LID - 10.1016/j.arr.2019.100936 [doi] AB - Alzheimer's disease (AD) is the most prevalent form of dementia, particularly in old age subjects. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of Type 2 Diabetes Mellitus (T2DM), have also been demonstrated to have a significant impact on cognitive impairment. Studies have shown that an altered insulin pathway may interact with amyloid-beta protein deposition and tau protein phosphorylation, both leading factors for AD development. Drugs used for T2DM treatment from insulin and metformin through dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists may represent a promising approach to fight AD. With this review from animal to human studies, we aim at responding to the reasons why drugs for diabetes may represent potential treatments for AD. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Boccardi, Virginia AU - Boccardi V AD - Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia-Santa Maria della Misericordia Hospital, Perugia, Italy. Electronic address: virginia.boccardi@unipg.it. FAU - Murasecco, Ilenia AU - Murasecco I AD - Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia-Santa Maria della Misericordia Hospital, Perugia, Italy. FAU - Mecocci, Patrizia AU - Mecocci P AD - Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia-Santa Maria della Misericordia Hospital, Perugia, Italy. LA - eng PT - Journal Article PT - Review DEP - 20190719 PL - England TA - Ageing Res Rev JT - Ageing research reviews JID - 101128963 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 9100L32L2N (Metformin) SB - IM MH - Alzheimer Disease/*drug therapy/metabolism/prevention & control MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Cognition MH - Diabetes Mellitus, Type 2/*drug therapy MH - Humans MH - Hypoglycemic Agents/*pharmacology/therapeutic use MH - Insulin/pharmacology/therapeutic use MH - *Insulin Resistance MH - Metformin/pharmacology/therapeutic use OTO - NOTNLM OT - Alzheimer's OT - Cognition OT - Diabetes OT - Drugs OT - Insulin EDAT- 2019/07/23 06:00 MHDA- 2020/05/01 06:00 CRDT- 2019/07/23 06:00 PHST- 2019/04/03 00:00 [received] PHST- 2019/06/20 00:00 [revised] PHST- 2019/07/17 00:00 [accepted] PHST- 2019/07/23 06:00 [pubmed] PHST- 2020/05/01 06:00 [medline] PHST- 2019/07/23 06:00 [entrez] AID - S1568-1637(19)30100-X [pii] AID - 10.1016/j.arr.2019.100936 [doi] PST - ppublish SO - Ageing Res Rev. 2019 Sep;54:100936. doi: 10.1016/j.arr.2019.100936. Epub 2019 Jul 19. PMID- 31300920 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20261012 IS - 1534-6293 (Electronic) IS - 1528-4042 (Linking) VI - 19 IP - 8 DP - 2019 Jul 12 TI - Diabetes Therapies for Dementia. PG - 58 LID - 10.1007/s11910-019-0973-4 [doi] AB - PURPOSE OF REVIEW: Type 2 diabetes (T2D) is a well-established risk factor for the development of dementia. Dementia and T2D share some underlying pathophysiology that has led to interest in the potential to repurpose drugs used in the management of T2D to benefit brain health. This review describes the scientific data available on the use of T2D medications for the risk reduction or management of dementia, in people with and without T2D. RECENT FINDINGS: Results from basic laboratory research support the potential for commonly-used medications for T2D, including those with direct glucose-lowering properties, to have a beneficial effect on brain health. However, human studies have been mostly observational in nature and report conflicting results. Preliminary data suggest that intranasal insulin, metformin, and GLP-1 agonists show promise for dementia, but confirmatory evidence for their benefit in dementia is still lacking. Current evidence does not support the repurposing of T2D medications for dementia risk reduction or management. Research in the field of T2D and dementia is active, and further data are required before definitive conclusions can be drawn. FAU - Moran, Chris AU - Moran C AD - Peninsula Clinical School, Central Clinical School, Monash University, 2 Hastings Road, Frankston, VIC, 3199, Australia. AD - Departments of Medicine and Geriatric Medicine, Peninsula Health, 2 Hastings Road, Frankston, VIC, 3199, Australia. AD - Department of Aged Care, Caulfield Hospital, Alfred Health, 260 Kooyong Rd, Caulfield, VIC, 3162, Australia. AD - Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool St, Hobart, TAS, 7000, Australia. FAU - Callisaya, Michele L AU - Callisaya ML AD - Peninsula Clinical School, Central Clinical School, Monash University, 2 Hastings Road, Frankston, VIC, 3199, Australia. AD - Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool St, Hobart, TAS, 7000, Australia. FAU - Srikanth, Velandai AU - Srikanth V AD - Peninsula Clinical School, Central Clinical School, Monash University, 2 Hastings Road, Frankston, VIC, 3199, Australia. AD - Departments of Medicine and Geriatric Medicine, Peninsula Health, 2 Hastings Road, Frankston, VIC, 3199, Australia. AD - Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool St, Hobart, TAS, 7000, Australia. FAU - Arvanitakis, Zoe AU - Arvanitakis Z AD - Department of Neurological Sciences, Rush Memory Clinic, Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W. Harrison Street, Suite 1000, Chicago, IL, 60612, USA. Zoe_Arvanitakis@rush.edu. LA - eng GR - RF1 AG059621/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20190712 PL - United States TA - Curr Neurol Neurosci Rep JT - Current neurology and neuroscience reports JID - 100931790 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Blood Glucose MH - Brain MH - Dementia/*drug therapy MH - Diabetes Mellitus, Type 2/*drug therapy MH - *Drug Repositioning MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Insulin MH - Risk Factors OTO - NOTNLM OT - Dementia OT - Drugs OT - Type 2 diabetes EDAT- 2019/07/14 06:00 MHDA- 2020/05/12 06:00 CRDT- 2019/07/14 06:00 PHST- 2019/07/14 06:00 [entrez] PHST- 2019/07/14 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] AID - 10.1007/s11910-019-0973-4 [pii] AID - 10.1007/s11910-019-0973-4 [doi] PST - epublish SO - Curr Neurol Neurosci Rep. 2019 Jul 12;19(8):58. doi: 10.1007/s11910-019-0973-4. PMID- 31256135 OWN - NLM STAT- MEDLINE DCOM- 20201009 LR - 20201009 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 70 IP - 3 DP - 2019 TI - Exenatide Reverts the High-Fat-Diet-Induced Impairment of BDNF Signaling and Inflammatory Response in an Animal Model of Alzheimer's Disease. PG - 793-810 LID - 10.3233/JAD-190237 [doi] AB - Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-beta (Abeta) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Abeta and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances. FAU - Bomba, Manuela AU - Bomba M AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Granzotto, Alberto AU - Granzotto A AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Castelli, Vanessa AU - Castelli V AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy. FAU - Onofrj, Marco AU - Onofrj M AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Lattanzio, Rossano AU - Lattanzio R AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Department of Medical, Oral, and Biotechnological Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Cimini, Annamaria AU - Cimini A AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy. AD - Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA. AD - National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy. FAU - Sensi, Stefano L AU - Sensi SL AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. AD - Departments of Neurology and Pharmacology, Institute for Mind Impairments and Neurological Disorders - iMIND, University of California - Irvine, Irvine, CA, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - Animals MH - Brain/*metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cognitive Dysfunction/metabolism MH - Disease Models, Animal MH - Exenatide/*pharmacology MH - Female MH - Glucagon-Like Peptide 1/metabolism MH - Glucose Tolerance Test/methods MH - Hypoglycemic Agents/pharmacology MH - Insulin/*metabolism MH - Insulin Resistance MH - Male MH - Mice MH - Neuroimmunomodulation/drug effects MH - *Neuronal Plasticity/drug effects/physiology MH - Neuroprotective Agents/pharmacology MH - Signal Transduction/drug effects OTO - NOTNLM OT - Aging OT - BDNF OT - T2DM OT - dementia OT - diabetes OT - exendin-4 OT - insulin OT - insulin resistance OT - neurotrophic factors EDAT- 2019/07/01 06:00 MHDA- 2020/10/10 06:00 CRDT- 2019/07/01 06:00 PHST- 2019/07/01 06:00 [pubmed] PHST- 2020/10/10 06:00 [medline] PHST- 2019/07/01 06:00 [entrez] AID - JAD190237 [pii] AID - 10.3233/JAD-190237 [doi] PST - ppublish SO - J Alzheimers Dis. 2019;70(3):793-810. doi: 10.3233/JAD-190237. PMID- 31221697 OWN - NLM STAT- MEDLINE DCOM- 20200320 LR - 20250103 IS - 1935-5548 (Electronic) IS - 0149-5992 (Linking) VI - 42 IP - 7 DP - 2019 Jul TI - Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies. PG - 1274-1283 LID - 10.2337/dc18-2584 [doi] AB - OBJECTIVE: Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks. RESEARCH DESIGN AND METHODS: Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes. RESULTS: Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation. CONCLUSIONS: Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients. CI - (c) 2019 by the American Diabetes Association. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Endocrinology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. FAU - Zhang, Bing AU - Zhang B AD - Department of Radiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. AD - Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China. FAU - Wang, Xin AU - Wang X AD - Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China. FAU - Zhang, Xin AU - Zhang X AD - Department of Radiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. FAU - Yang, Qing X AU - Yang QX AD - Center for NMR Research, Department of Radiology, Pennsylvania State University College of Medicine, Hershey, PA. AD - George M. Leader Foundation Alzheimer's Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA. FAU - Qing, Zhao AU - Qing Z AD - Department of Radiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. FAU - Zhang, Wen AU - Zhang W AD - Department of Radiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. FAU - Zhu, Dalong AU - Zhu D AD - Department of Endocrinology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China biyan@nju.edu.cn. LA - eng SI - ClinicalTrials.gov/NCT02738671 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190521 PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - 839I73S42A (Liraglutide) RN - 9100L32L2N (Metformin) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Adiposity/*physiology MH - Adult MH - Aged MH - Blood Glucose/metabolism MH - Brain/physiopathology MH - Cognition/physiology MH - Cognitive Dysfunction/*complications/diagnosis/physiopathology MH - Diabetes Mellitus, Type 2/*complications/diagnosis/drug therapy/*physiopathology MH - Exenatide/administration & dosage MH - Female MH - Functional Neuroimaging MH - Humans MH - Insulin/therapeutic use MH - Liraglutide/administration & dosage MH - Magnetic Resonance Imaging MH - Male MH - Metformin/administration & dosage MH - Middle Aged MH - Obesity/complications/diagnosis/physiopathology MH - Olfaction Disorders/*complications/*diagnosis/physiopathology MH - Olfactory Perception/physiology MH - Smell/physiology MH - Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2019/06/22 06:00 MHDA- 2020/03/21 06:00 CRDT- 2019/06/22 06:00 PHST- 2018/12/18 00:00 [received] PHST- 2019/04/17 00:00 [accepted] PHST- 2019/06/22 06:00 [entrez] PHST- 2019/06/22 06:00 [pubmed] PHST- 2020/03/21 06:00 [medline] AID - dc18-2584 [pii] AID - 10.2337/dc18-2584 [doi] PST - ppublish SO - Diabetes Care. 2019 Jul;42(7):1274-1283. doi: 10.2337/dc18-2584. Epub 2019 May 21. PMID- 31139140 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1664-2295 (Print) IS - 1664-2295 (Electronic) IS - 1664-2295 (Linking) VI - 10 DP - 2019 TI - Dipeptidyl Peptidase-4 Inhibitors for the Potential Treatment of Brain Disorders; A Mini-Review With Special Focus on Linagliptin and Stroke. PG - 493 LID - 10.3389/fneur.2019.00493 [doi] LID - 493 AB - Cerebral stroke is a leading cause of death and persistent disability of elderly in the world. Although stroke prevention by targeting several risk factors such as diabetes and hypertension has decreased the stroke incidence, the total number of strokes is increasing due to the population aging and new preventive therapies are needed. Moreover, post-stroke acute pharmacological strategies aimed to reduce stroke-induced brain injury have failed in clinical trials despite being effective in animal models. Finally, approximately 30% of surviving stroke patients do not recover from stroke and remain permanently dependent on supportive care in activities of daily living. Therefore, strategies to improve stroke recovery in the post-acute phase are highly needed. Linagliptin is a dipeptidyl peptidase-4 inhibitor which is clinically approved to reduce hyperglycemia in type 2 diabetes. The regulation of glycemia by dipeptidyl peptidase-4 inhibition is mainly achieved by preventing endogenous glucagon-like peptide-1 (GLP-1) degradation. Interestingly, linagliptin has also shown glycaemia-independent beneficial effects in animal models of stroke, Parkinson's disease and Alzheimer's disease. In some case the preclinical data have been supported with some clinical data. Although potentially very interesting for the development of new strategies against stroke and neurodegenerative disorders, the mode of action of linagliptin in the brain is still largely unknown and seems to occur in a GLP-1R-independent manner. The purpose of this mini-review is to summarize and discuss the recent experimental and clinical work regarding the effects of linagliptin in the central nervous system, with special emphasis on acute neuroprotection, stroke prevention and post-stroke recovery. We also highlight the main questions in this research field that need to be addressed in clinical perspective. FAU - Darsalia, Vladimer AU - Darsalia V AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Johansen, Odd Erik AU - Johansen OE AD - Boehringer Ingelheim, Asker, Norway. FAU - Lietzau, Grazyna AU - Lietzau G AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Nystrom, Thomas AU - Nystrom T AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Klein, Thomas AU - Klein T AD - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. FAU - Patrone, Cesare AU - Patrone C AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden. LA - eng PT - Journal Article PT - Review DEP - 20190508 PL - Switzerland TA - Front Neurol JT - Frontiers in neurology JID - 101546899 PMC - PMC6518970 OTO - NOTNLM OT - dipeptidyl peptidase-4 inhibitors OT - linagliptin OT - neuroprotection OT - stroke OT - stroke recovery EDAT- 2019/05/30 06:00 MHDA- 2019/05/30 06:01 PMCR- 2019/05/08 CRDT- 2019/05/30 06:00 PHST- 2019/03/12 00:00 [received] PHST- 2019/04/23 00:00 [accepted] PHST- 2019/05/30 06:00 [entrez] PHST- 2019/05/30 06:00 [pubmed] PHST- 2019/05/30 06:01 [medline] PHST- 2019/05/08 00:00 [pmc-release] AID - 10.3389/fneur.2019.00493 [doi] PST - epublish SO - Front Neurol. 2019 May 8;10:493. doi: 10.3389/fneur.2019.00493. eCollection 2019. PMID- 31126115 OWN - NLM STAT- MEDLINE DCOM- 20191121 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 10 DP - 2019 May 23 TI - The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice. LID - 10.3390/ijms20102539 [doi] LID - 2539 AB - Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer's disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate beta-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway. FAU - Nakaoku, Yuriko AU - Nakaoku Y AD - Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. yurikon@kuhp.kyoto-u.ac.jp. AD - Department of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan. yurikon@kuhp.kyoto-u.ac.jp. FAU - Saito, Satoshi AU - Saito S AD - Department of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan. saitosa@ncvc.go.jp. AD - Research Fellow of Japan Society for the Promotion of Science, Tokyo 102-0083, Japan. saitosa@ncvc.go.jp. FAU - Yamamoto, Yumi AU - Yamamoto Y AD - Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan. yumi.yamamoto@ncvc.go.jp. FAU - Maki, Takakuni AU - Maki T AD - Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. harutoma@kuhp.kyoto-u.ac.jp. FAU - Takahashi, Ryosuke AU - Takahashi R AD - Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ryosuket@kuhp.kyoto-u.ac.jp. FAU - Ihara, Masafumi AU - Ihara M AUID- ORCID: 0000-0002-7102-4048 AD - Department of Neurology, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan. ihara@ncvc.go.jp. LA - eng GR - 1/Boehringer Ingelheim/ PT - Journal Article DEP - 20190523 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 3X29ZEJ4R2 (Linagliptin) SB - IM MH - Animals MH - Cognitive Dysfunction/*drug therapy/etiology/pathology MH - Diet, High-Fat/adverse effects MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Disease Models, Animal MH - Humans MH - Hyperglycemia/complications/*drug therapy/pathology MH - Hypoglycemic Agents/*therapeutic use MH - Linagliptin/*therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Tauopathies/complications/*drug therapy/pathology PMC - PMC6566831 OTO - NOTNLM OT - cerebral blood flow OT - dipeptidyl peptidase-4 inhibitors OT - high-fat diet OT - spatial reference memory OT - tau COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/05/28 06:00 MHDA- 2019/11/22 06:00 PMCR- 2019/05/01 CRDT- 2019/05/26 06:00 PHST- 2019/03/31 00:00 [received] PHST- 2019/05/03 00:00 [revised] PHST- 2019/05/21 00:00 [accepted] PHST- 2019/05/26 06:00 [entrez] PHST- 2019/05/28 06:00 [pubmed] PHST- 2019/11/22 06:00 [medline] PHST- 2019/05/01 00:00 [pmc-release] AID - ijms20102539 [pii] AID - ijms-20-02539 [pii] AID - 10.3390/ijms20102539 [doi] PST - epublish SO - Int J Mol Sci. 2019 May 23;20(10):2539. doi: 10.3390/ijms20102539. PMID- 31103416 OWN - NLM STAT- MEDLINE DCOM- 20200330 LR - 20200330 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 166 DP - 2019 Aug TI - Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice. PG - 222-230 LID - S0006-2952(19)30195-9 [pii] LID - 10.1016/j.bcp.2019.05.020 [doi] AB - We recently reported that brain-specific human beta-secretase 1 (BACE1) knock-in (PLB4), a mouse model of sporadic Alzheimer's disease (AD), also develops a severe diabetic phenotype characterised by impaired glucose homeostasis, decreased insulin sensitivity and a fatty liver phenotype. Hence, we here aimed to assess if targeted anti-diabetic therapies (Liraglutide and Fenretinide) would attenuate the diabetic and behavioural phenotype of these mice. PLB4 mice and wild-type (WT) controls were administered Liraglutide or Fenretinide for ten consecutive weeks alongside vehicle-treated mice. Physiological (body weight and mass composition, glucose tolerance, serum hormone concentration), behavioural (locomotor activity) and molecular assessments were performed in mice pre- and post-treatment. Liraglutide and Fenretinide treatments inhibited adiposity gain and decreased circulating serum triglyceride (with Liraglutide) and leptin (with Fenretinide) levels in PLB4 mice. We also found that PLB4 mice exhibited increased levels of serum dipeptidyl peptidase 4 (DPP4), together with up-regulated hepatic expression of Dpp4, retinol binding protein 4 (Rbp4) and sterol regulatory element-binding 1c (Srebp1c), which was normalised by both treatments. Interestingly, Liraglutide treatment slowed down habituation to a novel environment and increased secondary night activity peak in WT mice, suggesting an impact on circadian activity regulation. However, neither treatment improved glucose homeostasis in PLB4 mice, implying that impaired glucose metabolism in this genotype may not be associated with glucagon like peptide 1 (GLP-1) and/or RBP4-mediated pathways. In summary, this study provides new insights into molecular mechanisms underlying neuronal BACE1-mediated metabolic regulation and implicates BACE1 as a putative regulator of systemic DPP4 levels. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Dekeryte, Ruta AU - Dekeryte R AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Hull, Claire AU - Hull C AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Plucinska, Kaja AU - Plucinska K AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Khan, Shakil AU - Khan S AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Kamli-Salino, Sarah AU - Kamli-Salino S AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Mody, Nimesh AU - Mody N AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - Morrice, Nicola AU - Morrice N AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. FAU - McLaughlin, Chris AU - McLaughlin C AD - School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. FAU - Gault, Victor AU - Gault V AD - School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. FAU - Platt, Bettina AU - Platt B AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. Electronic address: b.platt@abdn.ac.uk. FAU - Delibegovic, Mirela AU - Delibegovic M AD - Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. Electronic address: m.delibegovic@abdn.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190516 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Hypoglycemic Agents) RN - 187EJ7QEXL (Fenretinide) RN - 839I73S42A (Liraglutide) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.23.- (Aspartic Acid Endopeptidases) RN - EC 3.4.23.46 (BACE1 protein, human) SB - IM MH - Amyloid Precursor Protein Secretases/genetics/*metabolism MH - Animals MH - Aspartic Acid Endopeptidases/genetics/*metabolism MH - Diabetes Mellitus/*drug therapy/genetics/*metabolism MH - Fenretinide/pharmacology/*therapeutic use MH - Gene Knock-In Techniques MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Liraglutide/pharmacology/*therapeutic use MH - Male MH - Mice MH - Mice, Transgenic MH - Neurons/drug effects/metabolism MH - Phenotype MH - Treatment Outcome OTO - NOTNLM OT - BACE1 OT - DPP4 OT - Insulin resistance OT - Liraglutide OT - Type 2 diabetes EDAT- 2019/05/20 06:00 MHDA- 2020/03/31 06:00 CRDT- 2019/05/20 06:00 PHST- 2019/03/25 00:00 [received] PHST- 2019/05/14 00:00 [accepted] PHST- 2019/05/20 06:00 [pubmed] PHST- 2020/03/31 06:00 [medline] PHST- 2019/05/20 06:00 [entrez] AID - S0006-2952(19)30195-9 [pii] AID - 10.1016/j.bcp.2019.05.020 [doi] PST - ppublish SO - Biochem Pharmacol. 2019 Aug;166:222-230. doi: 10.1016/j.bcp.2019.05.020. Epub 2019 May 16. PMID- 31068799 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1663-4365 (Print) IS - 1663-4365 (Electronic) IS - 1663-4365 (Linking) VI - 11 DP - 2019 TI - Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer's Disease. PG - 88 LID - 10.3389/fnagi.2019.00088 [doi] LID - 88 AB - Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid. FAU - Holscher, Christian AU - Holscher C AD - Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China. LA - eng PT - Journal Article PT - Review DEP - 20190424 PL - Switzerland TA - Front Aging Neurosci JT - Frontiers in aging neuroscience JID - 101525824 PMC - PMC6491455 OTO - NOTNLM OT - GLP-1 OT - apoptosis OT - autophagy OT - brain OT - growth factor OT - inflammation OT - mitochondria EDAT- 2019/05/10 06:00 MHDA- 2019/05/10 06:01 PMCR- 2019/01/01 CRDT- 2019/05/10 06:00 PHST- 2019/02/02 00:00 [received] PHST- 2019/04/03 00:00 [accepted] PHST- 2019/05/10 06:00 [entrez] PHST- 2019/05/10 06:00 [pubmed] PHST- 2019/05/10 06:01 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fnagi.2019.00088 [doi] PST - epublish SO - Front Aging Neurosci. 2019 Apr 24;11:88. doi: 10.3389/fnagi.2019.00088. eCollection 2019. PMID- 30944040 OWN - NLM STAT- MEDLINE DCOM- 20190903 LR - 20260109 IS - 1745-6215 (Electronic) IS - 1745-6215 (Linking) VI - 20 IP - 1 DP - 2019 Apr 3 TI - Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). PG - 191 LID - 10.1186/s13063-019-3259-x [doi] LID - 191 AB - BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013. FAU - Femminella, Grazia Daniela AU - Femminella GD AD - Department of Medicine, Imperial College London, London, UK. FAU - Frangou, Eleni AU - Frangou E AD - Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. FAU - Love, Sharon B AU - Love SB AD - Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. FAU - Busza, Gail AU - Busza G AD - Department of Medicine, Imperial College London, London, UK. FAU - Holmes, Clive AU - Holmes C AD - Southern Health NHS Foundation Trust, Havant, UK. FAU - Ritchie, Craig AU - Ritchie C AD - Department of Medicine, Imperial College London, London, UK. FAU - Lawrence, Robert AU - Lawrence R AD - SW London and St George's Mental Health Trust, London , UK. FAU - McFarlane, Brady AU - McFarlane B AD - Southern Health NHS Foundation Trust, Havant, UK. FAU - Tadros, George AU - Tadros G AD - Aston Medical school, Aston University, Birmingham, UK. FAU - Ridha, Basil H AU - Ridha BH AD - Brighton and Sussex University Hospitals NHS Trust, Brighton, UK. FAU - Bannister, Carol AU - Bannister C AD - South London and Maudsley NHS Foundation Trust, London, UK. FAU - Walker, Zuzana AU - Walker Z AD - University College London and Essex Partnership University NHS Foundation Trust, Runwell, UK. FAU - Archer, Hilary AU - Archer H AD - North Bristol NHS Trust, Bristol, UK. FAU - Coulthard, Elizabeth AU - Coulthard E AD - North Bristol NHS Trust, Bristol, UK. FAU - Underwood, Ben R AU - Underwood BR AD - Cambridgeshire and Peterborough NHS Foundation Trust, Peterborough, UK. FAU - Prasanna, Aparna AU - Prasanna A AD - Black Country Partnership NHS Foundation Trust, West Bromwich, UK. FAU - Koranteng, Paul AU - Koranteng P AD - Northamptonshire Healthcare NHS Foundation Trust, Kettering, UK. FAU - Karim, Salman AU - Karim S AD - Lancashire Care NHS Foundation Trust, Preston, UK. FAU - Junaid, Kehinde AU - Junaid K AD - Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, UK. FAU - McGuinness, Bernadette AU - McGuinness B AD - Centre for Public Health, Queen's University Belfast, Belfast, UK. FAU - Nilforooshan, Ramin AU - Nilforooshan R AD - Surrey and Borders Partnership NHS Foundation Trust, Leatherhead, UK. FAU - Macharouthu, Ajay AU - Macharouthu A AD - NHS Ayrshire and Arran, Crosshouse, UK. FAU - Donaldson, Andrew AU - Donaldson A AD - NHS Lanarkshire, Glasgow, UK. FAU - Thacker, Simon AU - Thacker S AD - Derbyshire Healthcare NHS Foundation Trust, Derby, UK. FAU - Russell, Gregor AU - Russell G AD - Bradford District Care NHS Foundation Trust, Bradford, UK. FAU - Malik, Naghma AU - Malik N AD - 5 Boroughs Partnership NHS Foundation Trust, Warrington, UK. FAU - Mate, Vandana AU - Mate V AD - Cornwall Partnership NHS Foundation Trust, Redruth, UK. FAU - Knight, Lucy AU - Knight L AD - Somerset Partnership NHS Foundation Trust, Bridgwater, UK. FAU - Kshemendran, Sajeev AU - Kshemendran S AD - South Staffordshire and Shropshire Healthcare NHS Foundation Trust, Stafford, UK. FAU - Harrison, John AU - Harrison J AD - Alzheimer Center VUmc Amsterdam, Amsterdam, the Netherlands. AD - Institute of Psychiatry, Psychology & Neuroscience King's College London, London, UK. FAU - Holscher, Christian AU - Holscher C FAU - Brooks, David J AU - Brooks DJ AD - Department of Medicine, Imperial College London, London, UK. AD - Newcastle University, Newcastle upon Tyne, UK. FAU - Passmore, Anthony Peter AU - Passmore AP AD - Centre for Public Health, Queen's University Belfast, Belfast, UK. FAU - Ballard, Clive AU - Ballard C AD - South London and Maudsley NHS Foundation Trust, London, UK. FAU - Edison, Paul AU - Edison P AUID- ORCID: 0000-0002-6551-2002 AD - Department of Medicine, Imperial College London, London, UK. paul.edison@imperial.ac.uk. AD - School of Medicine, College of Biomedical and Life sciences, Cardiff University, Cardiff, CF14 4YS, UK. paul.edison@imperial.ac.uk. LA - eng SI - ClinicalTrials.gov/NCT01843075 GR - G84/6523/MRC_/Medical Research Council/United Kingdom PT - Clinical Trial Protocol PT - Journal Article DEP - 20190403 PL - England TA - Trials JT - Trials JID - 101263253 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 839I73S42A (Liraglutide) RN - IY9XDZ35W2 (Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM EIN - Trials. 2020 Jul 19;21(1):660. doi: 10.1186/s13063-020-04608-4. PMID: 32684162 MH - Activities of Daily Living MH - Alzheimer Disease/*drug therapy/metabolism/physiopathology/psychology MH - Brain/*drug effects/metabolism/physiopathology MH - Clinical Trials, Phase II as Topic MH - Cognition/drug effects MH - Double-Blind Method MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Glucose/*metabolism MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Liraglutide/adverse effects/*therapeutic use MH - Memory/drug effects MH - Multicenter Studies as Topic MH - Neuroprotective Agents/adverse effects/*therapeutic use MH - Randomized Controlled Trials as Topic MH - Severity of Illness Index MH - Time Factors MH - Treatment Outcome MH - United Kingdom MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC6448216 OTO - NOTNLM OT - Alzheimer's disease OT - Cerebral glucose metabolic rate OT - Dementia OT - Liraglutide OT - Randomised controlled trial COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the local and regional regulatory ethics committees (London Riverside Research Ethics Committee - study reference number 13/LO/0699, and Health Research Authority, UK), and the Medicines and Healthcare products Regulatory Agency (MHRA - EudraCT number 2013-000962-13). Approval for administration of radioactivity was given by the Administration of Radioactive Substances Advisory Committee (ARSAC). All participants and study partners signed an Informed Consent Form prior to entry into the study. CONSENT FOR PUBLICATION: NA. COMPETING INTERESTS: Dr Edison was funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer's Research, UK, Alzheimer's Drug Discovery Foundation, Alzheimer's Society, UK, Novo Nordisk, GE Healthcare, Astra Zeneca, Pfizer, Eli Lilly and Piramal Life Sciences. The other authors have nothing to declare. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/05 06:00 MHDA- 2019/09/04 06:00 PMCR- 2019/04/03 CRDT- 2019/04/05 06:00 PHST- 2018/03/23 00:00 [received] PHST- 2019/02/27 00:00 [accepted] PHST- 2019/04/05 06:00 [entrez] PHST- 2019/04/05 06:00 [pubmed] PHST- 2019/09/04 06:00 [medline] PHST- 2019/04/03 00:00 [pmc-release] AID - 10.1186/s13063-019-3259-x [pii] AID - 3259 [pii] AID - 10.1186/s13063-019-3259-x [doi] PST - epublish SO - Trials. 2019 Apr 3;20(1):191. doi: 10.1186/s13063-019-3259-x. PMID- 30833929 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240714 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 10 DP - 2019 TI - Diabetes and Aging: From Treatment Goals to Pharmacologic Therapy. PG - 45 LID - 10.3389/fendo.2019.00045 [doi] LID - 45 AB - Diabetes is becoming one of the most widespread health burning problems in the elderly. Worldwide prevalence of diabetes among subjects over 65 years was 123 million in 2017, a number that is expected to double in 2045. Old patients with diabetes have a higher risk of common geriatric syndromes, including frailty, cognitive impairment and dementia, urinary incontinence, traumatic falls and fractures, disability, side effects of polypharmacy, which have an important impact on quality of life and may interfere with anti-diabetic treatment. Because of all these factors, clinical management of type 2 diabetes in elderly patients currently represents a real challenge for the physician. Actually, the optimal glycemic target to achieve for elderly diabetic patients is still a matter of debate. The American Diabetes Association suggests a HbA1c goal <7.5% for older adults with intact cognitive and functional status, whereas, the American Association of Clinical Endocrinologists (AACE) recommends HbA1c levels of 6.5% or lower as long as it can be achieved safely, with a less stringent target (>6.5%) for patients with concurrent serious illness and at high risk of hypoglycemia. By contrast, the American College of Physicians (ACP) suggests more conservative goals (HbA1c levels between 7 and 8%) for most older patients, and a less intense pharmacotherapy, when HbA1C levels are 27 points). The subjects were on a 3-month treatment with a maximal dose of metformin as a stable regime, with the addition of incretins (liraglutide at doses of up to 1.8 mg/d; vildagliptin at 100 mg/d; sitagliptin 100 mg/d; and linagliptin 5 mg/d), or SGLT2-I (canagliflozin 300 mg/d; empagliflozin 25 mg/d; and dapagliflozin 10 mg/d). Glucose control was monitored by fasting glucose and glycosylated hemoglobin. Cognitive performance (by way of Verbal Fluency Test, Attentive Matrices Test, and Babcock Story Recall Test), anthropometric measures, and plasma lipids were also evaluated. RESULTS: Cognitive status did not change significantly during the 12 months of treatment in either group: Verbal Fluency Test: (SGLT2-I: P=1.00, incretins: P=0.598); Babcock Story Recall Test (SGLT2-I: P=0.391; incretins: P=0.351); and Attentive Matrices Test (SGLT2-I: P=0.679, incretins: P=0.901). SGLT2-I also resulted in a reduction in weight (-1.95 kg; P<0.05), in BMI (-0.69 kg/m(2); P<0.05) and an increase in high-density lipoprotein cholesterol (+5.73 mg/dl; P<0.01). CONCLUSION: Preliminary data show that patients treated with incretins and SGLT2-I have not suffered a reduction in cognitive performance during the 1 year of treatment. Metabolic outcome seemed to benefit, in particular, in patients who were treated with SGLT2-I. FAU - Perna, Simone AU - Perna S AD - Department of Biology, College of Science, University of Bahrain, Sakhir Campus, Kingdom of Bahrain, simoneperna@hotmail.it. FAU - Mainardi, Manuela AU - Mainardi M AD - University of Pavia, Department of Internal Medicine, Section of Geriatrics and Gerontology, Azienda di Servizi alla Persona "Istituto Santa Margherita", Pavia, Italy. FAU - Astrone, Paolo AU - Astrone P AD - University of Pavia, Department of Internal Medicine, Section of Geriatrics and Gerontology, Azienda di Servizi alla Persona "Istituto Santa Margherita", Pavia, Italy. FAU - Gozzer, Carlotta AU - Gozzer C AD - University of Pavia, Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ''Istituto SantaMargherita'', Pavia, Italy. FAU - Biava, Anna AU - Biava A AD - Department of Biology, College of Science, University of Bahrain, Sakhir Campus, Kingdom of Bahrain, simoneperna@hotmail.it. FAU - Bacchio, Ruben AU - Bacchio R AD - University of Pavia, Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ''Istituto SantaMargherita'', Pavia, Italy. FAU - Spadaccini, Daniele AU - Spadaccini D AD - University of Pavia, Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ''Istituto SantaMargherita'', Pavia, Italy. FAU - Solerte, Sebastiano Bruno AU - Solerte SB AD - University of Pavia, Department of Internal Medicine, Section of Geriatrics and Gerontology, Azienda di Servizi alla Persona "Istituto Santa Margherita", Pavia, Italy. FAU - Rondanelli, Mariangela AU - Rondanelli M AD - IRCCS Mondino Foundation, Pavia, Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Italy. LA - eng PT - Journal Article DEP - 20181009 PL - New Zealand TA - Clin Pharmacol JT - Clinical pharmacology : advances and applications JID - 101564865 PMC - PMC6186903 OTO - NOTNLM OT - SGLT-2 inhibitors OT - cognitive impairment OT - cognitive performance OT - incretins OT - metabolic outcome COIS- Disclosure The authors report no conflicts of interest in this work. EDAT- 2018/10/24 06:00 MHDA- 2018/10/24 06:01 PMCR- 2018/10/09 CRDT- 2018/10/24 06:00 PHST- 2018/10/24 06:00 [entrez] PHST- 2018/10/24 06:00 [pubmed] PHST- 2018/10/24 06:01 [medline] PHST- 2018/10/09 00:00 [pmc-release] AID - cpaa-10-141 [pii] AID - 10.2147/CPAA.S164785 [doi] PST - epublish SO - Clin Pharmacol. 2018 Oct 9;10:141-151. doi: 10.2147/CPAA.S164785. eCollection 2018. PMID- 30273843 OWN - NLM STAT- MEDLINE DCOM- 20191125 LR - 20191125 IS - 1872-6968 (Electronic) IS - 0303-8467 (Linking) VI - 174 DP - 2018 Nov TI - Low glucagon-like peptide-1 (GLP-1) concentration in serum is indicative of mild cognitive impairment in type 2 diabetes patients. PG - 203-206 LID - S0303-8467(18)30323-8 [pii] LID - 10.1016/j.clineuro.2018.08.012 [doi] AB - OBJECTIVES: To reveal potential association between glucagon-like peptide 1 (GLP-1) concentration in serum and mild cognitive function impairment (MCI) in type 2 diabetes mellitus (T2DM) patients. PATIENTS AND METHODS: A total of 106 T2DM patients and 47 normal controls were recruited in this study. Montreal Cognitive Assessment (MoCA) was performed in all subjects. Among the 106 patients, 52 presented with MCI. Fasting blood glucose (FBG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglyceride (TG), uric acid (UA) and GLP-1 levels were also assessed in all subjects. RESULTS: Patients with MCI had higher serum concentrations of FBG and TC and lower concentrations of GLP-1 and HDL-C than controls. Bivariate correlation analysis showed that MCI in T2DM patients closely correlated with FBG, HDL-C, and GLP-1 levels. Moreover, ordinal regression analysis showed that GLP-1 concentration in serum was protective for MCI in T2DM patients (OR = 0.025; 95%CI: 0.005-3.934). CONCLUSIONS: Our results indicated that low concentration of GLP-1 may play a role in the pathogenesis of MCI in T2DM patients. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Wu, Peipei AU - Wu P AD - Department of Endocrinology, The Second Hospital of Shandong University, 247 BeiYuan Road, JiNan, ShanDong, 250033, China. FAU - Zhao, Yuxiao AU - Zhao Y AD - Queen Mary School of Nanchang University, Nanchang, Jiangxi, 330031, China. FAU - Zhuang, Xianghua AU - Zhuang X AD - Department of Endocrinology, The Second Hospital of Shandong University, 247 BeiYuan Road, JiNan, ShanDong, 250033, China. FAU - Sun, Aili AU - Sun A AD - Department of Endocrinology, The Second Hospital of Shandong University, 247 BeiYuan Road, JiNan, ShanDong, 250033, China. FAU - Zhang, Yuan AU - Zhang Y AD - Department of Evidence-Based Medicine, The Second Hospital of Shandong University, 247 BeiYuan Road, JiNan, ShanDong, 250033, China. FAU - Ni, Yihong AU - Ni Y AD - Department of Endocrinology, The Second Hospital of Shandong University, 247 BeiYuan Road, JiNan, ShanDong, 250033, China. Electronic address: 454368810@qq.com. LA - eng PT - Journal Article DEP - 20180807 PL - Netherlands TA - Clin Neurol Neurosurg JT - Clinical neurology and neurosurgery JID - 7502039 RN - 0 (Biomarkers) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Adult MH - Biomarkers/blood MH - Cognitive Dysfunction/*blood/drug therapy/epidemiology MH - Diabetes Mellitus, Type 2/*blood/drug therapy/epidemiology MH - Female MH - Glucagon-Like Peptide 1/*blood MH - Humans MH - Hypertension/*blood/drug therapy/epidemiology MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Middle Aged MH - Risk Factors OTO - NOTNLM OT - Cognitive impairment OT - Glucagon-like peptide-1 OT - MoCA OT - Type 2 diabetes mellitus EDAT- 2018/10/03 06:00 MHDA- 2019/11/26 06:00 CRDT- 2018/10/02 06:00 PHST- 2018/02/20 00:00 [received] PHST- 2018/08/05 00:00 [revised] PHST- 2018/08/06 00:00 [accepted] PHST- 2018/10/03 06:00 [pubmed] PHST- 2019/11/26 06:00 [medline] PHST- 2018/10/02 06:00 [entrez] AID - S0303-8467(18)30323-8 [pii] AID - 10.1016/j.clineuro.2018.08.012 [doi] PST - ppublish SO - Clin Neurol Neurosurg. 2018 Nov;174:203-206. doi: 10.1016/j.clineuro.2018.08.012. Epub 2018 Aug 7. PMID- 30187176 OWN - NLM STAT- MEDLINE DCOM- 20190906 LR - 20260417 IS - 1539-0829 (Electronic) IS - 1534-4827 (Linking) VI - 18 IP - 10 DP - 2018 Sep 5 TI - Diabetes Treatment in the Elderly: Incorporating Geriatrics, Technology, and Functional Medicine. PG - 95 LID - 10.1007/s11892-018-1052-y [doi] AB - PURPOSE OF REVIEW: The current approach to diabetes in the elderly incorporates components from the comprehensive geriatric approach. The most updated guidelines from the American Diabetes Association reflect influence from the consensus made in 2012 with the American Geriatrics Society. Notably, the framework included the evaluation for geriatric syndromes (falls and urinary incontinence), functional and cognitive abilities. The goal for this review is to provide an updated summary of treatment strategies for community-dwelling older adults. We identified the need to expand our approach by addressing innovative approaches and scientific concepts from telemedicine, functional medicine, and geriatrics. RECENT FINDINGS: Findings on cardiovascular protection with sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and some glucagon-like peptide 1 receptor agonists (GLP-1RA) support their use for older patients with diabetes. However, careful consideration for agent selection must incorporate the presence of geriatric issues, such as geriatric syndromes, or functional and cognitive decline, as they could increase the risk and impact adverse reactions. Telemedicine interventions can improve communication and connection between older patients and their providers, and improve glycemic control. Functional medicine concepts can offer additional adjuvant strategies to support the therapeutic interventions and management of diabetes in the elderly. A systematic review confirmed the efficacy and safety of metformin as first-line therapy of type 2 diabetes in the older adult, but multiple reports highlighted the risk for vitamin B12 deficiency. Randomized controlled trials showed the efficacy and safety of antihyperglycemic agents in the elderly, including some with longer duration and lesser risk for hypoglycemia. Randomized clinical trials showed cardiovascular protection with SGLT-2i (empagliflozin, canagliflozin) and GLP-1RA (liraglutide, semaglutide). The most current guidelines recommend addressing for geriatric syndromes, physical and cognitive function in the elderly, in order to individualize targets and therapeutic strategies. Clinicians managing diabetes in the elderly can play a major role for the early detection and evaluation of geriatric issues in their patients. Telemedicine interventions improve glycemic control, and certain functional medicine strategies could be adjuvant interventions to reduce inflammation and stress, but more studies focused on the elderly population are needed. FAU - Valencia, Willy Marcos AU - Valencia WM AD - Geriatric Research, Education and Clinical Center (GRECC), Miami VA Healthcare System, 1201 NW 16th St. (11 GRC), Miami, FL, 33125, USA. willy.valencia-rodrigo@va.gov. AD - Department of Humanities, Health and Society, Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA. willy.valencia-rodrigo@va.gov. AD - Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA. willy.valencia-rodrigo@va.gov. FAU - Botros, Diana AU - Botros D AD - Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1611 NW 12th Ave, Miami, FL, 33136, USA. FAU - Vera-Nunez, Maria AU - Vera-Nunez M AD - Institute for NeuroImmune Medicine (INIM), Nova Southeastern University College of Osteopathic Medicine, 3301 College Ave, CCR 4th Floor, Fort Lauderdale, FL, 33314, USA. FAU - Dang, Stuti AU - Dang S AD - Geriatric Research, Education and Clinical Center (GRECC), Miami VA Healthcare System, 1201 NW 16th St. (11 GRC), Miami, FL, 33125, USA. AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. LA - eng PT - Journal Article PT - Systematic Review DEP - 20180905 PL - United States TA - Curr Diab Rep JT - Current diabetes reports JID - 101093791 RN - 0 (Hypoglycemic Agents) SB - IM MH - Aged MH - Cognition/drug effects MH - Diabetes Mellitus, Type 2/*drug therapy/physiopathology MH - *Geriatrics MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Telemedicine MH - Treatment Outcome OTO - NOTNLM OT - Diabetes OT - Functional medicine OT - Geriatrics OT - Management OT - Older adult OT - Telemedicine EDAT- 2018/09/07 06:00 MHDA- 2019/09/07 06:00 CRDT- 2018/09/07 06:00 PHST- 2018/09/07 06:00 [entrez] PHST- 2018/09/07 06:00 [pubmed] PHST- 2019/09/07 06:00 [medline] AID - 10.1007/s11892-018-1052-y [pii] AID - 10.1007/s11892-018-1052-y [doi] PST - epublish SO - Curr Diab Rep. 2018 Sep 5;18(10):95. doi: 10.1007/s11892-018-1052-y. PMID- 30186862 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20230928 IS - 2314-6141 (Electronic) IS - 2314-6133 (Print) VI - 2018 DP - 2018 TI - Neuroprotective Activity of Sitagliptin via Reduction of Neuroinflammation beyond the Incretin Effect: Focus on Alzheimer's Disease. PG - 6091014 LID - 10.1155/2018/6091014 [doi] LID - 6091014 AB - Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-alpha (tumor necrosis factor-alpha), IL-6 (interleukin-6), IL-17 (interleukin-17), and CD-163 (cluster of differentiation 163), and contributed to an increase in levels of anti-inflammatory factors: IL-10 (interleukin-10) and TGF-beta (transforming growth factor beta). Moreover, sitagliptin demonstrated antioxidative and antiapoptotic properties by modifying glutamate and glutathione levels within the region of hippocampus in mice. It has been observed that sitagliptin decreases accumulation of beta-amyloid within encephalon structures in experimental models of Alzheimer's dementia. This effect may be connected with SDF-1alpha (stromal cell-derived factor 1alpha) concentration. Administration of sitagliptin caused a significant improvement in MMSE (Mini-Mental State Examination) tests used for assessment of dementias. The paper presents potential mechanisms of sitagliptin activity in conditions connected with neuroinflammation with special emphasis on Alzheimer's disease. FAU - Wicinski, Michal AU - Wicinski M AUID- ORCID: 0000-0002-7222-0171 AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Wodkiewicz, Eryk AU - Wodkiewicz E AUID- ORCID: 0000-0002-2834-3414 AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Slupski, Maciej AU - Slupski M AD - Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Walczak, Maciej AU - Walczak M AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Socha, Maciej AU - Socha M AD - Department of Obstetrics, Gynecology and Gynecological Oncology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Ujejskiego 75, 85-168 Bydgoszcz, Poland. FAU - Malinowski, Bartosz AU - Malinowski B AD - Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. FAU - Pawlak-Osinska, Katarzyna AU - Pawlak-Osinska K AD - Department of Pathophysiology of Hearing and Balance System, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland. LA - eng PT - Journal Article PT - Review DEP - 20180816 PL - United States TA - Biomed Res Int JT - BioMed research international JID - 101600173 RN - 0 (Blood Glucose) RN - 0 (Cytokines) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - Alzheimer Disease/*drug therapy/immunology MH - Animals MH - Blood Glucose MH - Cytokines/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors MH - Glucagon-Like Peptide 1 MH - Hypoglycemic Agents/*pharmacology MH - Incretins MH - *Inflammation MH - Mice MH - Sitagliptin Phosphate/*pharmacology PMC - PMC6116461 EDAT- 2018/09/07 06:00 MHDA- 2018/12/12 06:00 PMCR- 2018/08/16 CRDT- 2018/09/07 06:00 PHST- 2018/03/29 00:00 [received] PHST- 2018/06/22 00:00 [revised] PHST- 2018/07/26 00:00 [accepted] PHST- 2018/09/07 06:00 [entrez] PHST- 2018/09/07 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/08/16 00:00 [pmc-release] AID - 10.1155/2018/6091014 [doi] PST - epublish SO - Biomed Res Int. 2018 Aug 16;2018:6091014. doi: 10.1155/2018/6091014. eCollection 2018. PMID- 30165597 OWN - NLM STAT- MEDLINE DCOM- 20190705 LR - 20250530 IS - 1460-2156 (Electronic) IS - 0006-8950 (Print) IS - 0006-8950 (Linking) VI - 141 IP - 10 DP - 2018 Oct 1 TI - Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy. PG - 2925-2942 LID - 10.1093/brain/awy220 [doi] AB - Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 microg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising. FAU - Rocha-Ferreira, Eridan AU - Rocha-Ferreira E AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. AD - EGA Institute for Women's Health, University College London, UK. FAU - Poupon, Laura AU - Poupon L AD - UCL School of Pharmacy, University College London, UK. FAU - Zelco, Aura AU - Zelco A AD - UCL School of Pharmacy, University College London, UK. FAU - Leverin, Anna-Lena AU - Leverin AL AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. FAU - Nair, Syam AU - Nair S AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. FAU - Jonsdotter, Andrea AU - Jonsdotter A AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. FAU - Carlsson, Ylva AU - Carlsson Y AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. FAU - Thornton, Claire AU - Thornton C AD - Department of Women and Children's Health, Centre for the Developing Brain, School of Life Course Sciences, King's College London, UK. FAU - Hagberg, Henrik AU - Hagberg H AD - Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. AD - Department of Perinatal Imaging and Health, Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King s College London, UK. FAU - Rahim, Ahad A AU - Rahim AA AD - UCL School of Pharmacy, University College London, UK. LA - eng GR - WT094823/WT_/Wellcome Trust/United Kingdom GR - P19381/MRC_/Medical Research Council/United Kingdom GR - MR/R025134/1/MRC_/Medical Research Council/United Kingdom GR - MR/M00676X/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - MR/N026101/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Neuroprotective Agents) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Animals, Newborn MH - Brain/*drug effects/pathology MH - Disease Models, Animal MH - Exenatide/*pharmacology MH - Humans MH - Hypothermia, Induced MH - Hypoxia-Ischemia, Brain/*pathology MH - Mice MH - Neuroprotective Agents/*pharmacology PMC - PMC6158761 EDAT- 2018/08/31 06:00 MHDA- 2019/07/06 06:00 PMCR- 2018/08/24 CRDT- 2018/08/31 06:00 PHST- 2018/03/01 00:00 [received] PHST- 2018/07/12 00:00 [accepted] PHST- 2018/08/31 06:00 [pubmed] PHST- 2019/07/06 06:00 [medline] PHST- 2018/08/31 06:00 [entrez] PHST- 2018/08/24 00:00 [pmc-release] AID - 5079387 [pii] AID - awy220 [pii] AID - 10.1093/brain/awy220 [doi] PST - ppublish SO - Brain. 2018 Oct 1;141(10):2925-2942. doi: 10.1093/brain/awy220. PMID- 30149534 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20181211 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 19 IP - 9 DP - 2018 Aug 24 TI - GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling. LID - 10.3390/ijms19092505 [doi] LID - 2505 AB - Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD. FAU - Chang, Ching-Chi AU - Chang CC AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. fmaj7@seed.net.tw. AD - Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. fmaj7@seed.net.tw. FAU - Lin, Tzu-Chin AU - Lin TC AD - Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. jamaalbest@gmail.com. FAU - Ho, Hsiao-Li AU - Ho HL AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. lily09102352000@gmail.com. FAU - Kuo, Chien-Yin AU - Kuo CY AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. a9704119@hotmail.com. FAU - Li, Hsin-Hua AU - Li HH AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. vivid529@hotmail.com. FAU - Korolenko, Tatiana A AU - Korolenko TA AD - Federal State Budgetary Scientific Institution, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk 630117, Russia. t.a.korolenko@physiol.ru. FAU - Chen, Wei-Jen AU - Chen WJ AD - Department of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. cwj519@csmu.edu.tw. FAU - Lai, Te-Jen AU - Lai TJ AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. ltj3123@ms2.hinet.net. AD - Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. ltj3123@ms2.hinet.net. FAU - Ho, Ying-Jui AU - Ho YJ AD - Department of Psychology, Chung Shan Medical University, Taichung 40201, Taiwan. yjho@csmu.edu.tw. FAU - Lin, Chih-Li AU - Lin CL AUID- ORCID: 0000-0003-4553-3727 AD - Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. dll@csmu.edu.tw. AD - Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. dll@csmu.edu.tw. LA - eng PT - Journal Article DEP - 20180824 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (HTT protein, human) RN - 0 (Huntingtin Protein) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Cell Line, Tumor MH - Glucagon-Like Peptide 1/analogs & derivatives/pharmacology MH - Humans MH - Huntingtin Protein/*genetics/metabolism MH - Hypoglycemic Agents/pharmacology MH - Immunohistochemistry MH - Insulin/*metabolism MH - Liraglutide/*pharmacology MH - Neurons/*drug effects/*metabolism MH - Neuroprotective Agents/*pharmacology MH - Signal Transduction/*drug effects PMC - PMC6164932 OTO - NOTNLM OT - autophagy OT - huntingtin OT - insulin signaling OT - liraglutide OT - oxidative stress COIS- The authors declare no conflict of interest. EDAT- 2018/08/29 06:00 MHDA- 2018/12/12 06:00 PMCR- 2018/09/01 CRDT- 2018/08/29 06:00 PHST- 2018/07/26 00:00 [received] PHST- 2018/08/18 00:00 [revised] PHST- 2018/08/22 00:00 [accepted] PHST- 2018/08/29 06:00 [entrez] PHST- 2018/08/29 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/09/01 00:00 [pmc-release] AID - ijms19092505 [pii] AID - ijms-19-02505 [pii] AID - 10.3390/ijms19092505 [doi] PST - epublish SO - Int J Mol Sci. 2018 Aug 24;19(9):2505. doi: 10.3390/ijms19092505. PMID- 30099030 OWN - NLM STAT- MEDLINE DCOM- 20190416 LR - 20190416 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 356 DP - 2019 Jan 1 TI - Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease. PG - 271-278 LID - S0166-4328(18)30643-0 [pii] LID - 10.1016/j.bbr.2018.08.006 [doi] AB - Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) was conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes. RESULTS: At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefits in individuals at risk for AD. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Watson, Kathleen T AU - Watson KT AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Wroolie, Tonita E AU - Wroolie TE AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Tong, Gabby AU - Tong G AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Foland-Ross, Lara C AU - Foland-Ross LC AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Frangou, Sophia AU - Frangou S AD - Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Singh, Manpreet AU - Singh M AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - McIntyre, Roger S AU - McIntyre RS AD - Department of Psychiatry, University of Toronto, Toronto, ON, Canada. FAU - Roat-Shumway, Siena AU - Roat-Shumway S AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Myoraku, Alison AU - Myoraku A AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Reiss, Allan L AU - Reiss AL AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. FAU - Rasgon, Natalie L AU - Rasgon NL AD - Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: nrasgon@stanford.edu. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180809 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) SB - IM MH - Adult MH - Aged MH - Alzheimer Disease/*drug therapy MH - Blood Glucose/drug effects/metabolism MH - Cognition/drug effects MH - Female MH - Hippocampus/*drug effects MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Insulin Resistance/physiology MH - Liraglutide/*therapeutic use MH - Male MH - Middle Aged MH - Risk OTO - NOTNLM OT - Cognitive function, fMRI OT - GLP-1 agonist OT - Hippocampus OT - Insulin resistance OT - Liraglutide EDAT- 2018/08/14 06:00 MHDA- 2019/04/17 06:00 CRDT- 2018/08/13 06:00 PHST- 2018/05/11 00:00 [received] PHST- 2018/07/30 00:00 [revised] PHST- 2018/08/08 00:00 [accepted] PHST- 2018/08/14 06:00 [pubmed] PHST- 2019/04/17 06:00 [medline] PHST- 2018/08/13 06:00 [entrez] AID - S0166-4328(18)30643-0 [pii] AID - 10.1016/j.bbr.2018.08.006 [doi] PST - ppublish SO - Behav Brain Res. 2019 Jan 1;356:271-278. doi: 10.1016/j.bbr.2018.08.006. Epub 2018 Aug 9. PMID- 30070753 OWN - NLM STAT- MEDLINE DCOM- 20200617 LR - 20200617 IS - 1460-9568 (Electronic) IS - 0953-816X (Linking) VI - 49 IP - 3 DP - 2019 Feb TI - Post hoc analysis of the Exenatide-PD trial-Factors that predict response. PG - 410-421 LID - 10.1111/ejn.14096 [doi] AB - Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson's disease in a randomized, placebo-controlled trial. In addition, there were trends favouring the exenatide group in assessments of nonmotor symptoms, cognition, and quality of life. The aim of this exploratory post hoc analysis was to generate new hypotheses regarding (a) whether candidate baseline factors might predict the magnitude of response to exenatide; and (b) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, nonmotor symptoms, cognition, and quality of life after 48-weeks treatment with exenatide were evaluated among post hoc subgroups defined by age, motor phenotype, disease duration, disease severity, body mass index (BMI), and insulin resistance. In the subgroup analyses, exenatide once-weekly was associated with broadly improved outcome measures assessing motor severity, nonmotor symptoms, cognition, and quality of life across all subgroups, however, tremor-dominant phenotype and lower Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of gluacagon-like peptide-1 (GLP-1) receptor agonists in Parkinson's disease (PD). CI - (c) 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd. FAU - Athauda, Dilan AU - Athauda D AUID- ORCID: 0000-0001-8594-2483 AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, London, UK. FAU - Maclagan, Kate AU - Maclagan K AD - UCL Comprehensive Clinical Trials Unit (UCL CCTU), London, UK. FAU - Budnik, Natalia AU - Budnik N AD - Leonard Wolfson Experimental Neuroscience Centre, London, UK. FAU - Zampedri, Luca AU - Zampedri L AD - Leonard Wolfson Experimental Neuroscience Centre, London, UK. FAU - Hibbert, Steve AU - Hibbert S AD - UCL Comprehensive Clinical Trials Unit (UCL CCTU), London, UK. FAU - Aviles-Olmos, Iciar AU - Aviles-Olmos I AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, London, UK. FAU - Chowdhury, Kashfia AU - Chowdhury K AD - UCL Comprehensive Clinical Trials Unit (UCL CCTU), London, UK. FAU - Skene, Simon S AU - Skene SS AD - UCL Comprehensive Clinical Trials Unit (UCL CCTU), London, UK. AD - School of Biosciences and Medicine, University of Surrey, Guildford, UK. FAU - Limousin, Patricia AU - Limousin P AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, London, UK. FAU - Foltynie, Thomas AU - Foltynie T AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, London, UK. LA - eng GR - Michael J. Fox Foundation for Parkinson's Research/International GR - Cure Parkinson's Trust/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181006 PL - France TA - Eur J Neurosci JT - The European journal of neuroscience JID - 8918110 RN - 0 (Hypoglycemic Agents) RN - 9P1872D4OL (Exenatide) SB - IM MH - Adult MH - Aged MH - Exenatide/*therapeutic use MH - Female MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Male MH - Middle Aged MH - Parkinson Disease/*drug therapy MH - *Predictive Value of Tests MH - Randomized Controlled Trials as Topic MH - *Treatment Outcome OTO - NOTNLM OT - Foltynie Parkinson's disease OT - clinical trial OT - exenatide OT - glucagon-like peptide-1 agonist EDAT- 2018/08/03 06:00 MHDA- 2020/06/18 06:00 CRDT- 2018/08/03 06:00 PHST- 2018/04/30 00:00 [received] PHST- 2018/06/27 00:00 [revised] PHST- 2018/07/23 00:00 [accepted] PHST- 2018/08/03 06:00 [pubmed] PHST- 2020/06/18 06:00 [medline] PHST- 2018/08/03 06:00 [entrez] AID - 10.1111/ejn.14096 [doi] PST - ppublish SO - Eur J Neurosci. 2019 Feb;49(3):410-421. doi: 10.1111/ejn.14096. Epub 2018 Oct 6. PMID- 30017231 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20260127 IS - 1532-2785 (Electronic) IS - 0143-4179 (Linking) VI - 71 DP - 2018 Oct TI - Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson's disease mouse model. PG - 70-80 LID - S0143-4179(18)30068-4 [pii] LID - 10.1016/j.npep.2018.07.003 [doi] AB - Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is no recognised therapy to cure it. Recently, it has been shown that treatments to improve insulin resistance in type 2 diabetes (T2DM) may be useful for PD patients. In previous studies, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide showed good neuroprotective effects in animal models of PD. In addition, the GLP-1 mimetic exendin-4 has shown good protective effects in PD patients in a phase II clinical trial. Here, we report the protective effects of semaglutide (25 nmol/kg ip. once-daily for 7 days), a new long-acting GLP-1 analogue, in the MPTP mouse model of PD. Moreover, we compared the neuroprotective effect of semaglutide with liraglutide given at the same dose. Our work shows that both semaglutide and liraglutide improved 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor impairments. In addition, both GLP-1 analogues rescued the decrease of tyrosine hydroxylase (TH) levels, alleviated the inflammation response, reduced lipid peroxidation, inhibited the apoptosis pathway, and also increased autophagy- related protein expression, to protect dopaminergic neurons in the substantia nigra and striatum. Moreover, the long-acting GLP-1 analogue semaglutide was superior to liraglutide in most parameters measured in this study. Our results demonstrate that the new long- acting GLP-1 analogue semaglutide may be a promising treatment for PD. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Zhang, Liping AU - Zhang L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Zhang, Lingyu AU - Zhang L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Second hospital Neurology Dept., Shanxi medical University, Taiyuan, Shanxi, PR China; Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article DEP - 20180711 PL - Netherlands TA - Neuropeptides JT - Neuropeptides JID - 8103156 RN - 62340-29-8 (Glucagon-Like Peptides) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Corpus Striatum/drug effects MH - Dopaminergic Neurons/*drug effects MH - Glucagon-Like Peptides/administration & dosage/*therapeutic use MH - Lipid Peroxidation/drug effects MH - Liraglutide/administration & dosage/therapeutic use MH - MPTP Poisoning/*drug therapy MH - Mice MH - Motor Activity/*drug effects MH - Neuroprotective Agents/*therapeutic use MH - Rotarod Performance Test MH - Substantia Nigra/drug effects MH - Semaglutide OTO - NOTNLM OT - Autophagy OT - Dopamine OT - Growth factor OT - Incretin OT - Inflammation OT - Insulin EDAT- 2018/07/19 06:00 MHDA- 2018/12/12 06:00 CRDT- 2018/07/19 06:00 PHST- 2018/04/15 00:00 [received] PHST- 2018/07/09 00:00 [revised] PHST- 2018/07/09 00:00 [accepted] PHST- 2018/07/19 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/07/19 06:00 [entrez] AID - S0143-4179(18)30068-4 [pii] AID - 10.1016/j.npep.2018.07.003 [doi] PST - ppublish SO - Neuropeptides. 2018 Oct;71:70-80. doi: 10.1016/j.npep.2018.07.003. Epub 2018 Jul 11. PMID- 29916537 OWN - NLM STAT- MEDLINE DCOM- 20181029 LR - 20260127 IS - 1791-3004 (Electronic) IS - 1791-2997 (Linking) VI - 18 IP - 2 DP - 2018 Aug TI - Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats. PG - 2449-2457 LID - 10.3892/mmr.2018.9180 [doi] AB - Liraglutide is a type of glucagon‑like‑peptide 1 receptor agonist, which has been reported as a novel type of antidiabetic agent with numerous benefits, including cardiovascular and neuroprotective effects. To the best of our knowledge, few studies to date have reported the potential mechanism underlying the neuroprotective effects of liraglutide on rats with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the neuroprotective actions of liraglutide in diabetic rats and to determine the mechanisms underlying these effects. A total of 30 male T2DM Goto‑Kakizaki (GK) rats (age, 32 weeks; weight, 300‑350 g) and 10 male Wistar rats (age, 32 weeks; weight, 300‑350 g) were used in the present study. Wistar rats received vehicle treatment, and GK rats randomly received treatment with vehicle, low dose of liraglutide (75 microg/kg) or high dose of liraglutide (200 microg/kg) for 28 days. Cognitive deficits were evaluated using the Morris water maze test. The expression levels of phosphoinositide 3‑kinase (PI3K), protein kinase B (Akt), phosphorylated (p)‑Akt, AMP‑activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Beclin‑1, microtubule‑associated protein light chain 3 (LC)‑3 II, caspase‑3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein and Bcl‑2 were assessed by western blot analysis. The results demonstrated that diabetic GK rats exhibited cognitive dysfunction, whereas treatment with liraglutide alleviated the learning and memory deficits, particularly in the high‑dose liraglutide group. The expression levels of Beclin‑1 and LC‑3 II were decreased in GK rats; however, this decrease was alleviated in the presence of liraglutide. Liraglutide also reversed T2DM model‑induced increases in mTOR, and decreases in p‑AMPK, PI3K and p‑Akt expression, and modulated the expression of apoptosis‑associated proteins. Furthermore, the administration of liraglutide inhibited apoptosis and exerted a protective effect against cognitive deficits via the activation of autophagy. In conclusion, the protective effects of liraglutide may be associated with increased mTOR expression via activation of the AMPK and PI3K/Akt signaling pathways. FAU - Yang, Ying AU - Yang Y AD - Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China. FAU - Fang, Hui AU - Fang H AD - Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China. FAU - Xu, Gang AU - Xu G AD - Department of Burns and Orthopedics, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Zhen, Yanfeng AU - Zhen Y AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Zhang, Yazhong AU - Zhang Y AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Tian, Jinli AU - Tian J AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Zhang, Dandan AU - Zhang D AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Zhang, Guyue AU - Zhang G AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. FAU - Xu, Jing AU - Xu J AD - Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China. LA - eng PT - Journal Article DEP - 20180618 PL - Greece TA - Mol Med Rep JT - Molecular medicine reports JID - 101475259 RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.1.1 (mTOR protein, rat) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects MH - Cognitive Dysfunction/*drug therapy/etiology/genetics/pathology MH - Diabetes Mellitus, Type 2/complications/*drug therapy/genetics/pathology MH - Gene Expression Regulation/drug effects MH - Humans MH - Liraglutide/*administration & dosage MH - Neuroprotective Agents/administration & dosage/adverse effects MH - Phosphatidylinositol 3-Kinases/genetics MH - Protein Kinases/*genetics MH - Proto-Oncogene Proteins c-akt/genetics MH - Rats MH - Rats, Wistar MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*genetics EDAT- 2018/06/20 06:00 MHDA- 2018/10/30 06:00 CRDT- 2018/06/20 06:00 PHST- 2017/10/13 00:00 [received] PHST- 2018/02/14 00:00 [accepted] PHST- 2018/06/20 06:00 [pubmed] PHST- 2018/10/30 06:00 [medline] PHST- 2018/06/20 06:00 [entrez] AID - 10.3892/mmr.2018.9180 [doi] PST - ppublish SO - Mol Med Rep. 2018 Aug;18(2):2449-2457. doi: 10.3892/mmr.2018.9180. Epub 2018 Jun 18. PMID- 29895889 OWN - NLM STAT- MEDLINE DCOM- 20191009 LR - 20191010 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Jun 12 TI - Dual Therapy with Liraglutide and Ghrelin Promotes Brain and Peripheral Energy Metabolism in the R6/2 Mouse Model of Huntington's Disease. PG - 8961 LID - 10.1038/s41598-018-27121-w [doi] LID - 8961 AB - Neuronal loss alongside altered energy metabolism, are key features of Huntington's disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 microg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD. FAU - Duarte, Ana I AU - Duarte AI AUID- ORCID: 0000-0002-0223-7867 AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. ana.duarte@cnc.uc.pt. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. ana.duarte@cnc.uc.pt. AD - Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. ana.duarte@cnc.uc.pt. FAU - Sjogren, Marie AU - Sjogren M AD - Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. FAU - Santos, Maria S AU - Santos MS AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. AD - Life Sciences Department, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal. FAU - Oliveira, Catarina R AU - Oliveira CR AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. AD - Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. FAU - Moreira, Paula I AU - Moreira PI AUID- ORCID: 0000-0001-5177-6747 AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. AD - Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. FAU - Bjorkqvist, Maria AU - Bjorkqvist M AD - Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180612 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Ghrelin) RN - 839I73S42A (Liraglutide) SB - IM MH - Animals MH - Brain/*metabolism/pathology MH - Disease Models, Animal MH - Drug Therapy, Combination MH - Energy Metabolism/*drug effects MH - Ghrelin/*pharmacology MH - Humans MH - Huntington Disease/*drug therapy/genetics/metabolism/pathology MH - Liraglutide/*pharmacology MH - Male MH - Mice MH - Mice, Transgenic PMC - PMC5997749 COIS- The authors declare no competing interests. EDAT- 2018/06/14 06:00 MHDA- 2019/10/11 06:00 PMCR- 2018/06/12 CRDT- 2018/06/14 06:00 PHST- 2018/01/30 00:00 [received] PHST- 2018/05/29 00:00 [accepted] PHST- 2018/06/14 06:00 [entrez] PHST- 2018/06/14 06:00 [pubmed] PHST- 2019/10/11 06:00 [medline] PHST- 2018/06/12 00:00 [pmc-release] AID - 10.1038/s41598-018-27121-w [pii] AID - 27121 [pii] AID - 10.1038/s41598-018-27121-w [doi] PST - epublish SO - Sci Rep. 2018 Jun 12;8(1):8961. doi: 10.1038/s41598-018-27121-w. PMID- 29893488 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20260127 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 20 IP - 11 DP - 2018 Nov TI - Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial. PG - 2565-2573 LID - 10.1111/dom.13422 [doi] AB - AIMS: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). METHODS: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). RESULTS: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m(2) , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. CONCLUSIONS: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D. CI - (c) 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Korsatko, Stefan AU - Korsatko S AD - Department of Internal Medicine, Medical University of Graz, Graz, Austria. FAU - Jensen, Lene AU - Jensen L AUID- ORCID: 0000-0002-7111-2486 AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Brunner, Martina AU - Brunner M AD - Department of Internal Medicine, Medical University of Graz, Graz, Austria. FAU - Sach-Friedl, Stefanie AU - Sach-Friedl S AD - Department of Internal Medicine, Medical University of Graz, Graz, Austria. FAU - Tarp, Maja D AU - Tarp MD AD - Novo Nordisk A/S, Aalborg, Denmark. FAU - Holst, Anders G AU - Holst AG AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Heller, Simon R AU - Heller SR AUID- ORCID: 0000-0002-2425-9565 AD - University of Sheffield Medical School, Sheffield, UK. FAU - Pieber, Thomas R AU - Pieber TR AUID- ORCID: 0000-0003-3554-0405 AD - Department of Internal Medicine, Medical University of Graz, Graz, Austria. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180716 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Blood Glucose) RN - 62340-29-8 (Glucagon-Like Peptides) RN - 0 (Placebos) RN - 53AXN4NNHX (Semaglutide) SB - IM MH - Adult MH - Blood Glucose/drug effects/metabolism MH - Cross-Over Studies MH - Diabetes Mellitus, Type 2/*complications/*drug therapy/metabolism MH - Double-Blind Method MH - Drug Administration Schedule MH - Female MH - Glucagon-Like Peptides/*administration & dosage/pharmacology MH - Humans MH - Hypoglycemia/blood/chemically induced/epidemiology/*metabolism MH - Male MH - Middle Aged MH - Placebos MH - Semaglutide PMC - PMC6221089 OTO - NOTNLM OT - GLP-1 OT - GLP-1 analogue OT - hypoglycaemia OT - type 2 diabetes COIS- No potential conflicts of interest relevant to this article are reported by S.K., M.B. or S.S. S.R.H. has served on speaker panels for AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi Aventis and Takeda, for which he has received personal remuneration. He has consulted for Boeringher Ingelheim, Eli Lilly, Novo Nordisk and Takeda, for which his institution has received remuneration. T.R.P. declares Board membership for Adocia, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi, and institutional grants from AstraZeneca and Novo Nordisk, and payment for lectures/speakers bureaus from Novo Nordisk. L.J., M.D.T. and A.G.H. are employed by and hold stock in Novo Nordisk. EDAT- 2018/06/13 06:00 MHDA- 2019/04/16 06:00 PMCR- 2018/11/07 CRDT- 2018/06/13 06:00 PHST- 2018/03/05 00:00 [received] PHST- 2018/06/08 00:00 [revised] PHST- 2018/06/09 00:00 [accepted] PHST- 2018/06/13 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2018/06/13 06:00 [entrez] PHST- 2018/11/07 00:00 [pmc-release] AID - DOM13422 [pii] AID - 10.1111/dom.13422 [doi] PST - ppublish SO - Diabetes Obes Metab. 2018 Nov;20(11):2565-2573. doi: 10.1111/dom.13422. Epub 2018 Jul 16. PMID- 29864411 OWN - NLM STAT- MEDLINE DCOM- 20181029 LR - 20260127 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 833 DP - 2018 Aug 15 TI - Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways. PG - 145-154 LID - S0014-2999(18)30315-7 [pii] LID - 10.1016/j.ejphar.2018.05.045 [doi] AB - Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity. Adult male Wistar rats were subjected to sham operation or global cerebral I/R injury. Rats were administered the following drugs in two scheduled doses at 1 h and 24 h after reperfusion: lixisenatide (1 and 10 nmole/kg), lixisenatide plus GLP-1 receptor (GLP-1R) antagonist (exendin(9-39)), and pentoxiphylline. Comparable to pentoxiphylline; both doses of lixisenatide produced a significant reduction in infarct volume and amelioration of neurobehavioural functions along with suppression of oxidative stress parameters (catalase, reduced glutathione, malondialdehyde and NO), inflammatory marker (tumor necrosis factor-alpha) and apoptotic marker (caspase-3) in ischemic rat brains. However, these effects weren'tinhibited by GLP-1R antagonist, exendin(9-39), indicating that they are independent on GLP-1R mediation. Also, lixisenatide upregulated protein expression of cerebral endothelial nitric oxide synthase and the angiogenic marker, vascular endothelial growth factor. It's worth noting that this effect was blocked by exendin(9-39). Overall, these data indicated that lixisenatide may offer a promising approach for alleviating cerebral I/R injury via different mechanisms that could be mediated, in part, through GLP-1R. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Abdel-Latif, Rania G AU - Abdel-Latif RG AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt. FAU - Heeba, Gehan H AU - Heeba GH AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt. Electronic address: gehan_heeba@mu.edu.eg. FAU - Taye, Ashraf AU - Taye A AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt. FAU - Khalifa, Mohamed M A AU - Khalifa MMA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt. LA - eng PT - Journal Article DEP - 20180601 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - EC 3.4.22.- (Caspase 3) RN - EC 1.11.1.6 (Catalase) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - GAN16C9B8O (Glutathione) RN - 0 (Neuroprotective Agents) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (exendin (1-9), Ser(2)-) RN - 0 (vascular endothelial growth factor A, rat) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) RN - EC 1.14.13.39 (Nos3 protein, rat) RN - EC 3.4.22.- (Casp3 protein, rat) SB - IM MH - Animals MH - Behavior, Animal/drug effects MH - Brain/drug effects/metabolism/pathology MH - Brain Ischemia/*drug therapy/metabolism/pathology MH - Caspase 3/metabolism MH - Catalase/metabolism MH - Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors/*metabolism MH - Glutathione/metabolism MH - Male MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Nitric Oxide/metabolism MH - Nitric Oxide Synthase Type III/metabolism MH - Peptide Fragments/pharmacology MH - Peptides/pharmacology/*therapeutic use MH - Rats, Wistar MH - Reperfusion Injury/*drug therapy/metabolism/pathology MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/metabolism MH - Vascular Endothelial Growth Factor A/metabolism MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - Cerebral ischemia/reperfusion OT - Exendin(9-39) OT - GLP-1 OT - Lixisenatide OT - Stroke EDAT- 2018/06/05 06:00 MHDA- 2018/10/30 06:00 CRDT- 2018/06/05 06:00 PHST- 2018/01/05 00:00 [received] PHST- 2018/05/25 00:00 [revised] PHST- 2018/05/29 00:00 [accepted] PHST- 2018/06/05 06:00 [pubmed] PHST- 2018/10/30 06:00 [medline] PHST- 2018/06/05 06:00 [entrez] AID - S0014-2999(18)30315-7 [pii] AID - 10.1016/j.ejphar.2018.05.045 [doi] PST - ppublish SO - Eur J Pharmacol. 2018 Aug 15;833:145-154. doi: 10.1016/j.ejphar.2018.05.045. Epub 2018 Jun 1. PMID- 29765322 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 9 DP - 2018 TI - Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes. PG - 423 LID - 10.3389/fphar.2018.00423 [doi] LID - 423 AB - Ginseng, one of the oldest traditional Chinese medicinal herbs, has been used widely in China and Asia for thousands of years. Ginsenosides extracted from ginseng, which is derived from the roots and rhizomes of Panax ginseng C. A. Meyer, have been used in China as an adjuvant in the treatment of diabetes mellitus. Owing to the technical complexity of ginsenoside production, the total ginsenosides are generally extracted. Accumulating evidence has shown that ginsenosides exert antidiabetic effects. In vivo and in vitro tests revealed the potential of ginsenoside Rg1, Rg3, Rg5, Rb1, Rb2, Rb3, compound K, Rk1, Re, ginseng total saponins, malonyl ginsenosides, Rd, Rh2, F2, protopanaxadiol (PPD) and protopanaxatriol (PPT)-type saponins to treat diabetes and its complications, including type 1 diabetes mellitus, type 2 diabetes mellitus, diabetic nephropathy, diabetic cognitive dysfunction, type 2 diabetes mellitus with fatty liver disease, diabetic cerebral infarction, diabetic cardiomyopathy, and diabetic erectile dysfunction. Many effects are attributed to ginsenosides, including gluconeogenesis reduction, improvement of insulin resistance, glucose transport, insulinotropic action, islet cell protection, hepatoprotective activity, anti-inflammatory effect, myocardial protection, lipid regulation, improvement of glucose tolerance, antioxidation, improvement of erectile dysfunction, regulation of gut flora metabolism, neuroprotection, anti-angiopathy, anti-neurotoxic effects, immunosuppression, and renoprotection effect. The molecular targets of these effects mainly contains GLUTs, SGLT1, GLP-1, FoxO1, TNF-alpha, IL-6, caspase-3, bcl-2, MDA, SOD, STAT5-PPAR gamma pathway, PI3K/Akt pathway, AMPK-JNK pathway, NF-kappaB pathway, and endoplasmic reticulum stress. Rg1, Rg3, Rb1, and compound K demonstrated the most promising therapeutic prospects as potential adjuvant medicines for the treatment of diabetes. This paper highlights the underlying pharmacological mechanisms of the anti-diabetic effects of ginsenosides. FAU - Bai, Litao AU - Bai L AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Gao, Jialiang AU - Gao J AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Wei, Fan AU - Wei F AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Zhao, Jing AU - Zhao J AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Wang, Danwei AU - Wang D AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Wei, Junping AU - Wei J AD - Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. LA - eng PT - Journal Article PT - Review DEP - 20180501 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC5938666 OTO - NOTNLM OT - anti-diabetic effect OT - diabetes mellitus OT - ginsenoside OT - herbal active compounds OT - herbal medicine EDAT- 2018/05/17 06:00 MHDA- 2018/05/17 06:01 PMCR- 2018/05/01 CRDT- 2018/05/17 06:00 PHST- 2018/02/12 00:00 [received] PHST- 2018/04/11 00:00 [accepted] PHST- 2018/05/17 06:00 [entrez] PHST- 2018/05/17 06:00 [pubmed] PHST- 2018/05/17 06:01 [medline] PHST- 2018/05/01 00:00 [pmc-release] AID - 10.3389/fphar.2018.00423 [doi] PST - epublish SO - Front Pharmacol. 2018 May 1;9:423. doi: 10.3389/fphar.2018.00423. eCollection 2018. PMID- 29614684 OWN - NLM STAT- MEDLINE DCOM- 20190528 LR - 20190606 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 62 IP - 4 DP - 2018 TI - Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. PG - 1725-1736 LID - 10.3233/JAD-171041 [doi] AB - Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3beta, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated. FAU - Popelova, Andrea AU - Popelova A AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Prazienkova, Veronika AU - Prazienkova V AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Neprasova, Barbora AU - Neprasova B AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. AD - Institute of Physiology, AS CR, Prague, Czech Republic. FAU - Kasperova, Barbora Judita AU - Kasperova BJ AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Hruba, Lucie AU - Hruba L AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Holubova, Martina AU - Holubova M AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Zemenova, Jana AU - Zemenova J AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. AD - University of Chemistry and Technology, Prague, Czech Republic. FAU - Blum, David AU - Blum D AD - Universite Lille, INSERM, CHU Lille, UMR - S 1172 - Jean Pierre Aubert Research Centre, Alzheimer and Tauopathies, Lille, France. FAU - Zelezna, Blanka AU - Zelezna B AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Galas, Marie-Christine AU - Galas MC AD - Universite Lille, INSERM, CHU Lille, UMR - S 1172 - Jean Pierre Aubert Research Centre, Alzheimer and Tauopathies, Lille, France. FAU - Kunes, Jaroslav AU - Kunes J AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. AD - Institute of Physiology, AS CR, Prague, Czech Republic. FAU - Maletinska, Lenka AU - Maletinska L AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Mapt protein, mouse) RN - 0 (Neuroprotective Agents) RN - 0 (Prolactin-Releasing Hormone) RN - 0 (palm11-PrRP31) RN - 0 (tau Proteins) SB - IM MH - Animals MH - Disease Models, Animal MH - Female MH - Hippocampus/drug effects/metabolism/pathology MH - Maze Learning/drug effects/physiology MH - Memory Disorders/*drug therapy/metabolism/pathology MH - Memory, Short-Term/drug effects/physiology MH - Mice, Transgenic MH - Neuroprotective Agents/*pharmacology MH - Phosphorylation/drug effects MH - Prolactin-Releasing Hormone/*analogs & derivatives/pharmacology/therapeutic use MH - Spatial Memory/drug effects/physiology MH - Tauopathies/*drug therapy/metabolism/pathology/psychology MH - tau Proteins/*metabolism OTO - NOTNLM OT - Alzheimer's disease OT - THY-Tau22 mice OT - palm11-PrRP31 OT - spatial memory OT - synaptic plasticity OT - tau hyperphosphorylation EDAT- 2018/04/05 06:00 MHDA- 2019/05/29 06:00 CRDT- 2018/04/05 06:00 PHST- 2018/04/05 06:00 [entrez] PHST- 2018/04/05 06:00 [pubmed] PHST- 2019/05/29 06:00 [medline] AID - JAD171041 [pii] AID - 10.3233/JAD-171041 [doi] PST - ppublish SO - J Alzheimers Dis. 2018;62(4):1725-1736. doi: 10.3233/JAD-171041. PMID- 29603541 OWN - NLM STAT- MEDLINE DCOM- 20190116 LR - 20190116 IS - 1879-0844 (Electronic) IS - 1388-9842 (Linking) VI - 20 IP - 6 DP - 2018 Jun TI - Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure. PG - 973-977 LID - 10.1002/ejhf.1185 [doi] AB - Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes. CI - (c) 2018 The Authors. European Journal of Heart Failure (c) 2018 European Society of Cardiology. FAU - Packer, Milton AU - Packer M AD - Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA. LA - eng PT - Journal Article PT - Review DEP - 20180330 PL - England TA - Eur J Heart Fail JT - European journal of heart failure JID - 100887595 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 3.4.24.11 (Neprilysin) SB - IM MH - Blood Glucose/*metabolism MH - Diabetes Mellitus, Type 2/complications/*drug therapy/metabolism MH - Glucagon-Like Peptide 1/analogs & derivatives/*therapeutic use MH - Heart Failure/etiology/metabolism/*prevention & control MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Neprilysin/*antagonists & inhibitors/metabolism OTO - NOTNLM OT - Glucagon-like peptide-1 OT - Incretin-based drugs OT - Neprilysin EDAT- 2018/04/01 06:00 MHDA- 2019/01/17 06:00 CRDT- 2018/04/01 06:00 PHST- 2017/12/08 00:00 [received] PHST- 2018/01/23 00:00 [revised] PHST- 2018/02/26 00:00 [accepted] PHST- 2018/04/01 06:00 [pubmed] PHST- 2019/01/17 06:00 [medline] PHST- 2018/04/01 06:00 [entrez] AID - 10.1002/ejhf.1185 [doi] PST - ppublish SO - Eur J Heart Fail. 2018 Jun;20(6):973-977. doi: 10.1002/ejhf.1185. Epub 2018 Mar 30. PMID- 29598932 OWN - NLM STAT- MEDLINE DCOM- 20180926 LR - 20180926 IS - 1878-0334 (Electronic) IS - 1871-4021 (Linking) VI - 12 IP - 3 DP - 2018 May TI - Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease. PG - 469-475 LID - S1871-4021(17)30478-2 [pii] LID - 10.1016/j.dsx.2018.03.002 [doi] AB - Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone derived from the proglucagon gene and secreted in the distal small intestine when food enters the duodenum. GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, and subsequently transported to a large number of regions in the CNS. Neuronal cells in nucleus tractus solitarius (NTS) can synthesize GLP-1 and extends to hypothalamus, some thalamic and cortical areas. A G protein coupled receptor (GPCR) provides the majority of GLP-1 actions. GLP-1 receptor activation triggers some in vivo signaling pathways. GLP-1 receptor agonists (GLP-1 RA) are used in the treatment diabetes and obesity. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, decreases food intake, reduces appetite, delays gastric emptying, provides weight reduction, and protects beta cells from apoptosis. Alzheimer's disease (AD) is the most prevalent form of dementia. It is characterized by cognitive insufficiencies and behavioral changes that impact memory and learning abilities, daily functioning and quality of life. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of the T2DM, have also been demonstrated to have significant impact on cognitive impairment. It is thought that GLP-1 affects neurological and cognitive functions, as well as its regulatory effect on glucose metabolism. The pathophysiological relationship between GLP-1 and AD is discussed in this review. CI - Copyright (c) 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved. FAU - Yildirim Simsir, Ilgin AU - Yildirim Simsir I AD - Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey. Electronic address: ilginyildirim@hotmail.com. FAU - Soyaltin, Utku Erdem AU - Soyaltin UE AD - Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey. FAU - Cetinkalp, Sevki AU - Cetinkalp S AD - Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey. LA - eng PT - Journal Article PT - Review DEP - 20180316 PL - Netherlands TA - Diabetes Metab Syndr JT - Diabetes & metabolic syndrome JID - 101462250 RN - 0 (Peptide Fragments) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*drug therapy/etiology/*metabolism MH - Diabetes Mellitus, Type 2/*complications MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Peptide Fragments/*agonists/*metabolism MH - Quality of Life OTO - NOTNLM OT - Alzheimer's disease OT - Diabetes OT - GLP-1 OT - Nervous system EDAT- 2018/03/31 06:00 MHDA- 2018/09/27 06:00 CRDT- 2018/03/31 06:00 PHST- 2017/12/23 00:00 [received] PHST- 2018/03/15 00:00 [accepted] PHST- 2018/03/31 06:00 [pubmed] PHST- 2018/09/27 06:00 [medline] PHST- 2018/03/31 06:00 [entrez] AID - S1871-4021(17)30478-2 [pii] AID - 10.1016/j.dsx.2018.03.002 [doi] PST - ppublish SO - Diabetes Metab Syndr. 2018 May;12(3):469-475. doi: 10.1016/j.dsx.2018.03.002. Epub 2018 Mar 16. PMID- 29551659 OWN - NLM STAT- MEDLINE DCOM- 20181009 LR - 20181022 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 827 DP - 2018 May 15 TI - DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease. PG - 215-226 LID - S0014-2999(18)30178-X [pii] LID - 10.1016/j.ejphar.2018.03.024 [doi] AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3beta in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Cao, Yue AU - Cao Y AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. FAU - Hu, Meng-Ming AU - Hu MM AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Wang, Ting AU - Wang T AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Zhao, Fang AU - Zhao F AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Bai, Yu AU - Bai Y AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Zhang, Jun AU - Zhang J AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. Electronic address: jinshunqi2009@163.com. LA - eng PT - Journal Article DEP - 20180315 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (DA5-CH peptide) RN - 0 (Peptides) RN - 0 (tau Proteins) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*complications MH - Animals MH - Cognition/drug effects MH - Cognitive Dysfunction/complications/*drug therapy MH - Disease Models, Animal MH - Female MH - Gastric Inhibitory Polypeptide/*agonists MH - Glucagon-Like Peptide 1/*agonists MH - Male MH - Maze Learning/drug effects MH - Memory, Short-Term/drug effects MH - Mice MH - Mice, Transgenic MH - Peptides/*pharmacology/therapeutic use MH - Phosphorylation/drug effects MH - Signal Transduction/drug effects MH - tau Proteins/metabolism OTO - NOTNLM OT - APP/PS1 AD mice OT - Amyloid-beta protein OT - GLP-1/GIP dual agonist OT - L-LTP OT - Long term memory OT - PI3K/AKT/GSK3beta OT - Phosphorylated tau protein OT - Working memory EDAT- 2018/03/20 06:00 MHDA- 2018/10/10 06:00 CRDT- 2018/03/20 06:00 PHST- 2017/11/24 00:00 [received] PHST- 2018/03/09 00:00 [revised] PHST- 2018/03/14 00:00 [accepted] PHST- 2018/03/20 06:00 [pubmed] PHST- 2018/10/10 06:00 [medline] PHST- 2018/03/20 06:00 [entrez] AID - S0014-2999(18)30178-X [pii] AID - 10.1016/j.ejphar.2018.03.024 [doi] PST - ppublish SO - Eur J Pharmacol. 2018 May 15;827:215-226. doi: 10.1016/j.ejphar.2018.03.024. Epub 2018 Mar 15. PMID- 29481915 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 136 IP - Pt B DP - 2018 Jul 1 TI - Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists? PG - 335-342 LID - S0028-3908(18)30054-6 [pii] LID - 10.1016/j.neuropharm.2018.01.048 [doi] AB - Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains. Conversely, weight-loss interventions, such as physical exercise and bariatric surgery, have been shown to beneficially affect cognitive function. This convergent phenomenology suggests that currently available agents that target metabolic systems may also be capable of mitigating deficits in cognitive functions, and are, therefore, candidates for repurposing. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors (GLP-1R) are widely expressed in the central nervous system. Activation of GLP-1R leads to facilitation of glucose utilization and antiapoptotic effects in various organs. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1, including protection from cell death, promotion of neuronal differentiation and proliferation; and facilitation of long-term potentiation. Liraglutide is a GLP-1R agonist that has been approved for the treatment of type 2 diabetes mellitus and obesity. Convergent preclinical and clinical evidence, including a proof-of-concept pilot study from group, has suggested that liraglutide may improve objective measures of cognitive function in adults with mood disorders. The safety and availability of GLP-1R agonists indicate that they are promising candidates for repurposing, and that they may be viable therapeutic options for mood disorders. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Mansur, Rodrigo B AU - Mansur RB AD - Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address: Rodrigo.mansur@uhn.ca. FAU - Lee, Yena AU - Lee Y AD - Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Canada. FAU - Subramaniapillai, Mehala AU - Subramaniapillai M AD - Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada. FAU - Brietzke, Elisa AU - Brietzke E AD - Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada; Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - McIntyre, Roger S AU - McIntyre RS AD - Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada. LA - eng PT - Journal Article PT - Review DEP - 20180223 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Cognitive Dysfunction/epidemiology/*metabolism MH - Comorbidity MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Metabolic Diseases/epidemiology/*metabolism/psychology MH - Mood Disorders/epidemiology/*metabolism/*psychology MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Bipolar disorder OT - GLP-1R agonists OT - Glucagon-like peptide-1 OT - Insulin resistance OT - Liraglutide OT - Major depressive disorder OT - Obesity OT - Weight loss EDAT- 2018/02/27 06:00 MHDA- 2019/01/18 06:00 CRDT- 2018/02/27 06:00 PHST- 2017/10/20 00:00 [received] PHST- 2018/01/26 00:00 [revised] PHST- 2018/01/30 00:00 [accepted] PHST- 2018/02/27 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2018/02/27 06:00 [entrez] AID - S0028-3908(18)30054-6 [pii] AID - 10.1016/j.neuropharm.2018.01.048 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 1;136(Pt B):335-342. doi: 10.1016/j.neuropharm.2018.01.048. Epub 2018 Feb 23. PMID- 29473979 OWN - NLM STAT- MEDLINE DCOM- 20190416 LR - 20190416 IS - 1098-1063 (Electronic) IS - 1050-9631 (Linking) VI - 28 IP - 5 DP - 2018 May TI - A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease. PG - 358-372 LID - 10.1002/hipo.22837 [doi] AB - Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-beta (Abeta) and phosphorylated tau aggregates, and upregulated the expression levels of (S133) p-CREB, (T286) p-CAMKII and (S9) p-GSK3beta in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD. CI - (c) 2018 Wiley Periodicals, Inc. FAU - Li, Tian AU - Li T AUID- ORCID: 0000-0002-1444-832X AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Jiao, Juan-Juan AU - Jiao JJ AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, LA1 4YQ, United Kingdom. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Zhang, Jun AU - Zhang J AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Tong, Jia-Qing AU - Tong JQ AD - Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. FAU - Dong, Xue-Fan AU - Dong XF AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Qu, Xue-Song AU - Qu XS AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Cao, Yue AU - Cao Y AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Immunology and Microbiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Su, Qiang AU - Su Q AD - Department of Neurology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Neurobiology and National Key Discipline of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180305 PL - United States TA - Hippocampus JT - Hippocampus JID - 9108167 RN - 0 (Blood Glucose) RN - 0 (Neuroprotective Agents) RN - 0 (Nootropic Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) SB - IM MH - Alzheimer Disease/*drug therapy/pathology/psychology MH - Animals MH - Blood Glucose/drug effects MH - Body Weight/drug effects MH - Cognition Disorders/*drug therapy/etiology/pathology MH - Disease Models, Animal MH - Female MH - Gene Expression/drug effects MH - Glucagon-Like Peptide 1/*agonists MH - Hippocampus/drug effects/pathology MH - Long-Term Potentiation/drug effects MH - Male MH - Memory/drug effects MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neuroprotective Agents/*pharmacology MH - Nootropic Agents/pharmacology MH - Receptors, Gastrointestinal Hormone/*agonists MH - Receptors, Glucagon/*agonists OTO - NOTNLM OT - 3xTg-AD mice OT - GLP-1/GIP/Gcg triagonist OT - amyloid-beta (Abeta) protein OT - learning and memory OT - long-term potentiation OT - p-CAMKII OT - p-CREB OT - p-GSK3beta OT - phosphorylated tau protein EDAT- 2018/02/24 06:00 MHDA- 2019/04/17 06:00 CRDT- 2018/02/24 06:00 PHST- 2017/11/02 00:00 [received] PHST- 2018/02/15 00:00 [revised] PHST- 2018/02/17 00:00 [accepted] PHST- 2018/02/24 06:00 [pubmed] PHST- 2019/04/17 06:00 [medline] PHST- 2018/02/24 06:00 [entrez] AID - 10.1002/hipo.22837 [doi] PST - ppublish SO - Hippocampus. 2018 May;28(5):358-372. doi: 10.1002/hipo.22837. Epub 2018 Mar 5. PMID- 29462693 OWN - NLM STAT- MEDLINE DCOM- 20181105 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 133 DP - 2018 May 1 TI - Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease. PG - 385-394 LID - S0028-3908(18)30069-8 [pii] LID - 10.1016/j.neuropharm.2018.02.012 [doi] AB - Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4 x 25 mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Feng, Peng AU - Feng P AD - Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, China; Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Zhang, Xiangjian AU - Zhang X AD - Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, China; Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, Shijiazhuang, China. Electronic address: zhang6xj@heinfo.net. FAU - Li, Dongfang AU - Li D AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Ji, Chenhui AU - Ji C AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Yuan, Ziyue AU - Yuan Z AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Wang, Ruifang AU - Wang R AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Xue, Guofang AU - Xue G AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Li, Guanglai AU - Li G AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. FAU - Holscher, Christian AU - Holscher C AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China; Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, LA1 4YQ, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180217 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Blood Glucose) RN - 0 (Cytokines) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Neurotoxins) RN - 0 (Peptides) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 839I73S42A (Liraglutide) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology MH - Animals MH - Blood Glucose/drug effects MH - Body Weight/drug effects MH - Cytokines/metabolism MH - Disease Models, Animal MH - Glial Cell Line-Derived Neurotrophic Factor/metabolism MH - Glucagon-Like Peptide-1 Receptor/chemistry/metabolism MH - Hypoglycemic Agents/therapeutic use MH - Liraglutide/therapeutic use MH - MPTP Poisoning/*drug therapy MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Neuroprotective Agents/*therapeutic use MH - Neurotoxins/toxicity MH - Peptides/*therapeutic use MH - Receptors, Gastrointestinal Hormone/*agonists/chemistry/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Brain OT - Dopamine OT - Growth factor OT - Incretins OT - Inflammation OT - Insulin EDAT- 2018/02/21 06:00 MHDA- 2018/11/06 06:00 CRDT- 2018/02/21 06:00 PHST- 2017/10/09 00:00 [received] PHST- 2018/02/13 00:00 [revised] PHST- 2018/02/14 00:00 [accepted] PHST- 2018/02/21 06:00 [pubmed] PHST- 2018/11/06 06:00 [medline] PHST- 2018/02/21 06:00 [entrez] AID - S0028-3908(18)30069-8 [pii] AID - 10.1016/j.neuropharm.2018.02.012 [doi] PST - ppublish SO - Neuropharmacology. 2018 May 1;133:385-394. doi: 10.1016/j.neuropharm.2018.02.012. Epub 2018 Feb 17. PMID- 29435980 OWN - NLM STAT- MEDLINE DCOM- 20191017 LR - 20191017 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 245 IP - 1 DP - 2018 May TI - The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease. PG - 85-100 LID - 10.1002/path.5056 [doi] AB - Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-beta oligomers (AbetaOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AbetaOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. CI - (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. FAU - Batista, Andre F AU - Batista AF AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Forny-Germano, Leticia AU - Forny-Germano L AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Clarke, Julia R AU - Clarke JR AD - School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Lyra E Silva, Natalia M AU - Lyra E Silva NM AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Brito-Moreira, Jordano AU - Brito-Moreira J AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Boehnke, Susan E AU - Boehnke SE AD - Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. FAU - Winterborn, Andrew AU - Winterborn A AD - Animal Care Service, Queen's University, Kingston, Ontario, Canada. FAU - Coe, Brian C AU - Coe BC AD - Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. FAU - Lablans, Ann AU - Lablans A AD - Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. FAU - Vital, Juliana F AU - Vital JF AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Marques, Suelen A AU - Marques SA AD - Departament of Neurobiology, Fluminense Federal University, Niteroi, Brazil. FAU - Martinez, Ana Mb AU - Martinez AM AD - Department of Pathology, Faculty of Medicine, Hospital Universitario Clementino Fraga Filho, UFRJ, Rio de Janeiro, Brazil. FAU - Gralle, Matthias AU - Gralle M AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, UK. FAU - Klein, William L AU - Klein WL AD - Department of Neurobiology, Northwestern University, Evanston, Illinois, USA. FAU - Houzel, Jean-Christophe AU - Houzel JC AD - Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Ferreira, Sergio T AU - Ferreira ST AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Munoz, Douglas P AU - Munoz DP AD - Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. FAU - De Felice, Fernanda G AU - De Felice FG AUID- ORCID: 0000-0001-8358-0589 AD - Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. AD - Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. LA - eng GR - CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180402 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - EC 2.7.10.1 (Receptor, Insulin) SB - IM MH - Alzheimer Disease/metabolism MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Cognitive Dysfunction/*drug therapy MH - Disease Models, Animal MH - Hippocampus/drug effects MH - Hypoglycemic Agents/pharmacology MH - Liraglutide/*pharmacology MH - Male MH - Memory/*drug effects MH - Mice MH - Receptor, Insulin/*drug effects/metabolism MH - Synapses/drug effects/*pathology PMC - PMC5947670 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 OT - PKA signaling OT - diabetes OT - insulin receptors OT - liraglutide OT - neurodegeneration OT - non-human primates OT - synapse damage OT - tau pathology EDAT- 2018/02/13 06:00 MHDA- 2019/10/18 06:00 PMCR- 2018/05/11 CRDT- 2018/02/14 06:00 PHST- 2017/08/28 00:00 [received] PHST- 2018/01/13 00:00 [revised] PHST- 2018/02/05 00:00 [accepted] PHST- 2018/02/13 06:00 [pubmed] PHST- 2019/10/18 06:00 [medline] PHST- 2018/02/14 06:00 [entrez] PHST- 2018/05/11 00:00 [pmc-release] AID - PATH5056 [pii] AID - 10.1002/path.5056 [doi] PST - ppublish SO - J Pathol. 2018 May;245(1):85-100. doi: 10.1002/path.5056. Epub 2018 Apr 2. PMID- 29421245 OWN - NLM STAT- MEDLINE DCOM- 20190312 LR - 20190312 IS - 1873-2747 (Electronic) IS - 0361-9230 (Linking) VI - 139 DP - 2018 May TI - Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin. PG - 67-80 LID - S0361-9230(17)30300-3 [pii] LID - 10.1016/j.brainresbull.2018.02.002 [doi] AB - BACKGROUND: Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. AIMS: to study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. METHODS: A total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-alpha) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. RESULTS: Compared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-alpha. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation of its protein level, increase in MDA, area of degenerated neurons and area of glial cells and reduction in area % of synaptophysin immunoexpression. These changes were paralleled with significant deterioration in spatial working memory and locomotion. Treatment of diabetic rats with Ex-4 reversed all these changes. CONCLUSION: T2DM has a negative impact on cognitive functions through different pathological and subcellular mechanisms. The current study provides evidence for involvement of BDNF and brain Visfatin in T2DM- associated cognitive dysfunction. BDNF and brain Visfatin were also found to contribute to the neuro-protective effect of Ex-4 via modulation of inflammation, oxidative stress, neuro-degeneration and synaptic function. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Abdelwahed, O M AU - Abdelwahed OM AD - Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: Omaima.M.Awadallah@kasralainy.edu.eg. FAU - Tork, O M AU - Tork OM AD - Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt. FAU - Gamal El Din, M M AU - Gamal El Din MM AD - Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt. FAU - Rashed, L AU - Rashed L AD - Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt. FAU - Zickri, M AU - Zickri M AD - Department of Medical Histology and Cell Biology, Faculty of Medicine, Cairo University, Cairo, Egypt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180205 PL - United States TA - Brain Res Bull JT - Brain research bulletin JID - 7605818 RN - 0 (Anti-Obesity Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Tumor Necrosis Factor-alpha) RN - 4Y8F71G49Q (Malondialdehyde) RN - 9P1872D4OL (Exenatide) RN - EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase) SB - IM MH - Animals MH - Anti-Obesity Agents/*therapeutic use MH - Brain/drug effects/*metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cognition Disorders/*drug therapy/etiology MH - Diabetes Mellitus, Type 2/complications MH - Disease Models, Animal MH - Exenatide/*therapeutic use MH - Male MH - Malondialdehyde/metabolism MH - Nicotinamide Phosphoribosyltransferase/*metabolism MH - Rats MH - Rats, Wistar MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Brain derived neurotrophic factor (BDNF) OT - Cognitive functions OT - Diabetes mellitus OT - Exendin-4 OT - Synaptophysin OT - Visfatin EDAT- 2018/02/09 06:00 MHDA- 2019/03/13 06:00 CRDT- 2018/02/09 06:00 PHST- 2017/05/24 00:00 [received] PHST- 2017/12/17 00:00 [revised] PHST- 2018/02/01 00:00 [accepted] PHST- 2018/02/09 06:00 [pubmed] PHST- 2019/03/13 06:00 [medline] PHST- 2018/02/09 06:00 [entrez] AID - S0361-9230(17)30300-3 [pii] AID - 10.1016/j.brainresbull.2018.02.002 [doi] PST - ppublish SO - Brain Res Bull. 2018 May;139:67-80. doi: 10.1016/j.brainresbull.2018.02.002. Epub 2018 Feb 5. PMID- 29412810 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20250103 IS - 1873-5169 (Electronic) IS - 0196-9781 (Linking) VI - 100 DP - 2018 Feb TI - GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes. PG - 101-107 LID - S0196-9781(17)30363-7 [pii] LID - 10.1016/j.peptides.2017.11.017 [doi] AB - Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide-1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Gault, Victor A AU - Gault VA AD - School of Biomedical Sciences, University of University, Coleraine, BT52 1SA, UK. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Sciences, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PT - Review PL - United States TA - Peptides JT - Peptides JID - 8008690 RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 9100L32L2N (Metformin) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Blood Glucose/drug effects MH - Brain/drug effects/pathology MH - Cognition/*drug effects MH - Diabetes Mellitus, Type 2/drug therapy/genetics/pathology MH - Disease Models, Animal MH - Glucagon-Like Peptide-1 Receptor/genetics/*therapeutic use MH - Humans MH - Incretins/metabolism MH - Metformin/therapeutic use MH - Neurodegenerative Diseases/*drug therapy/metabolism/pathology MH - Neuroprotective Agents/agonists/*therapeutic use MH - Oxidative Stress/drug effects MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Brain OT - GIP OT - GLP-1 OT - Growth factors OT - Inflammation OT - Neurodegeneration OT - Neurons EDAT- 2018/02/08 06:00 MHDA- 2018/12/12 06:00 CRDT- 2018/02/08 06:00 PHST- 2017/09/26 00:00 [received] PHST- 2017/11/24 00:00 [revised] PHST- 2017/11/24 00:00 [accepted] PHST- 2018/02/08 06:00 [entrez] PHST- 2018/02/08 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] AID - S0196-9781(17)30363-7 [pii] AID - 10.1016/j.peptides.2017.11.017 [doi] PST - ppublish SO - Peptides. 2018 Feb;100:101-107. doi: 10.1016/j.peptides.2017.11.017. PMID- 29402504 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 136 IP - Pt B DP - 2018 Jul 1 TI - Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. PG - 251-259 LID - S0028-3908(18)30040-6 [pii] LID - 10.1016/j.neuropharm.2018.01.040 [doi] AB - Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson' disease. Novel dual GLP-1/GIP receptor agonists have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the blood -brain barrier. They show clear neuroprotective effects by reducing inflammation and oxidative stress and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, dopaminergic neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PT - Review DEP - 20180131 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/*drug therapy/metabolism MH - Animals MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Parkinson Disease/*drug therapy/metabolism MH - Receptors, Gastrointestinal Hormone/*agonists/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - GIP OT - GLP-1 OT - Growth factors OT - Inflammation OT - Insulin OT - Neurodegeneration EDAT- 2018/02/07 06:00 MHDA- 2019/01/18 06:00 CRDT- 2018/02/07 06:00 PHST- 2017/08/29 00:00 [received] PHST- 2018/01/10 00:00 [revised] PHST- 2018/01/27 00:00 [accepted] PHST- 2018/02/07 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2018/02/07 06:00 [entrez] AID - S0028-3908(18)30040-6 [pii] AID - 10.1016/j.neuropharm.2018.01.040 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 1;136(Pt B):251-259. doi: 10.1016/j.neuropharm.2018.01.040. Epub 2018 Jan 31. PMID- 29337226 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 136 IP - Pt B DP - 2018 Jul 1 TI - GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence. PG - 343-349 LID - S0028-3908(18)30013-3 [pii] LID - 10.1016/j.neuropharm.2018.01.013 [doi] AB - Alcohol addiction, affecting approximately four percent of the population, contributes significantly to the global burden of diseases and is a substantial cost to the society. The neurochemical mechanisms regulating alcohol mediated behaviors is complex and in more recent years a new physiological role of the gut-brain peptides, traditionally known to regulate appetite and food intake, have been suggested. Indeed, regulators of alcohol-mediated behaviors. One of these gut-brain peptides is the annorexigenic peptide glucagon-like peptide-1 (GLP-1), Preclinical studies show that GLP-1 receptor activation, either by GLP-1 or analogues, attenuate the ability of alcohol to activate the mesolimbic dopamine system as well as decrease alcohol consumption and operant self-administration. In further support for the endogenous GLP-1 system in addiction processes are the experimental data showing that a GLP-1 receptor antagonist increases alcohol intake. Moreover, GLP-1 receptor agonists prevent the ability of other addictive drugs to activate the mesolimbic dopamine system. The number of clinical studies is limited, but show i) that genetic variation in the GLP-1 receptor gene is associated with alcohol addiction as well as increased alcohol infusion in humans, ii) that plasma levels of GLP-1 are associated with the subjective experience of cocaine and iii) that a GLP-1 receptor agonist reduces alcohol intake in patients with type-2 diabetes mellitus. These experimental and clinical studies raises the concern that clinically available GLP-1 receptor agonists deserves to be tested as potential treatments of patients with addictive disorders including alcohol addiction. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' CI - Copyright (c) 2018 The Author. Published by Elsevier Ltd.. All rights reserved. FAU - Jerlhag, Elisabet AU - Jerlhag E AD - Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Medicinaregatan 13A, SE-405 30 Gothenburg, Sweden. Electronic address: Elisabet.Jerlhag@pharm.gu.se. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20180112 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Central Nervous System Depressants) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 3K9958V90M (Ethanol) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alcohol Drinking/drug therapy/*metabolism/*psychology MH - Alcoholism/drug therapy/*metabolism MH - Animals MH - Central Nervous System Depressants/*pharmacology MH - Ethanol/*pharmacology MH - Glucagon-Like Peptide 1/*metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Dopamine OT - Gut-brain axis OT - Incentive salience OT - Motivation OT - Reinforcement EDAT- 2018/01/18 06:00 MHDA- 2019/01/18 06:00 CRDT- 2018/01/17 06:00 PHST- 2017/08/31 00:00 [received] PHST- 2017/12/18 00:00 [revised] PHST- 2018/01/09 00:00 [accepted] PHST- 2018/01/18 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2018/01/17 06:00 [entrez] AID - S0028-3908(18)30013-3 [pii] AID - 10.1016/j.neuropharm.2018.01.013 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 1;136(Pt B):343-349. doi: 10.1016/j.neuropharm.2018.01.013. Epub 2018 Jan 12. PMID- 29331730 OWN - NLM STAT- MEDLINE DCOM- 20180927 LR - 20260127 IS - 1558-1497 (Electronic) IS - 0197-4580 (Linking) VI - 64 DP - 2018 Apr TI - Exenatide exerts cognitive effects by modulating the BDNF-TrkB neurotrophic axis in adult mice. PG - 33-43 LID - S0197-4580(17)30404-9 [pii] LID - 10.1016/j.neurobiolaging.2017.12.009 [doi] AB - Modulation of insulin-dependent signaling is emerging as a valuable therapeutic tool to target neurodegeneration. In the brain, the activation of insulin receptors promotes cell growth, neuronal repair, and protection. Altered brain insulin signaling participates in the cognitive decline seen in Alzheimer's disease patients and the aging brain. Glucagon-like peptide-1 (GLP-1) regulates insulin secretion and, along with GLP-1 analogues, enhances neurotrophic signaling and counteracts cognitive deficits in preclinical models of neurodegeneration. Moreover, recent evidence indicates that GLP-1 modulates the activity of the brain-derived neurotrophic factor (BDNF). In this study, in adult wild-type mice, here employed as a model of mid-life brain aging, we evaluated the effects of a 2-month treatment with exenatide, a GLP-1 analogue. We found that exenatide promotes the enhancement of long-term memory performances. Biochemical and imaging analyses show that the drug promotes the activation of the BDNF-TrkB neurotrophic axis and inhibits apoptosis by decreasing p75NTR-mediated signaling. The study provides preclinical evidence for the use of exenatide to delay age-dependent cognitive decline. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Bomba, Manuela AU - Bomba M AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Granzotto, Alberto AU - Granzotto A AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Castelli, Vanessa AU - Castelli V AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy. FAU - Massetti, Noemi AU - Massetti N AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Silvestri, Elena AU - Silvestri E AD - Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento, Italy. FAU - Canzoniero, Lorella M T AU - Canzoniero LMT AD - Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento, Italy. FAU - Cimini, Annamaria AU - Cimini A AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, USA; National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy. FAU - Sensi, Stefano L AU - Sensi SL AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy; Departments of Neurology and Pharmacology, Institute for Mind Impairments and Neurological Disorders, University of California - Irvine, Irvine, USA. Electronic address: ssensi@uci.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171219 PL - United States TA - Neurobiol Aging JT - Neurobiology of aging JID - 8100437 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 9P1872D4OL (Exenatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Membrane Glycoproteins) RN - 0 (Nootropic Agents) RN - 0 (Peptides) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, Insulin) RN - 0 (Venoms) RN - EC 2.7.10.1 (Ntrk2 protein, mouse) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cells, Cultured MH - Cognition/*drug effects MH - Cognitive Aging MH - Cognitive Dysfunction/*drug therapy/etiology MH - Exenatide MH - Female MH - Glucagon-Like Peptide 1/analogs & derivatives/physiology MH - Hypoglycemic Agents/*pharmacology/*therapeutic use MH - Insulin/physiology MH - Male MH - Membrane Glycoproteins/*metabolism MH - Memory, Long-Term/*drug effects MH - Mice, Inbred Strains MH - *Nootropic Agents MH - Peptides/*pharmacology/*therapeutic use MH - Protein-Tyrosine Kinases/*metabolism MH - Receptor, Insulin/metabolism MH - Signal Transduction/drug effects/genetics MH - Venoms/*pharmacology/*therapeutic use MH - Receptor, trkB OTO - NOTNLM OT - Cognitive enhancement OT - GLP-1 OT - GLP-1 receptor OT - Long-term potentiation OT - Type 2 diabetes mellitus EDAT- 2018/01/15 06:00 MHDA- 2018/09/28 06:00 CRDT- 2018/01/15 06:00 PHST- 2017/06/13 00:00 [received] PHST- 2017/12/07 00:00 [revised] PHST- 2017/12/08 00:00 [accepted] PHST- 2018/01/15 06:00 [pubmed] PHST- 2018/09/28 06:00 [medline] PHST- 2018/01/15 06:00 [entrez] AID - S0197-4580(17)30404-9 [pii] AID - 10.1016/j.neurobiolaging.2017.12.009 [doi] PST - ppublish SO - Neurobiol Aging. 2018 Apr;64:33-43. doi: 10.1016/j.neurobiolaging.2017.12.009. Epub 2017 Dec 19. PMID- 29329976 OWN - NLM STAT- MEDLINE DCOM- 20181226 LR - 20181226 IS - 1873-5169 (Electronic) IS - 0196-9781 (Linking) VI - 101 DP - 2018 Mar TI - Therapeutic potential of spinal GLP-1 receptor signaling. PG - 89-94 LID - S0196-9781(18)30003-2 [pii] LID - 10.1016/j.peptides.2018.01.003 [doi] AB - GLP-1 signaling pathway has been well studied for its role in regulating glucose homeostasis, as well as its beneficial effects in energy and nutrient metabolism. A number of drugs based on GLP-1 have been used to treat type 2 diabetes mellitus. GLP-1R is expressed in multiple organs and numerous experimental studies have demonstrated that GLP-1 signaling pathway exhibits pro-survival functions in various disorders. In the central nervous system, stimulation of GLP-1R produces neuroprotective effects in specific neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The preproglucagon neurons located in the brainstem can also produce GLP-1. GLP-1 analogs have a long-acting effect and are able to pass the blood-brain barrier, which probably extends the therapeutic efficacy of GLP-1R activation. Neurodegenerative or traumatic conditions can damage the spinal cord and result in motor and sensory dysfunction. Evidence supports that GLP-1R activation in the spinal cord possesses beneficial effects and significant therapeutic potential. Herein, we review studies that have focused on GLP-1 and the spinal cord, and summarize the expression of GLP-1R and the innervation of PPG neurons in the spinal cord, as well as the potential therapeutic benefits of GLP-1R activation. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Zhang, Dongao AU - Zhang D AD - Department of Orthopaedics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Lv, Gang AU - Lv G AD - Department of Orthopaedics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address: ganglv_024@163.com. LA - eng PT - Journal Article PT - Review DEP - 20180109 PL - United States TA - Peptides JT - Peptides JID - 8008690 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/drug therapy/metabolism/pathology MH - Animals MH - Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology MH - Glucagon-Like Peptide 1/*therapeutic use MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Humans MH - Neuroprotective Agents/*therapeutic use MH - Parkinson Disease/drug therapy/metabolism/pathology MH - Signal Transduction/*drug effects MH - Spinal Cord/*metabolism/pathology MH - Spinal Cord Injuries/*drug therapy/metabolism/pathology OTO - NOTNLM OT - Glucagon-like peptide-1 OT - Glucagon-like peptide-1 receptor OT - Spinal cord EDAT- 2018/01/14 06:00 MHDA- 2018/12/27 06:00 CRDT- 2018/01/14 06:00 PHST- 2017/09/08 00:00 [received] PHST- 2017/12/24 00:00 [revised] PHST- 2018/01/08 00:00 [accepted] PHST- 2018/01/14 06:00 [pubmed] PHST- 2018/12/27 06:00 [medline] PHST- 2018/01/14 06:00 [entrez] AID - S0196-9781(18)30003-2 [pii] AID - 10.1016/j.peptides.2018.01.003 [doi] PST - ppublish SO - Peptides. 2018 Mar;101:89-94. doi: 10.1016/j.peptides.2018.01.003. Epub 2018 Jan 9. PMID- 29263141 OWN - NLM STAT- MEDLINE DCOM- 20190419 LR - 20240328 IS - 1573-4935 (Electronic) IS - 0144-8463 (Print) IS - 0144-8463 (Linking) VI - 38 IP - 4 DP - 2018 Aug 31 TI - GLP-1 receptor regulates cell growth through regulating IDE expression level in Abeta1-42-treated PC12 cells. LID - BSR20171284 [pii] LID - 10.1042/BSR20171284 [doi] AB - This study aimed to validate whether glucagon-like peptide-1 receptor (GLP-1R) / cyclic adenosine monophosphate (cAMP) / protein kinase (PKA) / insulin-degrading enzyme (IDE) signaling pathway was associated with neuronal apoptosis. We developed an animal model presenting both Alzheimer's disease (AD) and type 2 diabetes (T2D), by crossing APP/PS1 mice (AD model) with streptozotocin (STZ)-treated mice (a T2D model). Neuronal apoptosis was detected by TUNEL staining and the expression levels of apoptosis-related proteins were examined by Western blotting. The viability of PC12 cells was analyzed by MTT assay and apoptosis of PC12 cells was detected by flow cytometry. The mRNA expression level was detected by qRT-PCR. T2D contributes to AD progress by prompting neuronal apoptosis and increasing expression of pro-apoptotic protein. beta-Amyloid peptide1-42 (Abeta1-42) was shown to exert effects on inhibiting cell viability and prompting cell apoptosis of PC12 cells. However, GLP-1R agonist geniposide (Gen) significantly reversed them, exerting a protective role on PC12 cells. And IDE antagonist bacitracin (Bac) markedly reversed the protective effects of Gen on Abeta1-42-treated PC12 cells. Besides, Gen significantly reversed the effects of Abeta1-42 treatment on IDE expression, and the inhibitor of cAMP/PKA signaling pathway markedly reversed the effects of Gen on IDE expression level in Abeta1-42-treated PC12 cells. In conclusion, GLP-1R regulates cell growth, at least partially, through regulating cAMP/PKA/IDE signaling pathway in Abeta1-42-treated PC12 cells. CI - (c) 2018 The Author(s). FAU - Li, Huajie AU - Li H AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China lihuajie0589@sohu.com. FAU - Cao, Liping AU - Cao L AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China. FAU - Ren, Yi AU - Ren Y AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China. FAU - Jiang, Ying AU - Jiang Y AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China. FAU - Xie, Wei AU - Xie W AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China. FAU - Li, Dawen AU - Li D AD - Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180712 PL - England TA - Biosci Rep JT - Bioscience reports JID - 8102797 RN - 0 (Amyloid beta-Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-42)) RN - EC 3.4.24.56 (Insulysin) SB - IM MH - Alzheimer Disease/metabolism MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Apoptosis MH - *Cell Proliferation MH - Cell Survival MH - Diabetes Mellitus, Type 2/metabolism MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Insulysin/*metabolism MH - Mice MH - Neurons/*cytology/metabolism MH - PC12 Cells MH - Peptide Fragments/*metabolism MH - Rats MH - Signal Transduction PMC - PMC6043719 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor OT - IDE expression OT - type 2 diabetes COIS- The Authors declare that there are no competing interests associated with the manuscript. EDAT- 2017/12/22 06:00 MHDA- 2019/04/20 06:00 PMCR- 2018/07/13 CRDT- 2017/12/22 06:00 PHST- 2017/09/22 00:00 [received] PHST- 2017/12/12 00:00 [revised] PHST- 2017/12/19 00:00 [accepted] PHST- 2017/12/22 06:00 [pubmed] PHST- 2019/04/20 06:00 [medline] PHST- 2017/12/22 06:00 [entrez] PHST- 2018/07/13 00:00 [pmc-release] AID - BSR20171284 [pii] AID - 10.1042/BSR20171284 [doi] PST - epublish SO - Biosci Rep. 2018 Jul 12;38(4):BSR20171284. doi: 10.1042/BSR20171284. Print 2018 Aug 31. PMID- 29175324 OWN - NLM STAT- MEDLINE DCOM- 20171229 LR - 20260127 IS - 1090-2104 (Electronic) IS - 0006-291X (Linking) VI - 495 IP - 1 DP - 2018 Jan 1 TI - Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease. PG - 1034-1040 LID - S0006-291X(17)32293-3 [pii] LID - 10.1016/j.bbrc.2017.11.114 [doi] AB - Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: yancai1@163.com. FAU - Yang, Jun-Ting AU - Yang JT AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: 984647776@qq.com. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: wzhaojun1025@126.com. FAU - Zhang, Jun AU - Zhang J AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: zj2004081@163.com. FAU - Yang, Wei AU - Yang W AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: vividmail@163.com. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: wmna@163.com. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province, 030001, China. Electronic address: jinshunqi2009@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171122 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Alzheimer Disease/*drug therapy/*metabolism/pathology MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Dose-Response Relationship, Drug MH - Encephalitis/*drug therapy/*metabolism/pathology MH - Female MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurofibrillary Tangles/*drug effects/metabolism/pathology MH - Neuroprotective Agents/administration & dosage MH - Peptides/*administration & dosage MH - Treatment Outcome MH - Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-1 Receptor MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid plaques OT - Lixisenatide OT - Neurofibrillary tangles OT - Neuroinflammation EDAT- 2017/11/28 06:00 MHDA- 2017/12/30 06:00 CRDT- 2017/11/28 06:00 PHST- 2017/11/11 00:00 [received] PHST- 2017/11/18 00:00 [accepted] PHST- 2017/11/28 06:00 [pubmed] PHST- 2017/12/30 06:00 [medline] PHST- 2017/11/28 06:00 [entrez] AID - S0006-291X(17)32293-3 [pii] AID - 10.1016/j.bbrc.2017.11.114 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2018 Jan 1;495(1):1034-1040. doi: 10.1016/j.bbrc.2017.11.114. Epub 2017 Nov 22. PMID- 29165354 OWN - NLM STAT- MEDLINE DCOM- 20180703 LR - 20181113 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 11 DP - 2017 Nov 22 TI - The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. LID - 10.3390/ijms18112493 [doi] LID - 2493 AB - Alzheimer's disease (AD), characterized by the aggregation of amyloid-beta (Abeta) protein and neuroinflammation, is the most common neurodegenerative disease globally. Previous studies have reported that some AD patients show impaired glucose utilization in brain, leading to cognitive decline. Recently, diabetes-induced dementia has been called "type 3 diabetes", based on features in common with those of type 2 diabetes and the progression of AD. Impaired glucose uptake and insulin resistance in the brain are important issues in type 3 diabetes, because these problems ultimately aggravate memory dysfunction in the brain. Glucagon-like peptide 1 (GLP-1) has been known to act as a critical controller of the glucose metabolism. Several studies have demonstrated that GLP-1 alleviates learning and memory dysfunction by enhancing the regulation of glucose in the AD brain. However, the specific actions of GLP-1 in the AD brain are not fully understood. Here, we review evidences related to the role of GLP-1 in type 3 diabetes. FAU - Bae, Choon Sang AU - Bae CS AD - Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Korea. csbae@chonnam.ac.kr. FAU - Song, Juhyun AU - Song J AD - Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Korea. juhyunsong@chonnam.ac.kr. LA - eng PT - Journal Article PT - Review DEP - 20171122 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Brain/*metabolism/physiopathology MH - Dementia/*etiology/*metabolism MH - Diabetes Complications/*metabolism MH - Disease Susceptibility MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - *Insulin Resistance MH - *Neurogenesis/drug effects PMC - PMC5713459 OTO - NOTNLM OT - Alzheimer's disease (AD) OT - Amyloid beta (Abeta) OT - diabetes-induced dementia OT - glucagon like peptide 1 (GLP-1) OT - insulin resistance OT - type 3 diabetes COIS- The authors declare no conflict of interest. EDAT- 2017/11/23 06:00 MHDA- 2018/07/04 06:00 PMCR- 2017/11/22 CRDT- 2017/11/23 06:00 PHST- 2017/10/30 00:00 [received] PHST- 2017/11/17 00:00 [revised] PHST- 2017/11/20 00:00 [accepted] PHST- 2017/11/23 06:00 [entrez] PHST- 2017/11/23 06:00 [pubmed] PHST- 2018/07/04 06:00 [medline] PHST- 2017/11/22 00:00 [pmc-release] AID - ijms18112493 [pii] AID - ijms-18-02493 [pii] AID - 10.3390/ijms18112493 [doi] PST - epublish SO - Int J Mol Sci. 2017 Nov 22;18(11):2493. doi: 10.3390/ijms18112493. PMID- 29113464 OWN - NLM STAT- MEDLINE DCOM- 20180625 LR - 20240922 IS - 1555-3892 (Electronic) IS - 0963-6897 (Print) IS - 0963-6897 (Linking) VI - 26 IP - 9 DP - 2017 Sep TI - A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway. PG - 1560-1571 LID - 10.1177/0963689717721234 [doi] AB - Molecular communications in the gut-brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut-brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut-brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut-brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor. FAU - Kim, Dong Seok AU - Kim DS AD - 1 Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea. AD - 2 Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. FAU - Choi, Ho-Il AU - Choi HI AD - 1 Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea. FAU - Wang, Yun AU - Wang Y AD - 3 Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan. FAU - Luo, Yu AU - Luo Y AD - 4 Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Hoffer, Barry J AU - Hoffer BJ AD - 4 Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. FAU - Greig, Nigel H AU - Greig NH AD - 2 Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. LA - eng GR - R01 NS094152/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review PL - United States TA - Cell Transplant JT - Cell transplantation JID - 9208854 RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Blood Glucose/drug effects MH - Exenatide MH - Glucagon-Like Peptide 1/*therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Neuroprotective Agents/therapeutic use MH - Parkinson Disease/*drug therapy/*metabolism MH - Peptides/therapeutic use MH - Venoms/therapeutic use PMC - PMC5680957 OTO - NOTNLM OT - Parkinson disease OT - exenatide OT - exendin-4 OT - glucagon-like peptide-1 OT - gut-brain axis OT - neurogenesis OT - neuroinflammation OT - neuroprotection OT - neurotrophic COIS- Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2017/11/09 06:00 MHDA- 2018/06/26 06:00 PMCR- 2017/09/01 CRDT- 2017/11/09 06:00 PHST- 2017/11/09 06:00 [entrez] PHST- 2017/11/09 06:00 [pubmed] PHST- 2018/06/26 06:00 [medline] PHST- 2017/09/01 00:00 [pmc-release] AID - 10.1177_0963689717721234 [pii] AID - 10.1177/0963689717721234 [doi] PST - ppublish SO - Cell Transplant. 2017 Sep;26(9):1560-1571. doi: 10.1177/0963689717721234. PMID- 29091313 OWN - NLM STAT- MEDLINE DCOM- 20180917 LR - 20250103 IS - 1472-8206 (Electronic) IS - 0767-3981 (Linking) VI - 32 IP - 2 DP - 2018 Apr TI - Exenatide upregulates gene expression of glucagon-like peptide-1 receptor and nerve growth factor in streptozotocin/nicotinamide-induced diabetic mice. PG - 174-180 LID - 10.1111/fcp.12329 [doi] AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has modulating effects on insulin release. GLP-1 and receptors for GLP-1 are widely expressed throughout the body including the brain. The expression of GLP-1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP-1 receptor stimulation enhances glucose-dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose-derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP-1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP-1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 mug/kg, s.c., twice daily for 2 weeks) on GLP-1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice were assessed by quantitative real-time polymerase chain reaction (RT-PCR). The results of this study revealed that hippocampal gene expression of GLP-1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP-1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP-1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA-induced diabetes. CI - (c) 2017 Societe Francaise de Pharmacologie et de Therapeutique. FAU - Gumuslu, Esen AU - Gumuslu E AD - Department of Medical Genetics, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Cine, Naci AU - Cine N AD - Department of Medical Genetics, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Ertan, Merve AU - Ertan M AD - Department of Medical Genetics, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Mutlu, Oguz AU - Mutlu O AUID- ORCID: 0000-0003-0952-0742 AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Komsuoglu Celikyurt, Ipek AU - Komsuoglu Celikyurt I AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Ulak, Guner AU - Ulak G AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. LA - eng PT - Journal Article DEP - 20171120 PL - England TA - Fundam Clin Pharmacol JT - Fundamental & clinical pharmacology JID - 8710411 RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Peptides) RN - 0 (Venoms) RN - 25X51I8RD4 (Niacinamide) RN - 5W494URQ81 (Streptozocin) RN - 9061-61-4 (Nerve Growth Factor) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Diabetes Mellitus, Experimental/blood/chemically induced/*drug therapy/genetics MH - Diabetes Mellitus, Type 2/blood/chemically induced/*drug therapy/genetics MH - Exenatide MH - Glucagon-Like Peptide-1 Receptor/genetics/metabolism MH - Hippocampus/*drug effects/metabolism MH - Hypoglycemic Agents/*pharmacology MH - Incretins/*pharmacology MH - Male MH - Mice, Inbred BALB C MH - Nerve Growth Factor/genetics/*metabolism MH - *Niacinamide MH - Peptides/*pharmacology MH - *Streptozocin MH - Time Factors MH - Up-Regulation MH - Venoms/*pharmacology MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - GLP-1 receptor OT - diabetes OT - exenatide OT - hippocampus OT - nerve growth factor EDAT- 2017/11/02 06:00 MHDA- 2018/09/18 06:00 CRDT- 2017/11/02 06:00 PHST- 2017/04/14 00:00 [received] PHST- 2017/09/15 00:00 [revised] PHST- 2017/10/25 00:00 [accepted] PHST- 2017/11/02 06:00 [pubmed] PHST- 2018/09/18 06:00 [medline] PHST- 2017/11/02 06:00 [entrez] AID - 10.1111/fcp.12329 [doi] PST - ppublish SO - Fundam Clin Pharmacol. 2018 Apr;32(2):174-180. doi: 10.1111/fcp.12329. Epub 2017 Nov 20. PMID- 29050859 OWN - NLM STAT- MEDLINE DCOM- 20180302 LR - 20250103 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1678 DP - 2018 Jan 1 TI - Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease. PG - 64-74 LID - S0006-8993(17)30459-6 [pii] LID - 10.1016/j.brainres.2017.10.012 [doi] AB - Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10 nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of beta-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Tai, Jingjing AU - Tai J AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Liu, Weizhen AU - Liu W AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Yanwei AU - Li Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of Human Anatomy, Medical College, Shaoyang University, Shaoyang, Hunan, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Second Hospital Neurology Dept., Shanxi Medical University, Taiyuan, Shanxi, PR China; Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article DEP - 20171016 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Presenilin-1) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9007-92-5 (Glucagon) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/drug therapy/physiopathology MH - Amyloid beta-Protein Precursor/metabolism MH - Animals MH - Disease Models, Animal MH - Glucagon/pharmacology MH - Glucagon-Like Peptide 1/pharmacology MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Hippocampus/metabolism MH - Memory Disorders/drug therapy MH - Mice MH - Mice, Transgenic MH - Neuroprotective Agents/*metabolism/pharmacology MH - Plaque, Amyloid/drug therapy MH - Presenilin-1/metabolism MH - Receptors, Gastrointestinal Hormone/*agonists/metabolism MH - Receptors, Glucagon/*agonists/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - BDNF OT - Brain OT - Growth factor OT - Inflammation OT - Insulin OT - Neurodegeneration EDAT- 2017/10/21 06:00 MHDA- 2018/03/03 06:00 CRDT- 2017/10/21 06:00 PHST- 2017/07/05 00:00 [received] PHST- 2017/10/07 00:00 [revised] PHST- 2017/10/11 00:00 [accepted] PHST- 2017/10/21 06:00 [pubmed] PHST- 2018/03/03 06:00 [medline] PHST- 2017/10/21 06:00 [entrez] AID - S0006-8993(17)30459-6 [pii] AID - 10.1016/j.brainres.2017.10.012 [doi] PST - ppublish SO - Brain Res. 2018 Jan 1;1678:64-74. doi: 10.1016/j.brainres.2017.10.012. Epub 2017 Oct 16. PMID- 29044772 OWN - NLM STAT- MEDLINE DCOM- 20180731 LR - 20180815 IS - 1464-5491 (Electronic) IS - 0742-3071 (Linking) VI - 35 IP - 1 DP - 2018 Jan TI - RD Lawrence Lecture 2017 Incretins: the intelligent hormones in diabetes. PG - 33-40 LID - 10.1111/dme.13522 [doi] AB - The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have attracted considerable scientific and clinical interest due largely to their insulin-releasing and glucose-lowering properties. Indeed, GLP-1-based therapies are now key treatment options for many people with diabetes worldwide. In contrast, GIP-based agents have yet to reach the clinic based primarily on the impaired insulinotropic action of GIP observed in people with diabetes. Nevertheless, GIP is a key physiological regulator of insulin secretion and stable forms of GIP show much promise in rodent models to alleviate diabetes-obesity. Recent studies suggest that GIP may have an important role to play in a combination therapeutic approach or bioengineered with other gut peptides. Moreover, recent experimental studies indicate that incretins also exert pleiotropic effects in regions of the brain associated with learning and memory, thereby supporting preclinical data demonstrating that incretin-based drugs improve cognitive function. This review article, based on the RD Lawrence Lecture presented at Diabetes UK Annual Professional Conference (2017), provides a brief overview of incretins with a major focus on GIP, the development of designer GIP analogues, and how these molecules can improve cognition. Thus, incretins can be considered as 'the intelligent hormones' and may hold the key to successfully treating the alarming rise in neurodegenerative disorders. CI - (c) 2017 Diabetes UK. FAU - Gault, V A AU - Gault VA AUID- ORCID: 0000-0001-8501-1013 AD - School of Biomedical Sciences, University of Ulster, Coleraine, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20171101 PL - England TA - Diabet Med JT - Diabetic medicine : a journal of the British Diabetic Association JID - 8500858 RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Nootropic Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease MH - Animals MH - Cognition/drug effects MH - Diabetes Mellitus, Type 2/*drug therapy MH - Disease Models, Animal MH - Gastric Inhibitory Polypeptide/analogs & derivatives/pharmacology/*physiology/therapeutic use MH - Glucagon-Like Peptide 1/pharmacology/*physiology/therapeutic use MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Incretins/pharmacology/*physiology/therapeutic use MH - Learning/drug effects MH - Memory/drug effects MH - Nootropic Agents/pharmacology EDAT- 2017/10/19 06:00 MHDA- 2018/08/01 06:00 CRDT- 2017/10/19 06:00 PHST- 2017/10/12 00:00 [accepted] PHST- 2017/10/19 06:00 [pubmed] PHST- 2018/08/01 06:00 [medline] PHST- 2017/10/19 06:00 [entrez] AID - 10.1111/dme.13522 [doi] PST - ppublish SO - Diabet Med. 2018 Jan;35(1):33-40. doi: 10.1111/dme.13522. Epub 2017 Nov 1. PMID- 28927992 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20190117 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 136 IP - Pt B DP - 2018 Jul 1 TI - Protective effects of the GLP-1 mimetic exendin-4 in Parkinson's disease. PG - 260-270 LID - S0028-3908(17)30440-9 [pii] LID - 10.1016/j.neuropharm.2017.09.023 [doi] AB - There is increasing interest in the potential role of glucagon-like peptide-1 (GLP-1) receptor agonists as neuroprotective treatments in neurodegenerative diseases including Parkinson's disease following the publication of the results of the Exenatide-PD trial. Of the current GLP-1 receptor agonists already licensed to treat Type 2 diabetes several including exenatide, liraglutide and lixisenatide are the subject of ongoing clinical trials in PD. The underlying rationale for using drugs licensed and effective for T2DM in PD patients therefore needs to be scrutinized, and the results obtained to date critically reviewed. We review the relationship between insulin resistance and Parkinson's disease, the implications on pathogenesis and the efforts to reposition GLP-1 agonists as potential treatments for Parkinson's disease and give an overview of the pre-clinical and clinical data supporting the use of exenatide in Parkinson's disease with a discussion regarding possible mechanisms of action. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Athauda, Dilan AU - Athauda D AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, United Kingdom. FAU - Foltynie, Thomas AU - Foltynie T AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, United Kingdom. Electronic address: T.Foltynie@ucl.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20170918 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Exenatide/*pharmacology/therapeutic use MH - Glucagon-Like Peptide 1/agonists/metabolism MH - Humans MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Parkinson Disease/*drug therapy OTO - NOTNLM OT - Exenatide OT - Glucagon-like peptide-1 agonist OT - Insulin resistance OT - Neuroprotection OT - Parkinson's disease EDAT- 2017/09/21 06:00 MHDA- 2019/01/18 06:00 CRDT- 2017/09/21 06:00 PHST- 2017/08/22 00:00 [received] PHST- 2017/09/12 00:00 [revised] PHST- 2017/09/15 00:00 [accepted] PHST- 2017/09/21 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2017/09/21 06:00 [entrez] AID - S0028-3908(17)30440-9 [pii] AID - 10.1016/j.neuropharm.2017.09.023 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 1;136(Pt B):260-270. doi: 10.1016/j.neuropharm.2017.09.023. Epub 2017 Sep 18. PMID- 28885995 OWN - NLM STAT- MEDLINE DCOM- 20180525 LR - 20190606 IS - 1643-3750 (Electronic) IS - 1234-1010 (Print) IS - 1234-1010 (Linking) VI - 23 DP - 2017 Sep 8 TI - Glucagon-Like Peptide-1 (GLP-1) Treatment Ameliorates Cognitive Impairment by Attenuating Arc Expression in Type 2 Diabetic Rats. PG - 4334-4342 AB - BACKGROUND Glucagon-like peptide-1 (GLP-1) has been reported to exert some beneficial effects on the central nervous system (CNS). However, the effect of GLP-1 on cognitive impairment associated with type 2 diabetes is not well known. This study investigated the effect of GLP-1 on ameliorating memory deficits in type 2 diabetic rats. MATERIAL AND METHODS Type 2 diabetic rats were induced by a high-sugar, high-fat diet, followed by streptozotocin (STZ) injection and then tested in the Morris Water Maze (MWM) 1 week after the induction of diabetes. The mRNA expression of Arc, APP, BACE1, and PS1 were determined by real-time quantitative PCR, and the Arc protein was analyzed by immunoblotting and immunohistochemistry. RESULTS Type 2 diabetic rats exhibited a significant decline in learning and memory in the MWM tests, but GLP-1 treatment was able to protect this decline and significantly improved learning ability and memory. The mRNA expression assays showed that GLP-1 treatment markedly reduced Arc, APP, BACE1, and PS1 expressions, which were elevated in the diabetic rats. Immunoblotting and immunohistochemistry results also confirmed that Arc protein increased in the hippocampus of diabetic rats, but was reduced after GLP-1 treatment. CONCLUSIONS Our findings suggest that GLP-1 treatment improves learning and memory deficits in type 2 diabetic rats, and this effect is likely through the reduction of Arc expression in the hippocampus. FAU - Cai, Xiang-Sheng AU - Cai XS AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - International Center for Metabolic Diseases, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - Dongguan SMU Metabolic Medicine R&D Inc., Dongguan, Guangdong, China (mainland). FAU - Tan, Zhao-Guang AU - Tan ZG AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - International Center for Metabolic Diseases, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - Dongguan SMU Metabolic Medicine R&D Inc., Dongguan, Guangdong, China (mainland). FAU - Li, Jing-Jing AU - Li JJ AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). FAU - Gao, Wei-Hong AU - Gao WH AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - International Center for Metabolic Diseases, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - Dongguan SMU Metabolic Medicine R&D Inc., Dongguan, Guangdong, China (mainland). FAU - Li, Shu-Ji AU - Li SJ AD - Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China (mainland). FAU - Li, Jin-Long AU - Li JL AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). FAU - Tang, Yong-Ming AU - Tang YM AD - UCLA Center for Excellence in Pancreatic Disease, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. FAU - Li, Hong-Wei AU - Li HW AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). FAU - Hui, Hong-Xiang AU - Hui HX AD - School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - International Center for Metabolic Diseases, Southern Medical University, Guangzhou, Guangdong, China (mainland). AD - Dongguan SMU Metabolic Medicine R&D Inc., Dongguan, Guangdong, China (mainland). AD - UCLA Center for Excellence in Pancreatic Disease, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. LA - eng PT - Journal Article DEP - 20170908 PL - United States TA - Med Sci Monit JT - Medical science monitor : international medical journal of experimental and clinical research JID - 9609063 RN - 0 (Blood Glucose) RN - 0 (Cytoskeletal Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (activity regulated cytoskeletal-associated protein) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Blood Glucose/metabolism MH - Cognitive Dysfunction/blood/*drug therapy/metabolism MH - Cytoskeletal Proteins/metabolism MH - Diabetes Mellitus, Experimental/*metabolism MH - Diabetes Mellitus, Type 2/blood/*drug therapy/*metabolism MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Glucagon-Like Peptide 1/*pharmacology MH - Hippocampus/drug effects MH - Male MH - Maze Learning/drug effects MH - Memory Disorders/complications MH - Nerve Tissue Proteins/metabolism MH - Rats MH - Rats, Sprague-Dawley PMC - PMC5601394 EDAT- 2017/09/09 06:00 MHDA- 2018/05/26 06:00 PMCR- 2017/09/08 CRDT- 2017/09/09 06:00 PHST- 2017/09/09 06:00 [entrez] PHST- 2017/09/09 06:00 [pubmed] PHST- 2018/05/26 06:00 [medline] PHST- 2017/09/08 00:00 [pmc-release] AID - 903252 [pii] AID - 10.12659/msm.903252 [doi] PST - epublish SO - Med Sci Monit. 2017 Sep 8;23:4334-4342. doi: 10.12659/msm.903252. PMID- 28846606 OWN - NLM STAT- MEDLINE DCOM- 20180423 LR - 20200306 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 9 DP - 2017 Aug 26 TI - The Emerging Role of GLP-1 Receptors in DNA Repair: Implications in Neurological Disorders. LID - 10.3390/ijms18091861 [doi] LID - 1861 AB - Glucagon-like peptide-1 (GLP-1) is originally found as a metabolic hormone (incretin) that is able to regulate blood-glucose levels via promoting synthesis and secretion of insulin. GLP-1 and many analogues are approved for treatment of type II diabetes. Accumulating results imply that GLP-1 performs multiple functions in various tissues and organs beyond regulation of blood-glucose. The neuroprotective function of GLP-1 has been extensively explored during the past two decades. Three of our previous studies have shown that apurinic/apyrimidinic endonuclease 1 (APE1) is the only protein of the base excision repair (BER) pathway able to be regulated by oxidative stress or exogenous stimulations in rat primary cortical neurons. In this article, we review the role of APE1 in neurodegenerative diseases and its relationship to neuroprotective mechanisms of the activated GLP-1 receptor (GLP-1R) in neurodegenerative disorders. The purpose of this article is to provide new insight, from the aspect of DNA damage and repair, for studying potential treatments in neurodegenerative diseases. FAU - Yang, Jenq-Lin AU - Yang JL AD - Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan. jyang@adm.cgmh.org.tw. FAU - Chen, Wei-Yu AU - Chen WY AD - Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan. wychen624@cgmh.org.tw. FAU - Chen, Shang-Der AU - Chen SD AD - Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan. chensd@adm.cgmh.org.tw. AD - Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan. chensd@adm.cgmh.org.tw. AD - College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Taoyuan 33302, Taiwan. chensd@adm.cgmh.org.tw. LA - eng PT - Journal Article PT - Review DEP - 20170826 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase) SB - IM MH - Animals MH - *DNA Repair MH - DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/metabolism MH - Glucagon-Like Peptide-1 Receptor/genetics/*metabolism MH - Humans MH - Neurodegenerative Diseases/genetics/*metabolism PMC - PMC5618510 OTO - NOTNLM OT - DNA damage and repair OT - apurinic/apyrimidinic endonuclease 1 (APE1) OT - glucagon-like peptide 1 receptor (GLP-1R) OT - neurodegenerative disorders COIS- The authors declare no conflicts of interest. EDAT- 2017/08/29 06:00 MHDA- 2018/04/24 06:00 PMCR- 2017/09/01 CRDT- 2017/08/29 06:00 PHST- 2017/07/05 00:00 [received] PHST- 2017/08/19 00:00 [revised] PHST- 2017/08/23 00:00 [accepted] PHST- 2017/08/29 06:00 [entrez] PHST- 2017/08/29 06:00 [pubmed] PHST- 2018/04/24 06:00 [medline] PHST- 2017/09/01 00:00 [pmc-release] AID - ijms18091861 [pii] AID - ijms-18-01861 [pii] AID - 10.3390/ijms18091861 [doi] PST - epublish SO - Int J Mol Sci. 2017 Aug 26;18(9):1861. doi: 10.3390/ijms18091861. PMID- 28823610 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 136 IP - Pt B DP - 2018 Jul 1 TI - Glucagon-like receptor 1 agonists and DPP-4 inhibitors: Anti-diabetic drugs with anti-stroke potential. PG - 280-286 LID - S0028-3908(17)30389-1 [pii] LID - 10.1016/j.neuropharm.2017.08.022 [doi] AB - Stroke is one of the leading causes of death and serious disability in Westernized societies. The risk of stroke approximately doubles with each decade after the age of 55. Therefore, even though the incidence of stroke is declining, mostly because of the efforts to lower blood pressure and reduce smoking, the overall number of strokes is increasing due to the aging of the population. While stroke prevention by healthy lifestyle is effective in decreasing the risk of stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage and promoting recovery are highly needed. Unfortunately, several candidate drugs that have shown significant neuroprotective efficacy in experimental models have failed in clinical trials and no treatment for stroke based on pharmacological neuroprotection is available today. Glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used against type 2 diabetes. Interestingly, these drugs have also shown promising effects in decreasing stroke incidence and increasing neuroprotection in clinical and preclinical studies, respectively. However, the mode of action of these drugs in the brain is largely unknown. Moreover, while it was previously thought that GLP-1R agonists and DPP-4i act via similar mechanisms of action, recent data argue against this hypothesis. Herein, we review this promising research area and highlight the main questions in the field whose answers could reveal important aiming to developing effective anti-stroke therapies. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Darsalia, Vladimer AU - Darsalia V AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. FAU - Klein, Thomas AU - Klein T AD - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. FAU - Nystrom, Thomas AU - Nystrom T AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. FAU - Patrone, Cesare AU - Patrone C AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. Electronic address: cesare.patrone@ki.se. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20170818 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Dipeptidyl-Peptidase IV Inhibitors/*pharmacology/therapeutic use MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Humans MH - Hypoglycemic Agents/*pharmacology/therapeutic use MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Stroke/*drug therapy/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - DPP-4 inhibitors OT - Diabetes OT - GLP-1 OT - GLP-1R agonists OT - Neuroprotection OT - Stroke EDAT- 2017/08/22 06:00 MHDA- 2019/01/18 06:00 CRDT- 2017/08/22 06:00 PHST- 2017/06/15 00:00 [received] PHST- 2017/08/14 00:00 [revised] PHST- 2017/08/16 00:00 [accepted] PHST- 2017/08/22 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2017/08/22 06:00 [entrez] AID - S0028-3908(17)30389-1 [pii] AID - 10.1016/j.neuropharm.2017.08.022 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 1;136(Pt B):280-286. doi: 10.1016/j.neuropharm.2017.08.022. Epub 2017 Aug 18. PMID- 28779212 OWN - NLM STAT- MEDLINE DCOM- 20180702 LR - 20220409 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 60 IP - 11 DP - 2017 Nov TI - Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes. PG - 2285-2298 LID - 10.1007/s00125-017-4388-y [doi] AB - AIMS/HYPOTHESIS: The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. METHODS: To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and age-matched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate-aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. RESULTS: DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. CONCLUSIONS/INTERPRETATION: The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out. FAU - Hernandez, Cristina AU - Hernandez C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Bogdanov, Patricia AU - Bogdanov P AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Sola-Adell, Cristina AU - Sola-Adell C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Sampedro, Joel AU - Sampedro J AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. FAU - Valeri, Marta AU - Valeri M AD - Unit of High Technology, Vall d'Hebron Research Institute, Barcelona, Spain. FAU - Genis, Xavier AU - Genis X AD - Banco de Sangre y Tejidos, Passeig Taulat 116, 08005, Barcelona, Spain. FAU - Simo-Servat, Olga AU - Simo-Servat O AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Garcia-Ramirez, Marta AU - Garcia-Ramirez M AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. FAU - Simo, Rafael AU - Simo R AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rafael.simo@vhir.org. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. rafael.simo@vhir.org. LA - eng GR - SAF2016-77784/Ministerio de Economia y Competitividad/ PT - Journal Article DEP - 20170804 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Dipeptides) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9GB927LAJW (saxagliptin) RN - PJY633525U (Adamantane) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - Adamantane/analogs & derivatives/therapeutic use MH - Animals MH - Diabetes Mellitus, Experimental/*drug therapy/physiopathology MH - Dipeptides/therapeutic use MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Electroretinography MH - Glucagon-Like Peptide 1/metabolism MH - Humans MH - Immunohistochemistry MH - Male MH - Mice MH - Retina/*drug effects/*pathology MH - Sitagliptin Phosphate/therapeutic use OTO - NOTNLM OT - DPP-IV inhibitors OT - Diabetic retinopathy OT - Experimental diabetes OT - GLP-1 OT - Retinal neurodegeneration EDAT- 2017/08/06 06:00 MHDA- 2018/07/03 06:00 CRDT- 2017/08/06 06:00 PHST- 2017/02/02 00:00 [received] PHST- 2017/06/21 00:00 [accepted] PHST- 2017/08/06 06:00 [pubmed] PHST- 2018/07/03 06:00 [medline] PHST- 2017/08/06 06:00 [entrez] AID - 10.1007/s00125-017-4388-y [pii] AID - 10.1007/s00125-017-4388-y [doi] PST - ppublish SO - Diabetologia. 2017 Nov;60(11):2285-2298. doi: 10.1007/s00125-017-4388-y. Epub 2017 Aug 4. PMID- 28673587 OWN - NLM STAT- MEDLINE DCOM- 20180423 LR - 20181217 IS - 1532-2777 (Electronic) IS - 0306-9877 (Linking) VI - 104 DP - 2017 Jul TI - Bariatric surgery may reduce the risk of Alzheimer's diseases through GLP-1 mediated neuroprotective effects. PG - 4-9 LID - S0306-9877(16)30423-6 [pii] LID - 10.1016/j.mehy.2017.05.002 [doi] AB - Obesity and diabetes are associated with deficits in multiple neurocognitive domains and increased risk for dementia. Over the last two decades, there has been a significant increase in bariatric and metabolic surgery worldwide, driven by rising intertwined pandemics of obesity and diabetes, along with improvement in surgical techniques. Patients undergoing bariatric surgery achieve a significant decrease in their excess weight and a multitude of sequela associated with obesity, diabetes, and metabolic syndrome. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide that has been implicated as one of the weight loss-independent mechanisms in how bariatric surgery affects type 2 diabetes. GLP-1 improves insulin secretion, inhibits apoptosis and induce pancreatic islet neogenesis, promotes satiety, and can regulate heart rate and blood pressure. Moreover, numerous studies have demonstrated potential neuroprotective and neurotrophic effects of GLP-1. Increased GLP-1 activity has been shown to increase cortical activity, promote neuronal growth, and inhibit neuronal degeneration. Specifically, in experimental studies on Alzheimer's disease, GLP-1 decreases amyloid deposition and neurofibrillary tangles. Furthermore, recent studies have also suggested that GLP-1 based therapies, new class of antidiabetic drugs, have favorable effects on neurodegenerative disorders such as Alzheimer's disease. We present a hypothesis that bariatric surgery can help delay or even prevent the onset of Alzheimer's disease in long-term by increasing the levels of GLP-1. This hypothesis has a potential for many studies from basic science projects to large population studies to fully understand the neurological and cognitive consequences of bariatric surgery and associated rise in GLP-1. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Keshava, Hari B AU - Keshava HB AD - Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, United States. FAU - Mowla, Ashkan AU - Mowla A AD - Department of Neurology, Gates Vascular Institute, State University of New York (SUNY) at Buffalo, Buffalo, NY, United States. FAU - Heinberg, Leslie J AU - Heinberg LJ AD - Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, United States. FAU - Schauer, Philip R AU - Schauer PR AD - Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, United States. FAU - Brethauer, Stacy A AU - Brethauer SA AD - Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, United States. FAU - Aminian, Ali AU - Aminian A AD - Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, United States. Electronic address: aminiaa@ccf.org. LA - eng PT - Journal Article DEP - 20170503 PL - United States TA - Med Hypotheses JT - Medical hypotheses JID - 7505668 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/*prevention & control MH - Apoptosis MH - *Bariatric Surgery MH - Diabetes Mellitus, Type 2/metabolism MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin/metabolism MH - Insulin Secretion MH - Models, Theoretical MH - Neurons/*drug effects MH - Neuroprotective Agents/therapeutic use MH - Obesity/complications/metabolism MH - Risk MH - Weight Loss OTO - NOTNLM OT - Alzheimer's disease OT - Bariatric surgery OT - Dementia OT - Diabetes OT - Gastric bypass OT - Glucagon-like peptide 1 OT - Insulin OT - Metabolic surgery OT - Obesity OT - Weight loss EDAT- 2017/07/05 06:00 MHDA- 2018/04/24 06:00 CRDT- 2017/07/05 06:00 PHST- 2016/08/03 00:00 [received] PHST- 2017/04/26 00:00 [revised] PHST- 2017/05/01 00:00 [accepted] PHST- 2017/07/05 06:00 [entrez] PHST- 2017/07/05 06:00 [pubmed] PHST- 2018/04/24 06:00 [medline] AID - S0306-9877(16)30423-6 [pii] AID - 10.1016/j.mehy.2017.05.002 [doi] PST - ppublish SO - Med Hypotheses. 2017 Jul;104:4-9. doi: 10.1016/j.mehy.2017.05.002. Epub 2017 May 3. PMID- 28666800 OWN - NLM STAT- MEDLINE DCOM- 20180515 LR - 20250103 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 812 DP - 2017 Oct 5 TI - A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease. PG - 82-90 LID - S0014-2999(17)30436-3 [pii] LID - 10.1016/j.ejphar.2017.06.029 [doi] AB - Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Yuan, Ziyue AU - Yuan Z AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Dongfang AU - Li D AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: lidongfang898@163.com. FAU - Feng, Peng AU - Feng P AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Xue, Guofang AU - Xue G AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Ji, Chenhui AU - Ji C AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Guanglai AU - Li G AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Holscher, Christian AU - Holscher C AD - Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China; Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article DEP - 20170627 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Aif1 protein, mouse) RN - 0 (Blood Glucose) RN - 0 (Calcium-Binding Proteins) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Microfilament Proteins) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 839I73S42A (Liraglutide) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - VTD58H1Z2X (Dopamine) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*pharmacology MH - Animals MH - Blood Glucose/metabolism MH - Body Weight/drug effects MH - Brain/drug effects/metabolism MH - Calcium-Binding Proteins/metabolism MH - Dopamine/biosynthesis MH - Glial Cell Line-Derived Neurotrophic Factor/*metabolism MH - Hand Strength MH - Inflammation/drug therapy MH - Liraglutide/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microfilament Proteins/metabolism MH - Motor Activity/drug effects MH - Parkinson Disease/*drug therapy/etiology/*metabolism/physiopathology MH - Receptors, Gastrointestinal Hormone/*agonists MH - Rotarod Performance Test MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Brain OT - Dopamine OT - GIP OT - GLP-1 OT - Growth factor OT - Incretins OT - Inflammation OT - Insulin EDAT- 2017/07/02 06:00 MHDA- 2018/05/16 06:00 CRDT- 2017/07/02 06:00 PHST- 2017/03/02 00:00 [received] PHST- 2017/06/23 00:00 [revised] PHST- 2017/06/26 00:00 [accepted] PHST- 2017/07/02 06:00 [pubmed] PHST- 2018/05/16 06:00 [medline] PHST- 2017/07/02 06:00 [entrez] AID - S0014-2999(17)30436-3 [pii] AID - 10.1016/j.ejphar.2017.06.029 [doi] PST - ppublish SO - Eur J Pharmacol. 2017 Oct 5;812:82-90. doi: 10.1016/j.ejphar.2017.06.029. Epub 2017 Jun 27. PMID- 28649604 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240326 IS - 2373-8057 (Print) IS - 2373-8057 (Electronic) IS - 2373-8057 (Linking) VI - 3 DP - 2017 TI - Combined immunotherapy with "anti-insulin resistance" therapy as a novel therapeutic strategy against neurodegenerative diseases. PG - 4 LID - 10.1038/s41531-016-0001-1 [doi] LID - 4 AB - Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid beta and alpha-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid beta immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of alpha-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid beta monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "anti-insulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy. FAU - Takamatsu, Yoshiki AU - Takamatsu Y AD - Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan. FAU - Ho, Gilbert AU - Ho G AD - The PCND Neuroscience Research Institute, Poway, CA 92064 USA. FAU - Koike, Wakako AU - Koike W AD - Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan. FAU - Sugama, Shuei AU - Sugama S AD - Department of Physiology, Nippon Medical School, Tokyo, 113-8602 Japan. ISNI: 0000 0001 2173 8328. GRID: grid.410821.e FAU - Takenouchi, Takato AU - Takenouchi T AD - Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Ibaraki 305-8634 Japan. ISNI: 0000 0001 2222 0432. GRID: grid.416835.d FAU - Waragai, Masaaki AU - Waragai M AD - Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan. FAU - Wei, Jianshe AU - Wei J AD - Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, 475004 China. ISNI: 0000 0000 9139 560X. GRID: grid.256922.8 FAU - Sekiyama, Kazunari AU - Sekiyama K AD - Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan. FAU - Hashimoto, Makoto AU - Hashimoto M AD - Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan. LA - eng PT - Journal Article DEP - 20170123 PL - United States TA - NPJ Parkinsons Dis JT - NPJ Parkinson's disease JID - 101675390 PMC - PMC5445606 COIS- The authors declare no conflicts of interest. EDAT- 2017/06/27 06:00 MHDA- 2017/06/27 06:01 PMCR- 2017/01/23 CRDT- 2017/06/27 06:00 PHST- 2016/04/30 00:00 [received] PHST- 2016/08/07 00:00 [revised] PHST- 2016/10/30 00:00 [accepted] PHST- 2017/06/27 06:00 [entrez] PHST- 2017/06/27 06:00 [pubmed] PHST- 2017/06/27 06:01 [medline] PHST- 2017/01/23 00:00 [pmc-release] AID - 1 [pii] AID - 10.1038/s41531-016-0001-1 [doi] PST - epublish SO - NPJ Parkinsons Dis. 2017 Jan 23;3:4. doi: 10.1038/s41531-016-0001-1. eCollection 2017. PMID- 28573460 OWN - NLM STAT- MEDLINE DCOM- 20190226 LR - 20261012 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 55 IP - 5 DP - 2018 May TI - Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats. PG - 4030-4050 LID - 10.1007/s12035-017-0622-3 [doi] AB - Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD). Since impaired brain insulin signaling may constitute the crosslink between T2D and AD, its restoration may be potentially therapeutic herein. Accordingly, the insulinotropic anti-T2D drugs from glucagon-like peptide-1 (GLP-1) mimetics, namely, exendin-4 (Ex-4), could be a promising therapy. In line with this, we hypothesized that peripherally administered Ex-4 rescues brain intracellular signaling pathways, promoting autophagy and ultimately protecting against chronic T2D-induced apoptosis. Thus, we aimed to explore the effects of chronic, continuous, subcutaneous (s.c.) exposure to Ex-4 in brain cortical GLP-1/insulin/insulin-like growth factor-1 (IGF-1) signaling, and in autophagic and cell death mechanisms in middle-aged (8 months old), male T2D Goto-Kakizaki (GK) rats. We used brain cortical homogenates obtained from middle-aged (8 months old) male Wistar (control) and T2D GK rats. Ex-4 was continuously administered for 28 days, via s.c. implanted micro-osmotic pumps (5 mug/kg/day; infusion rate 2.5 muL/h). Peripheral characterization of the animal models was given by the standard biochemical analyses of blood or plasma, the intraperitoneal glucose tolerance test, and the heart rate. GLP-1, insulin, and IGF-1, their downstream signaling and autophagic markers were evaluated by specific ELISA kits and Western blotting. Caspase-like activities and other apoptotic markers were given by colorimetric methods and Western blotting. Chronic Ex-4 treatment attenuated peripheral features of T2D in GK rats, including hyperglycemia and insulin resistance. Furthermore, s.c. Ex-4 enhanced their brain cortical GLP-1 and IGF-1 levels, and subsequent signaling pathways. Specifically, Ex-4 stimulated protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/Akt signaling, increasing cGMP and AMPK levels, and decreasing GSK3beta and JNK activation in T2D rat brains. Moreover, Ex-4 regulated several markers for autophagy in GK rat brains (as mTOR, PI3K class III, LC3 II, Atg7, p62, LAMP-1, and Parkin), ultimately protecting against apoptosis (by decreasing several caspase-like activities and mitochondrial cytochrome c, and increasing Bcl2 levels upon T2D). Altogether, this study demonstrates that peripheral Ex-4 administration may constitute a promising therapy against the chronic complications of T2D affecting the brain. FAU - Candeias, Emanuel AU - Candeias E AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao - Polo II, Rua D. Francisco de Lemos, 3030-789, Coimbra, Portugal. FAU - Sebastiao, Ines AU - Sebastiao I AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. FAU - Cardoso, Susana AU - Cardoso S AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao - Polo II, Rua D. Francisco de Lemos, 3030-789, Coimbra, Portugal. FAU - Carvalho, Cristina AU - Carvalho C AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao - Polo II, Rua D. Francisco de Lemos, 3030-789, Coimbra, Portugal. FAU - Santos, Maria Sancha AU - Santos MS AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. AD - Life Sciences Department, University of Coimbra, Largo Marques de Pombal, 3004-517, Coimbra, Portugal. FAU - Oliveira, Catarina Resende AU - Oliveira CR AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. AD - Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal. FAU - Moreira, Paula I AU - Moreira PI AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. pimoreira@fmed.uc.pt. AD - Institute of Physiology, Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal. pimoreira@fmed.uc.pt. FAU - Duarte, Ana I AU - Duarte AI AD - CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Polo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal. anaimduarte@gmail.com. AD - Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemao - Polo II, Rua D. Francisco de Lemos, 3030-789, Coimbra, Portugal. anaimduarte@gmail.com. LA - eng GR - Programa Operacional Factores de Competitividade - COMPETE 2020/FEDER/ GR - PTDC/SAU-TOX/117481/2010/FCT - Fundacao para a Ciencia e a Tecnologia/ GR - Strategic Project UID/NEU/04539/2013/FCT - Fundacao para a Ciencia e a Tecnologia/ GR - Fellowship PTDC/SAU-TOX/117481/2010/European Social Fund/ GR - Fellowship PTDC/SAU-TOX/117481/2010/European Social Fund/ GR - Fellowship SFRH/BD/90036/2012/European Social Fund/ GR - Fellowship SFRH/BPD/84473/2012/European Social Fund/ PT - Journal Article DEP - 20170602 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - *Autophagy MH - Brain/*metabolism MH - Diabetes Mellitus, Experimental/metabolism/*pathology MH - Diabetes Mellitus, Type 2/metabolism/*pathology MH - Exenatide/administration & dosage/*pharmacology MH - Glucagon-Like Peptide 1/*metabolism MH - Insulin-Like Growth Factor I/*metabolism MH - Male MH - Models, Biological MH - Rats, Wistar MH - Signal Transduction OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Brain cortex OT - Exendin-4 OT - GLP-1 signaling OT - Type 2 diabetes EDAT- 2017/06/03 06:00 MHDA- 2019/02/27 06:00 CRDT- 2017/06/03 06:00 PHST- 2017/03/17 00:00 [received] PHST- 2017/05/16 00:00 [accepted] PHST- 2017/06/03 06:00 [pubmed] PHST- 2019/02/27 06:00 [medline] PHST- 2017/06/03 06:00 [entrez] AID - 10.1007/s12035-017-0622-3 [pii] AID - 10.1007/s12035-017-0622-3 [doi] PST - ppublish SO - Mol Neurobiol. 2018 May;55(5):4030-4050. doi: 10.1007/s12035-017-0622-3. Epub 2017 Jun 2. PMID- 28540646 OWN - NLM STAT- MEDLINE DCOM- 20180412 LR - 20261010 IS - 1179-1934 (Electronic) IS - 1172-7047 (Linking) VI - 31 IP - 7 DP - 2017 Jul TI - The Molecular Mechanism of Glucagon-Like Peptide-1 Therapy in Alzheimer's Disease, Based on a Mechanistic Target of Rapamycin Pathway. PG - 535-549 LID - 10.1007/s40263-017-0431-2 [doi] AB - The mechanistic target of rapamycin (mTOR) is an important molecule that connects aging, lifespan, energy balance, glucose and lipid metabolism, and neurodegeneration. Rapamycin exerts effects in numerous biological activities via its target protein, playing a key role in energy balance, regulation of autophagy, extension of lifespan, immunosuppression, and protection against neurodegeneration. There are many similar pathophysiological processes and molecular pathways between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), and pharmacologic agents used to treat T2DM, including glucagon-like peptide-1 (GLP-1) analogs, seem to be beneficial for AD. mTOR mediates the effects of GLP-1 analogs in the treatment of T2DM; hence, I hypothesize that mTOR is a key molecule for mediating the protective effects of GLP-1 for AD. FAU - Li, Lin AU - Li L AUID- ORCID: 0000-0001-7085-7075 AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, China. linlilin999@163.com. LA - eng PT - Journal Article PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Alzheimer Disease/*drug therapy/epidemiology/*metabolism MH - Animals MH - Diabetes Mellitus, Type 2/drug therapy/epidemiology/metabolism MH - Glucagon-Like Peptide 1/*analogs & derivatives/metabolism/therapeutic use MH - Humans MH - Neuroprotective Agents/*therapeutic use MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*metabolism EDAT- 2017/05/26 06:00 MHDA- 2018/04/13 06:00 CRDT- 2017/05/26 06:00 PHST- 2017/05/26 06:00 [pubmed] PHST- 2018/04/13 06:00 [medline] PHST- 2017/05/26 06:00 [entrez] AID - 10.1007/s40263-017-0431-2 [pii] AID - 10.1007/s40263-017-0431-2 [doi] PST - ppublish SO - CNS Drugs. 2017 Jul;31(7):535-549. doi: 10.1007/s40263-017-0431-2. PMID- 28342971 OWN - NLM STAT- MEDLINE DCOM- 20171219 LR - 20250103 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 327 DP - 2017 Jun 1 TI - A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. PG - 65-74 LID - S0166-4328(17)30224-3 [pii] LID - 10.1016/j.bbr.2017.03.032 [doi] AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1(Ser1101) levels and phospho-Akt(Ser473) up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Shi, Lijuan AU - Shi L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Zhang, Zhihua AU - Zhang Z AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China. LA - eng PT - Journal Article DEP - 20170323 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, rat) RN - 0 (Mapt protein, rat) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (tau Proteins) RN - 5W494URQ81 (Streptozocin) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/*drug therapy/metabolism/pathology MH - Animals MH - Apoptosis/drug effects/physiology MH - Brain/drug effects/physiology MH - Cognitive Dysfunction/*drug therapy/metabolism/pathology MH - Disease Models, Animal MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Inflammation/drug therapy/metabolism/pathology MH - Insulin/metabolism MH - Insulin Receptor Substrate Proteins/metabolism MH - Male MH - Maze Learning/drug effects/physiology MH - Neuroprotective Agents/*pharmacology MH - Peptides/*pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats, Sprague-Dawley MH - Receptors, Gastrointestinal Hormone/*agonists/metabolism MH - Streptozocin MH - tau Proteins/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Alzheimer's disease OT - Apoptosis OT - Incretin OT - Inflammation OT - Insulin signaling OT - Tau phosphorylation OT - Type 2 diabetes mellitus EDAT- 2017/03/28 06:00 MHDA- 2017/12/20 06:00 CRDT- 2017/03/27 06:00 PHST- 2017/02/03 00:00 [received] PHST- 2017/03/09 00:00 [revised] PHST- 2017/03/21 00:00 [accepted] PHST- 2017/03/28 06:00 [pubmed] PHST- 2017/12/20 06:00 [medline] PHST- 2017/03/27 06:00 [entrez] AID - S0166-4328(17)30224-3 [pii] AID - 10.1016/j.bbr.2017.03.032 [doi] PST - ppublish SO - Behav Brain Res. 2017 Jun 1;327:65-74. doi: 10.1016/j.bbr.2017.03.032. Epub 2017 Mar 23. PMID- 28315374 OWN - NLM STAT- MEDLINE DCOM- 20180307 LR - 20180322 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 326 DP - 2017 May 30 TI - GLP-1 analogue CJC-1131 prevents amyloid beta protein-induced impirments of spatial memory and synaptic plasticity in rats. PG - 237-243 LID - S0166-4328(16)31123-8 [pii] LID - 10.1016/j.bbr.2017.03.018 [doi] AB - Although amyloid beta protein (Abeta) has been recognized as one of the main pathological characteristics in the brain of Alzheimer's disease (AD), the effective strategies against Abeta neurotoxicity are still deficient up to now. Glucagon-like peptide 1 (GLP-1), a natural gut hormone, was found to be effective in modulating insulin signaling and neural protection, but short half-life limited its clinical application in AD treatment. CJC-1131, a newly designed GLP-1 analogue with very longer half-life, has shown good effectiveness in the treatment of type 2 diabetes mellitus (T2DM). However, it is unclear whether CJC-1131 could alleviate Abeta-induced neurotoxicity in cognitive behavior and electrophysiological property. The present study investigated the effects of CJC-1131 on the Abeta-induced impairments in spatial memory and synaptic plasticity of rats by using Morris water maze test and in vivo field potential recording. The results showed that Abeta1-42-induced increase in the escape latency of rats in hidden platform test and decrease in swimming time percent in target quadrant were effectively reversed by CJC-1131 pretreatment. Further, CJC-1131 prevented against Abeta1-42-induced suppression of hippocampal long term potentiation (LTP). In addition, Abeta1-42 injection resulted in a significant decrease of p-PKA in the hippocampus, which was effectively prevented by CJC-1131 treatment. These results indicated that CJC-1131 protected the cognitive function and synaptic plasticity of rats against Abeta-induced impairments, suggesting that GLP-1 analogue CJC-1131 might be potentially beneficial to the prevention and treatment of AD, especially those with T2DM or blood glucose abnormality. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Zhang, Sheng-Xiao AU - Zhang SX AD - Department of Rheumatology, The Second Hospital of Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Ma, Xiao-Wen AU - Ma XW AD - Department of Rheumatology, The Second Hospital of Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Yuan, Li AU - Yuan L AD - Department of Physiology and National Key Discipline of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Zhang, Jun AU - Zhang J AD - Department of Physiology and National Key Discipline of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Department of Physiology and National Key Discipline of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Li, Yu-Feng AU - Li YF AD - Department of Rheumatology, The Second Hospital of Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Physiology and National Key Discipline of Physiology, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. Electronic address: jinshunqi2009@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170315 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Amyloid beta-Peptides) RN - 0 (CJC 1131) RN - 0 (Maleimides) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Amyloid beta-Peptides/*adverse effects MH - Animals MH - Electrophysiological Phenomena MH - Glucagon-Like Peptide 1/*analysis MH - Hippocampus/*drug effects/physiopathology MH - Long-Term Potentiation/*drug effects MH - Male MH - Maleimides/administration & dosage/*pharmacology MH - Memory Disorders/chemically induced/*prevention & control MH - Neuronal Plasticity/*drug effects MH - Neuroprotective Agents/administration & dosage/*pharmacology MH - Peptides/administration & dosage/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Spatial Memory/*drug effects OTO - NOTNLM OT - Amyloid beta protein OT - CJC-1131 OT - Long-term potentiation OT - Morris water maze OT - Spatial memory OT - Synaptic plasticity EDAT- 2017/03/21 06:00 MHDA- 2018/03/08 06:00 CRDT- 2017/03/19 06:00 PHST- 2016/11/21 00:00 [received] PHST- 2017/03/04 00:00 [revised] PHST- 2017/03/08 00:00 [accepted] PHST- 2017/03/21 06:00 [pubmed] PHST- 2018/03/08 06:00 [medline] PHST- 2017/03/19 06:00 [entrez] AID - S0166-4328(16)31123-8 [pii] AID - 10.1016/j.bbr.2017.03.018 [doi] PST - ppublish SO - Behav Brain Res. 2017 May 30;326:237-243. doi: 10.1016/j.bbr.2017.03.018. Epub 2017 Mar 15. PMID- 28223210 OWN - NLM STAT- MEDLINE DCOM- 20180503 LR - 20250103 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 117 DP - 2017 May 1 TI - A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease. PG - 238-248 LID - S0028-3908(17)30058-8 [pii] LID - 10.1016/j.neuropharm.2017.02.013 [doi] AB - The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Jalewa, Jaishree AU - Jalewa J AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. FAU - Sharma, Mohit Kumar AU - Sharma MK AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. FAU - Gengler, Simon AU - Gengler S AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article DEP - 20170220 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Antiparkinson Agents) RN - 0 (Beclin-1) RN - 0 (Becn1 protein, rat) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 8HW4YBZ748 (Oxidopamine) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Antiparkinson Agents/*pharmacology MH - Beclin-1/metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Dopaminergic Neurons/drug effects/metabolism/pathology MH - Glial Cell Line-Derived Neurotrophic Factor/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Male MH - Motor Activity/drug effects MH - Neuroprotective Agents/*pharmacology MH - Oxidopamine MH - Parkinsonian Disorders/*drug therapy/metabolism/pathology MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats, Sprague-Dawley MH - Receptors, Gastrointestinal Hormone/*agonists/metabolism MH - Substantia Nigra/drug effects/metabolism/pathology MH - Tyrosine 3-Monooxygenase/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Brain OT - Incretin OT - Insulin OT - Neurodegeneration OT - Neuron OT - Neuroprotection EDAT- 2017/02/23 06:00 MHDA- 2018/05/04 06:00 CRDT- 2017/02/23 06:00 PHST- 2016/10/18 00:00 [received] PHST- 2017/02/13 00:00 [revised] PHST- 2017/02/14 00:00 [accepted] PHST- 2017/02/23 06:00 [pubmed] PHST- 2018/05/04 06:00 [medline] PHST- 2017/02/23 06:00 [entrez] AID - S0028-3908(17)30058-8 [pii] AID - 10.1016/j.neuropharm.2017.02.013 [doi] PST - ppublish SO - Neuropharmacology. 2017 May 1;117:238-248. doi: 10.1016/j.neuropharm.2017.02.013. Epub 2017 Feb 20. PMID- 28188240 OWN - NLM STAT- MEDLINE DCOM- 20171005 LR - 20260127 IS - 1935-5548 (Electronic) IS - 0149-5992 (Linking) VI - 40 IP - 4 DP - 2017 Apr TI - Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial. PG - 485-493 LID - 10.2337/dc16-2143 [doi] AB - OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged >/=70 years were randomized to receive once-daily lixisenatide 20 mug or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA(1c) from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA(1c) decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA(1c) reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings. CI - (c) 2017 by the American Diabetes Association. FAU - Meneilly, Graydon S AU - Meneilly GS AUID- ORCID: 0000-0002-2442-5260 AD - University of British Columbia, Vancouver, British Columbia, Canada meneilly@mail.ubc.ca. FAU - Roy-Duval, Christine AU - Roy-Duval C AD - Sanofi, Chilly-Mazarin, France. FAU - Alawi, Hasan AU - Alawi H AD - Diabetessaar-Center, Saarlouis, Germany. FAU - Dailey, George AU - Dailey G AD - Scripps Whittier Diabetes Institute, La Jolla, CA. FAU - Bellido, Diego AU - Bellido D AD - University Hospital of Ferrol, Ferrol (Galicia), Spain. FAU - Trescoli, Carlos AU - Trescoli C AD - Hospital de la Ribera, Alzira, Spain. FAU - Manrique Hurtado, Helard AU - Manrique Hurtado H AD - Centro de Investigacion en Diabetes, Obesidad y Nutricion, Lima, Peru. FAU - Guo, Hailing AU - Guo H AD - BMD Consulting, Inc., Somerset, NJ. FAU - Pilorget, Valerie AU - Pilorget V AD - Sanofi, Chilly-Mazarin, France. FAU - Perfetti, Riccardo AU - Perfetti R AD - Sanofi, Bridgewater, NJ. FAU - Simpson, Hamish AU - Simpson H AD - Townhead Surgery, Irvine, U.K. CN - GetGoal-O Trial Investigators LA - eng SI - ClinicalTrials.gov/NCT01798706 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20170210 PL - United States TA - Diabetes Care JT - Diabetes care JID - 7805975 RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Peptides) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Aged MH - Aged, 80 and over MH - Blood Glucose/metabolism MH - Body Weight MH - Diabetes Mellitus, Type 2/*drug therapy MH - Double-Blind Method MH - Endpoint Determination MH - Female MH - Glycated Hemoglobin/metabolism MH - Humans MH - Hyperglycemia/drug therapy MH - Hypoglycemia/etiology MH - Hypoglycemic Agents/*administration & dosage MH - Insulin/administration & dosage MH - Male MH - Nausea/etiology MH - Peptides/*administration & dosage MH - Postprandial Period MH - Vomiting/etiology MH - Glucagon-Like Peptide-2 Receptor EDAT- 2017/02/12 06:00 MHDA- 2017/10/06 06:00 CRDT- 2017/02/12 06:00 PHST- 2016/10/06 00:00 [received] PHST- 2017/01/24 00:00 [accepted] PHST- 2017/02/12 06:00 [pubmed] PHST- 2017/10/06 06:00 [medline] PHST- 2017/02/12 06:00 [entrez] AID - dc16-2143 [pii] AID - 10.2337/dc16-2143 [doi] PST - ppublish SO - Diabetes Care. 2017 Apr;40(4):485-493. doi: 10.2337/dc16-2143. Epub 2017 Feb 10. PMID- 28031898 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 2056-5623 (Print) IS - 2056-5623 (Electronic) IS - 2056-5623 (Linking) VI - 1 IP - 3 DP - 2015 Nov TI - Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases. PG - FSO25 LID - 10.4155/fso.15.23 [doi] LID - FSO25 AB - The changes in the brain signaling systems play an important role in etiology and pathogenesis of Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), being a possible cause of these diseases. Therefore, their restoration at the early stages of T2DM and MS can be regarded as a promising way to treat and prevent these diseases and their complications. The data on the functional state of the brain signaling systems regulated by insulin, IGF-1, leptin, dopamine, serotonin, melanocortins and glucagon-like peptide-1, in T2DM and MS, are analyzed. The pharmacological approaches to restoration of these systems and improvement of insulin sensitivity, energy expenditure, lipid metabolism, and to prevent diabetic complications are discussed. FAU - Shpakov, Alexander O AU - Shpakov AO AD - Laboratory of Molecular Endocrinology & Neurochemistry, I.M. Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, Thorez av. 44, 194223, St. Petersburg, Russia; Laboratory of Molecular Endocrinology & Neurochemistry, I.M. Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, Thorez av. 44, 194223, St. Petersburg, Russia. FAU - Derkach, Kira V AU - Derkach KV AD - Laboratory of Molecular Endocrinology & Neurochemistry, I.M. Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, Thorez av. 44, 194223, St. Petersburg, Russia; Laboratory of Molecular Endocrinology & Neurochemistry, I.M. Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, Thorez av. 44, 194223, St. Petersburg, Russia. FAU - Berstein, Lev M AU - Berstein LM AD - Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia; Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia. LA - eng PT - Journal Article PT - Review DEP - 20151101 PL - England TA - Future Sci OA JT - Future science OA JID - 101665030 PMC - PMC5137856 OTO - NOTNLM OT - brain OT - bromocryptine OT - diabetes mellitus OT - insulin OT - leptin OT - melanocortin OT - metabolic syndrome OT - neurodegeneration OT - signaling systems OT - treatment COIS- Financial & competing interests disclosure This work was supported by the Russian Science Foundation (project No 14-15-00413). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. EDAT- 2016/12/30 06:00 MHDA- 2016/12/30 06:01 PMCR- 2015/11/01 CRDT- 2016/12/30 06:00 PHST- 2016/12/30 06:00 [entrez] PHST- 2016/12/30 06:00 [pubmed] PHST- 2016/12/30 06:01 [medline] PHST- 2015/11/01 00:00 [pmc-release] AID - 10.4155/fso.15.23 [doi] PST - epublish SO - Future Sci OA. 2015 Nov 1;1(3):FSO25. doi: 10.4155/fso.15.23. eCollection 2015 Nov. PMID- 27913104 OWN - NLM STAT- MEDLINE DCOM- 20170407 LR - 20170407 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 797 DP - 2017 Feb 15 TI - D-Ala2-GIP-glu-PAL is neuroprotective in a chronic Parkinson's disease mouse model and increases BNDF expression while reducing neuroinflammation and lipid peroxidation. PG - 162-172 LID - S0014-2999(16)30762-2 [pii] LID - 10.1016/j.ejphar.2016.11.050 [doi] AB - Type 2 diabetes mellitus (T2DM) is a risk factor for Parkinson's disease (PD). Therefore, treatment to improve insulin resistance in T2DM may be useful for PD patients. Glucose dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family that can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. We had shown previously that D-Ala2-GIP-glu-PAL, a novel long-acting GIP analogue, can play a neuroprotective role in the PD mouse model induced by acute MPTP injection. The drug reduced damage to the dopaminergic neurons and increased CREB-mediated Bcl-2 expression to prevent apoptosis and reduced chronic inflammation in the brain. In the present study, we further tested the effects of chronic treatment by D-Ala2-GIP-glu-PAL in a chronic PD mouse model induced by MPTP (25mg/kg ip.) combination with probenecid (250mg/kg ip.) injection for 5 weeks. The results demonstrated that chronic treatment with D-Ala2-GIP-glu-PAL inhibits MPTP -induced Parkinsonism-like motor disorders in mice, and that the drug prevents dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). Moreover, D-Ala2-GIP-glu-PAL also inhibited the increased levels of expression of alpha-synuclein in the SNpc and striatum induced by MPTP. Furthermore, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of BDNF. These findings show that GIP signaling is neuroprotective and holds promise as a novel treatment of PD. CI - Copyright (c) 2017. Published by Elsevier B.V. FAU - Li, Yanwei AU - Li Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of human anatomy, Shaoyang Medical College, Shaoyang, Hunan, PR China. FAU - Liu, WeiZhen AU - Liu W AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second hospital, Neurology department, Shanxi medical University, Taiyuan, Shanxi, PR China. LA - eng PT - Journal Article DEP - 20161129 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Ala2-GIP-Glu-PAL) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (alpha-Synuclein) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) SB - IM MH - Animals MH - Astrocytes/drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Count MH - Chronic Disease MH - Disease Models, Animal MH - Dopaminergic Neurons/drug effects/pathology MH - Gastric Inhibitory Polypeptide/*analogs & derivatives/*pharmacology/therapeutic use MH - Gene Expression Regulation/*drug effects MH - Inflammation/drug therapy MH - Lipid Peroxidation/*drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microglia/drug effects/metabolism/pathology MH - Motor Activity/drug effects MH - Neostriatum/drug effects/metabolism/pathology MH - Parkinson Disease/*drug therapy/*metabolism/pathology/physiopathology MH - Pars Compacta/drug effects/metabolism/pathology MH - alpha-Synuclein/metabolism OTO - NOTNLM OT - Brain OT - Dopamine OT - Growth factor OT - Incretin OT - Insulin OT - Neurodegeneration EDAT- 2016/12/04 06:00 MHDA- 2017/04/08 06:00 CRDT- 2016/12/04 06:00 PHST- 2016/09/22 00:00 [received] PHST- 2016/11/18 00:00 [revised] PHST- 2016/11/28 00:00 [accepted] PHST- 2016/12/04 06:00 [pubmed] PHST- 2017/04/08 06:00 [medline] PHST- 2016/12/04 06:00 [entrez] AID - S0014-2999(16)30762-2 [pii] AID - 10.1016/j.ejphar.2016.11.050 [doi] PST - ppublish SO - Eur J Pharmacol. 2017 Feb 15;797:162-172. doi: 10.1016/j.ejphar.2016.11.050. Epub 2016 Nov 29. PMID- 27882091 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1792-0981 (Print) IS - 1792-1015 (Electronic) IS - 1792-0981 (Linking) VI - 12 IP - 5 DP - 2016 Nov TI - Exendin-4 antagonizes Abeta1-42-induced attenuation of spatial learning and memory ability. PG - 2885-2892 AB - beta-amyloid protein (Abeta) accumulation in cerebral centers involved in cognition and memory is a pivotal pathological feature of Alzheimer's disease (AD). The onset process of type 2 diabetes mellitus (T2DM) has a number of similarities compared with AD. Thus, it is hypothesized that the pharmacological therapy employed for the treatment of T2DM may help to prevent and ameliorate the symptoms of AD. This study demonstrated that Exendin-4, which is a glucagon-like peptide-1 analogue which is used as a therapeutic drug for T2DM, markedly antagonized Abeta fragment-induced attenuation of spatial learning and memory ability, as indicated by a Morris water maze experiment. In addition, we investigated the potential underlying electrophysiological and molecular mechanisms. The results indicate that Exendin-4 rescued long-term potentiation from Abeta1-42-induced damage in the rat hippocampal CA1 region in vivo, and antagonized Abeta1-42-induced reduction of cyclic adenosine monophosphate and phosphorylated-cAMP response element-binding protein in rat hippocampal tissue using ELISA and western blot analysis, respectively. Thus, the results of the present study provide theoretical support for the application of Exendin-4 for improving AD. FAU - Wang, Xiaohui AU - Wang X AD - Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. FAU - Wang, Li AU - Wang L AD - Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. FAU - Jiang, Ruirui AU - Jiang R AD - Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. FAU - Xu, Yunyun AU - Xu Y AD - Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. FAU - Zhao, Xueling AU - Zhao X AD - Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. FAU - Li, Yang AU - Li Y AD - Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. LA - eng PT - Journal Article DEP - 20160921 PL - Greece TA - Exp Ther Med JT - Experimental and therapeutic medicine JID - 101531947 PMC - PMC5103720 OTO - NOTNLM OT - Exendin-4 OT - mechanism OT - neuroprotection OT - beta-amyloid protein 1-42 EDAT- 2016/11/25 06:00 MHDA- 2016/11/25 06:01 PMCR- 2016/09/21 CRDT- 2016/11/25 06:00 PHST- 2015/06/30 00:00 [received] PHST- 2016/09/09 00:00 [accepted] PHST- 2016/11/25 06:00 [entrez] PHST- 2016/11/25 06:00 [pubmed] PHST- 2016/11/25 06:01 [medline] PHST- 2016/09/21 00:00 [pmc-release] AID - ETM-0-0-3742 [pii] AID - 10.3892/etm.2016.3742 [doi] PST - ppublish SO - Exp Ther Med. 2016 Nov;12(5):2885-2892. doi: 10.3892/etm.2016.3742. Epub 2016 Sep 21. PMID- 27871675 OWN - NLM STAT- MEDLINE DCOM- 20171218 LR - 20220409 IS - 1879-3061 (Electronic) IS - 1043-2760 (Linking) VI - 28 IP - 2 DP - 2017 Feb TI - Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. PG - 88-103 LID - S1043-2760(16)30126-6 [pii] LID - 10.1016/j.tem.2016.10.001 [doi] AB - Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary tract that project to multiple regions expressing GLP-1 receptors (GLP-1Rs). Treatment with GLP-1R agonists (GLP-1-RAs) reduces ischemia-induced hyperactivity, oxidative stress, neuronal damage and apoptosis, cerebral infarct volume, and neurologic damage, after cerebral ischemia, in experimental models. Ongoing human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection. CI - Copyright (c) 2016 Elsevier Ltd. All rights reserved. FAU - Muscogiuri, Giovanna AU - Muscogiuri G AD - Ios and Coleman Medicina Futura Medical Center, Naples, Italy. FAU - DeFronzo, Ralph A AU - DeFronzo RA AD - Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA. FAU - Gastaldelli, Amalia AU - Gastaldelli A AD - Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA; Institute of Clinical Physiology of the National Research Council (CNR), Pisa, Italy. Electronic address: amalia@ifc.cnr.it. FAU - Holst, Jens J AU - Holst JJ AD - NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark. LA - eng SI - ClinicalTrials.gov/NCT01255163 SI - ClinicalTrials.gov/NCT01469351 SI - ClinicalTrials.gov/NCT01843075 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20161027 PL - United States TA - Trends Endocrinol Metab JT - Trends in endocrinology and metabolism: TEM JID - 9001516 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Central Nervous System/*metabolism MH - Diabetes Mellitus/*metabolism MH - Diabetes Mellitus, Type 2/metabolism MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Neurodegenerative Diseases/metabolism MH - Peripheral Nervous System/*metabolism OTO - NOTNLM OT - appetite OT - central nervous system OT - glucagon-like peptide-1 OT - neurodegenerative diseases OT - type 2 diabetes EDAT- 2016/11/23 06:00 MHDA- 2017/12/19 06:00 CRDT- 2016/11/23 06:00 PHST- 2016/07/15 00:00 [received] PHST- 2016/09/30 00:00 [revised] PHST- 2016/10/03 00:00 [accepted] PHST- 2016/11/23 06:00 [pubmed] PHST- 2017/12/19 06:00 [medline] PHST- 2016/11/23 06:00 [entrez] AID - S1043-2760(16)30126-6 [pii] AID - 10.1016/j.tem.2016.10.001 [doi] PST - ppublish SO - Trends Endocrinol Metab. 2017 Feb;28(2):88-103. doi: 10.1016/j.tem.2016.10.001. Epub 2016 Oct 27. PMID- 27845037 OWN - NLM STAT- MEDLINE DCOM- 20170512 LR - 20250530 IS - 1090-2430 (Electronic) IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 288 DP - 2017 Feb TI - Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury. PG - 176-186 LID - S0014-4886(16)30369-7 [pii] LID - 10.1016/j.expneurol.2016.11.005 [doi] AB - Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism. CI - Published by Elsevier Inc. FAU - Tamargo, Ian A AU - Tamargo IA AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: iatamargo@gmail.com. FAU - Bader, Miaad AU - Bader M AD - Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. FAU - Li, Yazhou AU - Li Y AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. FAU - Yu, Seong-Jin AU - Yu SJ AD - Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan. FAU - Wang, Yun AU - Wang Y AD - Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan. FAU - Talbot, Konrad AU - Talbot K AD - Department of Neurology, UCLA, Los Angeles, CA, USA. FAU - DiMarchi, Richard D AU - DiMarchi RD AD - Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. FAU - Pick, Chaim G AU - Pick CG AD - Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: Greign@mail.nih.gov. LA - eng GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States GR - ZIA AG000333/ImNIH/Intramural NIH HHS/United States PT - Journal Article DEP - 20161111 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Body Temperature/drug effects MH - Brain Injuries, Traumatic/complications/*drug therapy MH - CREB-Binding Protein/metabolism MH - Cell Line, Tumor MH - Cells, Cultured MH - Disease Models, Animal MH - Embryo, Mammalian MH - Glucagon-Like Peptide 1/*metabolism MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Humans MH - Incretins/*therapeutic use MH - Male MH - Maze Learning/drug effects MH - Memory Disorders/etiology/prevention & control MH - Mice MH - Mice, Inbred ICR MH - Neuroblastoma/pathology MH - Neuroprotective Agents/*therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/metabolism MH - Receptors, Gastrointestinal Hormone/agonists/*metabolism MH - Recognition, Psychology/drug effects MH - Signal Transduction/drug effects MH - Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC5878017 MID - NIHMS942341 OTO - NOTNLM OT - Glucagon-like peptide-1 OT - Glucose-dependent insulinotropic peptide OT - Incretin OT - Incretin mimetic OT - Neurodegeneration OT - Traumatic brain injury COIS- Competing interests The other authors declare no competing interests. EDAT- 2016/11/16 06:00 MHDA- 2017/05/13 06:00 PMCR- 2018/03/30 CRDT- 2016/11/16 06:00 PHST- 2016/09/02 00:00 [received] PHST- 2016/11/08 00:00 [revised] PHST- 2016/11/10 00:00 [accepted] PHST- 2016/11/16 06:00 [pubmed] PHST- 2017/05/13 06:00 [medline] PHST- 2016/11/16 06:00 [entrez] PHST- 2018/03/30 00:00 [pmc-release] AID - S0014-4886(16)30369-7 [pii] AID - 10.1016/j.expneurol.2016.11.005 [doi] PST - ppublish SO - Exp Neurol. 2017 Feb;288:176-186. doi: 10.1016/j.expneurol.2016.11.005. Epub 2016 Nov 11. PMID- 27776993 OWN - NLM STAT- MEDLINE DCOM- 20171106 LR - 20260127 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 318 DP - 2017 Feb 1 TI - Lixisenatide attenuates the detrimental effects of amyloid beta protein on spatial working memory and hippocampal neurons in rats. PG - 28-35 LID - S0166-4328(16)30892-0 [pii] LID - 10.1016/j.bbr.2016.10.033 [doi] AB - Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimer's disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD-related impairments in rats. The results show that lixisenatide effectively alleviated amyloid beta protein (Abeta) 25-35-induced working memory impairment, reversed Abeta25-35-triggered cytotoxicity on hippocampal cell cultures, and prevented against Abeta25-35-induced suppression of the Akt-MEK1/2 signaling pathway. Lixisenatide also reduced the Abeta25-35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against Abeta-induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt-MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis. CI - Crown Copyright A(c) 2016. Published by Elsevier B.V. All rights reserved. FAU - Cai, Hong-Yan AU - Cai HY AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China. FAU - Wang, Zhao-Jun AU - Wang ZJ AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, LA1 4YQ, UK. FAU - Yuan, Li AU - Yuan L AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Zhang, Jun AU - Zhang J AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Sun, Peng AU - Sun P AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China. FAU - Li, Jing AU - Li J AD - Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China. FAU - Yang, Wei AU - Yang W AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Wu, Mei-Na AU - Wu MN AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: jinshunqi2009@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161021 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Amyloid beta-Peptides) RN - 0 (Butadienes) RN - SY7Q814VUP (Calcium) RN - 0 (Neuroprotective Agents) RN - 0 (Nitriles) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (U 0126) RN - 0 (amyloid beta-protein (25-35)) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Amyloid beta-Peptides/*antagonists & inhibitors/pharmacology MH - Animals MH - Butadienes/pharmacology MH - Calcium/metabolism MH - Cell Survival/drug effects MH - Hippocampus/*drug effects MH - Maze Learning/drug effects MH - Memory, Short-Term/*drug effects MH - Neurons/drug effects MH - Neuroprotective Agents/pharmacology MH - Nitriles/pharmacology MH - Peptide Fragments/*antagonists & inhibitors/pharmacology MH - Peptides/*pharmacology MH - Primary Cell Culture MH - Rats MH - Signal Transduction/drug effects MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - Akt-MEK1/2 signal pathway OT - Amyloid beta protein OT - Cell viability OT - Intracellular calcium concentration OT - Lixisenatide OT - Working memory EDAT- 2016/10/30 06:00 MHDA- 2017/11/07 06:00 CRDT- 2016/10/30 06:00 PHST- 2016/08/19 00:00 [received] PHST- 2016/10/17 00:00 [revised] PHST- 2016/10/20 00:00 [accepted] PHST- 2016/10/30 06:00 [pubmed] PHST- 2017/11/07 06:00 [medline] PHST- 2016/10/30 06:00 [entrez] AID - S0166-4328(16)30892-0 [pii] AID - 10.1016/j.bbr.2016.10.033 [doi] PST - ppublish SO - Behav Brain Res. 2017 Feb 1;318:28-35. doi: 10.1016/j.bbr.2016.10.033. Epub 2016 Oct 21. PMID- 27780892 OWN - NLM STAT- MEDLINE DCOM- 20171205 LR - 20181203 IS - 1573-4935 (Electronic) IS - 0144-8463 (Print) IS - 0144-8463 (Linking) VI - 36 IP - 6 DP - 2016 Dec TI - Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin-4. LID - 10.1042/BSR20160437 [doi] LID - e00421 AB - Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional gamma-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R). We determined the effect of T2D on cortical and striatal GABAergic neurons positive for glutamic acid decarboxylase-67 (GAD67), calbindin (CB), parvalbumin (PV) and calretinin (CR) by using immunohistochemistry and quantitative microscopy. Young and middle-aged T2D Goto-Kakizaki (GK) (a model of spontaneous T2D) and Wistar rats were used. Furthermore, we determined the therapeutic potential of the GLP1-R agonist exendin-4 (Ex-4) by treating middle-aged GK rats for 6 weeks with 0.1 mug/kg Ex-4 twice daily. We show that T2D reduced the density of GAD67-positive neurons in the striatum and of CB-positive neurons in both striatum and neocortex. T2D also increased the average volume of PV-positive interneurons in the striatum. Ex-4 treatment increased the density of CB-positive neurons in the striatum of GK rats. Our data demonstrate that T2D negatively affects GAD67 and CB-positive GABAergic neurons in the brain during aging, potentially identifying some of the pathophysiological mechanisms to explain the increased prevalence of neurological complications in T2D. We also show a specific, positive effect of Ex-4 on striatal CB-positive neurons, which could be exploited in therapeutic perspective. CI - (c) 2016 The Author(s). FAU - Larsson, Martin AU - Larsson M AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se. FAU - Lietzau, Grazyna AU - Lietzau G AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden. AD - Department of Anatomy and Neurobiology, Medical University of Gdansk, 80 221 Gdansk, Poland. FAU - Nathanson, David AU - Nathanson D AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden. FAU - Ostenson, Claes-Goran AU - Ostenson CG AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden. FAU - Mallard, Carina AU - Mallard C AD - Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden. FAU - Johansson, Maria E AU - Johansson ME AD - Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden. FAU - Nystrom, Thomas AU - Nystrom T AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden. FAU - Patrone, Cesare AU - Patrone C AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se. FAU - Darsalia, Vladimer AU - Darsalia V AD - Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se. LA - eng PT - Journal Article DEP - 20161205 PL - England TA - Biosci Rep JT - Bioscience reports JID - 8102797 RN - 0 (Calbindin 2) RN - 0 (Calbindins) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Parvalbumins) RN - 0 (Peptides) RN - 0 (Venoms) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 9P1872D4OL (Exenatide) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 1) SB - IM MH - Animals MH - Calbindin 2/metabolism MH - Calbindins/metabolism MH - Corpus Striatum/metabolism/physiopathology MH - Diabetes Mellitus/*metabolism/physiopathology MH - Diabetes Mellitus, Experimental/*metabolism/physiopathology MH - Exenatide MH - GABAergic Neurons/*metabolism/physiology MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Glutamate Decarboxylase/metabolism MH - Neocortex/metabolism/physiopathology MH - Parvalbumins/metabolism MH - Peptides/*metabolism MH - Rats MH - Rats, Wistar MH - Venoms/*metabolism MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC5137538 OTO - NOTNLM OT - diabetes OT - exendin-4 OT - glucagon-like peptide-1 receptor (GLP-1R) OT - interneurons OT - neurological complications OT - gamma-aminobutyric acid (GABA) EDAT- 2016/10/27 06:00 MHDA- 2017/12/06 06:00 PMCR- 2016/12/01 CRDT- 2016/10/27 06:00 PHST- 2016/09/30 00:00 [received] PHST- 2016/10/21 00:00 [revised] PHST- 2016/10/24 00:00 [accepted] PHST- 2016/10/27 06:00 [pubmed] PHST- 2017/12/06 06:00 [medline] PHST- 2016/10/27 06:00 [entrez] PHST- 2016/12/01 00:00 [pmc-release] AID - BSR20160437 [pii] AID - e00421 [pii] AID - 10.1042/BSR20160437 [doi] PST - epublish SO - Biosci Rep. 2016 Dec 5;36(6):e00421. doi: 10.1042/BSR20160437. Print 2016 Dec. PMID- 27715341 OWN - NLM STAT- MEDLINE DCOM- 20170724 LR - 20180531 IS - 1744-8360 (Electronic) IS - 1473-7175 (Linking) VI - 17 IP - 1 DP - 2017 Jan TI - Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer's disease pathology. PG - 59-75 AB - Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Post-mortem analyses of Alzheimer disease (AD) subjects revealed insulin resistance in the brain, suggesting a role of this condition in cognitive deficits observed in AD. In this review, we focus on the glucagon-like peptide-1 (GLP-1) signaling pathway, whose role in the brain is collecting increasing attention because of its association with insulin signaling activation. Areas covered: The role of GLP-1-mediated effects in the brain and how they are affected along the progression of AD pathology is discussed. Furthermore, we provide a comprehensive discussion about the use of GLP-1 mimetics drugs, which have been developed as a treatment for T2DM but seem to possess a number of other physiological properties, including neuroprotective and anti-inflammatory effects, that may be useful to slow AD progression. Expert commentary: The repurposing of antidiabetic drugs for the modulation of brain insulin resistance in AD appears to be of great interest. The beneficial effects on synaptogenesis, neurogenesis, and cell repair as well as the reduction of the chronic inflammatory response, and most importantly the reduction of amyloid plaques in the brain indicate that these drugs have promise as novel treatments for AD. FAU - Tramutola, Antonella AU - Tramutola A AD - a Department of Biochemical Sciences 'A. Rossi-Fanelli' , Sapienza University of Rome , Roma , Italy. FAU - Arena, Andrea AU - Arena A AD - a Department of Biochemical Sciences 'A. Rossi-Fanelli' , Sapienza University of Rome , Roma , Italy. FAU - Cini, Chiara AU - Cini C AD - a Department of Biochemical Sciences 'A. Rossi-Fanelli' , Sapienza University of Rome , Roma , Italy. FAU - Butterfield, D Allan AU - Butterfield DA AD - b Department of Chemistry and Sanders-Brown Center on Aging , University of Kentucky , Lexington , KY , USA. FAU - Barone, Eugenio AU - Barone E AD - a Department of Biochemical Sciences 'A. Rossi-Fanelli' , Sapienza University of Rome , Roma , Italy. AD - c Universidad Autonoma de Chile, Instituto de Ciencias Biomedicas , Facultad de Salud , Santiago , Chile. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20161020 PL - England TA - Expert Rev Neurother JT - Expert review of neurotherapeutics JID - 101129944 RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - *Glucagon-Like Peptide 1/metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Insulin Resistance MH - Molecular Targeted Therapy MH - Signal Transduction/drug effects OTO - NOTNLM OT - Alzheimer disease OT - GLP-1 OT - dementia OT - incretins OT - insulin resistance EDAT- 2016/10/08 06:00 MHDA- 2017/07/25 06:00 CRDT- 2016/10/08 06:00 PHST- 2016/10/08 06:00 [pubmed] PHST- 2017/07/25 06:00 [medline] PHST- 2016/10/08 06:00 [entrez] AID - 10.1080/14737175.2017.1246183 [doi] PST - ppublish SO - Expert Rev Neurother. 2017 Jan;17(1):59-75. doi: 10.1080/14737175.2017.1246183. Epub 2016 Oct 20. PMID- 27699599 OWN - NLM STAT- MEDLINE DCOM- 20180717 LR - 20181113 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 54 IP - 8 DP - 2017 Oct TI - Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Mitigates Cognitive Deficits and Pathology in the 3xTg-AD Mouse Model of Alzheimer's Disease. PG - 6074-6084 LID - 10.1007/s12035-016-0125-7 [doi] AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer's disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD. With this background, the present study was designed to examine the effectiveness of linagliptin, a DPP-4 inhibitor in the 3xTg-AD mouse model of Alzheimer's disease. Nine-month-old 3xTg-AD mice were administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. At the end of the linagliptin treatment, mice were evaluated for cognitive ability on the Morris Water Maze and Y-maze. Following cognitive evaluation, mice were sacrificed to determine the effect of the linagliptin on brain incretin levels, amyloid burden, tau phosphorylation, and neuroinflammation. We confirm that linagliptin treatment for 8 weeks mitigates the cognitive deficits present in 3xTg-AD mice. Moreover, linagliptin also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation. In conclusion, linagliptin possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain. FAU - Kosaraju, Jayasankar AU - Kosaraju J AD - Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China. FAU - Holsinger, R M Damian AU - Holsinger RMD AD - Laboratory of Molecular Neuroscience and Dementia, The Brain and Mind Centre, The University of Sydney, Camperdown, NSW, 2050, Australia. AD - The Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, The University of Sydney, Lidcombe, NSW, 1875, Australia. FAU - Guo, Lixia AU - Guo L AD - Chongqing Key Lab of Natural Medicine Research, Chongqing Technology and Business University, Chongqing, 400067, China. FAU - Tam, Kin Yip AU - Tam KY AD - Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China. kintam@umac.mo. LA - eng GR - 118/2013/A3/Science and Technology Development Fund, Macao S.A.R (FDCT)/ PT - Journal Article DEP - 20161003 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Amyloid beta-Peptides) RN - 0 (Blood Glucose) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (tau Proteins) RN - 3X29ZEJ4R2 (Linagliptin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*drug therapy/genetics/metabolism MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Blood Glucose/metabolism MH - Cognition Disorders/*drug therapy/genetics/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Disease Models, Animal MH - Female MH - Glucagon-Like Peptide 1/metabolism MH - Linagliptin/pharmacology/*therapeutic use MH - Maze Learning/*drug effects MH - Mice MH - Mice, Transgenic MH - tau Proteins/metabolism OTO - NOTNLM OT - Amyloid beta OT - Glucagon-like peptide-1 OT - Glucose-dependent insulinotropic polypeptide OT - Neuroinflammation OT - Tau phosphorylation EDAT- 2016/10/05 06:00 MHDA- 2018/07/18 06:00 CRDT- 2016/10/05 06:00 PHST- 2016/07/12 00:00 [received] PHST- 2016/09/12 00:00 [accepted] PHST- 2016/10/05 06:00 [pubmed] PHST- 2018/07/18 06:00 [medline] PHST- 2016/10/05 06:00 [entrez] AID - 10.1007/s12035-016-0125-7 [pii] AID - 10.1007/s12035-016-0125-7 [doi] PST - ppublish SO - Mol Neurobiol. 2017 Oct;54(8):6074-6084. doi: 10.1007/s12035-016-0125-7. Epub 2016 Oct 3. PMID- 27648144 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20160920 LR - 20201001 IS - 1943-8141 (Print) IS - 1943-8141 (Electronic) IS - 1943-8141 (Linking) VI - 8 IP - 8 DP - 2016 TI - Exendin-4 protects Abeta(1-42) oligomer-induced PC12 cell apoptosis. PG - 3540-8 AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease. Most recently, GLP-1 analogs have been shown to have a significant neuroprotective role in several neurodegenerative diseases. However, few are known on its potential mechanism. OBJECTIVE: In this study, we report the effect of exendin-4 (Ex-4), a GLP-1 receptor agonist, on amyloid-beta(1-42) peptide oligomer-induced apoptosis in a PC12 neuronal cell model. METHODS: MTT, DAPI and Annexin-V/PI assays revealed that the viability of PC12 cells decreased in a dose- and time-dependent manner after exposure to amyloid-beta(1-42) oligomers. This apoptotic effect could be attenuated by Ex-4 (100-300 nM) pre-treatment, compared with the PC12 cells treated with amyloid-beta(1-42) oligomers alone. Moreover, treatment with amyloid-beta(1-42) oligomers (10 muM) resulted in a decrease in active- and pro-caspase-3 expression, as well as in Bcl-2 protein expression; suggesting that amyloid-beta(1-42) oligomers impaired neuronal cells via the apoptosis signaling pathway. A further study of this mechanism revealed that amyloid-beta oligomers (AbetaOs) decreased the phosphorylation of Akt and CREB. As expected, pre-treatment with Ex-4 (300 nM) increased the expression of anti-apoptotic protein Bcl-2 and reduced active caspase-3 expression levels. In addition, Ex-4 upregulated the phosphorylation levels of Akt and CREB. CONCLUSIONS: These findings indicate that GLP-1 analogue Ex-4 has a neuroprotective effect against AbetaO-induced PC12 cell apoptosis through reversing the impairment of the neuronal survival signaling pathway. This strongly suggests that Ex-4 is a potential therapeutic option for ameliorating AbetaO-induced neurotoxicity in the clinical application of Ex-4 for AD treatment, particularly when associated with diabetes. FAU - Qiu, Chen AU - Qiu C AD - Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Endocrinology, People's Hospital Affiliated to Fujian University of Traditional Chinese MedicineFuzhou 350004, Fujian, China. FAU - Wang, Yan-Ping AU - Wang YP AD - Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Department of Geriatrics, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China. FAU - Pan, Xiao-Dong AU - Pan XD AD - Department of Neurology, Fujian Medical University Union Hospital Fuzhou 350001, Fujian, China. FAU - Liu, Xiao-Ying AU - Liu XY AD - Fujian Institute of Endocrinology, Fujian Medical University Union Hospital Fuzhou 350001, Fujian, China. FAU - Chen, Zhou AU - Chen Z AD - College of Pharmacy, Fujian Medical University Fuzhou 350108, Fujian, China. FAU - Liu, Li-Bin AU - Liu LB AD - Fujian Institute of Endocrinology, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China; Institute of Geriatric Health Science, Fujian Medical UniversityFuzhou 350001, Fujian, China. LA - eng PT - Journal Article DEP - 20160815 PL - United States TA - Am J Transl Res JT - American journal of translational research JID - 101493030 PMC - PMC5009406 OTO - NOTNLM OT - Exendin-4 OT - amyloid-beta(1-42) oligomers OT - apoptosis OT - neuronal cells OT - neuronal survival signaling EDAT- 2016/09/21 06:00 MHDA- 2016/09/21 06:01 PMCR- 2016/08/15 CRDT- 2016/09/21 06:00 PHST- 2015/12/08 00:00 [received] PHST- 2016/07/15 00:00 [accepted] PHST- 2016/09/21 06:00 [entrez] PHST- 2016/09/21 06:00 [pubmed] PHST- 2016/09/21 06:01 [medline] PHST- 2016/08/15 00:00 [pmc-release] PST - epublish SO - Am J Transl Res. 2016 Aug 15;8(8):3540-8. eCollection 2016. PMID- 27572131 OWN - NLM STAT- MEDLINE DCOM- 20171018 LR - 20171107 IS - 1937-6448 (Print) IS - 1937-6448 (Linking) VI - 326 DP - 2016 TI - Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon. PG - 279-341 LID - S1937-6448(16)30049-1 [pii] LID - 10.1016/bs.ircmb.2016.05.002 [doi] AB - Glucagon family of peptide hormones is a group of structurally related brain-gut peptides that exert their pleiotropic actions through interactions with unique members of class B1 G protein-coupled receptors (GPCRs). They are key regulators of hormonal homeostasis and are important drug targets for metabolic disorders such as type-2 diabetes mellitus (T2DM), obesity, and dysregulations of the nervous systems such as migraine, anxiety, depression, neurodegeneration, psychiatric disorders, and cardiovascular diseases. The current review aims to provide a detailed overview of the current understanding of the pharmacological actions and therapeutic advances of three members within this family including glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Sekar, R AU - Sekar R AD - School of Biological Sciences, University of Hong Kong, Hong Kong, China. FAU - Singh, K AU - Singh K AD - School of Biological Sciences, University of Hong Kong, Hong Kong, China. FAU - Arokiaraj, A W R AU - Arokiaraj AW AD - School of Biological Sciences, University of Hong Kong, Hong Kong, China. FAU - Chow, B K C AU - Chow BK AD - School of Biological Sciences, University of Hong Kong, Hong Kong, China. Electronic address: bkcc@hku.hk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20160625 PL - Netherlands TA - Int Rev Cell Mol Biol JT - International review of cell and molecular biology JID - 101475846 RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9007-92-5 (Glucagon) SB - IM MH - Animals MH - Female MH - Gastric Inhibitory Polypeptide/adverse effects/*pharmacology/therapeutic use MH - Glucagon/administration & dosage/*pharmacology/therapeutic use MH - Glucagon-Like Peptide 1/adverse effects/*pharmacology/therapeutic use MH - Humans MH - Male OTO - NOTNLM OT - gastric inhibitory polypeptide OT - glucagon OT - glucagon-like peptide-1 OT - pharmacology OT - type-2 diabetes mellitus EDAT- 2016/08/31 06:00 MHDA- 2017/10/19 06:00 CRDT- 2016/08/31 06:00 PHST- 2016/08/31 06:00 [entrez] PHST- 2016/08/31 06:00 [pubmed] PHST- 2017/10/19 06:00 [medline] AID - S1937-6448(16)30049-1 [pii] AID - 10.1016/bs.ircmb.2016.05.002 [doi] PST - ppublish SO - Int Rev Cell Mol Biol. 2016;326:279-341. doi: 10.1016/bs.ircmb.2016.05.002. Epub 2016 Jun 25. PMID- 27521218 OWN - NLM STAT- MEDLINE DCOM- 20171109 LR - 20171120 IS - 1095-6808 (Electronic) IS - 0091-3022 (Linking) VI - 42 DP - 2016 Jul TI - Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes. PG - 76-92 LID - S0091-3022(16)30033-4 [pii] LID - 10.1016/j.yfrne.2016.07.002 [doi] AB - Type 2 diabetes mellitus is a complex metabolic disease that can cause serious damage to various organs. Among the best-known complications, an important role is played by cognitive impairment. Impairment of cognitive functioning has been reported both in type 1 and 2 diabetes mellitus. While this comorbidity has long been known, no major advances have been achieved in clinical research; it is clear that appropriate control of blood glucose levels represents the best current (although unsatisfactory) approach in the prevention of cognitive impairment. We have focused our attention on the possible effect on the brain of antidiabetic drugs, despite their effects on blood glucose levels, giving a brief rationale on the mechanisms (e.g. GLP-1, BDNF, ghrelin) that might be involved. Indeed, GLP-1 agonists are currently clinically studied in other neurodegenerative diseases (i.e. Parkinson's and Alzheimer's disease); furthermore, also other antidiabetic drugs have proven efficacy in preclinical studies. Overall, promising results are already available and finding new intervention strategies represents a current need in this field of research. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Palleria, Caterina AU - Palleria C AD - Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. FAU - Leporini, Christian AU - Leporini C AD - Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. FAU - Maida, Francesca AU - Maida F AD - Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. FAU - Succurro, Elena AU - Succurro E AD - Department of Medical and Surgical Sciences, Internal Medicine Unit of "Mater Domini", University Hospital, University "Magna Graecia" of Catanzaro, Policlinico "Mater Domini", Campus Universitario, Viale Europa, 88100 Catanzaro, Italy. FAU - De Sarro, Giovambattista AU - De Sarro G AD - Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. FAU - Arturi, Franco AU - Arturi F AD - Department of Medical and Surgical Sciences, Internal Medicine Unit of "Mater Domini", University Hospital, University "Magna Graecia" of Catanzaro, Policlinico "Mater Domini", Campus Universitario, Viale Europa, 88100 Catanzaro, Italy. FAU - Russo, Emilio AU - Russo E AD - Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. Electronic address: erusso@unicz.it. LA - eng PT - Journal Article PT - Review DEP - 20160809 PL - United States TA - Front Neuroendocrinol JT - Frontiers in neuroendocrinology JID - 7513292 RN - 0 (Hypoglycemic Agents) SB - IM MH - Cognitive Dysfunction/*drug therapy/etiology MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Humans MH - Hypoglycemic Agents/*pharmacology OTO - NOTNLM OT - GLP-1 OT - Gliptins OT - Metformin OT - Neuroprotection OT - Sulfonylureas OT - Thiazolidinediones EDAT- 2016/08/16 06:00 MHDA- 2017/11/10 06:00 CRDT- 2016/08/14 06:00 PHST- 2015/04/20 00:00 [received] PHST- 2016/07/13 00:00 [revised] PHST- 2016/07/22 00:00 [accepted] PHST- 2016/08/14 06:00 [entrez] PHST- 2016/08/16 06:00 [pubmed] PHST- 2017/11/10 06:00 [medline] AID - S0091-3022(16)30033-4 [pii] AID - 10.1016/j.yfrne.2016.07.002 [doi] PST - ppublish SO - Front Neuroendocrinol. 2016 Jul;42:76-92. doi: 10.1016/j.yfrne.2016.07.002. Epub 2016 Aug 9. PMID- 27276528 OWN - NLM STAT- MEDLINE DCOM- 20180102 LR - 20181202 IS - 2191-0200 (Electronic) IS - 0334-1763 (Linking) VI - 27 IP - 7 DP - 2016 Oct 1 TI - Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. PG - 689-711 LID - 10.1515/revneuro-2016-0018 [doi] AB - Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer's disease (AD) and Parkinson's disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases. FAU - Li, Yanwei AU - Li Y FAU - Li, Lin AU - Li L FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Review PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Peptides) RN - 0 (Venoms) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/*drug therapy MH - Exenatide MH - Gastric Inhibitory Polypeptide/pharmacology MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Incretins/*therapeutic use MH - Neurodegenerative Diseases/*drug therapy MH - Peptides/therapeutic use MH - Venoms/therapeutic use EDAT- 2016/06/09 06:00 MHDA- 2018/01/03 06:00 CRDT- 2016/06/09 06:00 PHST- 2016/04/11 00:00 [received] PHST- 2016/05/02 00:00 [accepted] PHST- 2016/06/09 06:00 [pubmed] PHST- 2018/01/03 06:00 [medline] PHST- 2016/06/09 06:00 [entrez] AID - /j/revneuro.ahead-of-print/revneuro-2016-0018/revneuro-2016-0018.xml [pii] AID - 10.1515/revneuro-2016-0018 [doi] PST - ppublish SO - Rev Neurosci. 2016 Oct 1;27(7):689-711. doi: 10.1515/revneuro-2016-0018. PMID- 27186358 OWN - NLM STAT- MEDLINE DCOM- 20170208 LR - 20250103 IS - 2040-1124 (Electronic) IS - 2040-1116 (Print) IS - 2040-1116 (Linking) VI - 7 Suppl 1 IP - Suppl 1 DP - 2016 Apr TI - Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. PG - 64-9 LID - 10.1111/jdi.12464 [doi] AB - Glucagon-like peptide-1 (GLP-1) is derived from both the enteroendocrine L cells and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. As GLP-1 is cleaved by dipeptidyl peptidase-4 yielding a half-life of less than 2 min, it is plausible that the gut-derived GLP-1, released postprandially, exerts its effects on the brain mainly by interacting with vagal afferent neurons located at the intestinal or hepatic portal area. GLP-1 neurons in the NTS widely project in the central nervous system and act as a neurotransmitter. One of the physiological roles of brain-derived GLP-1 is restriction of feeding. GLP-1 receptor agonists have recently been used to treat type 2 diabetic patients, and have been shown to exhibit pleiotropic effects beyond incretin action, which involve brain functions. GLP-1 receptor agonist administered in the periphery is stable because of its resistance to dipeptidyl peptidase-4, and is highly likely to act on the brain by passing through the blood-brain barrier (BBB), as well as interacting with vagal afferent nerves. Central actions of GLP-1 have various roles including regulation of feeding, weight, glucose and lipid metabolism, cardiovascular functions, cognitive functions, and stress and emotional responses. In the present review, we focus on the source of GLP-1 and the pathway by which peripheral GLP-1 informs the brain, and then discuss recent findings on the central effects of GLP-1 and GLP-1 receptor agonists. FAU - Katsurada, Kenichi AU - Katsurada K AD - Division of Integrative PhysiologyDepartment of PhysiologyJichi Medical University School of MedicineShimotsukeTochigiJapan; Division of Cardiovascular MedicineDepartment of Internal MedicineJichi Medical University School of MedicineShimotsukeTochigiJapan. FAU - Yada, Toshihiko AU - Yada T AD - Division of Integrative Physiology Department of Physiology Jichi Medical University School of Medicine Shimotsuke Tochigi Japan. LA - eng PT - Journal Article PT - Review DEP - 20160331 PL - Japan TA - J Diabetes Investig JT - Journal of diabetes investigation JID - 101520702 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Cardiovascular Physiological Phenomena/drug effects MH - Enteroendocrine Cells/metabolism/*physiology MH - *Feeding Behavior MH - Glucagon-Like Peptide 1/metabolism/*physiology MH - Glucagon-Like Peptide-1 Receptor/metabolism/*physiology MH - Humans MH - Mice MH - Rats MH - Solitary Nucleus/metabolism/*physiology MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC4854507 OTO - NOTNLM OT - Brain stem OT - Cardiovascular OT - Feeding EDAT- 2016/05/18 06:00 MHDA- 2017/02/09 06:00 PMCR- 2016/04/01 CRDT- 2016/05/18 06:00 PHST- 2015/12/03 00:00 [received] PHST- 2015/12/21 00:00 [accepted] PHST- 2016/05/18 06:00 [entrez] PHST- 2016/05/18 06:00 [pubmed] PHST- 2017/02/09 06:00 [medline] PHST- 2016/04/01 00:00 [pmc-release] AID - JDI12464 [pii] AID - 10.1111/jdi.12464 [doi] PST - ppublish SO - J Diabetes Investig. 2016 Apr;7 Suppl 1(Suppl 1):64-9. doi: 10.1111/jdi.12464. Epub 2016 Mar 31. PMID- 27131827 OWN - NLM STAT- MEDLINE DCOM- 20170303 LR - 20170303 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 783 DP - 2016 Jul 15 TI - Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced alzheimer disease mouse model. PG - 23-32 LID - S0014-2999(16)30288-6 [pii] LID - 10.1016/j.ejphar.2016.04.052 [doi] AB - Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). The glucagon-like peptide-1 analog liraglutide, a novel long-lasting incretin hormone, has been used to treat type 2 diabetes mellitus. In addition, liraglutide has been shown to be neurotrophic and neuroprotective. Here, we investigated the effects of liraglutide on amyloid beta protein (Abeta)-induced AD in mice and explored its mechanism of action. The results showed that subcutaneous administration of liraglutide (25nmol/day), once daily for 8 weeks, prevented memory impairments in the Y Maze and Morris Water Maze following Abeta1-42 intracerebroventricular injection, and alleviated the ultra-structural changes of pyramidal neurons and chemical synapses in the hippocampal CA1 region. Furthermore, liraglutide reduced Abeta1-42-induced tau phosphorylation via the protein kinase B and glycogen synthase kinase-3beta pathways. Thus liraglutide may alleviate cognitive impairment in AD by at least decreasing the phosphorylation of tau. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Qi, Liqin AU - Qi L AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Ke, Linfang AU - Ke L AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Liu, Xiaohong AU - Liu X AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Liao, Lianming AU - Liao L AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Ke, Sujie AU - Ke S AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Liu, Xiaoying AU - Liu X AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Wang, Yanping AU - Wang Y AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Lin, Xiaowei AU - Lin X AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Zhou, Yu AU - Zhou Y AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Wu, Lijuan AU - Wu L AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. FAU - Chen, Zhou AU - Chen Z AD - Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, People's Republic of China. Electronic address: kellandchen1007@hotmail.com. FAU - Liu, Libin AU - Liu L AD - Department of Endocrinology, Union Hospital, Fujian Institute of Endocrinology, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China. Electronic address: libin_liu1@yeah.net. LA - eng PT - Journal Article DEP - 20160427 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Amyloid beta-Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-42)) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Alzheimer Disease/*drug therapy/*metabolism/pathology/physiopathology MH - Amyloid beta-Peptides/*pharmacology MH - Animals MH - Disease Models, Animal MH - Gene Expression Regulation/drug effects MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Glycogen Synthase Kinase 3 beta/*metabolism MH - Hippocampus/drug effects/physiopathology MH - Liraglutide/administration & dosage/*pharmacology/therapeutic use MH - Male MH - Maze Learning/drug effects MH - Memory/*drug effects MH - Mice MH - Mice, Inbred C57BL MH - Neurons/drug effects/ultrastructure MH - Peptide Fragments/*pharmacology MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Spatial Learning/drug effects MH - Synapses/drug effects/metabolism MH - tau Proteins/*metabolism OTO - NOTNLM OT - Alzheimer disease OT - Amyloid beta protein OT - GLP-1 OT - GSK-3beta OT - Tau protein EDAT- 2016/05/02 06:00 MHDA- 2017/03/04 06:00 CRDT- 2016/05/02 06:00 PHST- 2016/02/16 00:00 [received] PHST- 2016/03/18 00:00 [revised] PHST- 2016/04/26 00:00 [accepted] PHST- 2016/05/02 06:00 [entrez] PHST- 2016/05/02 06:00 [pubmed] PHST- 2017/03/04 06:00 [medline] AID - S0014-2999(16)30288-6 [pii] AID - 10.1016/j.ejphar.2016.04.052 [doi] PST - ppublish SO - Eur J Pharmacol. 2016 Jul 15;783:23-32. doi: 10.1016/j.ejphar.2016.04.052. Epub 2016 Apr 27. PMID- 27110066 OWN - NLM STAT- MEDLINE DCOM- 20170117 LR - 20220316 IS - 1466-1861 (Electronic) IS - 0962-9351 (Print) IS - 0962-9351 (Linking) VI - 2016 DP - 2016 TI - Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control. PG - 3094642 LID - 10.1155/2016/3094642 [doi] LID - 3094642 AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro, and their molecular mechanisms of anti-inflammatory action. FAU - Lee, Young-Sun AU - Lee YS AD - Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea. FAU - Jun, Hee-Sook AU - Jun HS AD - Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea; College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea; Gachon Medical Research Institute, Gil Hospital, Incheon 405-760, Republic of Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20160324 PL - United States TA - Mediators Inflamm JT - Mediators of inflammation JID - 9209001 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Blood Glucose) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Anti-Inflammatory Agents/therapeutic use MH - Blood Glucose/drug effects MH - Diabetes Mellitus, Type 2/blood/drug therapy MH - Glucagon-Like Peptide 1/*therapeutic use MH - Humans MH - Inflammation/blood/drug therapy PMC - PMC4823510 EDAT- 2016/04/26 06:00 MHDA- 2017/01/18 06:00 PMCR- 2016/03/24 CRDT- 2016/04/26 06:00 PHST- 2016/02/05 00:00 [received] PHST- 2016/03/02 00:00 [revised] PHST- 2016/03/03 00:00 [accepted] PHST- 2016/04/26 06:00 [entrez] PHST- 2016/04/26 06:00 [pubmed] PHST- 2017/01/18 06:00 [medline] PHST- 2016/03/24 00:00 [pmc-release] AID - 10.1155/2016/3094642 [doi] PST - ppublish SO - Mediators Inflamm. 2016;2016:3094642. doi: 10.1155/2016/3094642. Epub 2016 Mar 24. PMID- 27034187 OWN - NLM STAT- MEDLINE DCOM- 20170109 LR - 20181217 IS - 2245-1919 (Electronic) IS - 2245-1919 (Linking) VI - 63 IP - 4 DP - 2016 Apr TI - Glucose-dependent insulinotropic polypeptide: effects on insulin and glucagon secretion in humans. LID - B5230 [pii] AB - The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. They are called incretin hormones because of their ability to enhance insulin secretion. However, in recent years it has become clear that the incretin hormones also affect glucagon secretion. While GLP-1 decreases glucagon levels, the effect of GIP on glucagon levels has been unclear. The regulation of glucagon secretion is interesting, as the combination of inadequate insulin secretion and excessive glucagon secretion are essential contributors to the hyperglycaemia that characterise patients with type 2 diabetes. Moreover, the near absence of a well-timed glucagon response contributes to an increased risk of hypoglycaemia in patients with type 1 diabetes. The overall aim of this PhD thesis was to investigate how the blood glucose level affects the glucagon and insulin responses to GIP in healthy subjects (Study 1) and patients with Type 2 diabetes (Study 2), and more specifically to investigate the effects of GIP and GLP-1 at low blood glucose in patients with Type 1 diabetes without endogenous insulin secretion (Study 3). The investigations in the three mentioned study populations have been described in three original articles. The employed study designs were in randomised, placebo-controlled, crossover set-up, in which the same research subject is subjected to several study days thereby acting as his own control. Interventions were intravenous administration of hormones GIP, GLP-1 and placebo (saline) during different blood glucose levels maintained (clamped) at a certain level. The end-points were plasma concentrations of glucagon and insulin as well as the amount of glucose used to clamp the blood glucose levels. In Study 3, we also used stable glucose isotopes to estimate the endogenous glucose production and assessed symptoms and cognitive function during hypoglycaemia. The results from the three studies indicate that GIP has effects on insulin and glucagon responses highly dependent upon the blood glucose levels. At fasting glycaemia and lower levels of glycaemia, GIP acts to increase glucagon with little effect on insulin release. At hyperglycaemia the insulin releasing effect of GIP prevail, which lead to an increase in glucose disposal by approximately 75% in healthy subjects (Study 1) and 25% in patients with Type 2 diabetes (Study 2) relative to placebo. After insulin-induced hypoglycaemia in patients with type 1 diabetes (Study 3), GIP increase glucagon release, which probably augments endogenous glucose production. This was associated with a reduced need for exogenously added glucose to prevent hypoglycaemia. In conclusion, the studies position GIP as a bifunctional blood glucose stabilising hormone that glucose-dependently regulates insulin and glucagon responses in humans. FAU - Christensen, Mikkel Bring AU - Christensen MB AD - mch@dadlnet.dk. LA - eng PT - Journal Article PT - Review PL - Denmark TA - Dan Med J JT - Danish medical journal JID - 101576205 RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9007-92-5 (Glucagon) SB - IM MH - Adult MH - Blood Glucose/*metabolism MH - Diabetes Mellitus, Type 1/*metabolism MH - Diabetes Mellitus, Type 2/*metabolism MH - Gastric Inhibitory Polypeptide/administration & dosage/blood/*metabolism MH - Glucagon/*metabolism MH - Glucagon-Like Peptide 1/administration & dosage/metabolism MH - Humans MH - Hyperglycemia/chemically induced/metabolism MH - Hypoglycemia/chemically induced/metabolism MH - Insulin/*metabolism MH - Insulin Secretion MH - Male MH - Randomized Controlled Trials as Topic EDAT- 2016/04/02 06:00 MHDA- 2017/01/10 06:00 CRDT- 2016/04/02 06:00 PHST- 2016/04/02 06:00 [entrez] PHST- 2016/04/02 06:00 [pubmed] PHST- 2017/01/10 06:00 [medline] AID - B5230 [pii] PST - ppublish SO - Dan Med J. 2016 Apr;63(4):B5230. PMID- 27033055 OWN - NLM STAT- MEDLINE DCOM- 20171003 LR - 20220517 IS - 1875-5828 (Electronic) IS - 1567-2050 (Linking) VI - 13 IP - 12 DP - 2016 TI - Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer's Disease. PG - 1346-1355 AB - Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients. FAU - Qin, LiMei AU - Qin L FAU - Chong, Thomas AU - Chong T FAU - Rodriguez, Richard AU - Rodriguez R FAU - Pugazhenthi, Subbiah AU - Pugazhenthi S AD - Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Mail Stop 8106, 12801 E 17th Ave, Aurora, CO 80045, USA. subbiah.pugazhenthi@ucdenver.edu. LA - eng GR - I01 BX001837/BX/BLRD VA/United States GR - I01 BX004480/BX/BLRD VA/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United Arab Emirates TA - Curr Alzheimer Res JT - Current Alzheimer research JID - 101208441 RN - 0 (Blood Glucose) RN - 0 (Cytokines) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Nerve Tissue Proteins) RN - 0 (Piperidines) RN - 56HH86ZVCT (Uracil) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 3.4.14.5 (DPP4 protein, rat) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - JHC049LO86 (alogliptin) SB - IM MH - Alzheimer Disease/*physiopathology MH - Animals MH - Blood Glucose/drug effects MH - Body Weight/drug effects MH - Brain/immunology/*metabolism MH - Cytokines/genetics/*metabolism MH - Diabetes Mellitus, Experimental/drug therapy/genetics/*physiopathology MH - Dipeptidyl Peptidase 4/genetics/metabolism MH - Gene Expression Regulation/drug effects/genetics MH - Glucagon-Like Peptide 1/*blood/genetics/*metabolism MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Insulin/blood MH - Nerve Tissue Proteins/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Oxidative Stress/drug effects/genetics MH - Piperidines/pharmacology/therapeutic use MH - Rats MH - Rats, Zucker MH - Signal Transduction/drug effects MH - Transcriptome MH - Uracil/analogs & derivatives/pharmacology/therapeutic use EDAT- 2016/04/02 06:00 MHDA- 2017/10/04 06:00 CRDT- 2016/04/02 06:00 PHST- 2015/10/10 00:00 [received] PHST- 2016/03/16 00:00 [revised] PHST- 2016/03/29 00:00 [accepted] PHST- 2016/04/02 06:00 [pubmed] PHST- 2017/10/04 06:00 [medline] PHST- 2016/04/02 06:00 [entrez] AID - CAR-EPUB-74701 [pii] AID - 10.2174/1567205013666160401114751 [doi] PST - ppublish SO - Curr Alzheimer Res. 2016;13(12):1346-1355. doi: 10.2174/1567205013666160401114751. PMID- 26992957 OWN - NLM STAT- MEDLINE DCOM- 20161227 LR - 20181202 IS - 1873-507X (Electronic) IS - 0031-9384 (Linking) VI - 159 DP - 2016 May 15 TI - Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-beta peptide-induced impairment of spatial learning and memory in rats. PG - 72-9 LID - S0031-9384(16)30100-7 [pii] LID - 10.1016/j.physbeh.2016.03.016 [doi] AB - Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Abeta) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Abeta1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Abeta1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Abeta1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Abeta1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Jia, Xiao-Tao AU - Jia XT AD - Department of Neurology, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710003, PR China. FAU - Ye-Tian AU - Ye-Tian AD - Department of Neurology, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710003, PR China. FAU - Yuan-Li AU - Yuan-Li AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, PR China. FAU - Zhang, Ge-Juan AU - Zhang GJ AD - Department of Neurology, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710003, PR China. FAU - Liu, Zhi-Qin AU - Liu ZQ AD - Department of Neurology, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710003, PR China. FAU - Di, Zheng-Li AU - Di ZL AD - Department of Neurology, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710003, PR China. FAU - Ying, Xiao-Ping AU - Ying XP AD - Department of Pathology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, PR China. FAU - Fang, Yan AU - Fang Y AD - Department of Pathology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, PR China. FAU - Song, Er-Fei AU - Song EF AD - Department of Biology, York University, Toronto, ON M3J 1P3, Canada. FAU - Qi, Jin-Shun AU - Qi JS AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, PR China. Electronic address: jinshunqi2009@163.com. FAU - Pan, Yan-Fang AU - Pan YF AD - Department of Pathology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, PR China. Electronic address: panyanfang2000@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160316 PL - United States TA - Physiol Behav JT - Physiology & behavior JID - 0151504 RN - 0 (Amyloid beta-Peptides) RN - 0 (Peptides) RN - 0 (Venoms) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Amyloid beta-Peptides/*adverse effects/antagonists & inhibitors MH - Animals MH - Dose-Response Relationship, Drug MH - Exenatide MH - Glucagon-Like Peptide 1/*agonists MH - Male MH - Maze Learning/*drug effects MH - Memory/*drug effects/physiology MH - Peptides/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Spatial Learning/*drug effects/physiology MH - Venoms/*pharmacology OTO - NOTNLM OT - Amyloid-beta peptide OT - Bcl2/Bax OT - Caspase-3 OT - Exendin-4 OT - Spatial learning and memory EDAT- 2016/03/20 06:00 MHDA- 2016/12/28 06:00 CRDT- 2016/03/20 06:00 PHST- 2015/10/23 00:00 [received] PHST- 2016/03/10 00:00 [revised] PHST- 2016/03/14 00:00 [accepted] PHST- 2016/03/20 06:00 [entrez] PHST- 2016/03/20 06:00 [pubmed] PHST- 2016/12/28 06:00 [medline] AID - S0031-9384(16)30100-7 [pii] AID - 10.1016/j.physbeh.2016.03.016 [doi] PST - ppublish SO - Physiol Behav. 2016 May 15;159:72-9. doi: 10.1016/j.physbeh.2016.03.016. Epub 2016 Mar 16. PMID- 26935863 OWN - NLM STAT- MEDLINE DCOM- 20170406 LR - 20181202 IS - 1472-8206 (Electronic) IS - 0767-3981 (Linking) VI - 30 IP - 4 DP - 2016 Aug TI - Exenatide enhances cognitive performance and upregulates neurotrophic factor gene expression levels in diabetic mice. PG - 376-84 LID - 10.1111/fcp.12192 [doi] AB - Exenatide is a potent and selective agonist for the GLP-1 (glucagon-like peptide-1) receptor. Recent studies are focused on the effects of GLP-1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 mug/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real-time polymerase chain reaction (RT-PCR). This study revealed that in the mEPM and PA tests, type-2 diabetes-induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP-1 receptor agonist exenatide. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA-induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder. CI - (c) 2016 Societe Francaise de Pharmacologie et de Therapeutique. FAU - Gumuslu, Esen AU - Gumuslu E AD - Department of Medical Genetics, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Mutlu, Oguz AU - Mutlu O AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Celikyurt, Ipek K AU - Celikyurt IK AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Ulak, Guner AU - Ulak G AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Akar, Furuzan AU - Akar F AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Erden, Faruk AU - Erden F AD - Department of Medical Pharmacology, Psychopharmacology Lab., Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. FAU - Ertan, Merve AU - Ertan M AD - Department of Medical Genetics, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey. LA - eng PT - Journal Article DEP - 20160321 PL - England TA - Fundam Clin Pharmacol JT - Fundamental & clinical pharmacology JID - 8710411 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*biosynthesis/genetics MH - Cognition/*drug effects/physiology MH - Diabetes Mellitus, Experimental/drug therapy/genetics/*metabolism MH - Exenatide MH - Gene Expression Regulation MH - Hypoglycemic Agents/*pharmacology/therapeutic use MH - Male MH - Maze Learning/drug effects/physiology MH - Mice MH - Mice, Inbred BALB C MH - Peptides/*pharmacology/therapeutic use MH - Up-Regulation/drug effects/physiology MH - Venoms/*pharmacology/therapeutic use OTO - NOTNLM OT - BDNF OT - CREB OT - exenatide OT - memory OT - type-2 diabetes EDAT- 2016/03/05 06:00 MHDA- 2017/04/07 06:00 CRDT- 2016/03/04 06:00 PHST- 2015/10/17 00:00 [received] PHST- 2016/02/22 00:00 [revised] PHST- 2016/02/26 00:00 [accepted] PHST- 2016/03/04 06:00 [entrez] PHST- 2016/03/05 06:00 [pubmed] PHST- 2017/04/07 06:00 [medline] AID - 10.1111/fcp.12192 [doi] PST - ppublish SO - Fundam Clin Pharmacol. 2016 Aug;30(4):376-84. doi: 10.1111/fcp.12192. Epub 2016 Mar 21. PMID- 26920423 OWN - NLM STAT- MEDLINE DCOM- 20170130 LR - 20181202 IS - 1720-8319 (Electronic) IS - 1594-0667 (Linking) VI - 28 IP - 6 DP - 2016 Dec TI - Intranasal administration of Exendin-4 antagonizes Abeta31-35-induced disruption of circadian rhythm and impairment of learning and memory. PG - 1259-1266 AB - BACKGROUND: The deposition of beta-amyloid protein (Abeta) is one of the pathological characteristics of Alzheimer's disease (AD) and can disrupt circadian rhythm and impair learning and memory. Exendin-4, a therapeutic drug for type II diabetes mellitus (T2DM), exerts neuroprotective effects from the toxicity of Abeta. However, it is not clear whether Exendin-4 protects against Abeta-induced disruption of circadian rhythm. The neuroprotective effects of Exendin-4 have been studied using injection of Exendin-4 into the lateral ventricle and abdomen. However, these procedures are not suitable for clinical application. METHODS: First, male C57BL/6 mice received triple distilled water or Exendin-4 (0.1 nmol, 0.5 nmol) by intranasal administration. Exendin-4 levels were measured in the hippocampal samples using an ELISA Kit. Then, the study examined whether intranasal or hippocampal administration of Exendin-4 antagonized Abeta-induced disruption of circadian rhythm as well as impairment of learning and memory using the wheel-running activity assay and the Morris water maze test. RESULTS: The study showed that intranasally administered Exendin-4 passed through the blood-brain barrier. Abeta31-35 given by intrahippocampal injection disrupted circadian rhythm and impaired learning and memory in C57BL/6 mice, and Exendin-4 given by nasal cavity or hippocampal administration ameliorated Abeta31-35-induced circadian rhythm disturbance of locomotor activity and impairment of learning and memory. CONCLUSIONS: These findings provide pivotal experimental support for further study of the neuroprotective effects and clinical application of Exendin-4. FAU - Wang, Xiaohui AU - Wang X AD - Department of Pathology, Shanxi Medical University, Taiyuan, 030001, China. 163.wangxh@163.com. FAU - Wang, Li AU - Wang L AD - Department of Pathology, Shanxi Medical University, Taiyuan, 030001, China. FAU - Xu, Yunyun AU - Xu Y AD - Department of Pathology, Shanxi Medical University, Taiyuan, 030001, China. FAU - Yu, Qianqian AU - Yu Q AD - Department of Pathology, Shanxi Medical University, Taiyuan, 030001, China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. FAU - Guo, Yanlin AU - Guo Y AD - Department of Pathology, Shanxi Medical University, Taiyuan, 030001, China. LA - eng PT - Journal Article DEP - 20160226 PL - Germany TA - Aging Clin Exp Res JT - Aging clinical and experimental research JID - 101132995 RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (Venoms) RN - 0 (amyloid beta-protein (31-35)) RN - 9P1872D4OL (Exenatide) SB - IM MH - Administration, Intranasal MH - Alzheimer Disease/pathology MH - Amyloid beta-Peptides/metabolism/*toxicity MH - Animals MH - Circadian Rhythm/*drug effects MH - Exenatide MH - Hippocampus/drug effects MH - Male MH - Maze Learning MH - Memory/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/*pharmacology MH - Peptide Fragments/*toxicity MH - Peptides/*pharmacology MH - Venoms/*pharmacology OTO - NOTNLM OT - Ameliorate OT - Circadian rhythm OT - Exendin-4 OT - Intranasal administration OT - Learning and memory EDAT- 2016/02/28 06:00 MHDA- 2017/01/31 06:00 CRDT- 2016/02/28 06:00 PHST- 2015/11/25 00:00 [received] PHST- 2016/02/09 00:00 [accepted] PHST- 2016/02/28 06:00 [pubmed] PHST- 2017/01/31 06:00 [medline] PHST- 2016/02/28 06:00 [entrez] AID - 10.1007/s40520-016-0548-z [pii] AID - 10.1007/s40520-016-0548-z [doi] PST - ppublish SO - Aging Clin Exp Res. 2016 Dec;28(6):1259-1266. doi: 10.1007/s40520-016-0548-z. Epub 2016 Feb 26. PMID- 26917725 OWN - NLM STAT- MEDLINE DCOM- 20161110 LR - 20220312 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 291 IP - 18 DP - 2016 Apr 29 TI - Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic beta Cell Dysfunction. PG - 9648-56 LID - 10.1074/jbc.M115.702183 [doi] AB - Insulin resistance and beta cell dysfunction contribute to the pathogenesis of type 2 diabetes. Unlike insulin resistance, beta cell dysfunction remains difficult to predict and monitor, because of the inaccessibility of the endocrine pancreas, the integrated relationship with insulin sensitivity, and the paracrine effects of incretins. The goal of our study was to survey the plasma response to a metabolic challenge in order to identify factors predictive of beta cell dysfunction. To this end, we combined (i) the power of unbiased iTRAQ (isobaric tag for relative and absolute quantification) mass spectrometry with (ii) direct sampling of the portal vein following an intravenous glucose/arginine challenge (IVGATT) in (iii) mice with a genetic beta cell defect. By so doing, we excluded the effects of peripheral insulin sensitivity as well as those of incretins on beta cells, and focused on the first phase of insulin secretion to capture the early pathophysiology of beta cell dysfunction. We compared plasma protein profiles with ex vivo islet secretome and transcriptome analyses. We detected changes to 418 plasma proteins in vivo, and detected changes to 262 proteins ex vivo The impairment of insulin secretion was associated with greater overall changes in the plasma response to IVGATT, possibly reflecting metabolic instability. Reduced levels of proteins regulating redox state and neuronal stress markers, as well as increased levels of coagulation factors, antedated the loss of insulin secretion in diabetic mice. These results suggest that a reduced complement of antioxidants in response to a mixed secretagogue challenge is an early correlate of future beta cell failure. CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Kuo, Taiyi AU - Kuo T AD - From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and. FAU - Kim-Muller, Ja Young AU - Kim-Muller JY AD - From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and. FAU - McGraw, Timothy E AU - McGraw TE AD - the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065. FAU - Accili, Domenico AU - Accili D AD - From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and da230@columbia.edu. LA - eng GR - T32 DK007328/DK/NIDDK NIH HHS/United States GR - R01 DK064819/DK/NIDDK NIH HHS/United States GR - P30 DK020541/DK/NIDDK NIH HHS/United States GR - P30 DK026687/DK/NIDDK NIH HHS/United States GR - P30 DK063608/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160225 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Antioxidants) RN - 0 (Blood Proteins) RN - 0 (Incretins) SB - IM MH - Animals MH - Antioxidants/*metabolism MH - Blood Proteins/genetics/*metabolism MH - Diabetes Mellitus, Experimental/*blood/genetics/pathology MH - Diabetes Mellitus, Type 2/*blood/genetics/pathology MH - Incretins/blood/genetics MH - Insulin-Secreting Cells/*metabolism/pathology MH - Mice MH - Mice, Knockout PMC - PMC4850302 OTO - NOTNLM OT - FOXO OT - beta cell (B-cell) OT - biomarker OT - diabetes OT - neurodegeneration OT - oxidative stress EDAT- 2016/02/27 06:00 MHDA- 2016/11/11 06:00 PMCR- 2017/04/29 CRDT- 2016/02/27 06:00 PHST- 2015/11/04 00:00 [received] PHST- 2016/02/27 06:00 [entrez] PHST- 2016/02/27 06:00 [pubmed] PHST- 2016/11/11 06:00 [medline] PHST- 2017/04/29 00:00 [pmc-release] AID - S0021-9258(20)43104-7 [pii] AID - M115.702183 [pii] AID - 10.1074/jbc.M115.702183 [doi] PST - ppublish SO - J Biol Chem. 2016 Apr 29;291(18):9648-56. doi: 10.1074/jbc.M115.702183. Epub 2016 Feb 25. PMID- 26870815 OWN - NLM STAT- MEDLINE DCOM- 20161104 LR - 20261026 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 3 DP - 2016 Jan TI - Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma. PG - 26-42 LID - S2352-3964(15)30241-3 [pii] LID - 10.1016/j.ebiom.2015.12.008 [doi] AB - Obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D) are associated with decreased cognitive function. While weight loss and T2D remission result in improvements in metabolism and vascular function, it is less clear if these benefits extend to cognitive performance. Here, we highlight the malleable nature of MetS-associated cognitive dysfunction using a mouse model of high fat diet (HFD)-induced MetS. While learning and memory was generally unaffected in mice with type 1 diabetes (T1D), multiple cognitive impairments were associated with MetS, including deficits in novel object recognition, cued fear memory, and spatial learning and memory. However, a brief reduction in dietary fat content in chronic HFD-fed mice led to a complete rescue of cognitive function. Cerebral blood volume (CBV), a measure of vascular perfusion, was decreased during MetS, was associated with long term memory, and recovered following the intervention. Finally, repeated infusion of plasma collected from age-matched, low fat diet-fed mice improved memory in HFD mice, and was associated with a distinct metabolic profile. Thus, the cognitive dysfunction accompanying MetS appears to be amenable to treatment, related to cerebrovascular function, and mitigated by systemic factors. FAU - Johnson, Lance A AU - Johnson LA AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Zuloaga, Kristen L AU - Zuloaga KL AD - Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Kugelman, Tara L AU - Kugelman TL AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Mader, Kevin S AU - Mader KS AD - Swiss Federal Institute of Technology, Zurich, Switzerland; 4Quant, Paul Scherrer Institute, Villigen, Switzerland. FAU - Morre, Jeff T AU - Morre JT AD - Department of Pharmaceutical Sciences, and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. FAU - Zuloaga, Damian G AU - Zuloaga DG AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Weber, Sydney AU - Weber S AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Marzulla, Tessa AU - Marzulla T AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Mulford, Amelia AU - Mulford A AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Button, Dana AU - Button D AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Lindner, Jonathan R AU - Lindner JR AD - Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Alkayed, Nabil J AU - Alkayed NJ AD - Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Stevens, Jan F AU - Stevens JF AD - Department of Pharmaceutical Sciences, and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. FAU - Raber, Jacob AU - Raber J AD - Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA; Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC. Electronic address: raberj@ohsu.edu. LA - eng GR - T32 DA007262/DA/NIDA NIH HHS/United States GR - T32-ES07060/ES/NIEHS NIH HHS/United States GR - F32 NS082017/NS/NINDS NIH HHS/United States GR - P30ES000210/ES/NIEHS NIH HHS/United States GR - S10RR027878/RR/NCRR NIH HHS/United States GR - NIH R21AG043857/AG/NIA NIH HHS/United States GR - NIDA T32DA007262/PHS HHS/United States GR - T32 HL094294/HL/NHLBI NIH HHS/United States GR - T32-HL094294/HL/NHLBI NIH HHS/United States GR - R21 AG043857/AG/NIA NIH HHS/United States GR - NIH F32NS082017/NS/NINDS NIH HHS/United States GR - T32 ES007060/ES/NIEHS NIH HHS/United States GR - P30 ES000210/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20151212 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (Dietary Fats) SB - IM MH - Animals MH - Behavior, Animal MH - Cerebrovascular Circulation MH - Cluster Analysis MH - Cognition Disorders/*etiology/*metabolism MH - Diet, High-Fat MH - Dietary Fats/*metabolism MH - Disease Models, Animal MH - Female MH - Maze Learning MH - Metabolic Syndrome/*complications/*metabolism/physiopathology MH - Metabolome MH - Metabolomics/methods MH - Mice MH - Obesity/metabolism MH - Recognition, Psychology MH - Weight Loss PMC - PMC4739422 OTO - NOTNLM OT - ADMA, Asymmetric dimethylarginine OT - BDNF, Brain-derived neurotrophic factor OT - BW, Body weight OT - Br Fat, Brown adipose tissue OT - Brain OT - C-X-C motif, Chemokine OT - CBV, Cerebral blood volume OT - CH, Cholesterol OT - Cerebrovascular OT - Cognitive OT - Cxcl1, Ligand 1 OT - DG, Diacylglycerol OT - Diabetes OT - FFA, Free fatty acids OT - GL, Glycerolipid OT - GLP-1, Glucagon-like peptide 1 OT - GPL, Glycerophospholipid OT - GlcCer, Glucosylceramide OT - HFD, High fat diet OT - IFNgamma, Interferon-gamma OT - IL-10, Interleukin-10 OT - IL-12p70, Interleukin-12p70 OT - IL-6, Interleukin-6 OT - IR, Insulin resistance OT - ITT, Insulin tolerance test OT - Il-1b, Interleukin-1beta OT - KB, Total ketone bodies OT - LFD, Low fat diet OT - LPA, Lysophosphatidic acid OT - MetS, Metabolic syndrome OT - Metabolic syndrome OT - OGTT, Oral glucose tolerance test OT - Obesity OT - PC, Phosphatidylcholine OT - PE, Phosphatidylethanolamine OT - PG, Phosphatidylglycerol OT - PGP, Phosphatidylglycerolphosphate OT - PI, Phosphatidylinositol OT - PS, Phosphatidylserine OT - Plasma OT - SC Fat, Subcutaneous adipose tissue OT - T1D, Type 1 Diabetes OT - T2D, Type 2 Diabetes OT - TG, Triglycerides OT - TNFalpha, Tumor necrosis factor-alpha OT - V Fat, Visceral adipose tissue EDAT- 2016/02/13 06:00 MHDA- 2016/11/05 06:00 PMCR- 2015/12/12 CRDT- 2016/02/13 06:00 PHST- 2015/10/01 00:00 [received] PHST- 2015/11/26 00:00 [revised] PHST- 2015/12/11 00:00 [accepted] PHST- 2016/02/13 06:00 [entrez] PHST- 2016/02/13 06:00 [pubmed] PHST- 2016/11/05 06:00 [medline] PHST- 2015/12/12 00:00 [pmc-release] AID - S2352-3964(15)30241-3 [pii] AID - 10.1016/j.ebiom.2015.12.008 [doi] PST - epublish SO - EBioMedicine. 2015 Dec 12;3:26-42. doi: 10.1016/j.ebiom.2015.12.008. eCollection 2016 Jan. PMID- 26849938 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20220321 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 774 DP - 2016 Mar 5 TI - Neurobehavioral effects of liraglutide and sitagliptin in experimental models. PG - 64-70 LID - S0014-2999(16)30019-X [pii] LID - 10.1016/j.ejphar.2016.02.003 [doi] AB - Glucagon-like peptide (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are two currently approved therapies for type 2 diabetes mellitus (T2DM). Present study evaluated the effect of liraglutide (a long-acting GLP-1 agonist) and sitagliptin (a DPP-4 inhibitor) on nociception, anxiety, depression-like behavior and cognition in rats or mice. Nociception was assessed using tail-flick test; anxiety-behavior in open-field test and elevated plus maze (EPM) test while depression-like behavior was evaluated in forced swim test (FST) and tail-suspension test (TST). Cognition was assessed in EPM and Morris water maze (MWM) following memory deficit induced by pentylenetetrazole (PTZ) or scopolamine. In tail-flick test sitagliptin (6 mg/kg) produced transient nociceptive effect. Liraglutide (200 microg/kg) reduced peripheral square crossings by rats in open field test as well as reduced closed arm entries in the EPM, indicating a decline in exploratory behavior. In FST and TST models for depression, the duration of immobility with sitagliptin (6 mg/kg) was reduced significantly in comparison to control group suggesting its antidepressant effect. Liraglutide did not show any antidepressant action. In EPM test for cognition, liraglutide and sitagliptin ameliorated the increase in transfer latency caused by PTZ in a dose-dependent manner. In MWM liraglutide and sitagliptin prevented the scopolamine-induced increase of the escape latency. This study shows that sitagliptin has mild antinociceptive effect and anti-depressant effect in the animal models of depression while liraglutide did not have such an effect. Liraglutide showed anxiogenic effects in the animal models. Both liraglutide and sitagliptin produced cognitive improvement in the animal models. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Kamble, Mayur AU - Kamble M AD - Department of Pharmacology, Lady Hardinge Medical College & Smt. S.K. Hospital, New Delhi 110001, India. FAU - Gupta, Rachna AU - Gupta R AD - Department of Pharmacology, University College of Medical Sciences & GTB Hospital, New Delhi 110095, India. FAU - Rehan, Harmeet S AU - Rehan HS AD - Department of Pharmacology, Lady Hardinge Medical College & Smt. S.K. Hospital, New Delhi 110001, India. FAU - Gupta, Lalit K AU - Gupta LK AD - Department of Pharmacology, Lady Hardinge Medical College & Smt. S.K. Hospital, New Delhi 110001, India. Electronic address: lkg71@rediffmail.com. LA - eng PT - Journal Article DEP - 20160202 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 839I73S42A (Liraglutide) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - Animals MH - Anxiety/drug therapy MH - Behavior, Animal/*drug effects/physiology MH - Cognition/drug effects MH - Depression/drug therapy MH - Disease Models, Animal MH - Liraglutide/*pharmacology/therapeutic use MH - Male MH - Maze Learning/drug effects MH - Mice MH - Nociception/drug effects MH - Rats MH - Sitagliptin Phosphate/*pharmacology/therapeutic use OTO - NOTNLM OT - Anxiety OT - Cognition OT - Depression OT - GLP-1 OT - Liraglutide OT - Sitagliptin EDAT- 2016/02/07 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/07 06:00 PHST- 2015/08/09 00:00 [received] PHST- 2016/01/27 00:00 [revised] PHST- 2016/02/01 00:00 [accepted] PHST- 2016/02/07 06:00 [entrez] PHST- 2016/02/07 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S0014-2999(16)30019-X [pii] AID - 10.1016/j.ejphar.2016.02.003 [doi] PST - ppublish SO - Eur J Pharmacol. 2016 Mar 5;774:64-70. doi: 10.1016/j.ejphar.2016.02.003. Epub 2016 Feb 2. PMID- 26831302 OWN - NLM STAT- MEDLINE DCOM- 20170123 LR - 20220410 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 59 IP - 5 DP - 2016 May TI - GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. PG - 954-65 LID - 10.1007/s00125-016-3874-y [doi] AB - AIMS/HYPOTHESIS: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). METHODS: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. RESULTS: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 +/- 0.24, liraglutide -0.47 +/- 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. CONCLUSIONS/INTERPRETATION: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961. FAU - Farr, Olivia M AU - Farr OM AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. ofarr@bidmc.harvard.edu. FAU - Sofopoulos, Michail AU - Sofopoulos M AD - Department of Pathology, St Savvas Anticancer-Oncology Hospital, Athens, Greece. FAU - Tsoukas, Michael A AU - Tsoukas MA AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Dincer, Fadime AU - Dincer F AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Thakkar, Bindiya AU - Thakkar B AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Sahin-Efe, Ayse AU - Sahin-Efe A AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Filippaios, Andreas AU - Filippaios A AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Bowers, Jennifer AU - Bowers J AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Srnka, Alexandra AU - Srnka A AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Gavrieli, Anna AU - Gavrieli A AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Ko, Byung-Joon AU - Ko BJ AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. AD - Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. FAU - Liakou, Chrysoula AU - Liakou C AD - Department of Pathology, St Savvas Anticancer-Oncology Hospital, Athens, Greece. FAU - Kanyuch, Nickole AU - Kanyuch N AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. FAU - Tseleni-Balafouta, Sofia AU - Tseleni-Balafouta S AD - First Department of Pathology, University of Athens, Medical School, Athens, Greece. FAU - Mantzoros, Christos S AU - Mantzoros CS AD - Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA, 02215, USA. LA - eng SI - ClinicalTrials.gov/NCT01562678 GR - T32 HD052961/HD/NICHD NIH HHS/United States GR - UL1 RR025758/RR/NCRR NIH HHS/United States GR - 5T32HD05296/HD/NICHD NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160201 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Blood Glucose/drug effects MH - Brain/drug effects/*metabolism MH - Cross-Over Studies MH - Diabetes Mellitus, Type 2/drug therapy/*metabolism MH - Double-Blind Method MH - Female MH - Glucagon-Like Peptide 1/*analogs & derivatives MH - Glucagon-Like Peptide-1 Receptor/*metabolism MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Hypothalamus/drug effects/*metabolism MH - Liraglutide/*pharmacology/therapeutic use MH - Magnetic Resonance Imaging MH - Male MH - Medulla Oblongata/drug effects/*metabolism MH - Middle Aged PMC - PMC4826792 MID - NIHMS756722 OTO - NOTNLM OT - Brain OT - Diabetes OT - GLP-1 OT - Immunohistochemistry OT - Liraglutide OT - MRI OT - fMRI EDAT- 2016/02/03 06:00 MHDA- 2017/01/24 06:00 PMCR- 2017/05/01 CRDT- 2016/02/03 06:00 PHST- 2015/11/05 00:00 [received] PHST- 2016/01/04 00:00 [accepted] PHST- 2016/02/03 06:00 [entrez] PHST- 2016/02/03 06:00 [pubmed] PHST- 2017/01/24 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - 10.1007/s00125-016-3874-y [pii] AID - 10.1007/s00125-016-3874-y [doi] PST - ppublish SO - Diabetologia. 2016 May;59(5):954-65. doi: 10.1007/s00125-016-3874-y. Epub 2016 Feb 1. PMID- 26816596 OWN - NLM STAT- MEDLINE DCOM- 20161024 LR - 20240523 IS - 2040-1124 (Electronic) IS - 2040-1116 (Print) IS - 2040-1116 (Linking) VI - 7 IP - 1 DP - 2016 Jan TI - Potentials of incretin-based therapies in dementia and stroke in type 2 diabetes mellitus. PG - 5-16 LID - 10.1111/jdi.12420 [doi] AB - Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin-based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin-based therapies are currently available: the glucagon-like-peptide-1 agonists and the dipeptidyl peptidase-4 -inhibitors. Independent of their glucose-lowering effects, incretin-based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin-based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin-based therapies on cognition, synaptic plasticity and metabolism of amyloid-beta and microtubule-associated protein tau. Preclinical studies on incretin-based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin-based therapies at improving the outcome of Alzheimer's disease and stroke through glucose-independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact. FAU - Groeneveld, Onno N AU - Groeneveld ON AD - University Medical Center Utrecht Brain Center Rudolf Magnus Department of Neurology Utrecht the Netherlands. FAU - Kappelle, L Jaap AU - Kappelle LJ AD - University Medical Center Utrecht Brain Center Rudolf Magnus Department of Neurology Utrecht the Netherlands. FAU - Biessels, Geert Jan AU - Biessels GJ AD - University Medical Center Utrecht Brain Center Rudolf Magnus Department of Neurology Utrecht the Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20151003 PL - Japan TA - J Diabetes Investig JT - Journal of diabetes investigation JID - 101520702 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Clinical Trials as Topic/methods MH - Dementia/*drug therapy/metabolism MH - Diabetes Mellitus, Type 2/*drug therapy/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Glucagon-Like Peptide 1/*agonists MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Incretins/*therapeutic use MH - Stroke/*drug therapy/metabolism PMC - PMC4718099 OTO - NOTNLM OT - Dementia OT - Incretins OT - Stroke EDAT- 2016/01/28 06:00 MHDA- 2016/10/25 06:00 PMCR- 2016/01/01 CRDT- 2016/01/28 06:00 PHST- 2015/07/04 00:00 [received] PHST- 2015/08/12 00:00 [revised] PHST- 2015/08/17 00:00 [accepted] PHST- 2016/01/28 06:00 [entrez] PHST- 2016/01/28 06:00 [pubmed] PHST- 2016/10/25 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - JDI12420 [pii] AID - 10.1111/jdi.12420 [doi] PST - ppublish SO - J Diabetes Investig. 2016 Jan;7(1):5-16. doi: 10.1111/jdi.12420. Epub 2015 Oct 3. PMID- 26744321 OWN - NLM STAT- MEDLINE DCOM- 20161215 LR - 20250103 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 5 DP - 2016 Feb 2 TI - Type 2 diabetes-induced neuronal pathology in the piriform cortex of the rat is reversed by the GLP-1 receptor agonist exendin-4. PG - 5865-76 LID - 10.18632/oncotarget.6823 [doi] AB - Type 2 diabetes (T2D) patients often present olfactory dysfunction. However, the histopathological basis behind this has not been previously shown. Since the piriform cortex plays a crucial role in olfaction, we hypothesize that pathological changes in this brain area can occur in T2D patients along aging. Thus, we determined potential neuropathology in the piriform cortex of T2D rats, along aging. Furthermore, we determined the potential therapeutic role of the glucagon-like peptide-1 receptor (GLP1-R) agonist exendin-4 to counteract the identified T2D-induced neuropathology. Young-adult and middle-aged T2D Goto-Kakizaki rats were compared to age-matched Wistars. Additional Goto-Kakizaki rats were treated for six weeks with exendin-4/vehicle before sacrifice. Potential T2D-induced neuropathology was assessed by quantifying NeuN-positive neurons and Calbindin-D28k-positive interneurons by immunohistochemistry and stereology methods. We also quantitatively measured Calbindin-D28k neuronal morphology and JNK phosphorylation-mediated cellular stress. PI3K/AKT signalling was assessed by immunohistochemistry, and potential apoptosis by TUNEL.We show T2D-induced neuronal pathology in the piriform cortex along aging, characterized by atypical nuclear NeuN staining and increased JNK phosphorylation, without apoptosis. We also demonstrate the specific vulnerability of Calbindin-D28k interneurons. Finally, chronic treatment with exendin-4 substantially reversed the identified neuronal pathology in correlation with decreased JNK and increased AKT phosphorylation.Our results reveal the histopathological basis to explain T2D olfactory dysfunction. We also show that the identified T2D-neuropathology can be counteracted by GLP-1R activation supporting recent research promoting the use of GLP-1R agonists against brain diseases. Whether the identified neuropathology could represent an early hallmark of cognitive decline in T2D remains to be determined. FAU - Lietzau, Grazyna AU - Lietzau G AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. AD - Medical University of Gdansk, Department of Anatomy and Neurobiology, Gdansk, Poland. FAU - Nystrom, Thomas AU - Nystrom T AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. FAU - Ostenson, Claes-Goran AU - Ostenson CG AD - Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden. FAU - Darsalia, Vladimer AU - Darsalia V AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. FAU - Patrone, Cesare AU - Patrone C AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Internal Medicine, Stockholm, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Peptides) RN - 0 (Venoms) RN - 9P1872D4OL (Exenatide) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Cells, Cultured MH - Diabetes Mellitus, Experimental/*physiopathology MH - Diabetes Mellitus, Type 2/*physiopathology MH - Exenatide MH - Hypoglycemic Agents/*pharmacology MH - Immunoenzyme Techniques MH - Insulin/metabolism MH - Insulin Secretion MH - Male MH - Neurons/drug effects/*pathology MH - Peptides/*pharmacology MH - Piriform Cortex/drug effects/*pathology MH - Rats MH - Rats, Wistar MH - Signal Transduction/drug effects MH - Venoms/*pharmacology MH - *Glucagon-Like Peptide-1 Receptor Agonists PMC - PMC4868727 OTO - NOTNLM OT - GLP-1R OT - Goto-Kakizaki rats OT - diabetes OT - olfaction OT - piriform cortex COIS- CONFLICTS OF INTERESTS The work in the group is in part supported by Boehringer Ingelheim Pharma GmbH & Co.KG. Thomas Nystrom is on the national advisory board of Eli Lilly, Novonordisk and Sanofi. EDAT- 2016/01/09 06:00 MHDA- 2016/12/16 06:00 PMCR- 2016/02/02 CRDT- 2016/01/09 06:00 PHST- 2015/10/28 00:00 [received] PHST- 2015/12/24 00:00 [accepted] PHST- 2016/01/09 06:00 [entrez] PHST- 2016/01/09 06:00 [pubmed] PHST- 2016/12/16 06:00 [medline] PHST- 2016/02/02 00:00 [pmc-release] AID - 6823 [pii] AID - 10.18632/oncotarget.6823 [doi] PST - ppublish SO - Oncotarget. 2016 Feb 2;7(5):5865-76. doi: 10.18632/oncotarget.6823. PMID- 26640240 OWN - NLM STAT- MEDLINE DCOM- 20161013 LR - 20181202 IS - 1095-9327 (Electronic) IS - 1044-7431 (Linking) VI - 70 DP - 2016 Jan TI - Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level. PG - 68-75 LID - S1044-7431(15)30038-5 [pii] LID - 10.1016/j.mcn.2015.10.005 [doi] AB - Type 2 diabetes (T2D) is a high risk factor for Alzheimer's disease (AD). Our previous study identified that hyperphosphorylation of tau protein, which is one of the pathophysiologic hallmarks of AD, also occurred in T2D rats' brain; while glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, could decrease the phosphorylation of tau, probably via augmenting insulin signaling pathway. The purpose of this study was to further explore the mechanisms that underlie the effect of exendin-4 (ex-4, a GLP-1 receptor agonist) in reducing tau phosphorylation. We found that peripheral ex-4 injection in T2D rats reduced hyperphosphorylation of tau protein in rat hippocampus, probably via increasing hippocampal insulin which activated insulin signaling. Furthermore, we found that ex-4 could neither activate insulin signaling, nor reduce tau phosphorylation in HT22 neuronal cells in the absence of insulin. These results suggested that insulin is required in reduction of tau hyperphosphorylation by ex-4 in brain rats with T2D. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Yang, Yan AU - Yang Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Ma, Delin AU - Ma D AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Xu, Weijie AU - Xu W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Chen, Fuqiong AU - Chen F AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Du, Tingting AU - Du T AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Yue, Wenzhu AU - Yue W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. FAU - Shao, Shiying AU - Shao S AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. Electronic address: shaoshiying@hotmail.com. FAU - Yuan, Gang AU - Yuan G AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. PR China. Electronic address: nbtjh1986@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151127 PL - United States TA - Mol Cell Neurosci JT - Molecular and cellular neurosciences JID - 9100095 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Peptides) RN - 0 (Venoms) RN - 0 (tau Proteins) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Diabetes Mellitus, Experimental/*metabolism MH - Diabetes Mellitus, Type 2/*metabolism MH - Exenatide MH - Hippocampus/*drug effects/metabolism MH - Hypoglycemic Agents/*pharmacology MH - Insulin/*metabolism MH - Male MH - Peptides/*pharmacology MH - Phosphorylation/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Venoms/*pharmacology MH - tau Proteins/*metabolism OTO - NOTNLM OT - Blood brain barrier OT - Glucagon-like peptide-1 OT - Insulin signaling OT - Tau hyperphosphorylation OT - Type 2 diabetes EDAT- 2015/12/08 06:00 MHDA- 2016/10/14 06:00 CRDT- 2015/12/08 06:00 PHST- 2015/04/21 00:00 [received] PHST- 2015/08/30 00:00 [revised] PHST- 2015/10/15 00:00 [accepted] PHST- 2015/12/08 06:00 [entrez] PHST- 2015/12/08 06:00 [pubmed] PHST- 2016/10/14 06:00 [medline] AID - S1044-7431(15)30038-5 [pii] AID - 10.1016/j.mcn.2015.10.005 [doi] PST - ppublish SO - Mol Cell Neurosci. 2016 Jan;70:68-75. doi: 10.1016/j.mcn.2015.10.005. Epub 2015 Nov 27. PMID- 26453962 OWN - NLM STAT- MEDLINE DCOM- 20161005 LR - 20161230 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 101 DP - 2016 Feb TI - Neuroprotective effects of a GIP analogue in the MPTP Parkinson's disease mouse model. PG - 255-63 LID - S0028-3908(15)30126-X [pii] LID - 10.1016/j.neuropharm.2015.10.002 [doi] AB - Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve insulin resistance for T2DM may be useful for PD patients. Glucose-dependent insulinotropic polypeptide (GIP) belongs to the incretin hormone family, which can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue, D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. D-Ala2-GIP-glu-PAL treatment (25 nmol/kg ip.) for 7 days after MPTP treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. D-Ala2-GIP-glu-PAL treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc). D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (synaptophysin levels), decreased the ratio of growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREB(S133) growth factor signaling in the substantia nigra. Therefore, D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Li, Yanwei AU - Li Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of Human Anatomy, Shaoyang Medical College, Shaoyang, Hunan, PR China. FAU - Liu, WeiZhen AU - Liu W AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, PR China. LA - eng PT - Journal Article DEP - 20151110 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Aif1 protein, mouse) RN - 0 (Calcium-Binding Proteins) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Microfilament Proteins) RN - 0 (Neuroprotective Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) SB - IM MH - Analysis of Variance MH - Animals MH - Calcium-Binding Proteins/metabolism MH - Disease Models, Animal MH - Exploratory Behavior/drug effects MH - Gastric Inhibitory Polypeptide/pharmacology/*therapeutic use MH - Glial Fibrillary Acidic Protein/metabolism MH - MPTP Poisoning/chemically induced/*drug therapy MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microfilament Proteins/metabolism MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Postural Balance/drug effects MH - Tyrosine 3-Monooxygenase/metabolism OTO - NOTNLM OT - Apoptosis OT - Diabetes OT - Glucose-dependent insulinotropic polypeptide OT - Growth factors OT - Insulin OT - Neuroinflammation OT - Neuroprotection EDAT- 2015/10/11 06:00 MHDA- 2016/10/07 06:00 CRDT- 2015/10/11 06:00 PHST- 2015/06/08 00:00 [received] PHST- 2015/09/06 00:00 [revised] PHST- 2015/10/02 00:00 [accepted] PHST- 2015/10/11 06:00 [entrez] PHST- 2015/10/11 06:00 [pubmed] PHST- 2016/10/07 06:00 [medline] AID - S0028-3908(15)30126-X [pii] AID - 10.1016/j.neuropharm.2015.10.002 [doi] PST - ppublish SO - Neuropharmacology. 2016 Feb;101:255-63. doi: 10.1016/j.neuropharm.2015.10.002. Epub 2015 Nov 10. PMID- 26453833 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20250103 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1634 DP - 2016 Mar 1 TI - A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson's disease by increasing expression of BNDF. PG - 1-11 LID - S0006-8993(15)00733-7 [pii] LID - 10.1016/j.brainres.2015.09.035 [doi] AB - The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD. CI - Copyright (c) 2016. Published by Elsevier B.V. FAU - Ji, Chenhui AU - Ji C AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Xue, Guo-Fang AU - Xue GF AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Lijun, Cao AU - Lijun C AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Feng, Peng AU - Feng P AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Li, Dongfang AU - Li D AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. FAU - Li, Guanglai AU - Li G AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. Electronic address: smuneu@163.com. FAU - Holscher, Christian AU - Holscher C AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China; Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151011 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Corpus Striatum/drug effects/metabolism MH - Disease Models, Animal MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Muscle Strength/drug effects MH - Neurons/drug effects/metabolism MH - Neuroprotective Agents/*administration & dosage MH - Parkinsonian Disorders/*metabolism/prevention & control MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, Gastrointestinal Hormone/*agonists MH - Rotarod Performance Test MH - Substantia Nigra/drug effects/metabolism MH - Tyrosine 3-Monooxygenase/metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - AKT OT - Apoptosis OT - Growth factor OT - Incretin OT - Insulin OT - Neuron EDAT- 2015/10/11 06:00 MHDA- 2016/12/15 06:00 CRDT- 2015/10/11 06:00 PHST- 2015/07/29 00:00 [received] PHST- 2015/09/11 00:00 [revised] PHST- 2015/09/29 00:00 [accepted] PHST- 2015/10/11 06:00 [entrez] PHST- 2015/10/11 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S0006-8993(15)00733-7 [pii] AID - 10.1016/j.brainres.2015.09.035 [doi] PST - ppublish SO - Brain Res. 2016 Mar 1;1634:1-11. doi: 10.1016/j.brainres.2015.09.035. Epub 2015 Oct 11. PMID- 26390937 OWN - NLM STAT- MEDLINE DCOM- 20160817 LR - 20181202 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1627 DP - 2015 Nov 19 TI - Exendin-4 antagonizes Abeta1-42-induced suppression of long-term potentiation by regulating intracellular calcium homeostasis in rat hippocampal neurons. PG - 101-8 LID - S0006-8993(15)00713-1 [pii] LID - 10.1016/j.brainres.2015.09.015 [doi] AB - An imbalance of intracellular calcium homeostasis induced by amyloid beta-protein (Abeta) contributes to the pathogenesis of Alzheimer's disease (AD), such as deficits in learning and memory. Therefore, regulation of calcium homeostasis may represent a new strategy for treatment of AD. Growing evidence suggests that type 2 diabetes mellitus (T2DM) and AD are closely related in pathogenesis. Thus, drugs used in treatment of T2DM may modify the pathogenesis of AD. This study demonstrated that Exendin-4, which is a glucagon-like peptide-1 (GLP-1) analog used as a therapeutic drug for T2DM, significantly antagonized suppression of long-term potentiation (LTP) induced by Abeta1-42 in the rat hippocampal CA1 region in vivo. This neuroprotection may be mediated by regulation of calcium homeostasis. Pretreatment with Exendin-4 suppressed Abeta1-42-induced elevation in intracellular calcium concentration ([Ca(2+)]i) through L-type voltage-dependent calcium channels (L-VDCCs) and N-methyl-D-aspartate receptors (NMDARs). Furthermore, Exendin-4 antagonized the decrease in p-Ca(2+)/calmodulin-dependent protein kinase IIalpha (p-CaMKIIalpha) induced by Abeta1-42 in the rat hippocampal CA1 region. Thus, the neuroprotective effects of Exendin-4, which likely involve regulation of calcium homeostasis, provide theoretical support for using Exendin-4 to treat and prevent AD in the future. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Wang, Xiaohui AU - Wang X AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: 163.wangxh@163.com. FAU - Wang, Li AU - Wang L AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. FAU - Jiang, Ruirui AU - Jiang R AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. FAU - Yuan, Yuan AU - Yuan Y AD - Morphology Laboratory, Shanxi Medical University, Taiyuan 030001, China. FAU - Yu, Qianqian AU - Yu Q AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. FAU - Li, Yameng AU - Li Y AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150921 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Amyloid beta-Peptides) RN - 0 (Calcium Channel Blockers) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (Venoms) RN - 0 (amyloid beta-protein (1-42)) RN - 76326-31-3 (2-amino-5-phosphopentanoic acid) RN - 9P1872D4OL (Exenatide) RN - HG18B9YRS7 (Valine) RN - I9ZF7L6G2L (Nifedipine) RN - SY7Q814VUP (Calcium) SB - IM MH - Amyloid beta-Peptides/pharmacology MH - Animals MH - Calcium/*metabolism MH - Calcium Channel Blockers/pharmacology MH - Cells, Cultured MH - Electric Stimulation MH - Excitatory Amino Acid Antagonists/pharmacology MH - Exenatide MH - Hippocampus/*cytology MH - Homeostasis/drug effects MH - Hypoglycemic Agents/*pharmacology MH - Long-Term Potentiation/*drug effects MH - Microscopy, Confocal MH - Neurons/*drug effects MH - Nifedipine/pharmacology MH - Patch-Clamp Techniques MH - Peptide Fragments/pharmacology MH - Peptides/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Time Factors MH - Valine/analogs & derivatives/pharmacology MH - Venoms/*pharmacology OTO - NOTNLM OT - Abeta1-42 OT - Calcium homeostasis OT - Exendin-4 OT - Neuroprotection EDAT- 2015/09/24 06:00 MHDA- 2016/08/18 06:00 CRDT- 2015/09/23 06:00 PHST- 2015/05/25 00:00 [received] PHST- 2015/09/06 00:00 [revised] PHST- 2015/09/11 00:00 [accepted] PHST- 2015/09/23 06:00 [entrez] PHST- 2015/09/24 06:00 [pubmed] PHST- 2016/08/18 06:00 [medline] AID - S0006-8993(15)00713-1 [pii] AID - 10.1016/j.brainres.2015.09.015 [doi] PST - ppublish SO - Brain Res. 2015 Nov 19;1627:101-8. doi: 10.1016/j.brainres.2015.09.015. Epub 2015 Sep 21. PMID- 26386291 OWN - NLM STAT- MEDLINE DCOM- 20160808 LR - 20181202 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 765 DP - 2015 Oct 15 TI - Exenatide reduces TNF-alpha expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats. PG - 482-7 LID - S0014-2999(15)30255-7 [pii] LID - 10.1016/j.ejphar.2015.09.024 [doi] AB - Recent studies suggest a possible link between type 2 diabetes and Alzheimer's disease (AD). Glucogan-like peptide 1 (GLP-1) facilitates insulin release from pancreas under hyperglycemic conditions. In addition to its metabolic effects, GLP-1 and its long-lasting analogs, including exenatide can stimulate neurogenesis and improve cognition in rodent AD model. The aim of the present study was to investigate the effects of exenatide on hippocampal cellularity, cognitive performance and inflammation response in a rat model of AD. Fourteen rats were used to create AD model using intracerebroventricular (ICV) streptozotocin (STZ) infusion while 7 rats were administered 0.9% NaCl only (sham-operated group). Following stereotaxic surgery, STZ received rats were randomly distributed into two groups, and treated with either saline or exenatide 20 microgr/kg/day through intraperitoneally for two weeks. Then, cognitive performance (passive avoidance learning), brain tumor necrosis factor alpha (TNF-alpha) levels, choline acetyltransferase (ChAT) activity and hippocampal neuronal count were determined. While the brain TNF-alpha levels were significantly high in the saline-treated STZ group, exenatide treatment suppressed the increase in TNF-alpha levels. Saline-treated STZ group showed reduced ChAT activity compared to sham group. However, exenatide significantly preserved brain ChAT activity. The cognitive performance was also impaired in saline group while exenatide improved memory in rats. Moreover, exenatide treatment significantly prevented the decrease in hippocampal neurons. Overall, the results of the present study clearly indicated exenatide might have beneficial effects on impaired cognitive performance and hippocampal neuronal viability in AD by suppressing the inflammation response and increasing cholinergic activity. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Solmaz, Volkan AU - Solmaz V AD - Department of Neurology, Turhal State Hospital, Tokat, Turkey. Electronic address: solmaz.volkan@yahoo.com. FAU - Cinar, Bilge Piri AU - Cinar BP AD - Department of Neurology, Giresun State Hospital, Giresun, Turkey. FAU - Yigitturk, Gurkan AU - Yigitturk G AD - Department of Histology & Embryology, Ege University School of Medicine, Izmir, Turkey. FAU - Cavusoglu, Turker AU - Cavusoglu T AD - Department of Histology & Embryology, Ege University School of Medicine, Izmir, Turkey. FAU - Taskiran, Dilek AU - Taskiran D AD - Department of Physiology, Ege University School of Medicine, Izmir, Turkey. FAU - Erbas, Oytun AU - Erbas O AD - Department of Physiology, Istanbul Bilim University School of Medicine, Istanbul, Turkey. LA - eng PT - Journal Article DEP - 20150916 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Venoms) RN - 5W494URQ81 (Streptozocin) RN - 9P1872D4OL (Exenatide) SB - IM MH - Alzheimer Disease/chemically induced/metabolism/pathology MH - Animals MH - Cell Count/methods MH - Exenatide MH - Hippocampus/*drug effects/metabolism/pathology MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Infusions, Intraventricular MH - Male MH - Memory/*drug effects/physiology MH - Neurons/*drug effects/metabolism MH - Peptides/*pharmacology/therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Streptozocin/administration & dosage/*toxicity MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/biosynthesis MH - Venoms/*pharmacology/therapeutic use OTO - NOTNLM OT - Alzheimer's disease OT - Choline acetyltransferase OT - Exenatide OT - Streptozotocin OT - Tumor necrosing factor-alpha EDAT- 2015/09/20 06:00 MHDA- 2016/08/09 06:00 CRDT- 2015/09/20 06:00 PHST- 2015/04/15 00:00 [received] PHST- 2015/09/14 00:00 [revised] PHST- 2015/09/15 00:00 [accepted] PHST- 2015/09/20 06:00 [entrez] PHST- 2015/09/20 06:00 [pubmed] PHST- 2016/08/09 06:00 [medline] AID - S0014-2999(15)30255-7 [pii] AID - 10.1016/j.ejphar.2015.09.024 [doi] PST - ppublish SO - Eur J Pharmacol. 2015 Oct 15;765:482-7. doi: 10.1016/j.ejphar.2015.09.024. Epub 2015 Sep 16. PMID- 26384381 OWN - NLM STAT- MEDLINE DCOM- 20160428 LR - 20260127 IS - 1939-327X (Electronic) IS - 0012-1797 (Linking) VI - 65 IP - 1 DP - 2016 Jan TI - Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes. PG - 172-87 LID - 10.2337/db15-0443 [doi] AB - Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagon-like peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR. CI - (c) 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. FAU - Hernandez, Cristina AU - Hernandez C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain cristina.hernandez@vhir.org. FAU - Bogdanov, Patricia AU - Bogdanov P AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. FAU - Corraliza, Lidia AU - Corraliza L AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. FAU - Garcia-Ramirez, Marta AU - Garcia-Ramirez M AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. FAU - Sola-Adell, Cristina AU - Sola-Adell C AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. FAU - Arranz, Jose A AU - Arranz JA AD - Unidad de Metabolopatias, Laboratorios Clinicos, Hospital Universitari Vall d'Hebron, Barcelona, Spain. FAU - Arroba, Ana I AU - Arroba AI AD - CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomedicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas/Universidad Autonoma de Madrid, Madrid, Spain. FAU - Valverde, Angela M AU - Valverde AM AD - CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomedicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas/Universidad Autonoma de Madrid, Madrid, Spain. FAU - Simo, Rafael AU - Simo R AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150917 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 9P1872D4OL (Exenatide) RN - 0 (Glial Fibrillary Acidic Protein) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Administration, Ophthalmic MH - Aged MH - Animals MH - Apoptosis/drug effects MH - Blotting, Western MH - Diabetes Mellitus, Experimental/complications/*metabolism MH - Diabetes Mellitus, Type 2/complications/*metabolism MH - Diabetic Retinopathy/etiology/*prevention & control MH - Electroretinography MH - Exenatide MH - Female MH - Glial Fibrillary Acidic Protein/drug effects/metabolism MH - Glucagon-Like Peptide 1 MH - Glucagon-Like Peptide-1 Receptor/genetics/metabolism MH - Humans MH - Immunohistochemistry MH - Liraglutide/*pharmacology MH - Male MH - Mice MH - Middle Aged MH - Neuroprotective Agents/*pharmacology MH - Peptides/*pharmacology MH - Real-Time Polymerase Chain Reaction MH - Retina/drug effects/pathology MH - Retinal Neurons/*drug effects/pathology MH - Venoms/*pharmacology MH - *Glucagon-Like Peptide-1 Receptor Agonists MH - Glucagon-Like Peptide-2 Receptor EDAT- 2015/09/19 06:00 MHDA- 2016/04/29 06:00 CRDT- 2015/09/19 06:00 PHST- 2015/03/31 00:00 [received] PHST- 2015/09/08 00:00 [accepted] PHST- 2015/09/19 06:00 [entrez] PHST- 2015/09/19 06:00 [pubmed] PHST- 2016/04/29 06:00 [medline] AID - db15-0443 [pii] AID - 10.2337/db15-0443 [doi] PST - ppublish SO - Diabetes. 2016 Jan;65(1):172-87. doi: 10.2337/db15-0443. Epub 2015 Sep 17. PMID- 26351802 OWN - NLM STAT- MEDLINE DCOM- 20161020 LR - 20250103 IS - 2191-0200 (Electronic) IS - 0334-1763 (Linking) VI - 27 IP - 1 DP - 2016 Jan TI - Neuroprotective effects of glucose-dependent insulinotropic polypeptide in Alzheimer's disease. PG - 61-70 LID - 10.1515/revneuro-2015-0021 [doi] AB - Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormones and growth factors. Neurons express the GIP receptor, and GIP and its agonists can pass through the blood brain barrier and show remarkable neuroprotective effects by protecting synapse function and numbers, promoting neuronal proliferation, reducing amyloid plaques in the cortex and reducing the chronic inflammation response of the nervous system. Long-acting analogues of GIP that are protease resistant had been developed as a treatment for type 2 diabetes. It has been found that such GIP analogues show good protective effects in animal models of Alzheimer's disease. Novel dual agonist peptides that activate the GIP receptor and another incretin receptor, glucagon-like peptide -1 (GLP-1), are under development that show superior effects in diabetic patients compared to single GLP-1 agonists. The dual agonists also show great promise in treating neurodegenerative disorders, and there are currently several clinical trials ongoing, testing GLP-1 mimetics in people with Alzheimer's or Parkinson's disease. FAU - Ji, Chenhui AU - Ji C FAU - Xue, Guo-Fang AU - Xue GF FAU - Li, Guanglai AU - Li G FAU - Li, Dongfang AU - Li D FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Review PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Alzheimer Disease/*drug therapy/prevention & control MH - Animals MH - Gastric Inhibitory Polypeptide/*analogs & derivatives/pharmacology MH - Humans MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Receptors, Gastrointestinal Hormone/agonists MH - Signal Transduction MH - Synapses/drug effects MH - Glucagon-Like Peptide-1 Receptor Agonists EDAT- 2015/09/10 06:00 MHDA- 2016/10/21 06:00 CRDT- 2015/09/10 06:00 PHST- 2015/05/27 00:00 [received] PHST- 2015/07/20 00:00 [accepted] PHST- 2015/09/10 06:00 [entrez] PHST- 2015/09/10 06:00 [pubmed] PHST- 2016/10/21 06:00 [medline] AID - /j/revneuro.ahead-of-print/revneuro-2015-0021/revneuro-2015-0021.xml [pii] AID - 10.1515/revneuro-2015-0021 [doi] PST - ppublish SO - Rev Neurosci. 2016 Jan;27(1):61-70. doi: 10.1515/revneuro-2015-0021. PMID- 26336108 OWN - NLM STAT- MEDLINE DCOM- 20160216 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 43 DP - 2015 Oct 23 TI - Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed. PG - 26235-48 LID - 10.1074/jbc.M115.672097 [doi] AB - The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-gamma-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - King, Klim AU - King K AD - From the Genomics Research Center, bmkxk@ibms.sinica.edu.tw bmkxk@yahoo.com. FAU - Lin, Nai-Pin AU - Lin NP AD - Institutes of Chemistry and. FAU - Cheng, Yu-Hong AU - Cheng YH AD - From the Genomics Research Center. FAU - Chen, Gao-Hui AU - Chen GH AD - Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. FAU - Chein, Rong-Jie AU - Chein RJ AD - Institutes of Chemistry and rjchein@chem.sinica.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150902 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Plant Extracts) RN - 62340-29-8 (Glucagon-Like Peptides) SB - IM MH - Cell Line MH - Glucagon-Like Peptides/*metabolism MH - Humans MH - Plant Extracts/pharmacology MH - Seeds/*metabolism MH - Signal Transduction/*drug effects MH - Trigonella/chemistry/*embryology PMC - PMC4646272 OTO - NOTNLM OT - 4-hydroxyisoleucine OT - G protein-coupled receptor (GPCR) OT - bioluminescence resonance energy transfer (BRET) OT - cyclic AMP (cAMP) OT - diabetes OT - endocytosis OT - fenugreek OT - glucagon-like peptide-1 OT - natural product EDAT- 2015/09/04 06:00 MHDA- 2016/02/18 06:00 PMCR- 2016/10/23 CRDT- 2015/09/04 06:00 PHST- 2015/06/12 00:00 [received] PHST- 2015/09/04 06:00 [entrez] PHST- 2015/09/04 06:00 [pubmed] PHST- 2016/02/18 06:00 [medline] PHST- 2016/10/23 00:00 [pmc-release] AID - S0021-9258(20)49598-5 [pii] AID - M115.672097 [pii] AID - 10.1074/jbc.M115.672097 [doi] PST - ppublish SO - J Biol Chem. 2015 Oct 23;290(43):26235-48. doi: 10.1074/jbc.M115.672097. Epub 2015 Sep 2. PMID- 26302060 OWN - NLM STAT- MEDLINE DCOM- 20160812 LR - 20151020 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 765 DP - 2015 Oct 15 TI - Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease. PG - 284-90 LID - S0014-2999(15)30212-0 [pii] LID - 10.1016/j.ejphar.2015.08.038 [doi] AB - Oxyntomodulin is a hormone and a growth factor. It activates two receptors, the Glucagon-like peptide 1 (GLP-1) and the glucagon receptor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first positive results. D-Ser2-oxyntomodulin (Oxy) is a protease resistant oxyntomodulin analogue that has been developed to treat diabetes. Here we demonstrate for the first time that such analogues have neuroprotective effects. The drug showed protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected daily (20 mg/kg i.p.) for 7 days, and Oxy injected once-daily for 14 days i.p. Oxy treatment prevented or reversed the MPTP- induced motor impairment (Rotarod, spontaneous locomotion, swim activity, muscle strength test), the MPTP-induced reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, the reduction of the synaptic marker synapstophysin, the inactivation of the growth factor kinase Akt/PKB and of the anti-apoptotic signaling molecule Bcl-2, and the increase of levels of the pro-inflammatory cytokine TNF-alpha. The results demonstrate that oxyntomodulin analogues show promise as a novel treatment of PD. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Liu, WeiZhen AU - Liu W AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. FAU - Li, Yanwei AU - Li Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. FAU - Jalewa, Jaishree AU - Jalewa J AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. FAU - Saunders-Wood, Taylor AU - Saunders-Wood T AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second Hospital, Shanxi Medical University, Taiyuan, PR China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150821 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (D-Ser2-oxyntomodulin) RN - 0 (Neuroprotective Agents) RN - 0 (Oxyntomodulin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) SB - IM MH - Animals MH - Behavior, Animal/drug effects MH - Corpus Striatum/drug effects/enzymology MH - Dopaminergic Neurons/drug effects/enzymology MH - Glucagon-Like Peptide 1/metabolism MH - Male MH - Mice, Inbred C57BL MH - Muscle Strength/drug effects MH - Neuroprotective Agents/administration & dosage/*therapeutic use MH - Oxyntomodulin/administration & dosage/*therapeutic use MH - Parkinsonian Disorders/pathology/*prevention & control MH - Substantia Nigra/drug effects/enzymology MH - Swimming MH - Tyrosine 3-Monooxygenase/metabolism OTO - NOTNLM OT - GLP-1 OT - Glucagon OT - Growth factor OT - Incretin OT - Insulin OT - Mice OT - Neurodegeneration EDAT- 2015/08/25 06:00 MHDA- 2016/08/16 06:00 CRDT- 2015/08/25 06:00 PHST- 2015/05/19 00:00 [received] PHST- 2015/08/18 00:00 [revised] PHST- 2015/08/19 00:00 [accepted] PHST- 2015/08/25 06:00 [entrez] PHST- 2015/08/25 06:00 [pubmed] PHST- 2016/08/16 06:00 [medline] AID - S0014-2999(15)30212-0 [pii] AID - 10.1016/j.ejphar.2015.08.038 [doi] PST - ppublish SO - Eur J Pharmacol. 2015 Oct 15;765:284-90. doi: 10.1016/j.ejphar.2015.08.038. Epub 2015 Aug 21. PMID- 26279440 OWN - NLM STAT- MEDLINE DCOM- 20160524 LR - 20220408 IS - 1421-9778 (Electronic) IS - 1015-8987 (Linking) VI - 36 IP - 6 DP - 2015 TI - The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway. PG - 2366-78 LID - 10.1159/000430199 [doi] AB - BACKGROUND/AIMS: Glucagon-like peptide-1 (GLP-1)-based drugs are being used to achieve better glucose control in patients with type 2 diabetes, and GLP-1 mimetics such as liraglutide have shown therapeutic potential in preventing diabetes-related microvascular and macrovascular complications as well as comorbidities such as neurodegenerative disorders. In the present study, we investigated the effects of liraglutide on primary rat cortical astrocytes treated with advanced glycation end-products (AGEs). METHODS: Gene and protein expression was analyzed by quantitative real time PCR, western blots, and enzyme-linked immunosorbent assay. The caspase-3 activity was assessed using a caspase-3 colorimetric assay kit. The ROS production was measured with CM-H2DCFDA staining. The cell viability of rat astrocytes was determined using MTT assay. RESULTS: Liraglutide ameliorated AGEs-induced oxidative stress, inflammatory cytokine secretion, caspase activation, and cell death in astrocytes, and reversed the AGEs mediated reduction in intracellular cyclic AMP (cAMP) levels, protein kinase A (PKA) activity, and the phosphorylation of the cAMP response element-binding (CREB) protein. The protective effects of liraglutide against AGEs-mediated toxicity were abolished by GLP-1 receptor (GLP-1R) knockdown or pretreatment of cells with the adenylyl cyclase inhibitor SQ22536 or the PKA inhibitor Rp-cAMP. CONCLUSIONS: Liraglutide exerts its neuroprotective effects via the GLP-1R-mediated activation of the cAMP/PKA/CREB pathway. The results of the present study support the therapeutic potential of liraglutide for the treatment of neurodegenerative disorders. CI - (c) 2015 S. Karger AG, Basel. FAU - Bao, Yi AU - Bao Y AD - Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai, China. FAU - Jiang, Lei AU - Jiang L FAU - Chen, Haiyan AU - Chen H FAU - Zou, Junjie AU - Zou J FAU - Liu, Zhimin AU - Liu Z FAU - Shi, Yongquan AU - Shi Y LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150727 PL - Germany TA - Cell Physiol Biochem JT - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JID - 9113221 RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Cytokines) RN - 0 (Glycation End Products, Advanced) RN - 0 (Inflammation Mediators) RN - 0 (Neuroprotective Agents) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Glucagon) RN - 839I73S42A (Liraglutide) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Astrocytes/drug effects/metabolism MH - Cell Death/drug effects MH - Cell Proliferation/drug effects MH - Cyclic AMP/*metabolism MH - Cyclic AMP Response Element-Binding Protein/*metabolism MH - Cyclic AMP-Dependent Protein Kinases/*metabolism MH - Cytokines/metabolism MH - Glycation End Products, Advanced/pharmacology MH - Inflammation Mediators/metabolism MH - Liraglutide/*pharmacology MH - Neuroprotective Agents/*pharmacology MH - Oxidative Stress/drug effects MH - Rats, Wistar MH - Reactive Oxygen Species/metabolism MH - Receptors, Glucagon/*metabolism MH - Signal Transduction/*drug effects EDAT- 2015/08/19 06:00 MHDA- 2016/05/25 06:00 CRDT- 2015/08/18 06:00 PHST- 2015/07/01 00:00 [accepted] PHST- 2015/08/18 06:00 [entrez] PHST- 2015/08/19 06:00 [pubmed] PHST- 2016/05/25 06:00 [medline] AID - 000430199 [pii] AID - 10.1159/000430199 [doi] PST - ppublish SO - Cell Physiol Biochem. 2015;36(6):2366-78. doi: 10.1159/000430199. Epub 2015 Jul 27. PMID- 26205827 OWN - NLM STAT- MEDLINE DCOM- 20160602 LR - 20191210 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 293 DP - 2015 Oct 15 TI - Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. PG - 96-106 LID - S0166-4328(15)30096-6 [pii] LID - 10.1016/j.bbr.2015.07.024 [doi] AB - Type 2 diabetes is a risk factor for Alzheimer's disease (AD). Previously, we have shown that the diabetes drug liraglutide is protective in middle aged and in old APP/PS1 mice. Here, we show that liraglutide has prophylactic properties. When injecting liraglutide once-daily ip. in two months old mice for 8 months, the main hallmarks of AD were much reduced. Memory formation in object recognition and Morris water maze were normalised and synapse loss and the loss of synaptic plasticity was prevented. In addition, amyloid plaque load, including dense core congophilic plaques, was much reduced. Chronic inflammation (activated microglia) was also reduced in the cortex, and neurogenesis was enhanced in the dentate gyrus. The results demonstrate that liraglutide may protect from progressive neurodegeneration that develops in AD. The drug is currently in clinical trials in patients with AD. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - McClean, Paula L AU - McClean PL AD - Clinical, Translational and Research Innovation Centre (C-TRIC), Ulster University, Derry/Londonderry, BT47 6SB, Northern Ireland, UK. FAU - Jalewa, Jaishree AU - Jalewa J AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150720 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Presenilin-1) RN - 839I73S42A (Liraglutide) SB - IM MH - Alzheimer Disease/complications/genetics MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Blood Glucose/drug effects/genetics MH - Body Weight/drug effects/genetics MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - Hippocampus/pathology MH - Hypoglycemic Agents/*therapeutic use MH - Inflammation/genetics/*prevention & control MH - Liraglutide/*therapeutic use MH - Long-Term Potentiation/drug effects/genetics MH - Maze Learning/drug effects MH - Memory Disorders/genetics/*prevention & control MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Patch-Clamp Techniques MH - Plaque, Amyloid/drug therapy/*metabolism MH - Presenilin-1/genetics MH - Recognition, Psychology/drug effects OTO - NOTNLM OT - LTP OT - growth factor OT - incretin OT - insulin OT - memory loss OT - synaptic loss EDAT- 2015/07/25 06:00 MHDA- 2016/06/03 06:00 CRDT- 2015/07/25 06:00 PHST- 2015/06/05 00:00 [received] PHST- 2015/07/06 00:00 [revised] PHST- 2015/07/06 00:00 [accepted] PHST- 2015/07/25 06:00 [entrez] PHST- 2015/07/25 06:00 [pubmed] PHST- 2016/06/03 06:00 [medline] AID - S0166-4328(15)30096-6 [pii] AID - 10.1016/j.bbr.2015.07.024 [doi] PST - ppublish SO - Behav Brain Res. 2015 Oct 15;293:96-106. doi: 10.1016/j.bbr.2015.07.024. Epub 2015 Jul 20. PMID- 26187689 OWN - NLM STAT- MEDLINE DCOM- 20160602 LR - 20150911 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 293 DP - 2015 Oct 15 TI - Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson's disease mouse model. PG - 107-13 LID - S0166-4328(15)30094-2 [pii] LID - 10.1016/j.bbr.2015.07.021 [doi] AB - Glucagon-like peptide 1 (GLP-1) is a hormone and a growth factor. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. They also have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a first clinical trial in PD patients showed promising results. (Val8)GLP-1-glu-PAL is a new GLP-1 analogue which has a longer biological half-life than exendin-4. We previously showed that (Val8)GLP-1-glu-PAL has neuroprotective properties. Here we tested the drug in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected (30mg/kg i.p.) along with (Val8)GLP-1-glu-PAL (25nmol/kg i.p.) once-daily for 8 days. (Val8)GLP-1-glu-PAL showed good effects in preventing the MPTP-induced motor impairment (Rotarod, open field locomotion, swim test), reduction in tyrosine hydroxylase levels (dopamine synthesis) in the substantia nigra, a reduction of activated caspase 3 levels, of TUNEL positive cell numbers, of the pro-apoptotic signaling molecule BAX and an increase in the growth signaling molecule Bcl-2. The results demonstrate that (Val8)GLP-1-glu-PAL shows promise as a novel treatment of PD. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Zhang, YanFang AU - Zhang Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Chen, YiMei AU - Chen Y AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. FAU - Li, Lin AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second hospital, Shanxi Medical University, Taiyuan, Shanxi, PR China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150714 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 ((Val8)GLP-1-Glu-PAL) RN - 0 (Lipopeptides) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - *1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MH - Analysis of Variance MH - Animals MH - Caspase 3/metabolism MH - Disease Models, Animal MH - Exploratory Behavior/drug effects MH - Glucagon-Like Peptide 1/*analogs & derivatives/therapeutic use MH - Lipopeptides/*therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Neuroprotective Agents/*therapeutic use MH - Parkinsonian Disorders/*chemically induced/*prevention & control MH - Rotarod Performance Test MH - Swimming/psychology MH - Tyrosine 3-Monooxygenase/metabolism OTO - NOTNLM OT - Apoptosis OT - Growth factors OT - Incretin OT - Insulin OT - Neuroinflammation OT - Neuroprotection EDAT- 2015/07/19 06:00 MHDA- 2016/06/03 06:00 CRDT- 2015/07/19 06:00 PHST- 2015/06/11 00:00 [received] PHST- 2015/07/03 00:00 [revised] PHST- 2015/07/06 00:00 [accepted] PHST- 2015/07/19 06:00 [entrez] PHST- 2015/07/19 06:00 [pubmed] PHST- 2016/06/03 06:00 [medline] AID - S0166-4328(15)30094-2 [pii] AID - 10.1016/j.bbr.2015.07.021 [doi] PST - ppublish SO - Behav Brain Res. 2015 Oct 15;293:107-13. doi: 10.1016/j.bbr.2015.07.021. Epub 2015 Jul 14. PMID- 26183127 OWN - NLM STAT- MEDLINE DCOM- 20160111 LR - 20151010 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 135 IP - 2 DP - 2015 Oct TI - Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice. PG - 301-8 LID - 10.1111/jnc.13248 [doi] AB - Increasing evidence has shown that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease. Neurofibrillary tangles, which consist of hyperphosphorylated tau and misfolded microtubules, is one of the neuropathological hallmarks of Alzheimer's disease. Db/db mice, a rodent model of T2D, also exhibited age-dependent tau hyperphosphorylation. Glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, has been found to have neuroprotective effects. The aim of this study was to explore the potential effects of liraglutide (a GLP-1 analog), or insulin, on tau phosphorylation in T2D animals. Male db/db mice (3-3.5 weeks) were daily injected subcutaneously with liraglutide (n = 27), insulin (n = 27), or saline (n = 26), and five to seven mice were killed every 2 weeks for analysis of plasma and cerebrospinal (CSF) insulin levels by ELISA, and protein levels in the hippocampal formation by western blot. We found that db/db mice treated with saline exhibited an age-dependent decrease in CSF insulin and an increase in hippocampal tau phosphorylation. Liraglutide injection reversed the CSF insulin to ~1 mIU/L by the end of 8 weeks treatment, and prevented the hyperphosphorylation of tau protein in the hippocampal formation. By contrast, insulin injection had no effects on CSF insulin or phosphorylation of tau protein. In summary, this study indicates that early GLP-1 analog intervention prevented the age-dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta. CI - (c) 2015 International Society for Neurochemistry. FAU - Ma, De-Lin AU - Ma DL AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Chen, Fu-Qiong AU - Chen FQ AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Xu, Wei-Jie AU - Xu WJ AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Yue, Wen-Zhu AU - Yue WZ AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Yuan, Gang AU - Yuan G AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Yang, Yan AU - Yang Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150811 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Animals MH - Blood Glucose/analysis/metabolism MH - Brain Chemistry/drug effects MH - Diabetes Mellitus, Experimental/complications/*metabolism MH - Diabetic Neuropathies/*prevention & control MH - Glycogen Synthase Kinase 3/metabolism MH - Hippocampus/drug effects/metabolism MH - Hypoglycemic Agents/*therapeutic use MH - Insulin/blood/cerebrospinal fluid/pharmacology MH - Insulin Resistance MH - Liraglutide/*therapeutic use MH - Male MH - Mice MH - Oncogene Protein v-akt/biosynthesis MH - Phosphorylation/*drug effects MH - Weight Gain/drug effects MH - tau Proteins/*metabolism OTO - NOTNLM OT - blood-brain barrier OT - glucagon-like peptide-1 OT - hippocampal formation OT - tau hyperphosphorylation OT - type 2 diabetes EDAT- 2015/07/18 06:00 MHDA- 2016/01/12 06:00 CRDT- 2015/07/18 06:00 PHST- 2015/03/28 00:00 [received] PHST- 2015/07/09 00:00 [revised] PHST- 2015/07/10 00:00 [accepted] PHST- 2015/07/18 06:00 [entrez] PHST- 2015/07/18 06:00 [pubmed] PHST- 2016/01/12 06:00 [medline] AID - 10.1111/jnc.13248 [doi] PST - ppublish SO - J Neurochem. 2015 Oct;135(2):301-8. doi: 10.1111/jnc.13248. Epub 2015 Aug 11. PMID- 26141845 OWN - NLM STAT- MEDLINE DCOM- 20160506 LR - 20260128 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 303 DP - 2015 Sep 10 TI - Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. PG - 42-50 LID - S0306-4522(15)00595-3 [pii] LID - 10.1016/j.neuroscience.2015.06.054 [doi] AB - Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Liu, W AU - Liu W AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. FAU - Jalewa, J AU - Jalewa J AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. FAU - Sharma, M AU - Sharma M AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. FAU - Li, G AU - Li G AD - Second Hospital, Shanxi Medical University, Taiyuan, PR China. FAU - Li, L AU - Li L AD - Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. FAU - Holscher, C AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second Hospital, Shanxi Medical University, Taiyuan, PR China. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150702 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - 9P1872D4OL (Exenatide) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - 0 (Venoms) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MH - Animals MH - Apoptosis/drug effects MH - Basal Ganglia/drug effects/metabolism MH - Catalepsy/chemically induced MH - Disease Models, Animal MH - Dopaminergic Neurons/metabolism MH - Exenatide MH - Liraglutide/*administration & dosage MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Neuroprotective Agents/*administration & dosage MH - Parkinsonian Disorders/physiopathology/*prevention & control MH - Peptides/*administration & dosage MH - Rotarod Performance Test MH - Substantia Nigra/drug effects/metabolism MH - Tyrosine 3-Monooxygenase/metabolism MH - Venoms/administration & dosage MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - apoptosis OT - basal ganglia OT - growth factor OT - incretin OT - insulin OT - neurodegeneration EDAT- 2015/07/05 06:00 MHDA- 2016/05/07 06:00 CRDT- 2015/07/05 06:00 PHST- 2015/05/11 00:00 [received] PHST- 2015/06/16 00:00 [revised] PHST- 2015/06/24 00:00 [accepted] PHST- 2015/07/05 06:00 [entrez] PHST- 2015/07/05 06:00 [pubmed] PHST- 2016/05/07 06:00 [medline] AID - S0306-4522(15)00595-3 [pii] AID - 10.1016/j.neuroscience.2015.06.054 [doi] PST - ppublish SO - Neuroscience. 2015 Sep 10;303:42-50. doi: 10.1016/j.neuroscience.2015.06.054. Epub 2015 Jul 2. PMID- 26131323 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20150701 LR - 20201001 IS - 1948-9358 (Print) IS - 1948-9358 (Electronic) IS - 1948-9358 (Linking) VI - 6 IP - 6 DP - 2015 Jun 25 TI - Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. PG - 807-27 LID - 10.4239/wjd.v6.i6.807 [doi] AB - Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential. FAU - Candeias, Emanuel Monteiro AU - Candeias EM AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Sebastiao, Ines Carolina AU - Sebastiao IC AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Cardoso, Susana Maria AU - Cardoso SM AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Correia, Sonia Catarina AU - Correia SC AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Carvalho, Cristina Isabel AU - Carvalho CI AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Placido, Ana Isabel AU - Placido AI AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Santos, Maria Sancha AU - Santos MS AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Oliveira, Catarina Resende AU - Oliveira CR AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Moreira, Paula Isabel AU - Moreira PI AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. FAU - Duarte, Ana Isabel AU - Duarte AI AD - Emanuel Monteiro Candeias, Ines Carolina Sebastiao, Susana Maria Cardoso, Sonia Correia Correia, Cristina Isabel Carvalho, Ana Isabel Placido, Maria Sancha Santos, Catarina Resende Oliveira, Paula Isabel Moreira, Ana Isabel Duarte, CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (1 Floor), University of Coimbra, 3004-517 Coimbra, Portugal. LA - eng PT - Journal Article PT - Review PL - United States TA - World J Diabetes JT - World journal of diabetes JID - 101547524 PMC - PMC4478577 OTO - NOTNLM OT - Alzheimer disease OT - Brain OT - Glucagon-like peptide-1 OT - Gut OT - Insulin OT - Liraglutide OT - Neuroprotection OT - Type 2 diabetes EDAT- 2015/07/02 06:00 MHDA- 2015/07/02 06:01 PMCR- 2015/06/25 CRDT- 2015/07/02 06:00 PHST- 2014/11/17 00:00 [received] PHST- 2015/05/04 00:00 [revised] PHST- 2015/05/16 00:00 [accepted] PHST- 2015/07/02 06:00 [entrez] PHST- 2015/07/02 06:00 [pubmed] PHST- 2015/07/02 06:01 [medline] PHST- 2015/06/25 00:00 [pmc-release] AID - 10.4239/wjd.v6.i6.807 [doi] PST - ppublish SO - World J Diabetes. 2015 Jun 25;6(6):807-27. doi: 10.4239/wjd.v6.i6.807. PMID- 26069723 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20150613 LR - 20220330 IS - 1948-9358 (Print) IS - 1948-9358 (Electronic) IS - 1948-9358 (Linking) VI - 6 IP - 5 DP - 2015 Jun 10 TI - Emerging links between type 2 diabetes and Alzheimer's disease. PG - 744-51 LID - 10.4239/wjd.v6.i5.744 [doi] AB - Type 2 diabetes mellitus and Alzheimer's disease are both associated with increasing age, and each increases the risk of development of the other. Epidemiological, clinical, biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction, the most prevalent cause of which is Alzheimer's disease. Cross sectional studies have clearly shown such an association, whereas longitudinal studies are equivocal, reflecting the many complex ways in which the two interact. Despite the dichotomy, common risk and etiological factors (obesity, dyslipidemia, insulin resistance, and sedentary habits) are recognized; correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases. Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se, hyperinsulinemia, insulin resistance, acute hypoglycemic episodes, especially in the elderly, microvascular disease, fibrillar deposits (in brain in Alzheimer's disease and in pancreas in type 2 diabetes), altered insulin processing, inflammation, obesity, dyslipidemia, altered levels of insulin like growth factor and occurrence of variant forms of the protein butyrylcholinesterase. Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer's disease, but so do some of the pharmacological agents used in the treatment of diabetes such as insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors gamma agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes must be recognized as a risk for development of Alzheimer's disease; clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately. FAU - Sridhar, Gumpeny R AU - Sridhar GR AD - Gumpeny R Sridhar, Gumpeny Lakshmi, Gumpeny Nagamani, Endocrine and Diabetes Centre, Department of Obstetrics and Gynecology, Andhra Medical College, Visakhapatnam 530002, India. FAU - Lakshmi, Gumpeny AU - Lakshmi G AD - Gumpeny R Sridhar, Gumpeny Lakshmi, Gumpeny Nagamani, Endocrine and Diabetes Centre, Department of Obstetrics and Gynecology, Andhra Medical College, Visakhapatnam 530002, India. FAU - Nagamani, Gumpeny AU - Nagamani G AD - Gumpeny R Sridhar, Gumpeny Lakshmi, Gumpeny Nagamani, Endocrine and Diabetes Centre, Department of Obstetrics and Gynecology, Andhra Medical College, Visakhapatnam 530002, India. LA - eng PT - Journal Article PT - Review PL - United States TA - World J Diabetes JT - World journal of diabetes JID - 101547524 PMC - PMC4458503 OTO - NOTNLM OT - Butyrylcholinesterase OT - Cognition OT - Dementia OT - Insulin OT - Insulin resistance EDAT- 2015/06/13 06:00 MHDA- 2015/06/13 06:01 PMCR- 2015/06/10 CRDT- 2015/06/13 06:00 PHST- 2014/08/29 00:00 [received] PHST- 2014/12/04 00:00 [revised] PHST- 2015/03/16 00:00 [accepted] PHST- 2015/06/13 06:00 [entrez] PHST- 2015/06/13 06:00 [pubmed] PHST- 2015/06/13 06:01 [medline] PHST- 2015/06/10 00:00 [pmc-release] AID - 10.4239/wjd.v6.i5.744 [doi] PST - ppublish SO - World J Diabetes. 2015 Jun 10;6(5):744-51. doi: 10.4239/wjd.v6.i5.744. PMID- 26048772 OWN - NLM STAT- MEDLINE DCOM- 20160517 LR - 20211203 IS - 1872-8057 (Electronic) IS - 0303-7207 (Linking) VI - 412 DP - 2015 Sep 5 TI - Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice. PG - 95-103 LID - S0303-7207(15)00306-8 [pii] LID - 10.1016/j.mce.2015.05.035 [doi] AB - The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-gamma-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3beta. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-gamma-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice. CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved. FAU - Pathak, N M AU - Pathak NM AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. FAU - Pathak, V AU - Pathak V AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. FAU - Lynch, A M AU - Lynch AM AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. FAU - Irwin, N AU - Irwin N AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. FAU - Gault, V A AU - Gault VA AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. Electronic address: va.gault@ulster.ac.uk. FAU - Flatt, P R AU - Flatt PR AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150603 PL - Ireland TA - Mol Cell Endocrinol JT - Molecular and cellular endocrinology JID - 7500844 RN - 0 ((Ser2)Oxm(Lys38-gamma-Glu-PAL)) RN - 0 (Blood Glucose) RN - 0 (Doublecortin Domain Proteins) RN - 0 (Gastrointestinal Hormones) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Neuropeptides) SB - IM MH - Adiposity/drug effects MH - Animals MH - Blood Glucose MH - Body Weight MH - Diabetes Mellitus, Type 2/etiology/metabolism MH - Diet, High-Fat/*adverse effects MH - Doublecortin Domain Proteins MH - Drug Evaluation, Preclinical MH - Drug Stability MH - Energy Intake/drug effects MH - Gastrointestinal Hormones/*pharmacology MH - Gene Expression MH - Hippocampus/drug effects/*metabolism/pathology MH - Homeostasis MH - Hypoglycemic Agents/*pharmacology MH - Insulin/blood/metabolism MH - Insulin Secretion MH - Lipid Metabolism MH - Male MH - Mice MH - Microtubule-Associated Proteins/metabolism MH - Neurogenesis/*drug effects MH - Neuropeptides/metabolism MH - Obesity/etiology/metabolism MH - Pancreas/drug effects/metabolism/pathology OTO - NOTNLM OT - Cognition OT - Glucagon-like peptide-1 OT - Hippocampus OT - Oxyntomodulin OT - Oxyntomodulin analogues EDAT- 2015/06/07 06:00 MHDA- 2016/05/18 06:00 CRDT- 2015/06/07 06:00 PHST- 2015/03/30 00:00 [received] PHST- 2015/05/26 00:00 [revised] PHST- 2015/05/29 00:00 [accepted] PHST- 2015/06/07 06:00 [entrez] PHST- 2015/06/07 06:00 [pubmed] PHST- 2016/05/18 06:00 [medline] AID - S0303-7207(15)00306-8 [pii] AID - 10.1016/j.mce.2015.05.035 [doi] PST - ppublish SO - Mol Cell Endocrinol. 2015 Sep 5;412:95-103. doi: 10.1016/j.mce.2015.05.035. Epub 2015 Jun 3. PMID- 26037109 OWN - NLM STAT- MEDLINE DCOM- 20150925 LR - 20220410 IS - 1096-0953 (Electronic) IS - 0013-9351 (Linking) VI - 140 DP - 2015 Jul TI - Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease. PG - 579-92 LID - S0013-9351(15)00158-9 [pii] LID - 10.1016/j.envres.2015.05.012 [doi] AB - Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1+/-3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Calderon-Garciduenas, Lilian AU - Calderon-Garciduenas L AD - The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT 59812, USA; Hospital Central Militar, Mexico City 11649, Mexico. Electronic address: lilian.calderon-garciduenas@umontana.edu. FAU - Franco-Lira, Maricela AU - Franco-Lira M AD - Hospital Central Militar, Mexico City 11649, Mexico. FAU - D'Angiulli, Amedeo AU - D'Angiulli A AD - Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada K1S 5B6. FAU - Rodriguez-Diaz, Joel AU - Rodriguez-Diaz J AD - Escuela de Ciencias de la Salud, Universidad del Valle de Mexico, Saltillo, Coahuila 25204, Mexico. FAU - Blaurock-Busch, Eleonore AU - Blaurock-Busch E AD - Clinical and Environmental Laboratory Micro Trace Minerals (MTM), 91217 Hersbruck, Germany. FAU - Busch, Yvette AU - Busch Y AD - Clinical and Environmental Laboratory Micro Trace Minerals (MTM), 91217 Hersbruck, Germany. FAU - Chao, Chih-kai AU - Chao CK AD - The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT 59812, USA. FAU - Thompson, Charles AU - Thompson C AD - The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT 59812, USA. FAU - Mukherjee, Partha S AU - Mukherjee PS AD - Mathematics Department, Boise State University, Boise, Idaho, USA. FAU - Torres-Jardon, Ricardo AU - Torres-Jardon R AD - Centro de Ciencias de la Atmosfera, Universidad Nacional Autonoma de Mexico, 04510, Mexico. FAU - Perry, George AU - Perry G AD - College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA. LA - eng GR - G12-MD007591/MD/NIMHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150601 PL - Netherlands TA - Environ Res JT - Environmental research JID - 0147621 RN - 0 (Endothelin-1) RN - 0 (Hormones) RN - 0 (Leptin) RN - 0 (Particulate Matter) SB - IM MH - Adolescent MH - Alzheimer Disease/*physiopathology MH - Body Weight MH - Case-Control Studies MH - Child MH - Cohort Studies MH - Endothelin-1/*blood MH - Hormones/*physiology MH - Humans MH - Leptin/*blood MH - Mexico MH - Obesity/*physiopathology MH - Particulate Matter/*toxicity MH - Vitamin D Deficiency/*chemically induced OTO - NOTNLM OT - APOE OT - Alzheimer OT - Children OT - Fructose OT - Leptin OT - Mexico City OT - Obesity OT - PM(2.5) Air pollution OT - Vitamin D EDAT- 2015/06/04 06:00 MHDA- 2015/09/26 06:00 CRDT- 2015/06/04 06:00 PHST- 2015/03/31 00:00 [received] PHST- 2015/05/07 00:00 [revised] PHST- 2015/05/12 00:00 [accepted] PHST- 2015/06/04 06:00 [entrez] PHST- 2015/06/04 06:00 [pubmed] PHST- 2015/09/26 06:00 [medline] AID - S0013-9351(15)00158-9 [pii] AID - 10.1016/j.envres.2015.05.012 [doi] PST - ppublish SO - Environ Res. 2015 Jul;140:579-92. doi: 10.1016/j.envres.2015.05.012. Epub 2015 Jun 1. PMID- 25994073 OWN - NLM STAT- MEDLINE DCOM- 20160413 LR - 20181113 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 58 IP - 8 DP - 2015 Aug TI - Incretin-based therapies: where will we be 50 years from now? PG - 1745-50 LID - 10.1007/s00125-015-3608-6 [doi] AB - The development of incretin-based therapies (glucagon-like peptide 1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has changed the landscape of type 2 diabetes management over the past decade. Current developments include longer-acting GLP-1 receptor agonists, fixed-ratio combinations of GLP-1 analogues and basal insulin, as well as implantable osmotic minipumps for long-term delivery of GLP-1 receptor agonists. In longer terms, oral or inhaled GLP-1 analogues may become a reality. In addition, oral enhancers of GLP-1 secretion (e.g. via G-protein-coupled receptors, nuclear farnesoid-receptor X and the G-protein-coupled bile acid-activated receptor [TGR5]) are currently being explored in experimental studies. Combination of GLP-1 with other gut hormones (e.g. peptide YY, glucagon, gastrin, glucose-dependent insulinotropic polypeptide [GIP], secretin, cholecystokinin, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide) may enhance the glucose- and weight-lowering effect of GLP-1 alone, and dual or triple hormone receptor agonists may even exploit the properties of different peptides with just one molecule. There is also an increasing interest in employing incretin-based therapies in other areas, such as type 1 diabetes, impaired glucose metabolism, obesity, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), psoriasis or even neurodegeneration. Thus, incretin-based therapies may continue to broaden the therapeutic spectrum for type 2 diabetes and for various other indications in the coming years. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). FAU - Meier, Juris J AU - Meier JJ AD - Division of Diabetes and GI Endocrinology, University Hospital St Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany, juris.meier@rub.de. FAU - Nauck, Michael A AU - Nauck MA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150521 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Diabetes Mellitus, Type 2/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Glucagon-Like Peptide 1/*agonists MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Incretins/*therapeutic use EDAT- 2015/05/23 06:00 MHDA- 2016/04/14 06:00 CRDT- 2015/05/22 06:00 PHST- 2015/02/04 00:00 [received] PHST- 2015/03/17 00:00 [accepted] PHST- 2015/05/22 06:00 [entrez] PHST- 2015/05/23 06:00 [pubmed] PHST- 2016/04/14 06:00 [medline] AID - 10.1007/s00125-015-3608-6 [doi] PST - ppublish SO - Diabetologia. 2015 Aug;58(8):1745-50. doi: 10.1007/s00125-015-3608-6. Epub 2015 May 21. PMID- 25987199 OWN - NLM STAT- MEDLINE DCOM- 20160329 LR - 20250103 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 300 DP - 2015 Aug 6 TI - Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro. PG - 75-84 LID - S0306-4522(15)00455-8 [pii] LID - 10.1016/j.neuroscience.2015.05.023 [doi] AB - Our previous study has proved that glucagon-like peptide-1 (GLP-1), which is developed to treat type 2 diabetes, has a significant effect on neuroprotection against advanced glycation end product (AGE)-induced neuronal insult in vitro models of diabetes-related Alzheimer's disease (AD). However, the molecular mechanisms remain to be elucidated and it is not clear whether GLP-1 receptor mediates the down-regulation effects on AGE-induced AD-like changes in vivo. This study aims to explore the effect and mechanisms of GLP-1 receptor agonists (GLP-1RA) against the AGE-dependent signaling pathway both in vitro and in vivo. In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1mug/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3beta (GSK-3beta) to reverse tau hyperphosphorylation directly. Collectively, our results suggest that GLP-1RA protects neurons against AGE-induced tau hyperphosphorylation via regulating GSK-3beta and PGC-1alpha two cooperative signaling pathways. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - An, F-M AU - An FM AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. FAU - Chen, S AU - Chen S AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. FAU - Xu, Z AU - Xu Z AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. FAU - Yin, L AU - Yin L AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. FAU - Wang, Y AU - Wang Y AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. FAU - Liu, A-R AU - Liu AR AD - Medical School, Southeast University, Nanjing 210009, PR China. FAU - Yao, W-B AU - Yao WB AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: wbyao@cpu.edu.cn. FAU - Gao, X-D AU - Gao XD AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xdgao@cpu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150515 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Glp1r protein, mouse) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glycation End Products, Advanced) RN - 0 (Mapt protein, mouse) RN - 0 (Mapt protein, rat) RN - 0 (Neuroprotective Agents) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Ppargc1a protein, rat) RN - 0 (Transcription Factors) RN - 0 (tau Proteins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, mouse) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - 0 (Glucagon-Like Peptide-1 Receptor Agonists) SB - IM MH - Animals MH - Glucagon-Like Peptide 1/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism MH - Glycation End Products, Advanced/toxicity MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Male MH - Membrane Potential, Mitochondrial/physiology MH - Mice, Inbred ICR MH - Mitochondria/*drug effects/pathology/physiology MH - Neurons/drug effects/pathology/physiology MH - Neuroprotective Agents/*pharmacology MH - Organelle Biogenesis MH - PC12 Cells MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Phosphorylation/drug effects/physiology MH - Random Allocation MH - Rats MH - Transcription Factors/metabolism MH - tau Proteins/*metabolism MH - *Glucagon-Like Peptide-1 Receptor Agonists OTO - NOTNLM OT - Mitochondrial biogenesis OT - advanced glycation end products OT - glucagon-like peptide-1 OT - reactive oxygen species OT - tau pathology EDAT- 2015/05/20 06:00 MHDA- 2016/03/30 06:00 CRDT- 2015/05/20 06:00 PHST- 2015/04/10 00:00 [received] PHST- 2015/05/07 00:00 [revised] PHST- 2015/05/08 00:00 [accepted] PHST- 2015/05/20 06:00 [entrez] PHST- 2015/05/20 06:00 [pubmed] PHST- 2016/03/30 06:00 [medline] AID - S0306-4522(15)00455-8 [pii] AID - 10.1016/j.neuroscience.2015.05.023 [doi] PST - ppublish SO - Neuroscience. 2015 Aug 6;300:75-84. doi: 10.1016/j.neuroscience.2015.05.023. Epub 2015 May 15. PMID- 25903129 OWN - NLM STAT- MEDLINE DCOM- 20150824 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 23 DP - 2015 Jun 5 TI - Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling. PG - 14302-13 LID - 10.1074/jbc.M115.655662 [doi] AB - Glucagon-like peptide-1 (GLP-1) analogs are approved for treatment of type 2 diabetes and are in clinical trials for disorders including neurodegenerative diseases. GLP-1 receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1. Other than food intake, little is known about factors regulating GLP-1 secretion. Given a normally basal circulating level of GLP-1, knowledge of mechanisms regulating GLP-1R signaling, which has diverse functions in extrapancreatic tissues, remains elusive. In this study, we found that the potency of GLP-1, not exendin 4, is specifically enhanced by the endocannabinoid-like lipids oleoylethanolamide (OEA) and 2-oleoylglycerol but not by stearoylethanolamide (SEA) or palmitoylethanolamide. 9.2 muM OEA enhances the potency of GLP-1 in stimulating cAMP production by 10-fold but does not affect its receptor binding affinity. OEA and 2-oleoylglycerol, but not SEA, bind to GLP-1 in a dose-dependent and saturable manner. OEA but not SEA promoted GLP-1(7-36) amide to trypsin inactivation in a dose-dependent and saturable manner. Susceptibility of GLP-1(7-36) amide to trypsin inactivation is increased 40-fold upon binding to OEA but not to SEA. Our findings indicate that OEA binds to GLP-1(7-36) amide and enhances the potency that may result from a conformational change of the peptide. In conclusion, modulating potency of GLP-1 by physiologically regulated endocannabinoid-like lipids allows GLP-1R signaling to be regulated spatiotemporally at a constant basal GLP-1 level. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Cheng, Yu-Hong AU - Cheng YH AD - From the Genomic Research Center and. FAU - Ho, Mei-Shang AU - Ho MS AD - Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. FAU - Huang, Wei-Ting AU - Huang WT AD - From the Genomic Research Center and. FAU - Chou, Ying-Ting AU - Chou YT AD - Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. FAU - King, Klim AU - King K AD - From the Genomic Research Center and bmkxk@ibms.sinica.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150422 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Endocannabinoids) RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glycerides) RN - 0 (Oleic Acids) RN - 0 (Receptors, Glucagon) RN - 1HI5J9N8E6 (oleoylethanolamide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9A2389K694 (2-oleoylglycerol) RN - E0399OZS9N (Cyclic AMP) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cyclic AMP/metabolism MH - Endocannabinoids MH - Glucagon-Like Peptide 1/*metabolism MH - Glucagon-Like Peptide-1 Receptor MH - Glycerides/*metabolism MH - Humans MH - Oleic Acids/*metabolism MH - Rats MH - Receptors, Glucagon/*metabolism MH - *Signal Transduction PMC - PMC4505500 OTO - NOTNLM OT - G protein-coupled receptor (GPCR) OT - bioluminescence resonance energy transfer (BRET) OT - endocannabinoid OT - lipid OT - signaling EDAT- 2015/04/24 06:00 MHDA- 2015/08/25 06:00 PMCR- 2016/06/05 CRDT- 2015/04/24 06:00 PHST- 2015/03/30 00:00 [received] PHST- 2015/04/24 06:00 [entrez] PHST- 2015/04/24 06:00 [pubmed] PHST- 2015/08/25 06:00 [medline] PHST- 2016/06/05 00:00 [pmc-release] AID - S0021-9258(19)79493-9 [pii] AID - M115.655662 [pii] AID - 10.1074/jbc.M115.655662 [doi] PST - ppublish SO - J Biol Chem. 2015 Jun 5;290(23):14302-13. doi: 10.1074/jbc.M115.655662. Epub 2015 Apr 22. PMID- 25879319 OWN - NLM STAT- MEDLINE DCOM- 20151201 LR - 20150724 IS - 0334-1763 (Print) IS - 0334-1763 (Linking) VI - 26 IP - 4 DP - 2015 TI - Neuroprotective effects of geniposide on Alzheimer's disease pathology. PG - 371-83 LID - 10.1515/revneuro-2015-0005 [doi] AB - A growing body of evidence has linked two of the most common aged-related diseases: type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon-like peptide-1 (GLP-1R), which is a newer drug class to treat T2DM, geniposide shows clear effects in inhibiting pathological processes underlying AD, such as promoting neurite outgrowth. In the present article, we review the possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting tau phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD. FAU - Liu, WeiZhen AU - Liu W FAU - Li, Guanglai AU - Li G FAU - Holscher, Christian AU - Holscher C FAU - Li, Lin AU - Li L LA - eng PT - Journal Article PT - Review PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Iridoids) RN - 0 (Neuroprotective Agents) RN - 145295QLXY (geniposide) SB - IM MH - Alzheimer Disease/complications/pathology/*prevention & control MH - Animals MH - Diabetes Mellitus, Type 2/complications/drug therapy/pathology MH - Humans MH - Iridoids/pharmacology/*therapeutic use MH - Neuroprotective Agents/pharmacology/*therapeutic use EDAT- 2015/04/17 06:00 MHDA- 2015/12/15 06:00 CRDT- 2015/04/17 06:00 PHST- 2015/02/01 00:00 [received] PHST- 2015/02/25 00:00 [accepted] PHST- 2015/04/17 06:00 [entrez] PHST- 2015/04/17 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - /j/revneuro.ahead-of-print/revneuro-2015-0005/revneuro-2015-0005.xml [pii] AID - 10.1515/revneuro-2015-0005 [doi] PST - ppublish SO - Rev Neurosci. 2015;26(4):371-83. doi: 10.1515/revneuro-2015-0005. PMID- 25869785 OWN - NLM STAT- MEDLINE DCOM- 20160630 LR - 20181113 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 46 IP - 4 DP - 2015 TI - The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. PG - 877-88 LID - 10.3233/JAD-143090 [doi] AB - Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-beta (Abeta) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 mug/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-beta plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD. FAU - Hansen, Henrik H AU - Hansen HH AD - Gubra, Hoersholm, Denmark. FAU - Fabricius, Katrine AU - Fabricius K AD - Gubra, Hoersholm, Denmark. FAU - Barkholt, Pernille AU - Barkholt P AD - Gubra, Hoersholm, Denmark. FAU - Niehoff, Michael L AU - Niehoff ML AD - St. Louis University, Division of Geriatrics, St. Louis, MO, USA. FAU - Morley, John E AU - Morley JE AD - St. Louis University, Division of Geriatrics, St. Louis, MO, USA. AD - St. Louis University School of Medicine, Division of Endocrinology, St. Louis University, St. Louis, MO, USA. FAU - Jelsing, Jacob AU - Jelsing J AD - Gubra, Hoersholm, Denmark. FAU - Pyke, Charles AU - Pyke C AD - Diabetes Research, Novo Nordisk A/S, Maaloev, Denmark. FAU - Knudsen, Lotte Bjerre AU - Knudsen LB AD - Diabetes Research, Novo Nordisk A/S, Maaloev, Denmark. FAU - Farr, Susan A AU - Farr SA AD - St. Louis University, Division of Geriatrics, St. Louis, MO, USA. AD - Research and Development, Veterans Affairs Medical Center, St. Louis, MO, USA. FAU - Vrang, Niels AU - Vrang N AD - Gubra, Hoersholm, Denmark. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) SB - IM MH - Age Factors MH - Aging/genetics MH - Alzheimer Disease/complications/genetics/*pathology MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Avoidance Learning/drug effects MH - Body Weight/drug effects MH - Cell Count MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Eating/*drug effects MH - Hippocampus/drug effects/metabolism/*pathology MH - Hypoglycemic Agents/blood/pharmacology/*therapeutic use MH - Liraglutide/blood/pharmacology/*therapeutic use MH - Maze Learning/drug effects MH - *Memory Disorders/drug therapy/etiology/pathology MH - Mice MH - Mice, Inbred Strains PMC - PMC4878312 OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 receptor agonist OT - SAMP8 mouse OT - hippocampus OT - liraglutide OT - memory function OT - neuroprotection OT - stereology EDAT- 2015/04/15 06:00 MHDA- 2016/07/01 06:00 PMCR- 2015/06/26 CRDT- 2015/04/15 06:00 PHST- 2015/04/15 06:00 [entrez] PHST- 2015/04/15 06:00 [pubmed] PHST- 2016/07/01 06:00 [medline] PHST- 2015/06/26 00:00 [pmc-release] AID - A575J407143KL3M2 [pii] AID - JAD143090 [pii] AID - 10.3233/JAD-143090 [doi] PST - ppublish SO - J Alzheimers Dis. 2015;46(4):877-88. doi: 10.3233/JAD-143090. PMID- 25828597 OWN - NLM STAT- MEDLINE DCOM- 20160518 LR - 20150822 IS - 1095-8304 (Electronic) IS - 0195-6663 (Linking) VI - 93 DP - 2015 Oct TI - Artificial sweeteners are not the answer to childhood obesity. PG - 85-90 LID - S0195-6663(15)00129-4 [pii] LID - 10.1016/j.appet.2015.03.027 [doi] AB - While no single factor is responsible for the recent, dramatic increases in overweight and obesity, a scientific consensus has emerged suggesting that consumption of sugar-sweetened products, especially beverages, is casually linked to increases in risk of chronic, debilitating diseases including type 2 diabetes, cardiovascular disease, hypertension and stroke. One approach that might be beneficial would be to replace sugar-sweetened items with products manufactured with artificial sweeteners that provide sweet tastes but with fewer calories. Unfortunately, evidence now indicates that artificial sweeteners are also associated with increased risk of the same chronic diseases linked to sugar consumption. Several biologically plausible mechanisms may explain these counterintuitive negative associations. For example, artificial sweeteners can interfere with basic learning processes that serve to anticipate the normal consequences of consuming sugars, leading to overeating, diminished release of hormones such as GLP-1, and impaired blood glucose regulation. In addition, artificial sweeteners can alter gut microbiota in rodent models and humans, which can also contribute to impaired glucose regulation. Use of artificial sweeteners may also be particularly problematic in children since exposure to hyper-sweetened foods and beverages at young ages may have effects on sweet preferences that persist into adulthood. Taken as a whole, current evidence suggests that a focus on reducing sweetener intake, whether the sweeteners are caloric or non-caloric, remains a better strategy for combating overweight and obesity than use of artificial sweeteners. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Swithers, Susan E AU - Swithers SE AD - Department of Psychological Sciences, Purdue University, 703 Third Street, West Lafayette, IN 47907, USA. Electronic address: swithers@purdue.edu. LA - eng PT - Journal Article DEP - 20150328 PL - England TA - Appetite JT - Appetite JID - 8006808 RN - 0 (Blood Glucose) RN - 0 (Sweetening Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Blood Glucose/drug effects MH - Child MH - Cognition MH - Food Preferences/physiology/*psychology MH - Gastrointestinal Microbiome/drug effects MH - Glucagon-Like Peptide 1/drug effects MH - Humans MH - Hyperphagia MH - Learning MH - Pediatric Obesity/diet therapy/microbiology/*psychology MH - Risk Factors MH - Sweetening Agents/*adverse effects OTO - NOTNLM OT - Learning OT - Metabolic dysregulation OT - Obesity OT - Sweeteners EDAT- 2015/04/02 06:00 MHDA- 2016/05/19 06:00 CRDT- 2015/04/02 06:00 PHST- 2015/01/03 00:00 [received] PHST- 2015/02/23 00:00 [revised] PHST- 2015/03/24 00:00 [accepted] PHST- 2015/04/02 06:00 [entrez] PHST- 2015/04/02 06:00 [pubmed] PHST- 2016/05/19 06:00 [medline] AID - S0195-6663(15)00129-4 [pii] AID - 10.1016/j.appet.2015.03.027 [doi] PST - ppublish SO - Appetite. 2015 Oct;93:85-90. doi: 10.1016/j.appet.2015.03.027. Epub 2015 Mar 28. PMID- 25792818 OWN - NLM STAT- MEDLINE DCOM- 20151127 LR - 20220331 IS - 1178-1998 (Electronic) IS - 1176-9092 (Print) IS - 1176-9092 (Linking) VI - 10 DP - 2015 TI - Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. PG - 549-60 LID - 10.2147/CIA.S74042 [doi] AB - The aim of this paper is to provide a comprehensive review of the epidemiological evidence linking type 2 diabetes mellitus and its related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, to Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link; however, our focus is on insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-beta protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as "type 3 diabetes". Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. We mainly discuss the clinical trials on insulin, metformin, thiazolidinediones, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors in the treatment of AD. Although the results of these trials seem to be contradictory, this approach is also full of promise. It is worth mentioning that the therapeutic effects of these drugs are influenced by the apolipoprotein E (APOE)-epsilon4 genotype. Patients without the APOE-epsilon4 allele showed better treatment effects than those with this allele. FAU - Li, Xiaohua AU - Li X AD - Dalian Medical University, Dalian, People's Republic of China. FAU - Song, Dalin AU - Song D AD - Department of Geriatrics, Qingdao Municipal Hospital, Qingdao, People's Republic of China. FAU - Leng, Sean X AU - Leng SX AD - Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. LA - eng PT - Journal Article PT - Review DEP - 20150310 PL - New Zealand TA - Clin Interv Aging JT - Clinical interventions in aging JID - 101273480 RN - 0 (Hypoglycemic Agents) SB - IM CIN - Clin Interv Aging. 2015 Nov 03;10:1789-91. doi: 10.2147/CIA.S93925. PMID: 26622173 MH - Aged MH - Alzheimer Disease/*etiology/prevention & control MH - Diabetes Mellitus, Type 2/*complications/drug therapy MH - Humans MH - Hyperinsulinism/complications MH - Hypoglycemic Agents/therapeutic use MH - Insulin Resistance MH - Metabolic Syndrome/complications MH - Obesity/complications PMC - PMC4360697 OTO - NOTNLM OT - Alzheimer's disease OT - insulin OT - type 2 diabetes mellitus EDAT- 2015/03/21 06:00 MHDA- 2015/12/15 06:00 PMCR- 2015/03/10 CRDT- 2015/03/21 06:00 PHST- 2015/03/21 06:00 [entrez] PHST- 2015/03/21 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2015/03/10 00:00 [pmc-release] AID - cia-10-549 [pii] AID - 10.2147/CIA.S74042 [doi] PST - epublish SO - Clin Interv Aging. 2015 Mar 10;10:549-60. doi: 10.2147/CIA.S74042. eCollection 2015. PMID- 25723507 OWN - NLM STAT- MEDLINE DCOM- 20160113 LR - 20190823 IS - 1875-533X (Electronic) IS - 0929-8673 (Linking) VI - 22 IP - 13 DP - 2015 TI - Mechanisms of neurodegeration in type 2 diabetes and the neuroprotective potential of dipeptidyl peptidase 4 inhibitors. PG - 1573-81 AB - Prospective epidemiological studies suggest that type 2 diabetes is a risk factor for neurodegenerative pathologies such as Alzheimer disease, vascular dementia, and Parkinson disease. Drugs that act as incretin receptor agonists or inhibit the proteolytic degradation of incretins (dipeptidyl peptidase 4 inhibitors) have been approved since 2005 for use in diabetes treatment. Dipeptidyl peptidase 4 (DPP4) cleaves N-terminal dipeptides from polypeptides when the second residue is proline, hydroxyproline, dehydroproline or alanine. The inhibition of DPP4 hydrolytic activities extends the halflife of these peptides by preventing their degradation. Several peptides have been identified as DPP4 substrates, including neuropeptides, chemokines, and the incretin hormones; hence the pleomorphic effects of DPP4 inhibition. Recently, the neuroprotective properties of these drugs have been evaluated in cell cultures and animal models, not yet in human trials. Although mechanisms distinct from glycaemic control alone have been claimed to account for protection against neuronal degeneration, the precise cellular mechanism by which DPP4 inhibitors exert their neuroprotective effects remain unknown. The present review is focused on the candidate pathways that could be involved in mediating DPP4 inhibitors-mediated protection against neuronal degeneration. FAU - Matteucci, E AU - Matteucci E AD - Department of Clinical and Experimental Medicine, University of Pisa, Italy. matteucci@med.unipi.it. FAU - Giampietro, O AU - Giampietro O LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Med Chem JT - Current medicinal chemistry JID - 9440157 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Neuroprotective Agents) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/*complications/drug therapy MH - Dipeptidyl Peptidase 4/*metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/*pharmacology/therapeutic use MH - Humans MH - Neurodegenerative Diseases/*complications/*prevention & control MH - Neuroprotective Agents/*pharmacology/therapeutic use EDAT- 2015/02/28 06:00 MHDA- 2016/01/14 06:00 CRDT- 2015/02/28 06:00 PHST- 2014/07/04 00:00 [received] PHST- 2015/01/17 00:00 [revised] PHST- 2015/02/20 00:00 [accepted] PHST- 2015/02/28 06:00 [entrez] PHST- 2015/02/28 06:00 [pubmed] PHST- 2016/01/14 06:00 [medline] AID - CMC-EPUB-65506 [pii] AID - 10.2174/0929867322666150227153308 [doi] PST - ppublish SO - Curr Med Chem. 2015;22(13):1573-81. doi: 10.2174/0929867322666150227153308. PMID- 25695417 OWN - NLM STAT- MEDLINE DCOM- 20160805 LR - 20160822 IS - 0888-5109 (Print) IS - 0888-5109 (Linking) VI - 30 IP - 2 DP - 2015 Feb TI - Alzheimer's disease and type 2 diabetes: what is the connection? PG - 112-5 LID - 10.4140/TCP.n.2015.112 [doi] AB - Alzheimer's disease (AD) is a progressive neurodegenerative condition primarily affecting individuals 65 years of age and older. There are few therapies available, and the disease is eventually fatal. Although the molecular mechanisms responsible for the development of AD remain unknown, a strong correlation between insulin dysfunction in type 2 diabetes mellitus and AD has recently been established. This has led to innovative research in the prevention and treatment of AD. Currently the most promising antidiabetic treatment options for AD are intranasal insulin and liraglutide, both of which are being investigated in ongoing clinical trials. Intranasal insulin showed promise in a pilot human trial, and while initial results appear positive, the clinical significance is unknown. Whereas current treatments only slow disease progression for a relatively short time, these new therapies may be able to reverse damage that has already occurred and potentially restore neurological function. FAU - Greene, Angela AU - Greene A AD - MCPHS University School of Pharmacy-Worcester/Manchester, Worcester, Massachusetts, USA. FAU - Ng, Jaclynn AU - Ng J FAU - Shepherd, Luz AU - Shepherd L FAU - Carey, Katherine AU - Carey K LA - eng PT - Journal Article PL - United States TA - Consult Pharm JT - The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists JID - 9013983 RN - 0 (Insulin) RN - 839I73S42A (Liraglutide) SB - IM EIN - Consult Pharm. 2015 May;30(5):250 MH - Administration, Intranasal MH - Aged MH - Alzheimer Disease/drug therapy/*etiology MH - Diabetes Mellitus, Type 2/*complications MH - Humans MH - Insulin/administration & dosage MH - Liraglutide/therapeutic use EDAT- 2015/02/20 06:00 MHDA- 2016/08/06 06:00 CRDT- 2015/02/20 06:00 PHST- 2015/02/20 06:00 [entrez] PHST- 2015/02/20 06:00 [pubmed] PHST- 2016/08/06 06:00 [medline] AID - 10.4140/TCP.n.2015.112 [doi] PST - ppublish SO - Consult Pharm. 2015 Feb;30(2):112-5. doi: 10.4140/TCP.n.2015.112. PMID- 25660451 OWN - NLM STAT- MEDLINE DCOM- 20150501 LR - 20150302 IS - 1090-2104 (Electronic) IS - 0006-291X (Linking) VI - 458 IP - 2 DP - 2015 Mar 6 TI - Glucagon-like peptide-1 protects the murine hippocampus against stressors via Akt and ERK1/2 signaling. PG - 274-9 LID - S0006-291X(15)00137-0 [pii] LID - 10.1016/j.bbrc.2015.01.098 [doi] AB - Alzheimer's disease (AD) is a common neurodegenerative disease characterized by cognitive dysfunction and neuronal cell death in the hippocampus and cerebral cortex. Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptides. GLP-1-associated medicines are widely used as treatments for type 2 diabetes. In addition, they have been shown to ameliorate pathology in AD mouse models. Here, we investigated the effects of GLP-1 on different stressors in murine hippocampal HT22 cells. GLP-1 (7-36) prevented H2O2-, l-glutamate-, tunicamycin-, thapsigargin-, and amyloid beta1-42-induced neuronal cell death in a concentration-dependent manner. GLP-1 (7-36) treatment for 1 h significantly increased phosphorylated Akt and extracellular signal-regulated kinase 1 and 2 (ERK1/2) when compared with vehicle-treatment. These results suggest that GLP-1 (7-36) is protective against these stressors via activation of survival signaling molecules, such as Akt and ERK1/2 in HT22 cells. In conclusion, GLP-1 and activators of the GLP-1 receptor might be useful targets for the treatment of AD. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Yoshino, Yuta AU - Yoshino Y AD - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. FAU - Ishisaka, Mitsue AU - Ishisaka M AD - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. FAU - Tsujii, Saori AU - Tsujii S AD - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. FAU - Shimazawa, Masamitsu AU - Shimazawa M AD - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. FAU - Hara, Hideaki AU - Hara H AD - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Electronic address: hidehara@gifu-pu.ac.jp. LA - eng PT - Journal Article DEP - 20150207 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-42)) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Amyloid beta-Peptides/*administration & dosage MH - Animals MH - Apoptosis/drug effects/physiology MH - Cell Line MH - Cell Survival/drug effects/physiology MH - Drug Interactions MH - Glucagon-Like Peptide 1/*administration & dosage MH - Hippocampus/drug effects/*physiology MH - MAP Kinase Signaling System/*physiology MH - Mice MH - Neuroprotective Agents/administration & dosage MH - Oxidative Stress/drug effects/*physiology MH - Peptide Fragments/*administration & dosage MH - Proto-Oncogene Proteins c-akt/*metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid beta(1)(-)(42) OT - Endoplasmic reticulum stress OT - Glucagon-like peptide-1 OT - HT22 OT - Oxidative stress EDAT- 2015/02/11 06:00 MHDA- 2015/05/02 06:00 CRDT- 2015/02/10 06:00 PHST- 2015/01/13 00:00 [received] PHST- 2015/01/21 00:00 [accepted] PHST- 2015/02/10 06:00 [entrez] PHST- 2015/02/11 06:00 [pubmed] PHST- 2015/05/02 06:00 [medline] AID - S0006-291X(15)00137-0 [pii] AID - 10.1016/j.bbrc.2015.01.098 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2015 Mar 6;458(2):274-9. doi: 10.1016/j.bbrc.2015.01.098. Epub 2015 Feb 7. PMID- 25624414 OWN - NLM STAT- MEDLINE DCOM- 20160119 LR - 20150327 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 45 IP - 3 DP - 2015 TI - Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity. PG - 823-35 LID - 10.3233/JAD-143150 [doi] AB - Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3beta (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation. FAU - Spolcova, Andrea AU - Spolcova A AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic INSERM UMR837, Lille, France, Jean Pierre Aubert Research Centre, Faculte de Medecine-Pole Recherche, Institut de Medecine Predictive et de Recherche Therapeutique, Universite Droit et Sante de Lille, CHU-Lille, Lille, France. FAU - Mikulaskova, Barbora AU - Mikulaskova B AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Holubova, Martina AU - Holubova M AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Nagelova, Veronika AU - Nagelova V AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Pirnik, Zdenko AU - Pirnik Z AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic Laboratory of Functional Neuromorphology, Institute of Experimental Endocrinology, SAS, Bratislava, Slovak Republic Department of Human and Clinical Pharmacology, University of Veterinary Medicine, Kosice, Slovak Republic. FAU - Zemenova, Jana AU - Zemenova J AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic Institute of Chemical Technology, Department of Analytical Chemistry, Prague, Czech Republic. FAU - Haluzik, Martin AU - Haluzik M AD - Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. FAU - Zelezna, Blanka AU - Zelezna B AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. FAU - Galas, Marie-Christine AU - Galas MC AD - INSERM UMR837, Lille, France, Jean Pierre Aubert Research Centre, Faculte de Medecine-Pole Recherche, Institut de Medecine Predictive et de Recherche Therapeutique, Universite Droit et Sante de Lille, CHU-Lille, Lille, France. FAU - Maletinska, Lenka AU - Maletinska L AD - Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Flavoring Agents) RN - 0 (Insulins) RN - 0 (Lipopeptides) RN - 0 (Prolactin-Releasing Hormone) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (tau Proteins) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - W81N5U6R6U (Sodium Glutamate) SB - IM MH - Analysis of Variance MH - Animals MH - Body Weight/drug effects MH - Disease Models, Animal MH - Flavoring Agents/*toxicity MH - Glucagon-Like Peptide 1/genetics/pharmacology MH - Glucose Tolerance Test MH - Hippocampus/*drug effects/metabolism MH - Insulins/*metabolism MH - Lipopeptides/*metabolism/therapeutic use MH - Male MH - Mice MH - *Obesity/chemically induced/drug therapy/pathology MH - Phosphorylation/drug effects MH - Prolactin-Releasing Hormone/drug effects/pharmacology MH - Receptors, G-Protein-Coupled/metabolism MH - Signal Transduction/*drug effects MH - Sodium Glutamate/*toxicity MH - Time Factors MH - tau Proteins/*metabolism OTO - NOTNLM OT - Alzheimer's disease OT - insulin signaling OT - liraglutide OT - monosodium glutamate-obese mice OT - obesity OT - pre-diabetes OT - prolactin-releasing peptide OT - tau phosphorylation EDAT- 2015/01/28 06:00 MHDA- 2016/01/20 06:00 CRDT- 2015/01/28 06:00 PHST- 2015/01/28 06:00 [entrez] PHST- 2015/01/28 06:00 [pubmed] PHST- 2016/01/20 06:00 [medline] AID - D0843686074J7946 [pii] AID - 10.3233/JAD-143150 [doi] PST - ppublish SO - J Alzheimers Dis. 2015;45(3):823-35. doi: 10.3233/JAD-143150. PMID- 25558231 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20150105 LR - 20200929 IS - 1673-5374 (Print) IS - 1876-7958 (Electronic) IS - 1673-5374 (Linking) VI - 9 IP - 21 DP - 2014 Nov 1 TI - New drug treatments show neuroprotective effects in Alzheimer's and Parkinson's diseases. PG - 1870-3 LID - 10.4103/1673-5374.145342 [doi] AB - Type 2 diabetes is a risk factor for Alzheimer's disease and Parkinson's disease. Insulin signaling in the brains of people with Alzheimer's disease or Parkinson's disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alzheimer's disease and Parkinson's disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer's disease and Parkinson's disease. On the basis of these promising findings, several clinical trials are ongoing with the first encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer's disease and Parkinson's disease that are currently unavailable. FAU - Holscher, Christian AU - Holscher C AD - Neuroscience research group, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article PT - Review PL - India TA - Neural Regen Res JT - Neural regeneration research JID - 101316351 PMC - PMC4281420 OTO - NOTNLM OT - amyloid OT - growth factor OT - memory OT - neurodegeneration OT - neuroprotection OT - neurotrophic factors EDAT- 2015/01/06 06:00 MHDA- 2015/01/06 06:01 PMCR- 2014/11/01 CRDT- 2015/01/06 06:00 PHST- 2014/10/17 00:00 [accepted] PHST- 2015/01/06 06:00 [entrez] PHST- 2015/01/06 06:00 [pubmed] PHST- 2015/01/06 06:01 [medline] PHST- 2014/11/01 00:00 [pmc-release] AID - NRR-9-1870 [pii] AID - 10.4103/1673-5374.145342 [doi] PST - ppublish SO - Neural Regen Res. 2014 Nov 1;9(21):1870-3. doi: 10.4103/1673-5374.145342. PMID- 30289042 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1744-8417 (Electronic) IS - 1744-6651 (Linking) VI - 10 IP - 1 DP - 2015 Jan TI - The non-glycemic effects of incretin therapies on cardiovascular outcomes, cognitive function and bone health. PG - 101-114 LID - 10.1586/17446651.2015.972370 [doi] AB - The incretin therapies, glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors, have been developed to lower blood glucose levels in patients with Type 2 diabetes. However, in addition to being a treatment strategy to improve metabolic control, incretin therapies have shown effects independent of glycemic control, including the potential to positively impact cardiovascular events, cognitive deficits and bone mineral density. This paper outlines the non-glycemic effects of incretin therapies on cardiovascular disease, cognitive function and bone health. FAU - Hanna, Amir AU - Hanna A AD - a 1 Department of Medicine, University of Toronto, Toronto, ON, Canada. AD - b 2 Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada. FAU - Connelly, Kim A AU - Connelly KA AD - c 3 Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital and Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. FAU - Josse, Robert G AU - Josse RG AD - a 1 Department of Medicine, University of Toronto, Toronto, ON, Canada. AD - b 2 Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada. FAU - McIntyre, Roger S AU - McIntyre RS AD - d 4 Mood Disorder Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada. AD - e 5 Department of Psychiatry and Pharmacology, and Institute of Medical Science, University of Toronto, Toronto, ON, Canada. LA - eng PT - Journal Article DEP - 20141021 PL - England TA - Expert Rev Endocrinol Metab JT - Expert review of endocrinology & metabolism JID - 101278293 OTO - NOTNLM OT - DPP4 inhibitor OT - GLP-1 receptor agonist OT - Incretin OT - bone health OT - cardiovascular outcomes OT - cognitive function OT - dipeptidyl-peptidase-4 OT - glucagon-like peptide-1 OT - glucagon-like peptide-2 OT - glucose-dependent insulinotropic peptide EDAT- 2015/01/01 00:00 MHDA- 2015/01/01 00:01 CRDT- 2018/10/06 06:00 PHST- 2018/10/06 06:00 [entrez] PHST- 2015/01/01 00:00 [pubmed] PHST- 2015/01/01 00:01 [medline] AID - 10.1586/17446651.2015.972370 [doi] PST - ppublish SO - Expert Rev Endocrinol Metab. 2015 Jan;10(1):101-114. doi: 10.1586/17446651.2015.972370. Epub 2014 Oct 21. PMID- 25479064 OWN - NLM STAT- MEDLINE DCOM- 20150825 LR - 20220310 IS - 1708-8267 (Electronic) IS - 1081-5589 (Linking) VI - 63 IP - 2 DP - 2015 Feb TI - Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes. PG - 267-72 LID - 10.1097/JIM.0000000000000129 [doi] AB - BACKGROUND: Impaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D. MATERIALS AND METHODS: Type 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3beta (GSK-3beta) were analyzed with Western blots. RESULTS: The levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3beta in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3beta activity after 4 weeks intervention of EX-4. CONCLUSIONS: These results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D. FAU - Xu, Weijie AU - Xu W AD - From the Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yang, Yan AU - Yang Y FAU - Yuan, Gang AU - Yuan G FAU - Zhu, Wenjun AU - Zhu W FAU - Ma, Delin AU - Ma D FAU - Hu, Shuhong AU - Hu S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Investig Med JT - Journal of investigative medicine : the official publication of the American Federation for Clinical Research JID - 9501229 RN - 0 (Blood Glucose) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Venoms) RN - 0 (tau Proteins) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Alzheimer Disease/blood/*complications/*drug therapy MH - Animals MH - Blood Glucose/metabolism MH - Blotting, Western MH - Diabetes Mellitus, Type 2/blood/*complications/drug therapy MH - Exenatide MH - Glucagon-Like Peptide-1 Receptor MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hippocampus/drug effects/*metabolism/pathology MH - Hyperglycemia/complications/drug therapy MH - Insulin/blood MH - Insulin Resistance MH - Male MH - Peptides/administration & dosage/pharmacology/*therapeutic use MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats, Sprague-Dawley MH - Receptors, Glucagon/*agonists MH - Signal Transduction/drug effects MH - Venoms/administration & dosage/pharmacology/*therapeutic use MH - tau Proteins/*metabolism EDAT- 2014/12/06 06:00 MHDA- 2015/08/26 06:00 CRDT- 2014/12/06 06:00 PHST- 2014/12/06 06:00 [entrez] PHST- 2014/12/06 06:00 [pubmed] PHST- 2015/08/26 06:00 [medline] AID - 10.1097/JIM.0000000000000129 [doi] PST - ppublish SO - J Investig Med. 2015 Feb;63(2):267-72. doi: 10.1097/JIM.0000000000000129. PMID- 25331995 OWN - NLM STAT- MEDLINE DCOM- 20150516 LR - 20260128 IS - 0371-0874 (Print) IS - 0371-0874 (Linking) VI - 66 IP - 5 DP - 2014 Oct 25 TI - Drugs developed for treatment of diabetes show protective effects in Alzheimer's and Parkinson's diseases. PG - 497-510 AB - Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Sciences, Lancaster University, Lancaster LA1 4YQ, UK. c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PT - Review PL - China TA - Sheng Li Xue Bao JT - Sheng li xue bao : [Acta physiologica Sinica] JID - 20730130R RN - 9P1872D4OL (Exenatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Venoms) RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Alzheimer Disease/*drug therapy MH - Animals MH - Diabetes Mellitus, Type 2/*drug therapy MH - Disease Models, Animal MH - Exenatide MH - Glucagon-Like Peptide 1/analogs & derivatives/pharmacology MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Liraglutide MH - Mice MH - Mice, Transgenic MH - Neuroprotective Agents/*pharmacology MH - Parkinson Disease/*drug therapy MH - Peptides/pharmacology MH - Receptors, Glucagon/agonists MH - Venoms/pharmacology MH - Glucagon-Like Peptide-2 Receptor EDAT- 2014/10/22 06:00 MHDA- 2015/05/20 06:00 CRDT- 2014/10/22 06:00 PHST- 2014/10/22 06:00 [entrez] PHST- 2014/10/22 06:00 [pubmed] PHST- 2015/05/20 06:00 [medline] PST - ppublish SO - Sheng Li Xue Bao. 2014 Oct 25;66(5):497-510. PMID- 25107586 OWN - NLM STAT- MEDLINE DCOM- 20150714 LR - 20260128 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 86 DP - 2014 Nov TI - Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease. PG - 241-58 LID - S0028-3908(14)00277-9 [pii] LID - 10.1016/j.neuropharm.2014.07.015 [doi] AB - Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1DeltaE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - McClean, Paula L AU - McClean PL AD - Clinical Translational Research and Innovation Centre, University of Ulster, Derry/Londonderry, BT47 6SB, Northern Ireland, UK. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140808 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amyloid beta-Protein Precursor) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 839I73S42A (Liraglutide) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Presenilin-1) RN - 0 (APP protein, human) RN - 0 (PSEN1 protein, human) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Alzheimer Disease/*drug therapy/pathology/physiopathology MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Animals MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology MH - Hippocampus/drug effects/physiology MH - Liraglutide MH - Long-Term Potentiation/drug effects/physiology MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neuroprotective Agents/*pharmacology MH - Peptides/*pharmacology MH - Plaque, Amyloid/drug therapy/pathology/physiopathology MH - Presenilin-1/genetics/metabolism MH - Random Allocation MH - Recognition, Psychology/drug effects/physiology MH - Synapses/drug effects/pathology/physiology MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - Cognition OT - GLP-1 OT - Growth factor OT - Incretins OT - Inflammation OT - Insulin OT - Long-term potentiation OT - Memory OT - Neurodegeneration OT - Neuroprotection OT - Synapse EDAT- 2014/08/12 06:00 MHDA- 2015/07/15 06:00 CRDT- 2014/08/10 06:00 PHST- 2014/04/14 00:00 [received] PHST- 2014/07/18 00:00 [revised] PHST- 2014/07/23 00:00 [accepted] PHST- 2014/08/10 06:00 [entrez] PHST- 2014/08/12 06:00 [pubmed] PHST- 2015/07/15 06:00 [medline] AID - S0028-3908(14)00277-9 [pii] AID - 10.1016/j.neuropharm.2014.07.015 [doi] PST - ppublish SO - Neuropharmacology. 2014 Nov;86:241-58. doi: 10.1016/j.neuropharm.2014.07.015. Epub 2014 Aug 8. PMID- 25071725 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20140729 LR - 20231110 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 5 DP - 2014 TI - Insulin as a Bridge between Type 2 Diabetes and Alzheimer Disease - How Anti-Diabetics Could be a Solution for Dementia. PG - 110 LID - 10.3389/fendo.2014.00110 [doi] LID - 110 AB - Type 2 diabetes (T2D) and Alzheimer disease (AD) are two major health issues nowadays. T2D is an ever increasing epidemic, affecting millions of elderly people worldwide, with major repercussions in the patients' daily life. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD. T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases. This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. As such, it is not surprising that AD has been considered as the "type 3 diabetes" or a "brain-specific T2D," supporting the idea that a beneficial therapeutic strategy against T2D might be also beneficial against AD. Herewith, we aim to review some of the recent developments on the common features between T2D and AD, namely on insulin signaling and its participation in the regulation of amyloid beta (Abeta) plaque and neurofibrillary tangle formation (the two major neuropathological hallmarks of AD). We also critically analyze the promising field that some anti-T2D drugs may protect against dementia and AD, with a special emphasis on the novel incretin/glucagon-like peptide-1 receptor agonists. FAU - Sebastiao, Ines AU - Sebastiao I AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Department of Life Sciences, University of Coimbra , Coimbra , Portugal ; Institute for Interdisciplinary Research (IIIUC), University of Coimbra , Coimbra , Portugal. FAU - Candeias, Emanuel AU - Candeias E AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Institute for Interdisciplinary Research (IIIUC), University of Coimbra , Coimbra , Portugal. FAU - Santos, Maria S AU - Santos MS AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Department of Life Sciences, University of Coimbra , Coimbra , Portugal ; Institute for Interdisciplinary Research (IIIUC), University of Coimbra , Coimbra , Portugal. FAU - de Oliveira, Catarina R AU - de Oliveira CR AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Institute of Biochemistry, Faculty of Medicine, University of Coimbra , Coimbra , Portugal. FAU - Moreira, Paula I AU - Moreira PI AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Institute of Physiology, Faculty of Medicine, University of Coimbra , Coimbra , Portugal. FAU - Duarte, Ana I AU - Duarte AI AD - Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra , Portugal ; Institute for Interdisciplinary Research (IIIUC), University of Coimbra , Coimbra , Portugal. LA - eng PT - Journal Article PT - Review DEP - 20140708 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 PMC - PMC4086025 OTO - NOTNLM OT - Alzheimer disease OT - anti-type 2 diabetes compounds OT - brain OT - exendin-4 OT - incretins/glucagon-like peptide-1/glucagon-like peptide-1 receptor OT - insulin/insulin receptor signaling OT - type 2 diabetes EDAT- 2014/07/30 06:00 MHDA- 2014/07/30 06:01 PMCR- 2014/01/01 CRDT- 2014/07/30 06:00 PHST- 2014/04/21 00:00 [received] PHST- 2014/06/24 00:00 [accepted] PHST- 2014/07/30 06:00 [entrez] PHST- 2014/07/30 06:00 [pubmed] PHST- 2014/07/30 06:01 [medline] PHST- 2014/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2014.00110 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2014 Jul 8;5:110. doi: 10.3389/fendo.2014.00110. eCollection 2014. PMID- 24998752 OWN - NLM STAT- MEDLINE DCOM- 20150714 LR - 20191210 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 86 DP - 2014 Nov TI - Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. PG - 22-30 LID - S0028-3908(14)00248-2 [pii] LID - 10.1016/j.neuropharm.2014.06.026 [doi] AB - Cognitive dysfunction is more common in individuals with type 2 diabetes (T2DM). Currently, glucagon-like peptide-1 (GLP-1) and metformin are important therapeutic options for patients with T2DM. However, their potential effects on cognitive function, including underlying mechanisms, are yet to be fully determined. We have compared the individual and combined effects of treatment for 20 days with (Val(8))GLP-1(GluPAL), an enzymatically stable GLP-1-receptor agonist, and metformin on metabolic control and aspects of learning and memory in high fat fed mice. (Val(8))GLP-1(GluPAL) treatment for 20 days alone, or in combination with metformin, improved (p < 0.05) the recognition index in high fat mice, indicating enhanced learning and memory. In addition, these mice exhibited a complete reversal of the deleterious effects of prolonged high-fat feeding on long-term potentiation in the hippocampal CA1 region. This was linked to reduced hippocampal levels of 8-oxoguanine (p < 0.01) and glial fibriallary acidic protein (p < 0.001), indicating decreased oxidative stress and inflammation; respectively. Expression of fundamental hippocampal genes including mTOR, VEGF, NTRK2 and SIRT1 was also increased significantly (p < 0.001) by all treatments. (Val(8))GLP-1(GluPAL) monotherapy, or in combination with metformin, reduced circulating glucose (p < 0.05) and increased insulin (p < 0.05 to p < 0.01) concentrations, as well as improving glucose tolerance (p < 0.001) and glucose-stimulated insulin secretion (p < 0.05 to p < 0.01). Insulin sensitivity and measurements of energy regulation and metabolic rate were not altered. These studies highlight the neuroprotective properties of (Val(8))GLP-1(GluPAL), alone and in combination with metformin, in T2DM. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Lennox, Rachael AU - Lennox R AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. FAU - Porter, David W AU - Porter DW AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. FAU - Flatt, Peter R AU - Flatt PR AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. FAU - Irwin, Nigel AU - Irwin N AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. Electronic address: n.irwin@ulster.ac.uk. FAU - Gault, Victor A AU - Gault VA AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140703 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Nootropic Agents) RN - 0 (Receptors, Glucagon) RN - 9100L32L2N (Metformin) SB - IM MH - Animals MH - Anxiety/drug therapy/physiopathology MH - Body Weight/drug effects MH - CA1 Region, Hippocampal/*drug effects/pathology/physiopathology MH - Cognition/*drug effects/physiology MH - Diet, High-Fat/*adverse effects MH - Drug Therapy, Combination MH - Eating/drug effects MH - Exploratory Behavior/drug effects/physiology MH - Gene Expression/drug effects MH - Glucagon-Like Peptide-1 Receptor MH - Learning/drug effects/physiology MH - Long-Term Potentiation/drug effects/physiology MH - Male MH - Metformin/*pharmacology MH - Mice MH - Neuroprotective Agents/*pharmacology MH - Nootropic Agents/pharmacology MH - Oxidative Stress/drug effects/physiology MH - Random Allocation MH - Receptors, Glucagon/*agonists/metabolism MH - Recognition, Psychology/drug effects OTO - NOTNLM OT - Cognitive function OT - Glucagon-like peptide-1 (GLP-1) OT - Hippocampus OT - Long-term potentiation (LTP) OT - Metformin EDAT- 2014/07/08 06:00 MHDA- 2015/07/15 06:00 CRDT- 2014/07/08 06:00 PHST- 2014/02/25 00:00 [received] PHST- 2014/06/26 00:00 [revised] PHST- 2014/06/27 00:00 [accepted] PHST- 2014/07/08 06:00 [entrez] PHST- 2014/07/08 06:00 [pubmed] PHST- 2015/07/15 06:00 [medline] AID - S0028-3908(14)00248-2 [pii] AID - 10.1016/j.neuropharm.2014.06.026 [doi] PST - ppublish SO - Neuropharmacology. 2014 Nov;86:22-30. doi: 10.1016/j.neuropharm.2014.06.026. Epub 2014 Jul 3. PMID- 24936731 OWN - NLM STAT- MEDLINE DCOM- 20150518 LR - 20260128 IS - 1677-9487 (Electronic) IS - 0004-2730 (Linking) VI - 58 IP - 4 DP - 2014 Jun TI - Effect of treatment with sitagliptin on somatosensory-evoked potentials and metabolic control in patients with type 2 diabetes mellitus. PG - 369-76 LID - S0004-27302014000400369 [pii] AB - OBJECTIVE: To evaluate the effect of sitagliptin on somatosensory-evoked potentials (SEPs) and metabolic control in patients with type 2 diabetes mellitus without clinical diabetic neuropathy. MATERIALS AND METHODS: Interventional, prospective, and open study. Patients with less than six months from the diagnosis were included. Examinations of SEPs and laboratory tests at fasting and after food stimulation were performed before and after three months of treatment with sitagliptin (100 mg/day). RESULTS: There was a reduction in the mean levels of HbA1c (P < 0.0001), fasting glucose (P = 0.001), total cholesterol (P = 0.019), and ALT (P = 0.022). An increase in active GLP-1 was found at the end of the study (P = 0.0025). Several SEPs showed statistically significant differences when analyzed before and after treatment with sitagliptin. CONCLUSION: The results give a glimpse of the possible use of sitagliptin in the treatment of some neurodegenerative conditions of the peripheral nervous system, in addition to its already established role in glycemic control. FAU - Barros, Joelma Ines Tagliapietra AU - Barros JI AD - Clinical Pharmacology Unit, Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceara, Fortaleza, CE, Brazil. FAU - Fechine, Francisco Vagnaldo AU - Fechine FV AD - Clinical Pharmacology Unit, Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceara, Fortaleza, CE, Brazil. FAU - Montenegro Junior, Renan Magalhaes AU - Montenegro Junior RM AD - Department of Community Health, School of Medicine, UFC, Fortaleza, CE, Brazil. FAU - Vale, Otoni Cardoso do AU - Vale OC AD - Department of Clinical Medicine, School of Medicine, UFC, Fortaleza, CE, Brazil. FAU - Fernandes, Virginia Oliveira AU - Fernandes VO AD - University Hospital Walter Cantidio, UFC, Fortaleza, CE, Brazil. FAU - Souza, Marcellus Henrique Loiola Ponte de AU - Souza MH AD - Department of Physiology and Pharmacology, School of Medicine, UFC, Fortaleza, CE, Brazil. FAU - Cunha, Gilmara Holanda da AU - Cunha GH AD - Department of Nursing, UFC, Fortaleza, CE, Brazil. FAU - Moraes, Manoel Odorico de AU - Moraes MO AD - Clinical Pharmacology Unit, Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceara, Fortaleza, CE, Brazil. FAU - d'Alva, Catarina Brasil AU - d'Alva CB AD - Clinical Pharmacology Unit, Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceara, Fortaleza, CE, Brazil. FAU - Moraes, Maria Elisabete Amaral de AU - Moraes ME AD - Clinical Pharmacology Unit, Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceara, Fortaleza, CE, Brazil. LA - eng PT - Clinical Trial PT - Journal Article PL - Brazil TA - Arq Bras Endocrinol Metabol JT - Arquivos brasileiros de endocrinologia e metabologia JID - 0403437 RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - 0 (Blood Glucose) RN - 97C5T2UQ7J (Cholesterol) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 0 (Pyrazines) RN - TS63EW8X6F (Sitagliptin Phosphate) RN - 0 (Triazoles) RN - 0 (Triglycerides) RN - EC 2.3.2.2 (gamma-Glutamyltransferase) SB - IM MH - Activation, Metabolic MH - Adult MH - Alanine Transaminase/blood MH - Area Under Curve MH - Aspartate Aminotransferases/blood MH - Blood Glucose/analysis MH - Cholesterol/blood MH - Diabetes Mellitus, Type 2/*drug therapy/metabolism/physiopathology MH - Evoked Potentials, Somatosensory/*drug effects MH - Fasting/metabolism MH - Female MH - Food, Formulated MH - Glucagon-Like Peptide 1/blood MH - Glycated Hemoglobin/analysis MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Middle Aged MH - Prospective Studies MH - Pyrazines/*therapeutic use MH - Sitagliptin Phosphate MH - Statistics, Nonparametric MH - Triazoles/*therapeutic use MH - Triglycerides/blood MH - gamma-Glutamyltransferase/blood EDAT- 2014/06/18 06:00 MHDA- 2015/05/20 06:00 CRDT- 2014/06/18 06:00 PHST- 2013/08/02 00:00 [received] PHST- 2014/01/24 00:00 [accepted] PHST- 2014/06/18 06:00 [entrez] PHST- 2014/06/18 06:00 [pubmed] PHST- 2015/05/20 06:00 [medline] AID - S0004-27302014000400369 [pii] AID - 10.1590/0004-2730000002914 [doi] PST - ppublish SO - Arq Bras Endocrinol Metabol. 2014 Jun;58(4):369-76. doi: 10.1590/0004-2730000002914. PMID- 24867662 OWN - NLM STAT- MEDLINE DCOM- 20151028 LR - 20260128 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 17 IP - 2 DP - 2015 Feb TI - Dipeptidyl peptidase-4 inhibitors can minimize the hypoglycaemic burden and enhance safety in elderly people with diabetes. PG - 107-15 LID - 10.1111/dom.12319 [doi] AB - The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self-manage the disease. The lack of solid evidence-based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP-4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM. CI - (c) 2014 John Wiley & Sons Ltd. FAU - Avogaro, A AU - Avogaro A AD - Department of Medicine, Section of Diabetes and Metabolic Diseases, University of Padova, Padua, Italy. FAU - Dardano, A AU - Dardano A FAU - de Kreutzenberg, S V AU - de Kreutzenberg SV FAU - Del Prato, S AU - Del Prato S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140625 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - PJY633525U (Adamantane) RN - 0 (Blood Glucose) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glycated Hemoglobin) RN - 0 (Nitriles) RN - 0 (Pyrrolidines) RN - I6B4B2U96P (Vildagliptin) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Adamantane/*analogs & derivatives/therapeutic use MH - Aged MH - Aged, 80 and over MH - Blood Glucose/*drug effects MH - Body Weight/drug effects MH - Cardiovascular Diseases/blood/etiology/*prevention & control MH - Diabetes Mellitus, Type 2/blood/complications/*drug therapy MH - Diabetic Angiopathies/blood/*prevention & control MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Evidence-Based Medicine MH - Glycated Hemoglobin/drug effects MH - Humans MH - Hypoglycemia/chemically induced/*prevention & control MH - Nitriles/*therapeutic use MH - Practice Guidelines as Topic MH - Pyrrolidines/*therapeutic use MH - Quality of Life MH - Vildagliptin OTO - NOTNLM OT - comorbidities OT - diabetes treatment OT - frailty OT - hypoglycaemia OT - incretin therapy OT - renal impairment EDAT- 2014/05/29 06:00 MHDA- 2015/10/29 06:00 CRDT- 2014/05/29 06:00 PHST- 2013/12/20 00:00 [received] PHST- 2014/05/19 00:00 [revised] PHST- 2014/05/20 00:00 [accepted] PHST- 2014/05/29 06:00 [entrez] PHST- 2014/05/29 06:00 [pubmed] PHST- 2015/10/29 06:00 [medline] AID - 10.1111/dom.12319 [doi] PST - ppublish SO - Diabetes Obes Metab. 2015 Feb;17(2):107-15. doi: 10.1111/dom.12319. Epub 2014 Jun 25. PMID- 24769307 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20260128 IS - 1873-1686 (Electronic) IS - 0167-0115 (Linking) VI - 190-191 DP - 2014 May TI - Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex. PG - 1-11 LID - S0167-0115(14)00036-6 [pii] LID - 10.1016/j.regpep.2014.04.003 [doi] AB - Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Abeta) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Abeta in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the alpha-C terminal fragment (alpha-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the alpha-secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in alpha-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP-1 facilitates the GluR1 membrane insertion through CREB activation and increases alpha-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Abeta oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Ohtake, Nobuaki AU - Ohtake N AD - Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan. FAU - Saito, Mieko AU - Saito M AD - Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan. FAU - Eto, Masaaki AU - Eto M AD - Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan. FAU - Seki, Kenjiro AU - Seki K AD - Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan. Electronic address: k-seki@pha.ohu-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140424 PL - Netherlands TA - Regul Pept JT - Regulatory peptides JID - 8100479 RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.81 (ADAM10 Protein) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - 9P1872D4OL (Exenatide) RN - 0 (Membrane Proteins) RN - 0 (Peptides) RN - 0 (Receptors, AMPA) RN - 0 (Venoms) RN - EC 3.4.24.81 (Adam10 protein, mouse) SB - IM CIN - Regul Pept. 2014 Jun-Aug;192-193:55-6. doi: 10.1016/j.regpep.2014.05.002. PMID: 24882709 MH - ADAM Proteins/*metabolism MH - ADAM10 Protein MH - Amyloid Precursor Protein Secretases/*metabolism MH - Animals MH - Cell Membrane/*drug effects/*metabolism MH - Exenatide MH - Infusions, Intraventricular MH - Male MH - Membrane Proteins/*metabolism MH - Mice MH - Neocortex/*cytology/*drug effects MH - Peptides/administration & dosage/*pharmacology MH - Receptors, AMPA/*metabolism MH - Venoms/administration & dosage/*pharmacology OTO - NOTNLM OT - ADAM10 OT - AMPA receptor GluR1 subunit OT - Exendin-4 OT - Glucagon-like peptide-1 OT - Mouse neocortex EDAT- 2014/04/29 06:00 MHDA- 2015/03/31 06:00 CRDT- 2014/04/29 06:00 PHST- 2013/12/20 00:00 [received] PHST- 2014/04/06 00:00 [revised] PHST- 2014/04/12 00:00 [accepted] PHST- 2014/04/29 06:00 [entrez] PHST- 2014/04/29 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] AID - S0167-0115(14)00036-6 [pii] AID - 10.1016/j.regpep.2014.04.003 [doi] PST - ppublish SO - Regul Pept. 2014 May;190-191:1-11. doi: 10.1016/j.regpep.2014.04.003. Epub 2014 Apr 24. PMID- 24684709 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20151119 IS - 1742-7843 (Electronic) IS - 1742-7835 (Linking) VI - 115 IP - 2 DP - 2014 Aug TI - At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose. PG - 162-71 LID - 10.1111/bcpt.12240 [doi] AB - Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with both pancreatic and extrapancreatic effects. Studies of GLP-1 reveal significant effects in regions of brain tissue that regulate appetite and satiety. GLP-1 mimetics are used for the treatment of type 2 diabetes mellitus. GLP-1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging pre-clinical findings indicate a potential neuroprotective role of the peptide, for example in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis and Maud Menten described the steady-state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose-dependent impact of GLP-1 on blood-brain glucose transfer and metabolism. This MiniReview examines the potential of GLP-1 as a molecule of interest for the understanding of brain energy metabolism and with reference to the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders. These effects can be understood only by reference to the original formulation of the Michaelis-Menten equation as applied to a chain of kinetically controlled steps. Indeed, the effects of GLP-1 receptor activation on blood-brain glucose transfer and brain metabolism of glucose depend on the glucose concentration and relative affinities of the steps both in vitro and in vivo, as in the pancreas. CI - (c) 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). FAU - Gejl, Michael AU - Gejl M AD - Department of Biomedicine - Pharmacology, Aarhus University, Aarhus, Denmark; Centre for Advanced Imaging, The University of Queensland, Brisbane, Qld, Australia. FAU - Rungby, Jorgen AU - Rungby J FAU - Brock, Birgitte AU - Brock B FAU - Gjedde, Albert AU - Gjedde A LA - eng PT - Journal Article PT - Review DEP - 20140430 PL - England TA - Basic Clin Pharmacol Toxicol JT - Basic & clinical pharmacology & toxicology JID - 101208422 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Biological Transport MH - Blood-Brain Barrier MH - Brain/metabolism MH - Diabetes Mellitus, Type 2/drug therapy/physiopathology MH - Glucagon-Like Peptide 1/*metabolism MH - Glucagon-Like Peptide-1 Receptor MH - Glucose/*metabolism MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Neurodegenerative Diseases/physiopathology MH - Receptors, Glucagon/*metabolism MH - Stroke/physiopathology EDAT- 2014/04/02 06:00 MHDA- 2015/03/31 06:00 CRDT- 2014/04/02 06:00 PHST- 2013/12/30 00:00 [received] PHST- 2014/03/17 00:00 [accepted] PHST- 2014/04/02 06:00 [entrez] PHST- 2014/04/02 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] AID - 10.1111/bcpt.12240 [doi] PST - ppublish SO - Basic Clin Pharmacol Toxicol. 2014 Aug;115(2):162-71. doi: 10.1111/bcpt.12240. Epub 2014 Apr 30. PMID- 24667360 OWN - NLM STAT- MEDLINE DCOM- 20141211 LR - 20151119 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 267 DP - 2014 Jul 1 TI - Dipeptidyl peptidase-4 inhibition by Pterocarpus marsupium and Eugenia jambolana ameliorates streptozotocin induced Alzheimer's disease. PG - 55-65 LID - S0166-4328(14)00180-6 [pii] LID - 10.1016/j.bbr.2014.03.026 [doi] AB - Alzheimer's disease (AD), the most common form of dementia, is characterized by the loss of normal functions of brain cells and neuronal death, ultimately leading to memory loss. Recent accumulating evidences have demonstrated the therapeutic potential of anti-diabetic agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, for the treatment of Alzheimer's disease (AD), providing opportunities to explore and test the DPP-4 inhibitors for treating this fatal disease. Prior studies determining the efficacy of Pterocarpus marsupium (PM, Fabaceae) and Eugenia jambolana (EJ, Myrtaceae) extracts for ameliorating type 2 diabetes have demonstrated the DPP-4 inhibitory properties indicating the possibility of using of these extracts even for the treating AD. Therefore, in the present study, the neuroprotective roles of PM and EJ for ameliorating the streptozotocin (STZ) induced AD have been tested in rat model. Experimentally, PM and EJ extracts, at a dose range of 200 and 400mg/kg, were administered orally to STZ induced AD Wistar rats and cognitive evaluation tests were performed using radial arm maze and hole-board apparatus. Following 30 days of treatment with the extracts, a dose- and time-dependent attenuation of AD pathology, as evidenced by decreasing amyloid beta 42, total tau, phosphorylated tau and neuro-inflammation with an increase in glucagon-like peptide-1 (GLP-1) levels was observed. Therefore, PM and EJ extracts contain cognitive enhancers as well as neuroprotective agents against STZ induced AD. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Kosaraju, Jayasankar AU - Kosaraju J AD - Department of Pharmacognosy, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. Electronic address: jayasankar87@hotmail.com. FAU - Madhunapantula, Subbarao V AU - Madhunapantula SV AD - Department of Biochemistry, JSS Medical College, Sri Shivarathresshwara Nagar, Mysore 570015, India. FAU - Chinni, Santhivardhan AU - Chinni S AD - Department of Pharmacology, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. FAU - Khatwal, Rizwan Basha AU - Khatwal RB AD - Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. FAU - Dubala, Anil AU - Dubala A AD - Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. FAU - Muthureddy Nataraj, Satish Kumar AU - Muthureddy Nataraj SK AD - Department of Pharmacology, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. FAU - Basavan, Duraiswamy AU - Basavan D AD - Department of Pharmacognosy, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140322 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Amyloid beta-Peptides) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Mapt protein, rat) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (Plant Preparations) RN - 0 (amyloid beta-protein (1-42)) RN - 0 (tau Proteins) RN - 5W494URQ81 (Streptozocin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/complications/*drug therapy/metabolism/pathology MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Cognition Disorders/drug therapy/etiology/metabolism/pathology MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Glucagon-Like Peptide 1/metabolism MH - Hippocampus/drug effects/metabolism/pathology MH - Male MH - Maze Learning/drug effects MH - Neuroprotective Agents/*therapeutic use MH - Peptide Fragments/metabolism MH - Phosphorylation/drug effects MH - *Phytotherapy MH - Plant Preparations/*therapeutic use MH - Plaque, Amyloid/drug therapy MH - *Pterocarpus MH - Rats, Wistar MH - Streptozocin MH - *Syzygium MH - Time Factors MH - tau Proteins/metabolism OTO - NOTNLM OT - Amyloid load OT - Eugenia jambolana OT - Glucagon-like peptide-1 OT - Neuro-inflammation OT - Pterocarpus marsupium OT - Tau phosphorylation EDAT- 2014/03/29 06:00 MHDA- 2014/12/17 06:00 CRDT- 2014/03/27 06:00 PHST- 2013/12/18 00:00 [received] PHST- 2014/03/13 00:00 [revised] PHST- 2014/03/15 00:00 [accepted] PHST- 2014/03/27 06:00 [entrez] PHST- 2014/03/29 06:00 [pubmed] PHST- 2014/12/17 06:00 [medline] AID - S0166-4328(14)00180-6 [pii] AID - 10.1016/j.bbr.2014.03.026 [doi] PST - ppublish SO - Behav Brain Res. 2014 Jul 1;267:55-65. doi: 10.1016/j.bbr.2014.03.026. Epub 2014 Mar 22. PMID- 24646283 OWN - NLM STAT- MEDLINE DCOM- 20150605 LR - 20140320 IS - 1470-8752 (Electronic) IS - 0300-5127 (Linking) VI - 42 IP - 2 DP - 2014 Apr TI - Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases. PG - 593-9 LID - 10.1042/BST20140016 [doi] AB - Recently, it has been shown that in patients with AD (Alzheimer's disease) and, to some degree, in patients with PD (Parkinson's disease) insulin signalling is impaired. This finding has initiated a range of research projects that showed remarkable improvements using treatments that initially had been developed to treat diabetes. Pre-clinical studies showed good neuroprotective effects when applying insulin or long-lasting analogues of incretin peptides. In transgenic animal models of AD and PD, analogues of the incretin GLP-1 (glucagon-like peptide 1) prevented neurodegenerative processes and improved neuronal and synaptic functionality in AD and PD. Amyloid plaque load and synaptic loss as well as cognitive impairment had been ameliorated in AD models, and dopaminergic loss of transmission and motor function was reversed in models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results being published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for Type 2 diabetes also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients. The present review summarizes the range of neuroprotective effects that these drugs have demonstrated and emphasizes the great promise that this approach has in providing novel treatments that have protective and even restorative properties that no current drug treatment can offer. FAU - Holscher, Christian AU - Holscher C AD - *Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, U.K. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - England TA - Biochem Soc Trans JT - Biochemical Society transactions JID - 7506897 RN - 0 (Incretins) RN - 0 (Insulin) RN - 0 (Intercellular Signaling Peptides and Proteins) SB - IM MH - Alzheimer Disease/*drug therapy/metabolism MH - Animals MH - Humans MH - Incretins/*therapeutic use MH - Insulin/*therapeutic use MH - Intercellular Signaling Peptides and Proteins/*therapeutic use MH - Neuronal Plasticity/drug effects MH - Oxidative Stress/drug effects MH - Parkinson Disease/*drug therapy/metabolism EDAT- 2014/03/22 06:00 MHDA- 2015/06/06 06:00 CRDT- 2014/03/21 06:00 PHST- 2014/03/21 06:00 [entrez] PHST- 2014/03/22 06:00 [pubmed] PHST- 2015/06/06 06:00 [medline] AID - BST20140016 [pii] AID - 10.1042/BST20140016 [doi] PST - ppublish SO - Biochem Soc Trans. 2014 Apr;42(2):593-9. doi: 10.1042/BST20140016. PMID- 24622756 OWN - NLM STAT- MEDLINE DCOM- 20150223 LR - 20160525 IS - 2213-8595 (Electronic) IS - 2213-8587 (Linking) VI - 2 IP - 3 DP - 2014 Mar TI - Diabetes drugs and neurological disorders: new views and therapeutic possibilities. PG - 256-62 LID - S2213-8587(13)70125-6 [pii] LID - 10.1016/S2213-8587(13)70125-6 [doi] AB - Type 2 diabetes is a metabolic disease characterised by insulin resistance with hyperglycaemia and dyslipidaemia. It is associated with increased risk of stroke and vascular dementia, and might contribute to the development of Alzheimer's disease. Recent studies have shown that several antidiabetic drugs can promote neuronal survival and lead to a significant clinical improvement of memory and cognition in different clinical settings. We discuss these emerging data, with a focus on metformin, thiazolidinediones, and the more recently developed compounds targeting the glucagon-like peptide-1 receptor. Data show that these antidiabetic drugs affect brain metabolism, neuroinflammation, and regeneration. Evidence thus far strongly indicates that these antidiabetic drugs could be developed as disease-modifying therapies for human brain diseases in patients with and without diabetes. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Patrone, Cesare AU - Patrone C AD - Internal Medicine, Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden. FAU - Eriksson, Ove AU - Eriksson O AD - Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Biomedicum, Finland. FAU - Lindholm, Dan AU - Lindholm D AD - Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Biomedicum, Finland; Minerva Medical Research Institute, Helsinki, Finland. Electronic address: dan.lindholm@helsinki.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131122 PL - England TA - Lancet Diabetes Endocrinol JT - The lancet. Diabetes & endocrinology JID - 101618821 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) SB - IM MH - Brain/drug effects/*metabolism MH - Brain Diseases/complications/prevention & control MH - Diabetes Mellitus, Type 2/*complications MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Insulin/*metabolism MH - Insulin Resistance MH - Nervous System Diseases/*complications/prevention & control MH - Risk Factors MH - Signal Transduction/drug effects EDAT- 2014/03/14 06:00 MHDA- 2015/02/24 06:00 CRDT- 2014/03/14 06:00 PHST- 2014/03/14 06:00 [entrez] PHST- 2014/03/14 06:00 [pubmed] PHST- 2015/02/24 06:00 [medline] AID - S2213-8587(13)70125-6 [pii] AID - 10.1016/S2213-8587(13)70125-6 [doi] PST - ppublish SO - Lancet Diabetes Endocrinol. 2014 Mar;2(3):256-62. doi: 10.1016/S2213-8587(13)70125-6. Epub 2013 Nov 22. PMID- 24604239 OWN - NLM STAT- MEDLINE DCOM- 20150624 LR - 20261011 IS - 1559-0100 (Electronic) IS - 1355-008X (Linking) VI - 47 IP - 2 DP - 2014 Nov TI - Extra-pancreatic effects of incretin-based therapies. PG - 360-71 LID - 10.1007/s12020-014-0223-0 [doi] AB - Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion in the pancreatic islets of Langerhans under hyperglycaemia. In type 2 diabetes (T2DM), GLP-1 improves glycaemic control without a hypoglycaemia risk. GLP-1 receptors have also been found in extra-pancreatic tissues, e.g., the cardiovascular system, the gastrointestinal system, and the central nervous system. Since cardiovascular comorbidities and degenerative neurological changes are associated with T2DM, the interest in the extrapancreatic effects of GLP-1 has increased. GLP-1-based therapies with either GLP-1 receptor agonists (GLP-1 RA) or DPP-4 inhibitors (that delay the degradation of endogenous GLP-1) have become widely used therapeutic options in T2DM. In clinical studies, GLP-1 RA have demonstrated a significant lowering of blood pressure that is independent of body weight changes. Preclinical data and small short-term studies with GLP-1 and GLP-1 RA have shown cardioprotective effects in ischaemia models. GLP-1 as well as a treatment with GLP-1 RA also induces a stable body weight loss by affecting GLP-1 signaling in the hypothalamus and by slowing gastric emptying. Regarding neuroprotective actions in degenerative neurological disease models for Parkinson's- or Alzheimer's disease or neurovascular complications like stroke, animal studies have shown positive results. In this article, a summary of the extrapancreatic effects of GLP-1 and GLP-1-based therapies is presented. FAU - Gallwitz, Baptist AU - Gallwitz B AD - Department of Medicine IV, Eberhard-Karls-University, Otfried-Muller-Str. 10, 72076, Tubingen, Germany, baptist.gallwitz@med.uni-tuebingen.de. LA - eng PT - Journal Article PT - Review DEP - 20140307 PL - United States TA - Endocrine JT - Endocrine JID - 9434444 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Glucagon) SB - IM MH - Animals MH - Brain/drug effects MH - Diabetes Mellitus, Type 2/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Gastric Emptying/drug effects MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Incretins/pharmacology/*therapeutic use MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Receptors, Glucagon/*agonists MH - Weight Loss/drug effects EDAT- 2014/03/08 06:00 MHDA- 2015/06/25 06:00 CRDT- 2014/03/08 06:00 PHST- 2014/01/23 00:00 [received] PHST- 2014/02/19 00:00 [accepted] PHST- 2014/03/08 06:00 [entrez] PHST- 2014/03/08 06:00 [pubmed] PHST- 2015/06/25 06:00 [medline] AID - 10.1007/s12020-014-0223-0 [doi] PST - ppublish SO - Endocrine. 2014 Nov;47(2):360-71. doi: 10.1007/s12020-014-0223-0. Epub 2014 Mar 7. PMID- 24583037 OWN - NLM STAT- MEDLINE DCOM- 20150608 LR - 20260128 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 277 DP - 2014 Sep 26 TI - Lixisenatide rescues spatial memory and synaptic plasticity from amyloid beta protein-induced impairments in rats. PG - 6-13 LID - S0306-4522(14)00133-X [pii] LID - 10.1016/j.neuroscience.2014.02.022 [doi] AB - Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) has shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor (GLP-1R) agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. However, the neuroprotective effects of lixisenatide in the brain remain to be clarified. In the present study, we report for the first time the effects of lixisenatide on the amyloid beta (Abeta) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Abeta25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Abeta25-35-induced impairments; (3) lixisenatide inhibited the Abeta25-35 injection-induced activation of glycogen synthase kinase 3beta (GSK3beta), with a significant increase in the phosphorylation of ser9 and a significant decrease in the phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3beta pathway, can prevent Abeta-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD. CI - Copyright (c) 2014. Published by Elsevier Ltd. FAU - Cai, H-Y AU - Cai HY AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Holscher, C AU - Holscher C AD - Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster LA1 4YQ, UK. FAU - Yue, X-H AU - Yue XH AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Zhang, S-X AU - Zhang SX AD - Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China. FAU - Wang, X-H AU - Wang XH AD - Department of Pathology, Shanxi Medical University, Taiyuan 030001, China. FAU - Qiao, F AU - Qiao F AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Yang, W AU - Yang W AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. FAU - Qi, J-S AU - Qi JS AD - Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: jinshunqi2006@yahoo.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140227 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Amyloid beta-Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Glp1r protein, rat) RN - 0 (amyloid beta-protein (25-35)) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) RN - EC 2.7.11.1 (Gsk3b protein, rat) SB - IM MH - Alzheimer Disease/drug therapy/physiopathology MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Disease Models, Animal MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Glucagon-Like Peptide-1 Receptor MH - Glycogen Synthase Kinase 3/genetics/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hippocampus/drug effects/physiopathology MH - Long-Term Potentiation/*drug effects/physiology MH - Male MH - Maze Learning/drug effects/physiology MH - Memory Disorders/*drug therapy/physiopathology MH - Neuroprotective Agents/*pharmacology MH - Peptide Fragments/*metabolism MH - Peptides/*pharmacology MH - Phosphorylation/drug effects MH - Random Allocation MH - Rats, Sprague-Dawley MH - Receptors, Glucagon/agonists/metabolism MH - Spatial Memory/*drug effects/physiology MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - Alzheimer's disease OT - Morris water maze OT - amyloid beta-protein OT - glycogen synthase kinase 3beta OT - lixisenatide OT - long-term potentiation EDAT- 2014/03/04 06:00 MHDA- 2015/06/09 06:00 CRDT- 2014/03/04 06:00 PHST- 2014/01/18 00:00 [received] PHST- 2014/02/15 00:00 [revised] PHST- 2014/02/18 00:00 [accepted] PHST- 2014/03/04 06:00 [entrez] PHST- 2014/03/04 06:00 [pubmed] PHST- 2015/06/09 06:00 [medline] AID - S0306-4522(14)00133-X [pii] AID - 10.1016/j.neuroscience.2014.02.022 [doi] PST - ppublish SO - Neuroscience. 2014 Sep 26;277:6-13. doi: 10.1016/j.neuroscience.2014.02.022. Epub 2014 Feb 27. PMID- 24529525 OWN - NLM STAT- MEDLINE DCOM- 20141006 LR - 20160226 IS - 1552-5279 (Electronic) IS - 1552-5260 (Linking) VI - 10 IP - 1 Suppl DP - 2014 Feb TI - The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. PG - S47-54 LID - S1552-5260(13)02923-3 [pii] LID - 10.1016/j.jalz.2013.12.009 [doi] AB - The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide (GIP) have been developed to treat type 2 diabetes and also act as growth factors. We have tested several long-acting incretin mimetics in the amyloid precursor protein (APP)(Swe)/presenilin 1 (PS1)(DeltaE9) model of Alzheimer's disease (AD). We found that liraglutide, lixisenatide, and D-Ala2-GIP cross the blood-brain barrier and prevent the impairment in memory formation and synaptic plasticity, increase synapse numbers, reduce amyloid plaque load and soluble amyloid-beta levels, reduce oxidative stress and the chronic inflammation response in the brain, enhance the proliferation of neuronal progenitor cells, and increase neurogenesis in the dentate gyrus. In an (18)fluorodeoxyglucoe positron emission tomographic/computed tomographic imaging study in PLB1-triple mice, a mouse model that expresses human mutated APP, PS1, and tau proteins, glucose metabolism was found to be normalized in forebrain areas after liraglutide treatment, demonstrating that neuronal metabolic activity was normalized. A clinical trial testing liraglutide in patients with AD is currently ongoing. CI - Copyright (c) 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Sciences, Lancaster University, Lancaster, UK. Electronic address: c.holscher@lancaster.ac.uk. LA - eng PT - Journal Article PL - United States TA - Alzheimers Dement JT - Alzheimer's & dementia : the journal of the Alzheimer's Association JID - 101231978 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Neuroprotective Agents) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM EIN - Alzheimers Dement. 2015 Nov;11(11):1395 MH - Alzheimer Disease/*drug therapy/genetics/pathology MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Disease Models, Animal MH - Gastric Inhibitory Polypeptide/*therapeutic use MH - Glucagon-Like Peptide 1/*therapeutic use MH - Humans MH - Mice MH - Mice, Transgenic MH - Neuroprotective Agents/*therapeutic use MH - Presenilin-1/genetics OTO - NOTNLM OT - Alzheimer's disease OT - GLP-1 OT - Growth factors OT - Liraglutide OT - Lixisenatide OT - Parkinson's disease EDAT- 2014/02/18 06:00 MHDA- 2014/10/07 06:00 CRDT- 2014/02/18 06:00 PHST- 2013/11/18 00:00 [received] PHST- 2013/12/05 00:00 [accepted] PHST- 2014/02/18 06:00 [entrez] PHST- 2014/02/18 06:00 [pubmed] PHST- 2014/10/07 06:00 [medline] AID - S1552-5260(13)02923-3 [pii] AID - 10.1016/j.jalz.2013.12.009 [doi] PST - ppublish SO - Alzheimers Dement. 2014 Feb;10(1 Suppl):S47-54. doi: 10.1016/j.jalz.2013.12.009. PMID- 24373150 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20260128 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 16 IP - 8 DP - 2014 Aug TI - The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. PG - 673-88 LID - 10.1111/dom.12251 [doi] AB - The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future. CI - (c) 2013 John Wiley & Sons Ltd. FAU - Seufert, J AU - Seufert J AD - Division of Endocrinology and Diabetology, Department of Medicine II, Albert-Ludwigs University Medical Center, Freiburg, Germany. FAU - Gallwitz, B AU - Gallwitz B LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140116 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 9P1872D4OL (Exenatide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 839I73S42A (Liraglutide) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Venoms) RN - 0 (GLP1R protein, human) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM MH - Animals MH - Diabetes Complications/*prevention & control MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Diabetic Cardiomyopathies/prevention & control MH - Diabetic Neuropathies/prevention & control MH - *Evidence-Based Medicine MH - Exenatide MH - Gastrointestinal Diseases/prevention & control MH - Glucagon-Like Peptide 1/adverse effects/analogs & derivatives/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Incretins/adverse effects/*therapeutic use MH - Liraglutide MH - Obesity/complications/prevention & control MH - Peptides/adverse effects/therapeutic use MH - Receptors, Glucagon/*agonists MH - Venoms/adverse effects/therapeutic use MH - Glucagon-Like Peptide-2 Receptor OTO - NOTNLM OT - GLP-1 OT - cardiovascular OT - central nervous system OT - exenatide OT - gastrointestinal OT - liraglutide OT - lixisenatide OT - receptor agonists EDAT- 2014/01/01 06:00 MHDA- 2015/03/31 06:00 CRDT- 2013/12/31 06:00 PHST- 2013/06/20 00:00 [received] PHST- 2013/08/09 00:00 [revised] PHST- 2013/12/13 00:00 [accepted] PHST- 2013/12/31 06:00 [entrez] PHST- 2014/01/01 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] AID - 10.1111/dom.12251 [doi] PST - ppublish SO - Diabetes Obes Metab. 2014 Aug;16(8):673-88. doi: 10.1111/dom.12251. Epub 2014 Jan 16. PMID- 24333407 OWN - NLM STAT- MEDLINE DCOM- 20140806 LR - 20131216 IS - 1944-7930 (Electronic) IS - 1539-6509 (Linking) VI - 16 IP - 90 DP - 2013 Dec TI - Antidiabetic drugs and their potential role in treating mild cognitive impairment and Alzheimer's disease. PG - 277-86 AB - The incidence of both diabetes mellitus (DM) and dementia increases with aging and the incidence of dementia are higher in people with diabetes. Epidemiological and pathological data suggest that DM contributes to mild cognitive impairment (MCI) and dementia. DM seems to be an independent risk factor for MCI and Alzheimer's disease (AD) and is associated with more rapid cognitive decline. Recent evidence points out that insulin affects central nervous system functions, and can modulate cognitive functions. Impaired insulin signaling and insulin resistance in brain have been found to play an important role in the pathogenesis of AD. Human studies have shown that some oral antidiabetic medications can improve cognition in patients with MCI and AD. Intranasal insulin has also been shown to improve memory and cognitive abilities in MCI and AD patients. While it remains unclear whether management of diabetes will reduce the incidence of MCI and AD, emerging evidence suggests that diabetes therapies may improve cognitive function. FAU - Alagiakrishnan, Kannayiram AU - Alagiakrishnan K AD - Division of Geriatric Medicine, University of Alberta, Edmonton, Alberta T6G 2G3, Canada. FAU - Sankaralingam, Sowndramalingam AU - Sankaralingam S FAU - Ghosh, Mahua AU - Ghosh M FAU - Mereu, Laurie AU - Mereu L FAU - Senior, Peter AU - Senior P LA - eng PT - Journal Article PT - Review PL - United States TA - Discov Med JT - Discovery medicine JID - 101250006 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Sulfonylurea Compounds) RN - 0 (Thiazolidinediones) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9100L32L2N (Metformin) SB - IM MH - Aged MH - Aged, 80 and over MH - Aging MH - Alzheimer Disease/*drug therapy MH - Animals MH - Clinical Trials as Topic MH - Cognition Disorders/*drug therapy MH - Diabetes Complications/drug therapy MH - Diabetes Mellitus, Type 2/complications/drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Disease Progression MH - Glucagon-Like Peptide 1/chemistry MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Insulin/administration & dosage MH - Metformin/therapeutic use MH - Middle Aged MH - Risk Factors MH - Sulfonylurea Compounds/therapeutic use MH - Thiazolidinediones/therapeutic use EDAT- 2013/12/18 06:00 MHDA- 2014/08/07 06:00 CRDT- 2013/12/17 06:00 PHST- 2013/12/17 06:00 [entrez] PHST- 2013/12/18 06:00 [pubmed] PHST- 2014/08/07 06:00 [medline] PST - ppublish SO - Discov Med. 2013 Dec;16(90):277-86. PMID- 24329968 OWN - NLM STAT- MEDLINE DCOM- 20141128 LR - 20211021 IS - 1750-3639 (Electronic) IS - 1015-6305 (Print) IS - 1015-6305 (Linking) VI - 24 IP - 3 DP - 2014 Apr TI - Geniposide ameliorates learning memory deficits, reduces tau phosphorylation and decreases apoptosis via GSK3beta pathway in streptozotocin-induced alzheimer rat model. PG - 261-9 LID - 10.1111/bpa.12116 [doi] AB - Intracerebral-ventricular (ICV) injection of streptozotocin (STZ) induces an insulin-resistant brain state that may underlie the neural pathogenesis of sporadic Alzheimer disease (AD). Our previous work showed that prior ICV treatment of glucagon-like peptide-1 (GLP-1) could prevent STZ-induced learning memory impairment and tau hyperphosphorylation in the rat brain. The Chinese herbal medicine geniposide is known to relieve symptoms of type 2 diabetes. Because geniposide is thought to act as a GLP-1 receptor agonist, we investigated the potential therapeutic effect of geniposide on STZ-induced AD model in rats. Our result showed that a single injection of geniposide (50 muM, 10 muL) to the lateral ventricle prevented STZ-induced spatial learning deficit by about 40% and reduced tau phosphorylation by about 30% with Morris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that tau protein can be phosphorylated by glycogen synthase kinase-3 (GSK3) and STZ can increase the activity of GSK3beta. Our result with Western blot analysis showed that central administration of geniposide resulted in an elevated expression of GSK3beta(pS-9) but suppressed GSK3beta(pY-216) indicating that geniposide reduced STZ-induced GSK3beta hyperactivity. In addition, ultrastructure analysis showed that geniposide averted STZ-induced neural pathology, including paired helical filament (PHF)-like structures, accumulation of vesicles in synaptic terminal, abnormalities of endoplasmic reticulum (ER) and early stage of apoptosis. In summary, our study suggests that the water soluble and orally active monomer of Chinese herbal medicine geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD. CI - (c) 2013 International Society of Neuropathology. FAU - Gao, Chong AU - Gao C AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. FAU - Liu, Yueze AU - Liu Y FAU - Jiang, Yuanhong AU - Jiang Y FAU - Ding, Jianming AU - Ding J FAU - Li, Lin AU - Li L LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140212 PL - Switzerland TA - Brain Pathol JT - Brain pathology (Zurich, Switzerland) JID - 9216781 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Iridoids) RN - 0 (tau Proteins) RN - 145295QLXY (geniposide) RN - 5W494URQ81 (Streptozocin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Alzheimer Disease/chemically induced/complications MH - Animals MH - Antibiotics, Antineoplastic/toxicity MH - Apoptosis/*drug effects MH - Disease Models, Animal MH - Glycogen Synthase Kinase 3/*metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hippocampus/drug effects/pathology/ultrastructure MH - Iridoids/*therapeutic use MH - Male MH - Maze Learning/drug effects MH - Memory Disorders/*drug therapy/etiology MH - Microscopy, Electron, Transmission MH - Phosphorylation/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/*drug effects MH - Streptozocin/toxicity MH - Vacuoles/pathology/ultrastructure MH - tau Proteins/metabolism PMC - PMC8029432 OTO - NOTNLM OT - Alzheimer's disease OT - geniposide OT - glucagon-like peptide-1 receptor OT - glycogen synthase kinase-3beta OT - tau hyperphosphorylation OT - type 2 diabetes EDAT- 2013/12/18 06:00 MHDA- 2014/12/15 06:00 PMCR- 2014/02/12 CRDT- 2013/12/17 06:00 PHST- 2013/10/01 00:00 [received] PHST- 2013/12/06 00:00 [revised] PHST- 2013/12/17 06:00 [entrez] PHST- 2013/12/18 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2014/02/12 00:00 [pmc-release] AID - BPA12116 [pii] AID - 10.1111/bpa.12116 [doi] PST - ppublish SO - Brain Pathol. 2014 Apr;24(3):261-9. doi: 10.1111/bpa.12116. Epub 2014 Feb 12. PMID- 24312624 OWN - NLM STAT- MEDLINE DCOM- 20140927 LR - 20220316 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 12 DP - 2013 TI - Exendin-4 ameliorates traumatic brain injury-induced cognitive impairment in rats. PG - e82016 LID - 10.1371/journal.pone.0082016 [doi] LID - e82016 AB - Traumatic brain injury represents a major public health issue that affects 1.7 million Americans each year and is a primary contributing factor (30.5%) of all injury-related deaths in the United States. The occurrence of traumatic brain injury is likely underestimated and thus has been termed "a silent epidemic". Exendin-4 is a long-acting glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus that not only effectively induces glucose-dependent insulin secretion to regulate blood glucose levels but also reduces apoptotic cell death of pancreatic beta-cells. Accumulating evidence also supports a neurotrophic and neuroprotective role of glucagon-like peptide-1 in an array of cellular and animal neurodegeneration models. In this study, we evaluated the neuroprotective effects of Exendin-4 using a glutamate toxicity model in vitro and fluid percussion injury in vivo. We found neuroprotective effects of Exendin-4 both in vitro, using markers of cell death, and in vivo, using markers of cognitive function, as assessed by Morris Water Maze. In combination with the reported benefits of ex-4 in other TBI models, these data support repositioning of Exendin-4 as a potential treatment for traumatic brain injury. FAU - Eakin, Katharine AU - Eakin K AD - Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America. FAU - Li, Yazhou AU - Li Y FAU - Chiang, Yung-Hsiao AU - Chiang YH FAU - Hoffer, Barry J AU - Hoffer BJ FAU - Rosenheim, Hilary AU - Rosenheim H FAU - Greig, Nigel H AU - Greig NH FAU - Miller, Jonathan P AU - Miller JP LA - eng GR - R01 NS070825/NS/NINDS NIH HHS/United States GR - NSC98-2321-B-038-002-MY3/PHS HHS/United States GR - ImNIH/Intramural NIH HHS/United States GR - NS070825/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20131202 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Venoms) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Brain Injuries/*drug therapy/*physiopathology/prevention & control MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Cognition/*drug effects MH - Drug Repositioning MH - Exenatide MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents MH - Male MH - Neurons/cytology/drug effects/pathology MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Peptides/*pharmacology/*therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Glucagon/metabolism MH - Signal Transduction/drug effects MH - Venoms/*pharmacology/*therapeutic use PMC - PMC3847068 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2013/12/07 06:00 MHDA- 2014/09/28 06:00 PMCR- 2013/12/02 CRDT- 2013/12/07 06:00 PHST- 2013/09/19 00:00 [received] PHST- 2013/10/29 00:00 [accepted] PHST- 2013/12/07 06:00 [entrez] PHST- 2013/12/07 06:00 [pubmed] PHST- 2014/09/28 06:00 [medline] PHST- 2013/12/02 00:00 [pmc-release] AID - PONE-D-13-38413 [pii] AID - 10.1371/journal.pone.0082016 [doi] PST - epublish SO - PLoS One. 2013 Dec 2;8(12):e82016. doi: 10.1371/journal.pone.0082016. eCollection 2013. PMID- 24259244 OWN - NLM STAT- MEDLINE DCOM- 20140422 LR - 20131122 IS - 0334-1763 (Print) IS - 0334-1763 (Linking) VI - 24 IP - 6 DP - 2013 TI - New animal models of Alzheimer's disease that display insulin desensitization in the brain. PG - 607-15 LID - /j/revneuro.2013.24.issue-6/revneuro-2013-0034/revneuro-2013-0034.xml [pii] LID - 10.1515/revneuro-2013-0034 [doi] AB - Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves many underlying pathological processes. Recently, it has been demonstrated that AD also includes impairments of insulin signaling in the brain. Type 2 diabetes is a risk factor for AD, and AD and diabetes share a number of pathologies. The classical hallmarks of AD are senile plaques and neurofibrillary tangles, which consist of amyloid-beta and hyperphosphorylated tau. Based on the two hallmarks, transgenic animal models of AD have been developed, which express mutant human genes of amyloid precursor protein, presenilin-1/2, and tau. It is likely that these mouse models are too limited in their pathology. In this work, we describe mouse models that model diabetes and show insulin signaling impairment as well as neurodegenerative pathologies that are similar to those seen in the brains of AD patients. The combination of traditional AD mouse models with induced insulin impairments in the brain may be a more complete model of AD. Interestingly, AD mouse models treated with drugs that have been developed to cure type 2 diabetes have shown impressive outcomes. Based on these findings, several ongoing clinical trials are testing long lasting insulin analogues or GLP-1 mimetics in patients with AD. FAU - Gao, Chong AU - Gao C FAU - Liu, Yueze AU - Liu Y FAU - Li, Lin AU - Li L FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Review PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Insulin) SB - IM MH - Alzheimer Disease/etiology/genetics/*pathology MH - Animals MH - Brain/*metabolism MH - Diabetes Mellitus, Type 2/complications/etiology MH - *Disease Models, Animal MH - Humans MH - Insulin/*metabolism MH - Mice MH - Neurofibrillary Tangles/pathology EDAT- 2013/11/22 06:00 MHDA- 2014/04/23 06:00 CRDT- 2013/11/22 06:00 PHST- 2013/08/10 00:00 [received] PHST- 2013/09/29 00:00 [accepted] PHST- 2013/11/22 06:00 [entrez] PHST- 2013/11/22 06:00 [pubmed] PHST- 2014/04/23 06:00 [medline] AID - /j/revneuro.2013.24.issue-6/revneuro-2013-0034/revneuro-2013-0034.xml [pii] AID - 10.1515/revneuro-2013-0034 [doi] PST - ppublish SO - Rev Neurosci. 2013;24(6):607-15. doi: 10.1515/revneuro-2013-0034. PMID- 24117480 OWN - NLM STAT- MEDLINE DCOM- 20140905 LR - 20220321 IS - 2042-7158 (Electronic) IS - 0022-3573 (Linking) VI - 65 IP - 12 DP - 2013 Dec TI - Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer's disease. PG - 1773-84 LID - 10.1111/jphp.12148 [doi] AB - OBJECTIVES: Adults who develop type 2 diabetes (T2D) at later stages are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon-like peptide-1 (GLP-1) and ameliorate T2D have also become promising candidates as disease-modifying agents in the treatment of AD. The present study investigates the efficacy of vildagliptin, a DPP-4 inhibitor in a streptozotocin (STZ)-induced rat model of AD. METHODS: Three months following the induction of AD by intracerebral injection of STZ, animals were orally administered with vildagliptin (2.5, 5 and 10 mg/kg) for 30 days. Dose-dependent and time-course effects of vildagliptin on memory retention were investigated during the course of treatment. Following treatment, the animals were sacrificed, and brain tissues were used to evaluate the effects of vildagliptin on hippocampal and cortical GLP-1 levels, amyloid beta (Abeta) burden, tau phosphorylation and inflammatory markers. KEY FINDINGS: The results reveal a time-dependent improvement in memory retention and a dose-dependent attenuation of Abeta, tau phosphorylation and inflammatory markers and increased GLP-1 levels. CONCLUSIONS: These robust therapeutic effects of vildagliptin demonstrate a unique mechanism for Abeta and tau clearance and reverse the cognitive deficits and pathology observed in AD. CI - (c) 2013 Royal Pharmaceutical Society. FAU - Kosaraju, Jayasankar AU - Kosaraju J AD - Department of Pharmacognosy, JSS College of Pharmacy, Udhagamandalam, Tamilnadu, India. FAU - Murthy, Vishakantha AU - Murthy V FAU - Khatwal, Rizwan Basha AU - Khatwal RB FAU - Dubala, Anil AU - Dubala A FAU - Chinni, Santhivardhan AU - Chinni S FAU - Muthureddy Nataraj, Satish Kumar AU - Muthureddy Nataraj SK FAU - Basavan, Duraiswamy AU - Basavan D LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131010 PL - England TA - J Pharm Pharmacol JT - The Journal of pharmacy and pharmacology JID - 0376363 RN - 0 (Amyloid beta-Peptides) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Interleukin-1beta) RN - 0 (Nitriles) RN - 0 (Pyrrolidines) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (tau Proteins) RN - 5W494URQ81 (Streptozocin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - I6B4B2U96P (Vildagliptin) RN - PJY633525U (Adamantane) SB - IM MH - Adamantane/*analogs & derivatives/therapeutic use MH - Alzheimer Disease/chemically induced/*drug therapy/pathology MH - Amyloid beta-Peptides/analysis MH - Animals MH - Cognition Disorders/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Glucagon-Like Peptide 1/analysis MH - Hippocampus/chemistry MH - Hypoglycemic Agents/*therapeutic use MH - Interleukin-1beta/analysis MH - Male MH - Maze Learning/drug effects MH - Nitriles/*therapeutic use MH - Pyrrolidines/*therapeutic use MH - Rats MH - Rats, Wistar MH - Streptozocin MH - Tumor Necrosis Factor-alpha/analysis MH - Vildagliptin MH - tau Proteins/analysis OTO - NOTNLM OT - amyloid beta OT - dipeptidyl peptidase-4 OT - glucagon-like peptide-1 OT - tau OT - type 2 diabetes EDAT- 2013/10/15 06:00 MHDA- 2014/09/06 06:00 CRDT- 2013/10/15 06:00 PHST- 2013/04/24 00:00 [received] PHST- 2013/08/25 00:00 [accepted] PHST- 2013/10/15 06:00 [entrez] PHST- 2013/10/15 06:00 [pubmed] PHST- 2014/09/06 06:00 [medline] AID - 10.1111/jphp.12148 [doi] PST - ppublish SO - J Pharm Pharmacol. 2013 Dec;65(12):1773-84. doi: 10.1111/jphp.12148. Epub 2013 Oct 10. PMID- 24112036 OWN - NLM STAT- MEDLINE DCOM- 20140312 LR - 20191210 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 128 IP - 3 DP - 2014 Feb TI - Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress. PG - 459-71 LID - 10.1111/jnc.12469 [doi] AB - Glucagon-like peptide 1 (GLP-1) is a growth factor that has demonstrated neuroprotective properties in a range of studies. In an APPswe/PS1DeltaE9 mouse model of Alzheimer's disease (AD), we previously found protective effects on memory formation, synaptic plasticity, synapse survival and a reduction of amyloid synthesis and plaque load in the brain. Here, we analyse the neuroprotective properties of the GLP-1 analogue liraglutide in human neuroblastoma cell line SH-SY5Y during methyl glyoxal stress. We show for the first time that cell viability was enhanced by liraglutide (XTT assay) in a dose-dependent way, while cytotoxicity (LDH assay) and apoptosis were reduced. Expression of the pro-survival Mcl1 signaling protein was increased, as was activation of cell survival kinases Akt, MEK1/2 and the transcription factor p90RSK. Liraglutide also decreased pro-apoptotic Bax and Bik expression. In addition, the membrane potential and the influx of calcium into the cell were enhanced by liraglutide. GLP-1 receptor expression was also increased by the drug. The results demonstrate a range of growth factor-related cytoprotective processes induced by liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(R)). It is also tested in clinical trials in patients with Alzheimer disease. CI - (c) 2013 International Society for Neurochemistry. FAU - Sharma, Mohit K AU - Sharma MK AD - Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK. FAU - Jalewa, Jaishree AU - Jalewa J FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131028 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (BIK protein, human) RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Membrane Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Glucagon) RN - 0 (bcl-2-Associated X Protein) RN - 722KLD7415 (Pyruvaldehyde) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.4.22.- (Caspase 3) RN - SY7Q814VUP (Calcium) SB - IM MH - Apoptosis/*drug effects MH - Apoptosis Regulatory Proteins/metabolism MH - Blotting, Western MH - Calcium/metabolism MH - Caspase 3/metabolism MH - Cell Line MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Immunohistochemistry MH - Liraglutide MH - Membrane Potentials MH - Membrane Proteins/metabolism MH - Mitochondrial Proteins MH - Mitogen-Activated Protein Kinases/metabolism MH - *Neuroprotective Agents MH - Oncogene Protein v-akt/metabolism MH - Pyruvaldehyde/*toxicity MH - Receptors, Glucagon/biosynthesis/genetics MH - Stress, Physiological/*drug effects MH - bcl-2-Associated X Protein/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - apoptosis OT - incretins OT - insulin OT - neurodegeneration OT - neuroprotection EDAT- 2013/10/12 06:00 MHDA- 2014/03/13 06:00 CRDT- 2013/10/12 06:00 PHST- 2013/07/13 00:00 [received] PHST- 2013/09/10 00:00 [revised] PHST- 2013/09/19 00:00 [accepted] PHST- 2013/10/12 06:00 [entrez] PHST- 2013/10/12 06:00 [pubmed] PHST- 2014/03/13 06:00 [medline] AID - 10.1111/jnc.12469 [doi] PST - ppublish SO - J Neurochem. 2014 Feb;128(3):459-71. doi: 10.1111/jnc.12469. Epub 2013 Oct 28. PMID- 24074446 OWN - NLM STAT- MEDLINE DCOM- 20141205 LR - 20191027 IS - 1996-3181 (Electronic) IS - 1871-5273 (Linking) VI - 13 IP - 2 DP - 2014 Mar TI - Epigenomic approach in understanding Alzheimer's disease and type 2 diabetes mellitus. PG - 283-9 AB - Cognitive decline is a debilitating feature of Alzheimer's disease (AD). The causes leading to such impairment are still poorly understood and effective treatments for AD are still unavailable. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for AD due to desensitisation of insulin receptors in the brain. Recent studies have suggested that epigenetic mechanisms may also play a pivotal role in the pathogenesis of both AD and T2DM. This article describes the correlation between AD and T2DM and provides the insights to the epigenetics of AD. Currently, more research is needed to clarify the exact role of epigenetic regulation in the course and development of AD and also in relation to insulin. Research conducted especially in the earlier stages of the disease could provide more insight into its underlying pathophysiology to help in early diagnosis and the development of more effective treatment strategies. FAU - Shaik, Munvar M AU - Shaik MM FAU - Gan, Siew H AU - Gan SH FAU - Kamal, Mohammad A AU - Kamal MA AD - Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia. munvar.shaik@gmail.com. LA - eng PT - Journal Article PL - United Arab Emirates TA - CNS Neurol Disord Drug Targets JT - CNS & neurological disorders drug targets JID - 101269155 RN - 0 (Insulin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*genetics/*physiopathology MH - Animals MH - DNA Methylation MH - Diabetes Mellitus, Type 2/*genetics/*physiopathology MH - *Epigenesis, Genetic MH - Epigenomics/*methods MH - Gene Expression MH - Glucagon-Like Peptide 1/genetics/metabolism MH - Humans MH - Insulin/genetics/metabolism EDAT- 2013/10/01 06:00 MHDA- 2014/12/15 06:00 CRDT- 2013/10/01 06:00 PHST- 2013/01/10 00:00 [received] PHST- 2013/02/10 00:00 [revised] PHST- 2013/02/19 00:00 [accepted] PHST- 2013/10/01 06:00 [entrez] PHST- 2013/10/01 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - CNSNDDT-EPUB-56465 [pii] AID - 10.2174/18715273113126660181 [doi] PST - ppublish SO - CNS Neurol Disord Drug Targets. 2014 Mar;13(2):283-9. doi: 10.2174/18715273113126660181. PMID- 24059324 OWN - NLM STAT- MEDLINE DCOM- 20141205 LR - 20191027 IS - 1996-3181 (Electronic) IS - 1871-5273 (Linking) VI - 13 IP - 2 DP - 2014 Mar TI - Fighting Alzheimer's disease and type 2 diabetes: pathological links and treatment strategies. PG - 271-82 AB - The incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) with associated serious complications continues to grow rapidly especially in developed countries. Emerging evidence indicates that AD and T2DM share some common risk factors with comparable pathological features including insulin resistance, amyloidogenesis, glucocorticoid imbalance, inflammation, mitochondrial function and oxidative stress. T2DM has been identified as a risk factor for AD. It has even been hypothesized that AD might be "type 3 diabetes". In addition to amyloid precursor protein processing and tau phosphorylation, commonalities between T2DM and AD in molecular mechanisms provide clues to the identification of novel therapeutic targets such as glucagon-like peptide 1, butyrylcholinesterase, and receptor for advanced glycosylation end products. Although several classes of anti-diabetic drugs are available, achieving long-term glycaemic control without side effects is often challenging. This review summarizes recent evidence for the pathological links, common therapeutic targets, currently the U.S. Food and Drug Administration approved and potential future therapies, giving special attention to ongoing clinical trials of antidiabetic drugs in AD patients and common therapeutic strategies in the management of both AD and T2DM. FAU - Dai, Ying AU - Dai Y FAU - Kamal, Mohammad A AU - Kamal MA AD - Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room CLS- 628, Brookline, MA 02445, USA. ydai@bidmc.harvard.edu. LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - CNS Neurol Disord Drug Targets JT - CNS & neurological disorders drug targets JID - 101269155 SB - IM MH - Alzheimer Disease/*drug therapy/*physiopathology MH - Animals MH - Diabetes Mellitus, Type 2/*drug therapy/*physiopathology MH - Humans EDAT- 2013/09/26 06:00 MHDA- 2014/12/15 06:00 CRDT- 2013/09/25 06:00 PHST- 2012/12/03 00:00 [received] PHST- 2013/02/17 00:00 [revised] PHST- 2013/02/19 00:00 [accepted] PHST- 2013/09/25 06:00 [entrez] PHST- 2013/09/26 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - CNSNDDT-EPUB-56136 [pii] AID - 10.2174/18715273113126660134 [doi] PST - ppublish SO - CNS Neurol Disord Drug Targets. 2014 Mar;13(2):271-82. doi: 10.2174/18715273113126660134. PMID- 24059307 OWN - NLM STAT- MEDLINE DCOM- 20150107 LR - 20220321 IS - 1996-3181 (Electronic) IS - 1871-5273 (Linking) VI - 13 IP - 3 DP - 2014 Apr TI - Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments? PG - 418-28 AB - Parkinson's disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of PD and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960's and there is still controversy. Insulin and dopamine may exert reciprocal regulation hence; hypoinsulinemia induced by streptozotocin decreased the amounts of dopamine transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta. Accordingly, dopamine depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that peroxisome proliferator-activated receptor-gamma, ATP-sensitive K(+) channels, AMP-activated protein kinase, glucagon-like peptide-1 and dipeptidyl peptidase-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments. FAU - Lima, Marcelo M S AU - Lima MM FAU - Targa, Adriano D S AU - Targa AD FAU - Noseda, Ana C D AU - Noseda AC FAU - Rodrigues, Lais S AU - Rodrigues LS FAU - Delattre, Ana Marcia AU - Delattre AM FAU - dos Santos, Fabiola V AU - dos Santos FV FAU - Fortes, Mariana H AU - Fortes MH FAU - Maturana, Maira J AU - Maturana MJ FAU - Ferraz, Anete C AU - Ferraz AC AD - Universidade Federal do Parana, Setor de Ciencias Biologicas, Departamento de Fisiologia, Av. Francisco H. dos Santos s/n, ZIP: 81.531 - 990, Caixa Postal: 19031, Curitiba, Parana, Brasil. mmslima@ufpr.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United Arab Emirates TA - CNS Neurol Disord Drug Targets JT - CNS & neurological disorders drug targets JID - 101269155 RN - 0 (Insulin) RN - IY9XDZ35W2 (Glucose) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/*complications/epidemiology/*therapy MH - Disease Models, Animal MH - Dopamine/metabolism MH - Glucose/metabolism MH - Humans MH - Insulin/metabolism MH - Insulin Resistance/physiology MH - Parkinson Disease/*complications/epidemiology/*therapy EDAT- 2013/09/26 06:00 MHDA- 2015/01/08 06:00 CRDT- 2013/09/25 06:00 PHST- 2013/02/01 00:00 [received] PHST- 2013/04/05 00:00 [revised] PHST- 2013/04/05 00:00 [accepted] PHST- 2013/09/25 06:00 [entrez] PHST- 2013/09/26 06:00 [pubmed] PHST- 2015/01/08 06:00 [medline] AID - CNSNDDT-EPUB-56160 [pii] AID - 10.2174/18715273113126660155 [doi] PST - ppublish SO - CNS Neurol Disord Drug Targets. 2014 Apr;13(3):418-28. doi: 10.2174/18715273113126660155. PMID- 23999914 OWN - NLM STAT- MEDLINE DCOM- 20140512 LR - 20140310 IS - 1479-6805 (Electronic) IS - 0022-0795 (Linking) VI - 221 IP - 1 DP - 2014 Apr TI - Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. PG - T31-41 LID - 10.1530/JOE-13-0221 [doi] AB - The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for the 'incretin effect', facilitating insulin release from the pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment for type 2 diabetes. In the course of monitoring of patients, it has become apparent that GLP-1 mimetics have a range of other physiological effects in the body. In preclinical trials, a substantial body of evidence has been built that these mimetics have neuroprotective and anti-inflammatory effects. GLP-1 also has very similar growth-factor-like properties to insulin, which is presumably the underlying basis of the neuroprotective effects. In preclinical studies of Alzheimer's disease (AD), Parkinson's disease (PD), stroke and other neurodegenerative disorders, it has been shown that most GLP-1 mimetics cross the blood-brain barrier and show impressive neuroprotective effects in numerous studies. In animal models of AD, GLP-1 mimetics such as exendin-4, liraglutide and lixisenatide have shown protective effects in the CNS by reducing beta-amyloid plaques, preventing loss of synapses and memory impairments, and reducing oxidative stress and the chronic inflammatory response in the brain. In animal models of PD, exendin-4 showed protection of dopaminergic neurons in the substantia nigra and prevention of dopamine loss in the basal ganglia while preserving motor control. These encouraging findings have spawned several clinical trials, some of which have shown encouraging initial results. Therefore, GLP-1 mimetics show great promise as a novel treatment for neurodegenerative conditions. FAU - Holscher, Christian AU - Holscher C AD - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140307 PL - England TA - J Endocrinol JT - The Journal of endocrinology JID - 0375363 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Glucagon-Like Peptide 1/*therapeutic use MH - Humans MH - Neurodegenerative Diseases/*drug therapy MH - Neuroprotective Agents/*therapeutic use OTO - NOTNLM OT - Alzheimer's disease OT - Parkinson's disease OT - amyotrophic lateral sclerosis OT - glucagon-like peptide 1 OT - incretins OT - ischaemia OT - multiple sclerosis OT - neurodegeneration OT - stroke EDAT- 2013/09/04 06:00 MHDA- 2014/05/13 06:00 CRDT- 2013/09/04 06:00 PHST- 2013/09/04 06:00 [entrez] PHST- 2013/09/04 06:00 [pubmed] PHST- 2014/05/13 06:00 [medline] AID - JOE-13-0221 [pii] AID - 10.1530/JOE-13-0221 [doi] PST - epublish SO - J Endocrinol. 2014 Mar 7;221(1):T31-41. doi: 10.1530/JOE-13-0221. Print 2014 Apr. PMID- 23973293 OWN - NLM STAT- MEDLINE DCOM- 20140605 LR - 20151119 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 76 Pt A DP - 2014 Jan TI - Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. PG - 57-67 LID - S0028-3908(13)00362-6 [pii] LID - 10.1016/j.neuropharm.2013.08.005 [doi] AB - Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza((R))) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1DeltaE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - McClean, Paula L AU - McClean PL AD - School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK. FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130821 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Neuroprotective Agents) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - *Aging/drug effects/pathology MH - Alzheimer Disease/complications/*drug therapy/metabolism/physiopathology/psychology MH - Amyloid beta-Peptides/metabolism MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Animals MH - Cell Count MH - Disease Models, Animal MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology/therapeutic use MH - Inflammation/drug therapy MH - Liraglutide MH - Long-Term Potentiation/drug effects/physiology MH - Male MH - Memory/drug effects MH - Memory Disorders/complications/*drug therapy MH - Mice MH - Mice, Transgenic MH - Nerve Degeneration/complications/drug therapy/metabolism MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Plaque, Amyloid/complications/*drug therapy MH - Stem Cells/drug effects MH - Synapses/*drug effects/pathology OTO - NOTNLM OT - Cognition OT - GLP-1 OT - Incretins OT - Inflammation OT - Insulin OT - Memory OT - Neurodegeneration OT - Neuroprotection OT - Stem cells OT - Synapse EDAT- 2013/08/27 06:00 MHDA- 2014/06/06 06:00 CRDT- 2013/08/27 06:00 PHST- 2013/01/15 00:00 [received] PHST- 2013/08/06 00:00 [revised] PHST- 2013/08/08 00:00 [accepted] PHST- 2013/08/27 06:00 [entrez] PHST- 2013/08/27 06:00 [pubmed] PHST- 2014/06/06 06:00 [medline] AID - S0028-3908(13)00362-6 [pii] AID - 10.1016/j.neuropharm.2013.08.005 [doi] PST - ppublish SO - Neuropharmacology. 2014 Jan;76 Pt A:57-67. doi: 10.1016/j.neuropharm.2013.08.005. Epub 2013 Aug 21. PMID- 23948890 OWN - NLM STAT- MEDLINE DCOM- 20140627 LR - 20151119 IS - 1875-8908 (Electronic) IS - 1387-2877 (Linking) VI - 37 IP - 3 DP - 2013 TI - Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. PG - 637-48 LID - 10.3233/JAD-130491 [doi] AB - BACKGROUND/OBJECTIVE: Type 2 diabetes increases the risk for developing Alzheimer's disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. METHODS: Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. RESULTS: We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3beta (GSK-3beta) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3beta, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. CONCLUSION: Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes. FAU - Yang, Yan AU - Yang Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Zhang, Jing AU - Zhang J FAU - Ma, Delin AU - Ma D FAU - Zhang, Muxun AU - Zhang M FAU - Hu, Shuhong AU - Hu S FAU - Shao, Shiying AU - Shao S FAU - Gong, Cheng-Xin AU - Gong CX LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Hypoglycemic Agents) RN - 0 (Mapt protein, rat) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*metabolism/prevention & control MH - Animals MH - Diabetes Mellitus, Type 2/*metabolism/prevention & control MH - Glucagon-Like Peptide 1/administration & dosage/*analogs & derivatives MH - Hypoglycemic Agents/*administration & dosage MH - Injections, Subcutaneous MH - Liraglutide MH - Male MH - Phosphorylation/drug effects/physiology MH - Random Allocation MH - Rats MH - Rats, Wistar MH - tau Proteins/antagonists & inhibitors/*metabolism EDAT- 2013/08/21 06:00 MHDA- 2014/06/28 06:00 CRDT- 2013/08/17 06:00 PHST- 2013/08/17 06:00 [entrez] PHST- 2013/08/21 06:00 [pubmed] PHST- 2014/06/28 06:00 [medline] AID - 42H181M42816H076 [pii] AID - 10.3233/JAD-130491 [doi] PST - ppublish SO - J Alzheimers Dis. 2013;37(3):637-48. doi: 10.3233/JAD-130491. PMID- 29922362 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240327 IS - 1758-3780 (Electronic) IS - 1758-3772 (Print) IS - 1758-3772 (Linking) VI - 9 IP - 2 DP - 2013 Aug TI - The Emerging Health Benefits of Coffee with an Emphasis on Type 2 Diabetes and Cardiovascular Disease. PG - 99-106 LID - 10.17925/EE.2013.09.02.99 [doi] AB - Debate persists whether coffee is beneficial or problematic for human health. Coffee consumption has been associated with a decrease in risk of developing type 2 diabetes, and numerous epidemiological studies have demonstrated that healthy, habitual coffee drinkers are more protected from the risk of contracting diabetes than individuals who do not drink coffee. Coffee consumption has been associated with a reduced incidence of impaired glucose tolerance, hyperglycaemia and insulin sensitivity. Data suggest that several coffee components, such as chlorogenic acids, are involved in the health benefits of coffee. Various mechanisms for this protective effect have been proposed, including effects on incretin release, liver glucose metabolism and insulin sensitivity. Epidemiological data support numerous other health benefits for coffee, including reduced cardiovascular disease (CVD), a protective effect against some neurodegenerative conditions, a favourable effect on liver function and a protective effect against certain cancers These associations are based mainly on observational studies and are currently insufficient to recommend coffee consumption as an interventional strategy for risk reduction in type 2 diabetes and other metabolic diseases While excessive consumption can have adverse effects on some conditions, particularly in terms of sleep quality, these effects vary among individuals and most people do not have any symptoms from coffee drinking. Moderate coffee consumption is associated with no or little risk of severe diseases and may offer substantial health benefits. Thus, coffee is a safe, low-energy beverage and suitable for most adult people. FAU - Bidel, Siamak AU - Bidel S AD - National institute for Health and Welfare and Hjelt institute, University of Helsinki, Finland. FAU - Tuomilehto, Jaakko AU - Tuomilehto J AD - Centre for Vascular Prevention, Danube-University Krems, Austria; Red RECAVA Grupo, Hospital Universitario La Paz, Madrid, Spain; King Abdulaziz University, Jeddah, Saudi Arabia; Department of Public Health, University of Helsinki, Finland. LA - eng PT - Journal Article PT - Review DEP - 20130823 PL - England TA - Eur Endocrinol JT - European endocrinology JID - 101574781 PMC - PMC6003581 OTO - NOTNLM OT - Caffeine OT - Parkinson's disease OT - chlorogenic acid OT - coffee OT - diabetes OT - mortality COIS- Disclosure: Siamak Bidel has no conflicts of interest to declare. Jaakko Tuomilehto has received research funding for investigator-initiated research from the Institute for Scientific Information on Coffee, and has received travel and lecture fees from Programa de Promoci6n de Consumo Toma Cafe, Colombia. EDAT- 2013/08/01 00:00 MHDA- 2013/08/01 00:01 PMCR- 2013/08/01 CRDT- 2018/06/21 06:00 PHST- 2013/04/10 00:00 [received] PHST- 2013/05/20 00:00 [accepted] PHST- 2018/06/21 06:00 [entrez] PHST- 2013/08/01 00:00 [pubmed] PHST- 2013/08/01 00:01 [medline] PHST- 2013/08/01 00:00 [pmc-release] AID - 10.17925/EE.2013.09.02.99 [doi] PST - ppublish SO - Eur Endocrinol. 2013 Aug;9(2):99-106. doi: 10.17925/EE.2013.09.02.99. Epub 2013 Aug 23. PMID- 23868462 OWN - NLM STAT- Publisher LR - 20250610 IS - 1520-7560 (Electronic) IS - 1520-7552 (Linking) DP - 2013 Jul 18 TI - Type 2 Diabetes Mellitus and Alzheimer's Disease: from physiopathology to treatment implications. LID - 10.1002/dmrr.2442 [doi] AB - Alzheimer's Disease (AD) is the most common cause of dementia worldwide. Type 2 Diabetes Mellitus (T2DM) is a disease characterized by insulin resistance (IR) and progressive beta cell failure, and affected individuals are at increased risk to develop several forms of cognitive dysfunction, including AD. Different mechanisms have already been identified linking visceral obesity, IR and AD. Insulin resistance is associated with a decrease in glucose uptake by neurons, an increase in Amyloid beta production and secretion, in the formation of senile plaques, and also in tau protein phosphorylation. Other mechanisms also include a decrease in Insulin Degrading Enzyme (IDE) activity and an increase in oxidative stress secondary to hyperglycemia. Taken together, these mechanisms suggest that drugs used to ameliorate hyperglycemia and IR may also have beneficial effects in diabetic patients with AD. Indeed, manuscripts investigating the effects of metformin, thiazolinediones, leptin, GLP-1 therapies, insulin and bariatric surgery in cognition and AD have been published with very promising results, and may indicate an alternative approach for these patients. This article is protected by copyright. All rights reserved. CI - This article is protected by copyright. All rights reserved. FAU - Moreira, Rodrigo O AU - Moreira RO AD - Instituto Estadual de Diabetes e Endocrinologia (IEDE) e Pontificia Universidade Catolica do Rio de Janeiro (PUC-RJ), Rio de Janeiro, Brasil. FAU - Campos, Stella C AU - Campos SC FAU - Soldera, Ana L AU - Soldera AL LA - eng PT - Journal Article PT - Retracted Publication DEP - 20130718 PL - England TA - Diabetes Metab Res Rev JT - Diabetes/metabolism research and reviews JID - 100883450 RIN - Diabetes Metab Res Rev. 2025 May;41(4):e2442. doi: 10.1002/dmrr.2442. PMID: 40476325 OTO - NOTNLM OT - Alzheimer's Disease OT - Cognition OT - Diabetes Mellitus EDAT- 2013/07/23 06:00 MHDA- 2013/07/23 06:00 CRDT- 2013/07/23 06:00 PHST- 2012/08/06 00:00 [received] PHST- 2013/02/14 00:00 [revised] PHST- 2013/06/03 00:00 [accepted] PHST- 2013/07/23 06:00 [entrez] PHST- 2013/07/23 06:00 [pubmed] PHST- 2013/07/23 06:00 [medline] AID - 10.1002/dmrr.2442 [doi] PST - aheadofprint SO - Diabetes Metab Res Rev. 2013 Jul 18. doi: 10.1002/dmrr.2442. PMID- 23850509 OWN - NLM STAT- MEDLINE DCOM- 20140319 LR - 20220311 IS - 1873-5118 (Electronic) IS - 0301-0082 (Linking) VI - 108 DP - 2013 Sep TI - Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. PG - 21-43 LID - S0301-0082(13)00053-1 [pii] LID - 10.1016/j.pneurobio.2013.06.004 [doi] AB - Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease-modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - Chen, Zhichun AU - Chen Z AD - Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Zhong, Chunjiu AU - Zhong C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20130711 PL - England TA - Prog Neurobiol JT - Progress in neurobiology JID - 0370121 RN - 0 (Biomarkers) RN - 0 (Glucose Transport Proteins, Facilitative) RN - IY9XDZ35W2 (Glucose) RN - X66NSO3N35 (Thiamine) SB - IM MH - Alzheimer Disease/*chemically induced/*metabolism/therapy MH - Biomarkers MH - Brain Chemistry/*physiology MH - Diabetes Mellitus, Type 2/complications MH - Glucose/*metabolism MH - Glucose Transport Proteins, Facilitative/metabolism MH - Humans MH - Oxidative Stress/physiology MH - Thiamine/metabolism OTO - NOTNLM OT - (11)C-Pittsbergh compound OT - (18)F-fluorodeoxyglucose OT - 8-OHG OT - 8-hydroxyguanosine OT - AD OT - AD neuroimaging initiative OT - ADNI OT - ADP OT - AGEs OT - APOE OT - APP OT - APP C-terminal fragments OT - APP-CTFs OT - ATP OT - Advanced glycation endproducts OT - Alzheimer's disease OT - Apoptosis OT - Autophagy OT - Abeta OT - BBB OT - CHEIs OT - CMRglu OT - CNS OT - COX OT - CSF OT - Cerebral hypometabolism OT - Excitotoxicity OT - FDG OT - G6PDH OT - GLP-1 OT - GLUT OT - GSK-3 OT - Glucagon-like peptide-1 OT - Glycogen synthase kinase 3 OT - IDE OT - IGF-1 OT - IR OT - IR substrate-1 OT - IRS-1 OT - Insulin resistance OT - KGDHC OT - LTP OT - MAPK OT - MCI OT - MMSE OT - MR OT - Mitochondrial dysfunction OT - N-methyl-D-aspartic acid receptor OT - NFTs OT - NMDAR OT - NSAID OT - Oxidative stress OT - PDHC OT - PET OT - PI3K OT - PKM2 OT - PPP OT - PS1 OT - Peroxisome proliferator-activated receptors OT - PiB OT - Positron emission tomography OT - RAGE OT - ROS OT - STZ OT - T1DM OT - T2DM OT - TCA OT - TD OT - TDP OT - TDPase OT - TGF OT - TMP OT - TMPase OT - TPK OT - Tau OT - Thiamine OT - adenosine driphosphate OT - adenosine triphosphate OT - advanced glycation end products OT - amyloid precursor protein OT - apolipoprotein E OT - blood brain barrier OT - central nervous system OT - cerebral metabolic rate of glucose OT - cerebrospinal fluid OT - cholinesterase inhibitors OT - cytochrome c oxidase OT - glucagon-like peptide-1 OT - glucose transporter OT - glucose-6-phosphate dehydrogenase OT - glycogen synthase kinase-3 OT - insulin receptor OT - insulin-degrading enzyme OT - insulin-like growth factor-1 OT - long term potentiation OT - mTOR OT - magnetic resonance OT - mild cognitive impairment OT - mitogen-activated protein kinase OT - neurofibrillary tangles OT - non-steroidal anti-inflammatory drug OT - pentose phosphate pathway OT - phosphatidylinositide 3-kinases OT - positron emission tomography OT - presenilin-1 OT - pyruvate dehydrogenase complex OT - pyruvate kinase isozyme type M2 OT - rCBF OT - rCMRGlu OT - reactive oxygen species OT - regional CMRGlu OT - regional cerebral blood flow OT - streptozotocin OT - the Mini-Mental State Examination OT - the mammalian target of rapamycin OT - the receptor of AGEs OT - thiamine deficiency OT - thiamine diphosphatase OT - thiamine diphosphate OT - thiamine monophosphatase OT - thiamine monophosphate OT - thiamine pyrophosphokinase OT - transformation growth factor OT - tricarboxylic acid OT - type 1 diabetes mellitus OT - type 2 diabetes mellitus OT - alpha-ketoglutarate dehydrogenase complex OT - beta-amyloid OT - gamma-PPAR OT - gamma-peroxisome proliferator-actived receptor EDAT- 2013/07/16 06:00 MHDA- 2014/03/22 06:00 CRDT- 2013/07/16 06:00 PHST- 2013/04/06 00:00 [received] PHST- 2013/06/03 00:00 [revised] PHST- 2013/06/18 00:00 [accepted] PHST- 2013/07/16 06:00 [entrez] PHST- 2013/07/16 06:00 [pubmed] PHST- 2014/03/22 06:00 [medline] AID - S0301-0082(13)00053-1 [pii] AID - 10.1016/j.pneurobio.2013.06.004 [doi] PST - ppublish SO - Prog Neurobiol. 2013 Sep;108:21-43. doi: 10.1016/j.pneurobio.2013.06.004. Epub 2013 Jul 11. PMID- 23728174 OWN - NLM STAT- MEDLINE DCOM- 20130802 LR - 20241219 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 123 IP - 6 DP - 2013 Jun TI - Exenatide and the treatment of patients with Parkinson's disease. PG - 2730-6 AB - BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01174810. FUNDING: Cure Parkinson's Trust. FAU - Aviles-Olmos, Iciar AU - Aviles-Olmos I AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, United Kingdom. FAU - Dickson, John AU - Dickson J FAU - Kefalopoulou, Zinovia AU - Kefalopoulou Z FAU - Djamshidian, Atbin AU - Djamshidian A FAU - Ell, Peter AU - Ell P FAU - Soderlund, Therese AU - Soderlund T FAU - Whitton, Peter AU - Whitton P FAU - Wyse, Richard AU - Wyse R FAU - Isaacs, Tom AU - Isaacs T FAU - Lees, Andrew AU - Lees A FAU - Limousin, Patricia AU - Limousin P FAU - Foltynie, Thomas AU - Foltynie T LA - eng SI - ClinicalTrials.gov/NCT01174810 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Antiparkinson Agents) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 9P1872D4OL (Exenatide) SB - IM CIN - J Clin Invest. 2013 Jun;123(6):2364-5. doi: 10.1172/JCI69690. PMID: 23728166 MH - Aged MH - Antiparkinson Agents/*administration & dosage/adverse effects MH - Constipation/chemically induced MH - Disease Progression MH - Drug Repositioning MH - Exenatide MH - Female MH - Humans MH - Hypoglycemic Agents/administration & dosage/adverse effects MH - Injections, Subcutaneous MH - Male MH - Middle Aged MH - Motor Activity/drug effects MH - Off-Label Use MH - Parkinson Disease/*drug therapy/physiopathology MH - Peptides/*administration & dosage/adverse effects MH - Venoms/*administration & dosage/adverse effects MH - Weight Loss/drug effects PMC - PMC3668846 EDAT- 2013/06/04 06:00 MHDA- 2013/08/03 06:00 PMCR- 2013/05/20 CRDT- 2013/06/04 06:00 PHST- 2013/02/07 00:00 [received] PHST- 2013/03/21 00:00 [accepted] PHST- 2013/06/04 06:00 [entrez] PHST- 2013/06/04 06:00 [pubmed] PHST- 2013/08/03 06:00 [medline] PHST- 2013/05/20 00:00 [pmc-release] AID - 68295 [pii] AID - 10.1172/JCI68295 [doi] PST - ppublish SO - J Clin Invest. 2013 Jun;123(6):2730-6. doi: 10.1172/JCI68295. PMID- 23640454 OWN - NLM STAT- MEDLINE DCOM- 20131023 LR - 20211021 IS - 2041-4889 (Electronic) VI - 4 IP - 5 DP - 2013 May 2 TI - Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. PG - e612 LID - 10.1038/cddis.2013.139 [doi] AB - Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate. FAU - Bomba, M AU - Bomba M AD - Molecular Neurology Unit, Center of Excellence on Aging (CeSI), University Gd Annunzio Chieti-Pescara, Chieti, Italy. FAU - Ciavardelli, D AU - Ciavardelli D FAU - Silvestri, E AU - Silvestri E FAU - Canzoniero, L M T AU - Canzoniero LM FAU - Lattanzio, R AU - Lattanzio R FAU - Chiappini, P AU - Chiappini P FAU - Piantelli, M AU - Piantelli M FAU - Di Ilio, C AU - Di Ilio C FAU - Consoli, A AU - Consoli A FAU - Sensi, S L AU - Sensi SL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130502 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Amyloid beta-Peptides) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 0 (tau Proteins) RN - 33X04XA5AT (Lactic Acid) RN - 9P1872D4OL (Exenatide) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 1.9.3.1 (Electron Transport Complex IV) SB - IM MH - Alzheimer Disease/metabolism/pathology MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Brain/*drug effects/enzymology/metabolism MH - Cognition Disorders/drug therapy/metabolism/pathology MH - Diabetes Mellitus, Experimental/drug therapy MH - Disease Models, Animal MH - Electron Transport Complex IV/metabolism MH - Exenatide MH - Female MH - Hypoglycemic Agents/*pharmacology/therapeutic use MH - L-Lactate Dehydrogenase/metabolism MH - Lactic Acid/metabolism MH - Male MH - Memory, Long-Term/drug effects MH - Memory, Short-Term/drug effects MH - Mice MH - Mice, Transgenic MH - Mitochondria/enzymology MH - Peptides/*pharmacology/therapeutic use MH - Venoms/*pharmacology/therapeutic use MH - tau Proteins/metabolism PMC - PMC3674348 EDAT- 2013/05/04 06:00 MHDA- 2013/10/24 06:00 PMCR- 2013/05/01 CRDT- 2013/05/04 06:00 PHST- 2013/05/04 06:00 [entrez] PHST- 2013/05/04 06:00 [pubmed] PHST- 2013/10/24 06:00 [medline] PHST- 2013/05/01 00:00 [pmc-release] AID - cddis2013139 [pii] AID - 10.1038/cddis.2013.139 [doi] PST - epublish SO - Cell Death Dis. 2013 May 2;4(5):e612. doi: 10.1038/cddis.2013.139. PMID- 23637538 OWN - NLM STAT- MEDLINE DCOM- 20131017 LR - 20220409 IS - 1178-2048 (Electronic) IS - 1176-6344 (Print) IS - 1176-6344 (Linking) VI - 9 DP - 2013 TI - Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. PG - 155-63 LID - 10.2147/VHRM.S33934 [doi] AB - Type 2 diabetes carries a risk for hypoglycemia, particularly in patients on an intensive glucose control plan as a glucose-lowering strategy, where hypoglycemia may be a limitation for the therapy and also a factor underlying clinical inertia. Glucose-lowering medications that increase circulating insulin in a glucose-independent manner, such as insulin and sulfonylurea therapy, are the most common cause of hypoglycemia. However, other factors such as a delayed or missed meal, physical exercise, or drug or alcohol consumption may also contribute. Specific risk factors for development of hypoglycemia are old age, long duration of diabetes, some concomitant medication, renal dysfunction, hypoglycemia unawareness, and cognitive dysfunction. Hypoglycemia is associated with acute short-term symptoms related to either counterregulation, such as tachycardia and sweating, or to neuroglycopenia, such as irritability, confusion, and in severe cases stupor, coma, and even death. However, there are also long-term consequences of hypoglycemia such as reduced working capacity, weight gain, loss of self-confidence with reduced quality of life, and increased risk for cardiovascular diseases. For both the patients, the health care system, and the society at large, hypoglycemia carries a high cost. Strategies to mitigate the risk of hypoglycemia include awareness of the condition; education of patients, relatives, and health care providers; and selecting appropriate glucose-lowering medication that also judges the risk for hypoglycemia to prevent this complication. This article summarizes the current knowledge of hypoglycemia and its consequences with a special emphasis on its consequences for the choice of glucose-lowering therapy. FAU - Ahren, Bo AU - Ahren B AD - Department of Clinical Sciences, Lund, Faculty of Medicine, Lund University, Lund, Sweden. bo.ahren@med.lu.se LA - eng PT - Journal Article PT - Review DEP - 20130424 PL - New Zealand TA - Vasc Health Risk Manag JT - Vascular health and risk management JID - 101273479 RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) SB - IM MH - Biomarkers/blood MH - Blood Glucose/*drug effects/metabolism MH - Diabetes Mellitus, Type 2/blood/diagnosis/*drug therapy/economics MH - Health Care Costs MH - Health Knowledge, Attitudes, Practice MH - Humans MH - Hypoglycemia/blood/chemically induced/economics/epidemiology/*prevention & control MH - Hypoglycemic Agents/*adverse effects/economics MH - Incidence MH - Patient Education as Topic MH - Patient Selection MH - Risk Assessment MH - Risk Factors MH - Risk Reduction Behavior MH - Treatment Outcome PMC - PMC3639216 OTO - NOTNLM OT - hypoglycemia OT - incretin therapy OT - insulin OT - sulfonylurea OT - treatment OT - type 2 diabetes EDAT- 2013/05/03 06:00 MHDA- 2013/10/18 06:00 PMCR- 2013/04/24 CRDT- 2013/05/03 06:00 PHST- 2013/05/03 06:00 [entrez] PHST- 2013/05/03 06:00 [pubmed] PHST- 2013/10/18 06:00 [medline] PHST- 2013/04/24 00:00 [pmc-release] AID - vhrm-9-155 [pii] AID - 10.2147/VHRM.S33934 [doi] PST - ppublish SO - Vasc Health Risk Manag. 2013;9:155-63. doi: 10.2147/VHRM.S33934. Epub 2013 Apr 24. PMID- 23615668 OWN - NLM STAT- MEDLINE DCOM- 20140107 LR - 20260128 IS - 1873-5126 (Electronic) IS - 1353-8020 (Linking) VI - 19 IP - 7 DP - 2013 Jul TI - Multicentre analysis of 178,992 type 2 diabetes patients revealed better metabolic control despite higher rates of hypertension, stroke, dementia and repeated inpatient care in patients with comorbid Parkinson's disease. PG - 687-92 LID - S1353-8020(13)00127-2 [pii] LID - 10.1016/j.parkreldis.2013.03.011 [doi] AB - BACKGROUND: Especially in older people, physicians are faced with the coexistence of type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). Therefore, this research aimed to compare diabetes endpoints between T2DM with and without PD. METHODS: Based on the standardized, multicenter, prospective DPV database, 178,992 T2DM patients (>/=40 years) were analyzed. 1579 were diagnosed with PD and/or received specific treatment. Hierarchical multivariable regression models were used for group comparisons; adjusted estimates based on observed marginal frequencies were calculated. RESULTS: PD patients were significantly older (77.9 vs. 70.0 years; p < 0.0001) and had a longer diabetes duration (10.3 vs. 8.4 years; p < 0.0001). In young PD patients (<50 years), percentage of females was significantly higher compared to age-matched T2DM patients without PD or people of the German population (66.7 vs. 38.1 vs. 49.0%; p < 0.0001, p < 0.02). After demographic adjustment, T2DM patients with PD showed a significantly lower HbA1c (58.0 vs. 60.3 mmol/mol; p < 0.0001), OAD/GLP-1 treatment (41.9 vs. 45.9%; p < 0.01) and frequency of dyslipidemia (62.0 vs. 64.5%; p < 0.05). In contrast, rates of insulin therapy (57.8 vs. 54.8%; p < 0.05), hypertension (73.3 vs. 68.6%; p < 0.001), antihypertensive medication (60.4 vs. 56.1%; p < 0.01), stroke (12.0 vs. 7.3%; p < 0.0001), dementia (9.2 vs. 2.6%; p < 0.0001) and repeated inpatient care (15.7 vs. 12.0%; p < 0.0001) were significantly higher and duration of hospital stay (6.2 vs. 4.7 days; p < 0.0001) was significantly longer in T2DM with PD. CONCLUSION: Clear demographic and clinical differences were observed between T2DM with and without PD. In PD patients, metabolic control is better, potentially due to more intensive medical care. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - Scheuing, Nicole AU - Scheuing N AD - University of Ulm, Institute of Epidemiology and Medical Biometry, ZIBMT, Albert-Einstein-Allee 41, 89081 Ulm, Germany. nicole.scheuing@uni-ulm.de FAU - Best, Frank AU - Best F FAU - Dapp, Albrecht AU - Dapp A FAU - Dreyhaupt, Ines AU - Dreyhaupt I FAU - Filz, Hans-Peter AU - Filz HP FAU - Krakow, Dietmar AU - Krakow D FAU - Lang, Wolfgang AU - Lang W FAU - Siegel, Erhard AU - Siegel E FAU - Zeyfang, Andrej AU - Zeyfang A FAU - Holl, Reinhard W AU - Holl RW CN - DPV initiative and the German BMBF Competence Network Diabetes mellitus LA - eng PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20130421 PL - England TA - Parkinsonism Relat Disord JT - Parkinsonism & related disorders JID - 9513583 RN - 0 (Glycated Hemoglobin) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Austria MH - Chi-Square Distribution MH - Comorbidity MH - Dementia/*complications MH - Diabetes Mellitus, Type 2/*complications/epidemiology MH - Female MH - Germany MH - Glycated Hemoglobin/metabolism MH - Humans MH - Hypertension/*complications MH - *Inpatients MH - Male MH - Middle Aged MH - Parkinson Disease/*epidemiology MH - Prospective Studies MH - Statistics, Nonparametric MH - Stroke/*complications EDAT- 2013/04/26 06:00 MHDA- 2014/01/08 06:00 CRDT- 2013/04/26 06:00 PHST- 2012/12/20 00:00 [received] PHST- 2013/03/13 00:00 [revised] PHST- 2013/03/19 00:00 [accepted] PHST- 2013/04/26 06:00 [entrez] PHST- 2013/04/26 06:00 [pubmed] PHST- 2014/01/08 06:00 [medline] AID - S1353-8020(13)00127-2 [pii] AID - 10.1016/j.parkreldis.2013.03.011 [doi] PST - ppublish SO - Parkinsonism Relat Disord. 2013 Jul;19(7):687-92. doi: 10.1016/j.parkreldis.2013.03.011. Epub 2013 Apr 21. PMID- 23603201 OWN - NLM STAT- MEDLINE DCOM- 20140211 LR - 20130628 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 72 DP - 2013 Sep TI - Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer's disease. PG - 291-300 LID - S0028-3908(13)00145-7 [pii] LID - 10.1016/j.neuropharm.2013.04.008 [doi] AB - Type 2 diabetes (T2D) is one of the major risk factors associated with Alzheimer's disease (AD). Recent studies have found similarities in molecular mechanisms that underlie the respective degenerative developments in the two diseases. Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level of glucagon-like peptide-1 (GLP-1) and ameliorate T2D, have become valuable candidates as disease modifying agents in the treatment of AD. In addition, endogenous GLP-1 levels decrease amyloid beta (Abeta) peptide and tau phosphorylation in AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin (STZ) induced rat model of AD. Three months following induction of AD by intracerebral administration of streptozotocin, animals were orally administered Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. The effect of the DPP-4 inhibitor on hippocampal GLP-1 levels, Abeta burden, tau phosphorylation, inflammatory markers and memory retention were evaluated. The results reveal an attenuation of Abeta, tau phosphorylation and inflammatory markers and an improvement in hippocampal GLP-1 and memory retention following treatment. This remarkable therapeutic effect of Saxagliptin mediated through DPP-4 inhibition demonstrates a unique mechanism for Abeta and tau clearance by increasing GLP-1 levels and reverses the behavioural deficits and pathology observed in AD. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - Kosaraju, Jayasankar AU - Kosaraju J AD - Department of Pharmacognosy, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. jayasankar87@hotmail.com FAU - Gali, Chaitanya Chakravarthi AU - Gali CC FAU - Khatwal, Rizwan Basha AU - Khatwal RB FAU - Dubala, Anil AU - Dubala A FAU - Chinni, Santhivardhan AU - Chinni S FAU - Holsinger, R M Damian AU - Holsinger RM FAU - Madhunapantula, V Subba Rao AU - Madhunapantula VS FAU - Muthureddy Nataraj, Satish Kumar AU - Muthureddy Nataraj SK FAU - Basavan, Duraiswamy AU - Basavan D LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130417 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amyloid beta-Peptides) RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Dipeptides) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (tau Proteins) RN - 5W494URQ81 (Streptozocin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9GB927LAJW (saxagliptin) RN - PJY633525U (Adamantane) SB - IM MH - Adamantane/*analogs & derivatives/therapeutic use MH - Alzheimer Disease/*chemically induced/*drug therapy/pathology MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Antibiotics, Antineoplastic/*toxicity MH - Dipeptides/*therapeutic use MH - Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use MH - Disease Models, Animal MH - Dogs MH - Dose-Response Relationship, Drug MH - Exploratory Behavior/drug effects MH - Gene Expression Regulation/drug effects MH - Glucagon-Like Peptide 1/metabolism MH - Hippocampus/drug effects/metabolism/pathology MH - Interleukin-1beta/metabolism MH - Male MH - Maze Learning/drug effects MH - Rats MH - Rats, Wistar MH - Streptozocin/*toxicity MH - Tumor Necrosis Factor-alpha/metabolism MH - tau Proteins/metabolism EDAT- 2013/04/23 06:00 MHDA- 2014/02/12 06:00 CRDT- 2013/04/23 06:00 PHST- 2012/11/29 00:00 [received] PHST- 2013/03/15 00:00 [revised] PHST- 2013/04/05 00:00 [accepted] PHST- 2013/04/23 06:00 [entrez] PHST- 2013/04/23 06:00 [pubmed] PHST- 2014/02/12 06:00 [medline] AID - S0028-3908(13)00145-7 [pii] AID - 10.1016/j.neuropharm.2013.04.008 [doi] PST - ppublish SO - Neuropharmacology. 2013 Sep;72:291-300. doi: 10.1016/j.neuropharm.2013.04.008. Epub 2013 Apr 17. PMID- 23601582 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20140520 LR - 20211021 IS - 1758-9193 (Print) IS - 1758-9193 (Electronic) VI - 5 IP - 2 DP - 2013 TI - Neuroprotective effects of D-Ala(2)GIP on Alzheimer's disease biomarkers in an APP/PS1 mouse model. PG - 20 LID - 10.1186/alzrt174 [doi] AB - INTRODUCTION: Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala(2)GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9). METHODS: D-Ala(2)GIP was injected for 21 days at 25 nmol/kg ip once daily in APP/PS1 male mice and wild type (WT) littermates aged 6 or 12 months of age. Amyloid plaque load, inflammation biomarkers, synaptic plasticity in the brain (LTP), and memory were measured. RESULTS: D-Ala(2)GIP improved memory in WT mice and rescued the cognitive decline of 12 months old APP/PS1 mice in two different memory tasks. Furthermore, deterioration of synaptic function in the dentate gyrus and cortex was prevented in 12 months old APP/PS1 mice. D-Ala(2)GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala(2)GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced. CONCLUSION: The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD. FAU - Faivre, Emilie AU - Faivre E AD - School of Biomedical Sciences, Ulster University, Cromore road, Coleraine, BT52 1SA, UK. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, Ulster University, Cromore road, Coleraine, BT52 1SA, UK. LA - eng PT - Journal Article DEP - 20130419 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 PMC - PMC3706793 EDAT- 2013/04/23 06:00 MHDA- 2013/04/23 06:01 PMCR- 2013/04/19 CRDT- 2013/04/23 06:00 PHST- 2012/12/28 00:00 [received] PHST- 2013/03/09 00:00 [revised] PHST- 2013/04/08 00:00 [accepted] PHST- 2013/04/23 06:00 [entrez] PHST- 2013/04/23 06:00 [pubmed] PHST- 2013/04/23 06:01 [medline] PHST- 2013/04/19 00:00 [pmc-release] AID - alzrt174 [pii] AID - 10.1186/alzrt174 [doi] PST - epublish SO - Alzheimers Res Ther. 2013 Apr 19;5(2):20. doi: 10.1186/alzrt174. eCollection 2013. PMID- 23536825 OWN - NLM STAT- MEDLINE DCOM- 20131227 LR - 20211203 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 3 DP - 2013 TI - Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PG - e58784 LID - 10.1371/journal.pone.0058784 [doi] LID - e58784 AB - Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Abeta in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD) mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers). Moreover, numbers of immature neurons (DCX) were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker). A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(TM)), increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD. FAU - Parthsarathy, Vadivel AU - Parthsarathy V AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130311 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Dcx protein, mouse) RN - 0 (Doublecortin Protein) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Age Factors MH - Alzheimer Disease/*metabolism MH - Animals MH - Cell Differentiation/*drug effects MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Disease Models, Animal MH - Doublecortin Protein MH - Female MH - Glucagon-Like Peptide 1/administration & dosage/*analogs & derivatives/pharmacology MH - Liraglutide MH - Mice MH - Neurogenesis/*drug effects MH - Neurons/*cytology/drug effects/*metabolism PMC - PMC3594148 COIS- Competing Interests: Dr. C. Holscher is an editor on PLOS ONE. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2013/03/29 06:00 MHDA- 2013/12/29 06:00 PMCR- 2013/03/11 CRDT- 2013/03/29 06:00 PHST- 2012/07/13 00:00 [received] PHST- 2013/02/08 00:00 [accepted] PHST- 2013/03/29 06:00 [entrez] PHST- 2013/03/29 06:00 [pubmed] PHST- 2013/12/29 06:00 [medline] PHST- 2013/03/11 00:00 [pmc-release] AID - PONE-D-12-21092 [pii] AID - 10.1371/journal.pone.0058784 [doi] PST - ppublish SO - PLoS One. 2013;8(3):e58784. doi: 10.1371/journal.pone.0058784. Epub 2013 Mar 11. PMID- 23506375 OWN - NLM STAT- MEDLINE DCOM- 20131112 LR - 20260128 IS - 1875-6417 (Electronic) IS - 1573-3998 (Linking) VI - 9 IP - 3 DP - 2013 May TI - The science of hypoglycemia in patients with diabetes. PG - 195-208 AB - The risk of hypoglycemia with anti-hyperglycemic agents is an important limiting factor in the management of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. While hypoglycemia is more common in T1DM, the incidence is high in T2DM patients who use insulin or secretagogues, particularly patients with longer duration of diabetes. The underlying cause of hypoglycemia in diabetes is a complex interaction between hyperinsulinemia and compromised physiologic and behavioral responses to falling glucose levels. Pancreatic dysfunction also causes loss of normal therapeutic response to hypoglycemia--a reduction in circulating insulin (in T2DM only) and an increase in glucagon secretion. In T1DM and advanced T2DM, the third defense against hypoglycemia is increase in adrenomedullary sympathoadrenal epinephrine secretion, which is also compromised, causing the syndrome of defective glucose counterregulation. Diminished increase in epinephrine, also called hypoglycemia-associated autonomic failure (HAAF), is largely responsible for defective glucose counterregulation. HAAF can result in recurrent hypoglycemia and lowering of glycemic threshold that typically triggers sympathoadrenal response to hypoglycemia. This results in hypoglycemia without warning symptoms, or "hypoglycemia unawareness," which increases the risk of severe hypoglycemia associated with substantial morbidity and mortality. Long-term effects of severe hypoglycemia, aside from causing accidents, may include adverse cardiovascular outcomes and cognitive impairment. To reduce the impact of hypoglycemia, it is important to identify patients at risk and use careful consideration when choosing antidiabetes medications. Newer insulin analogs that more accurately replicate endogenous insulin secretion and incretin therapies that cause glucose-sensitive insulin secretion may ultimately reduce the risk of hypoglycemia. FAU - Oyer, David S AU - Oyer DS AD - Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, 211 E. Chicago Avenue, Suite 1050, Chicago IL 60611, USA. davidoyer@gmail.com LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United Arab Emirates TA - Curr Diabetes Rev JT - Current diabetes reviews JID - 101253260 RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin) RN - 0 (Hypoglycemic Agents) RN - 0 (hemoglobin A1c protein, human) SB - IM MH - Accidents MH - Autonomic Nervous System/drug effects/*physiopathology MH - Blood Glucose/*metabolism MH - Cardiovascular Diseases/blood/etiology MH - Cognition Disorders/blood/etiology MH - Diabetes Complications/blood/*etiology/physiopathology MH - Diabetes Mellitus/blood/*physiopathology MH - Diabetes Mellitus, Type 1/blood/*complications/drug therapy/physiopathology MH - Diabetes Mellitus, Type 2/blood/complications/drug therapy/physiopathology MH - Diabetic Angiopathies/blood/etiology MH - Female MH - Glycated Hemoglobin/metabolism MH - Health Knowledge, Attitudes, Practice MH - Humans MH - Hyperinsulinism/blood/etiology MH - Hypoglycemia/blood/chemically induced/*etiology/physiopathology MH - Hypoglycemic Agents/administration & dosage/*adverse effects MH - Male MH - Patient Selection MH - Risk Factors MH - Severity of Illness Index EDAT- 2013/03/20 06:00 MHDA- 2013/11/13 06:00 CRDT- 2013/03/20 06:00 PHST- 2012/08/27 00:00 [received] PHST- 2013/01/30 00:00 [revised] PHST- 2013/01/30 00:00 [accepted] PHST- 2013/03/20 06:00 [entrez] PHST- 2013/03/20 06:00 [pubmed] PHST- 2013/11/13 06:00 [medline] AID - CDR-EPUB-20130314-1 [pii] AID - 10.2174/15733998113099990059 [doi] PST - ppublish SO - Curr Diabetes Rev. 2013 May;9(3):195-208. doi: 10.2174/15733998113099990059. PMID- 23363296 OWN - NLM STAT- MEDLINE DCOM- 20131112 LR - 20191112 IS - 1875-6417 (Electronic) IS - 1573-3998 (Linking) VI - 9 IP - 3 DP - 2013 May TI - Alzheimer's disease and diabetes: new insights and unifying therapies. PG - 218-27 AB - Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral beta-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (beta-site APP Cleaving Enzime 1). Similarly, deposits of Abeta produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies. FAU - Vignini, Arianna AU - Vignini A AD - Department of Clinical Science, Section of Biochemistry, Universita Politecnica delle Marche, Via Tronto 10 A, 60020 Ancona, Italy. FAU - Giulietti, Alessia AU - Giulietti A FAU - Nanetti, Laura AU - Nanetti L FAU - Raffaelli, Francesca AU - Raffaelli F FAU - Giusti, Lucia AU - Giusti L FAU - Mazzanti, Laura AU - Mazzanti L FAU - Provinciali, Leandro AU - Provinciali L LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Curr Diabetes Rev JT - Current diabetes reviews JID - 101253260 RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9100L32L2N (Metformin) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.23.- (Aspartic Acid Endopeptidases) RN - EC 3.4.23.46 (BACE1 protein, human) SB - IM MH - Alzheimer Disease/blood/*drug therapy/physiopathology MH - Amyloid Precursor Protein Secretases/blood MH - Aspartic Acid Endopeptidases/blood MH - Diabetes Mellitus/blood/*drug therapy/physiopathology MH - Diabetes Mellitus, Type 1/drug therapy MH - Diabetes Mellitus, Type 2/drug therapy MH - Female MH - Glucagon-Like Peptide 1/analogs & derivatives/therapeutic use MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use MH - Hypercholesterolemia/blood/*drug therapy/physiopathology MH - Hypoglycemic Agents/*therapeutic use MH - Incidence MH - Liraglutide MH - Male MH - Metformin/therapeutic use MH - Receptor, Insulin/*metabolism MH - Risk Factors MH - tau Proteins/blood EDAT- 2013/02/01 06:00 MHDA- 2013/11/13 06:00 CRDT- 2013/02/01 06:00 PHST- 2013/07/23 00:00 [received] PHST- 2013/01/17 00:00 [revised] PHST- 2013/01/18 00:00 [accepted] PHST- 2013/02/01 06:00 [entrez] PHST- 2013/02/01 06:00 [pubmed] PHST- 2013/11/13 06:00 [medline] AID - CDR-EPUB-20130122-1 [pii] AID - 10.2174/1573399811309030003 [doi] PST - ppublish SO - Curr Diabetes Rev. 2013 May;9(3):218-27. doi: 10.2174/1573399811309030003. PMID- 23335292 OWN - NLM STAT- MEDLINE DCOM- 20130805 LR - 20131121 IS - 1097-4547 (Electronic) IS - 0360-4012 (Linking) VI - 91 IP - 4 DP - 2013 Apr TI - Val(8)-GLP-1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid beta peptide in rats. PG - 568-77 LID - 10.1002/jnr.23181 [doi] AB - Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) in the elderly. Glucagon-like peptide-1 (GLP-1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP-1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP-1 in the central nervous system is still an open question, and whether GLP-1 can prevent amyloid beta (Abeta)-induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val(8)-GLP-1(7-36), a GLP-1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca(2)(+)](i) ) in the absence or presence of Abeta1-40. The results showed that 1) Abeta1-40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val(8)-GLP-1(7-36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Abeta1-40-induced decrease in mEPSC and mIPSC frequency; 3) Abeta1-40 significantly increased [Ca(2)(+)](i) in primary neuronal cultures; and 4) Val(8)-GLP-1(7-36) alone did not change the intracellular calcium level but prevented Abeta1-40-induced persistent elevation of [Ca(2)(+)](i). These findings demonstrate for the first time that central application of Val(8)-GLP-1(7-36) could protect against Abeta-induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP-1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain. CI - Copyright (c) 2013 Wiley Periodicals, Inc. FAU - Wang, Xiao-Hui AU - Wang XH AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China. FAU - Yang, Wei AU - Yang W FAU - Holscher, Christian AU - Holscher C FAU - Wang, Zhao-Jun AU - Wang ZJ FAU - Cai, Hong-Yan AU - Cai HY FAU - Li, Qing-Shan AU - Li QS FAU - Qi, Jin-Shun AU - Qi JS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130118 PL - United States TA - J Neurosci Res JT - Journal of neuroscience research JID - 7600111 RN - 0 (Amyloid beta-Peptides) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-40)) RN - 0 (glucagon-like peptide 1 (7-36), Val(8)-) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - SY7Q814VUP (Calcium) SB - IM MH - Amyloid beta-Peptides/*pharmacology MH - Animals MH - CA1 Region, Hippocampal/drug effects/metabolism MH - Calcium/*metabolism MH - Cells, Cultured MH - Cerebral Cortex/drug effects/metabolism MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Glucagon-Like Peptide 1/*pharmacology MH - Homeostasis MH - Inhibitory Postsynaptic Potentials/drug effects/physiology MH - Miniature Postsynaptic Potentials/drug effects/physiology MH - Neurons/*drug effects/metabolism MH - Peptide Fragments/*pharmacology MH - Rats MH - Rats, Wistar MH - Synapses/*drug effects/physiology MH - Synaptic Transmission/*drug effects/physiology EDAT- 2013/01/22 06:00 MHDA- 2013/08/06 06:00 CRDT- 2013/01/22 06:00 PHST- 2012/08/19 00:00 [received] PHST- 2012/10/12 00:00 [revised] PHST- 2012/10/30 00:00 [accepted] PHST- 2013/01/22 06:00 [entrez] PHST- 2013/01/22 06:00 [pubmed] PHST- 2013/08/06 06:00 [medline] AID - 10.1002/jnr.23181 [doi] PST - ppublish SO - J Neurosci Res. 2013 Apr;91(4):568-77. doi: 10.1002/jnr.23181. Epub 2013 Jan 18. PMID- 23314196 OWN - NLM STAT- MEDLINE DCOM- 20130613 LR - 20181202 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1832 IP - 4 DP - 2013 Apr TI - Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration. PG - 527-41 LID - S0925-4439(13)00012-4 [pii] LID - 10.1016/j.bbadis.2013.01.008 [doi] AB - According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - Duarte, A I AU - Duarte AI AD - Life Sciences Department, University of Coimbra, Largo Marques de Pombal, Coimbra, Portugal. anaimduarte@gmail.com FAU - Candeias, E AU - Candeias E FAU - Correia, S C AU - Correia SC FAU - Santos, R X AU - Santos RX FAU - Carvalho, C AU - Carvalho C FAU - Cardoso, S AU - Cardoso S FAU - Placido, A AU - Placido A FAU - Santos, M S AU - Santos MS FAU - Oliveira, C R AU - Oliveira CR FAU - Moreira, P I AU - Moreira PI LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20130111 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Peptides) RN - 0 (Venoms) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) RN - IY9XDZ35W2 (Glucose) SB - IM MH - *Alzheimer Disease/complications/drug therapy/metabolism/physiopathology MH - *Biomimetics MH - Brain/metabolism/physiopathology MH - Central Nervous System/drug effects/physiopathology MH - *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism/physiopathology MH - Exenatide MH - *Glucagon-Like Peptide 1/analogs & derivatives/genetics/metabolism/therapeutic use MH - Glucose/metabolism MH - Humans MH - Insulin Resistance/genetics MH - Liraglutide MH - Peptides/therapeutic use MH - Venoms/therapeutic use EDAT- 2013/01/15 06:00 MHDA- 2013/06/14 06:00 CRDT- 2013/01/15 06:00 PHST- 2012/08/08 00:00 [received] PHST- 2012/12/18 00:00 [revised] PHST- 2013/01/06 00:00 [accepted] PHST- 2013/01/15 06:00 [entrez] PHST- 2013/01/15 06:00 [pubmed] PHST- 2013/06/14 06:00 [medline] AID - S0925-4439(13)00012-4 [pii] AID - 10.1016/j.bbadis.2013.01.008 [doi] PST - ppublish SO - Biochim Biophys Acta. 2013 Apr;1832(4):527-41. doi: 10.1016/j.bbadis.2013.01.008. Epub 2013 Jan 11. PMID- 23276669 OWN - NLM STAT- MEDLINE DCOM- 20130805 LR - 20220408 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 700 IP - 1-3 DP - 2013 Jan 30 TI - The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. PG - 42-50 LID - S0014-2999(12)01017-5 [pii] LID - 10.1016/j.ejphar.2012.12.012 [doi] AB - Chronic inflammation in the brain is found in a range of neurodegenerative diseases such as Parkinson's or Alzheimer's disease. We have recently shown that analogues of the glucagon-like polypeptide 1 (GLP-1) such as liraglutide have potent neuroprotective properties in a mouse model of Alzheimer's disease. We also found a reduction of activated microglia in the brain. This finding suggests that GLP-1 analogues such as liraglutide have anti-inflammatory properties. To further characterise this property, we tested the effects of liraglutide on the chronic inflammation response induced by exposure of the brain to 6 Gy (X-ray). Animals were injected i.p. with 25 nmol/kg once daily for 30 days. Brains were analysed for cytokine levels, activated microglia and astrocyte levels, and nitrite levels as a measure for nitric oxide production and protein expression of iNOS. Exposure of the brain to 6 Gy induced a pronounced chronic inflammation response in the brain. The activated microglia load in the cortex and dentate gyrus region of hippocampus (P<0.001), and the activated astrocyte load in the cortex (P<0.01) was reduced by liraglutide. Furthermore, the pro-inflammatory cytokine levels of IL-6 (P<0.01), IL-12p70 (P<0.01), IL-1beta (P<0.05), and total nitrite concentration were reduced in the brains of animals treated with liraglutide. The results demonstrate that liraglutide is effective in reducing a number of parameters linked to the chronic inflammation response. Liraglutide or similar GLP-1 analogues may be a suitable treatment for reducing the chronic inflammatory response in the brain found in several neurodegenerative conditions. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - Parthsarathy, Vadivel AU - Parthsarathy V AD - School of Biomedical Sciences, Ulster University, Cromore Road, BT52 1SA Coleraine, Northern Ireland. FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121228 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cytokines) RN - 0 (Nitrites) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology/therapeutic use MH - Astrocytes/drug effects/metabolism/pathology/radiation effects MH - Body Weight/drug effects/radiation effects MH - Brain/*drug effects/pathology/*radiation effects MH - Cytokines/metabolism MH - Diabetes Mellitus, Type 2/*drug therapy MH - Eating/drug effects/radiation effects MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology/therapeutic use MH - Inflammation/drug therapy/metabolism/pathology/physiopathology MH - Liraglutide MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microglia/drug effects/metabolism/pathology/radiation effects MH - Nitric Oxide Synthase Type II/metabolism MH - Nitrites/metabolism MH - Radiation Injuries, Experimental/*drug therapy/metabolism/pathology/physiopathology EDAT- 2013/01/02 06:00 MHDA- 2013/08/06 06:00 CRDT- 2013/01/02 06:00 PHST- 2012/08/21 00:00 [received] PHST- 2012/12/03 00:00 [revised] PHST- 2012/12/07 00:00 [accepted] PHST- 2013/01/02 06:00 [entrez] PHST- 2013/01/02 06:00 [pubmed] PHST- 2013/08/06 06:00 [medline] AID - S0014-2999(12)01017-5 [pii] AID - 10.1016/j.ejphar.2012.12.012 [doi] PST - ppublish SO - Eur J Pharmacol. 2013 Jan 30;700(1-3):42-50. doi: 10.1016/j.ejphar.2012.12.012. Epub 2012 Dec 28. PMID- 23271639 OWN - NLM STAT- MEDLINE DCOM- 20130904 LR - 20250306 IS - 1573-6830 (Electronic) IS - 0272-4340 (Print) IS - 0272-4340 (Linking) VI - 33 IP - 3 DP - 2013 Apr TI - Therapeutic potential of N-acetyl-glucagon-like peptide-1 in primary motor neuron cultures derived from non-transgenic and SOD1-G93A ALS mice. PG - 347-57 LID - 10.1007/s10571-012-9900-9 [doi] AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS. FAU - Sun, Hui AU - Sun H AD - Department of Neurology, Hannover Medical School, OE 7210, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany. FAU - Knippenberg, Sarah AU - Knippenberg S FAU - Thau, Nadine AU - Thau N FAU - Ragancokova, Daniela AU - Ragancokova D FAU - Korner, Sonja AU - Korner S FAU - Huang, Dongya AU - Huang D FAU - Dengler, Reinhard AU - Dengler R FAU - Dohler, Klaus AU - Dohler K FAU - Petri, Susanne AU - Petri S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121228 PL - Netherlands TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Neurotoxins) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - SIV03811UC (Kainic Acid) RN - SY7Q814VUP (Calcium) SB - IM MH - Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology MH - Animals MH - Astrocytes/drug effects/metabolism/pathology MH - Calcium/metabolism MH - Calcium Signaling/drug effects MH - Cells, Cultured MH - Coculture Techniques MH - Cytosol/drug effects/metabolism MH - Female MH - Fluorometry MH - Glucagon-Like Peptide 1/pharmacology/*therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Intracellular Space/metabolism MH - Kainic Acid/toxicity MH - Male MH - Mice MH - Mice, Transgenic MH - Motor Neurons/drug effects/metabolism/*pathology MH - Neuroprotective Agents/pharmacology/therapeutic use MH - Neurotoxins/toxicity MH - Receptors, Glucagon/metabolism MH - Superoxide Dismutase/*genetics/metabolism PMC - PMC11498007 COIS- The authors declare that they have no conflict of interest. EDAT- 2012/12/29 06:00 MHDA- 2013/09/05 06:00 PMCR- 2012/12/28 CRDT- 2012/12/29 06:00 PHST- 2012/10/04 00:00 [received] PHST- 2012/12/13 00:00 [accepted] PHST- 2012/12/29 06:00 [entrez] PHST- 2012/12/29 06:00 [pubmed] PHST- 2013/09/05 06:00 [medline] PHST- 2012/12/28 00:00 [pmc-release] AID - 9900 [pii] AID - 10.1007/s10571-012-9900-9 [doi] PST - ppublish SO - Cell Mol Neurobiol. 2013 Apr;33(3):347-57. doi: 10.1007/s10571-012-9900-9. Epub 2012 Dec 28. PMID- 23259618 OWN - NLM STAT- MEDLINE DCOM- 20130701 LR - 20211021 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 9 DP - 2012 Dec 23 TI - GLP-1 secretion by microglial cells and decreased CNS expression in obesity. PG - 276 LID - 10.1186/1742-2094-9-276 [doi] AB - BACKGROUND: Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain. METHODS: Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA. RESULTS: We show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon. CONCLUSION: The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders. FAU - Kappe, Camilla AU - Kappe C AD - Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Stockholm 11883, Sweden. FAU - Tracy, Linda M AU - Tracy LM FAU - Patrone, Cesare AU - Patrone C FAU - Iverfeldt, Kerstin AU - Iverfeldt K FAU - Sjoholm, Ake AU - Sjoholm A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121223 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (CD11b Antigen) RN - 0 (Palmitates) RN - 0 (Plant Proteins) RN - 0 (Polysaccharides) RN - 0 (RNA, Messenger) RN - 0 (Tumor Necrosis Factor-alpha) RN - 55963-74-1 (Proglucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - E0399OZS9N (Cyclic AMP) RN - EC 3.2.1.14 (Chitinases) RN - EC 3.2.1.14 (chitinase C) RN - EC 3.5.3.1 (Arg1 protein, mouse) RN - EC 3.5.3.1 (Arginase) SB - IM MH - Animals MH - Arginase/metabolism MH - CD11b Antigen/genetics/metabolism MH - Cell Line, Transformed MH - Central Nervous System/*metabolism/*pathology MH - Chitinases/metabolism MH - Cyclic AMP/pharmacology MH - Disease Models, Animal MH - Gene Expression Regulation/genetics MH - Glucagon-Like Peptide 1/genetics/*metabolism MH - Insulin Resistance/genetics MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Obese MH - Microglia/*metabolism MH - Obesity/*pathology MH - Palmitates/pharmacology MH - Plant Proteins MH - Polysaccharides/pharmacology MH - Proglucagon/genetics/metabolism MH - RNA, Messenger/metabolism MH - Statistics, Nonparametric MH - Transfection MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC3546916 EDAT- 2012/12/25 06:00 MHDA- 2013/07/03 06:00 PMCR- 2012/12/23 CRDT- 2012/12/25 06:00 PHST- 2012/10/24 00:00 [received] PHST- 2012/11/29 00:00 [accepted] PHST- 2012/12/25 06:00 [entrez] PHST- 2012/12/25 06:00 [pubmed] PHST- 2013/07/03 06:00 [medline] PHST- 2012/12/23 00:00 [pmc-release] AID - 1742-2094-9-276 [pii] AID - 10.1186/1742-2094-9-276 [doi] PST - epublish SO - J Neuroinflammation. 2012 Dec 23;9:276. doi: 10.1186/1742-2094-9-276. PMID- 23158895 OWN - NLM STAT- MEDLINE DCOM- 20130507 LR - 20151119 IS - 2245-1919 (Electronic) IS - 2245-1919 (Linking) VI - 59 IP - 10 DP - 2012 Oct TI - Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease - protocol for a controlled, randomized double-blinded trial. PG - A4519 AB - INTRODUCTION: Type 2 diabetes (DM-2) increases the risk of developing Alzheimer s disease (AD), and patients with AD are more likely to develop DM-2. DM-2 and AD share some pathophysiological features. In AD, amyloid-beta (Abeta) is accumulated as extracellular plaques in the gray matter of the brain, while in DM-2 islet amyloid polypeptide (IAPP) is accumulated in the pancreas. Premature cellular degeneration is seen in both diseases. Glucagon-like peptide-1 (GLP-1) reduces the amount of Abeta and improves cognition in animal studies. The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Abeta in patients with AD. MATERIAL AND METHODS: This is a randomized, controlled, double-blinded intervention study with AD patients treated for six months with liraglutide (n = 20) or placebo (n = 20). The primary outcome is change in deposition of Abeta in the central nervous system (CNS) by Pittsburgh compound B positron emission tomography (PET). The secondary outcome is evaluation of cognition using a neuro-psychological test battery, and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET. Finally, a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow. CONCLUSION: No registered drug affects the deposition of Abeta in the brain of AD patients. Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Abeta plaques and thereby presumably improves the cognitive function. FUNDING: The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Scandinavia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01469351. FAU - Egefjord, Laerke AU - Egefjord L AD - Institute of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. laerke.egefjord@farm.au.dk FAU - Gejl, Michael AU - Gejl M FAU - Moller, Arne AU - Moller A FAU - Braendgaard, Hans AU - Braendgaard H FAU - Gottrup, Hanne AU - Gottrup H FAU - Antropova, Olga AU - Antropova O FAU - Moller, Niels AU - Moller N FAU - Poulsen, Henrik E AU - Poulsen HE FAU - Gjedde, Albert AU - Gjedde A FAU - Brock, Birgitte AU - Brock B FAU - Rungby, Jorgen AU - Rungby J LA - eng SI - ClinicalTrials.gov/NCT01469351 PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - Denmark TA - Dan Med J JT - Danish medical journal JID - 101576205 RN - 0 (Amyloid beta-Peptides) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/diagnosis/*drug therapy/physiopathology MH - Amyloid beta-Peptides/*metabolism MH - Blood Flow Velocity/*drug effects MH - Brain/*metabolism/physiopathology MH - Cerebrovascular Circulation/drug effects/*physiology MH - Cognition/drug effects/*physiology MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Follow-Up Studies MH - Glucagon-Like Peptide 1/administration & dosage/*analogs & derivatives MH - Humans MH - Liraglutide MH - Magnetic Resonance Imaging/methods MH - Positron-Emission Tomography MH - Treatment Outcome EDAT- 2012/11/20 06:00 MHDA- 2013/05/08 06:00 CRDT- 2012/11/20 06:00 PHST- 2012/11/20 06:00 [entrez] PHST- 2012/11/20 06:00 [pubmed] PHST- 2013/05/08 06:00 [medline] AID - A4519 [pii] PST - ppublish SO - Dan Med J. 2012 Oct;59(10):A4519. PMID- 23103794 OWN - NLM STAT- MEDLINE DCOM- 20130923 LR - 20220408 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 228 DP - 2013 Jan 3 TI - The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer's disease. PG - 294-300 LID - S0306-4522(12)01060-3 [pii] LID - 10.1016/j.neuroscience.2012.10.045 [doi] AB - Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease. CI - Copyright (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Duffy, A M AU - Duffy AM AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Holscher, C AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121026 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Incretins) RN - 0 (Presenilin-1) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) SB - IM MH - Alzheimer Disease/drug therapy/*metabolism/pathology MH - Amyloid beta-Protein Precursor/*genetics MH - Animals MH - Disease Models, Animal MH - Female MH - Gastric Inhibitory Polypeptide/analogs & derivatives/pharmacology/*therapeutic use MH - Gliosis/drug therapy/*metabolism/pathology MH - Incretins/pharmacology/therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Oxidative Stress/drug effects/*physiology MH - Plaque, Amyloid/drug therapy/*metabolism/pathology MH - Presenilin-1/*genetics EDAT- 2012/10/30 06:00 MHDA- 2013/09/24 06:00 CRDT- 2012/10/30 06:00 PHST- 2012/09/10 00:00 [received] PHST- 2012/10/19 00:00 [accepted] PHST- 2012/10/30 06:00 [entrez] PHST- 2012/10/30 06:00 [pubmed] PHST- 2013/09/24 06:00 [medline] AID - S0306-4522(12)01060-3 [pii] AID - 10.1016/j.neuroscience.2012.10.045 [doi] PST - ppublish SO - Neuroscience. 2013 Jan 3;228:294-300. doi: 10.1016/j.neuroscience.2012.10.045. Epub 2012 Oct 26. PMID- 23020846 OWN - NLM STAT- MEDLINE DCOM- 20130214 LR - 20220517 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 123 IP - 6 DP - 2012 Dec TI - Neuroprotective actions of glucagon-like peptide-1 in differentiated human neuroprogenitor cells. PG - 919-31 LID - 10.1111/jnc.12036 [doi] AB - Glucagon-like peptide-1 (GLP-1)-based therapies are currently available for the treatment of type 2 diabetes, based on their actions on pancreatic beta cells. GLP-1 is also known to exert neuroprotective actions. To determine its mechanism of action, we developed a neuron-rich cell culture system by differentiating human neuroprogenitor cells in the presence of a combination of neurotrophins and retinoic acid. The neuronal nature of these cells was characterized by neurogenesis pathway-specific array. GLP-1 receptor expression was seen mainly in the neuronal population. Culture of neurons in the presence of Abeta oligomers resulted in the induction of apoptosis as shown by the activation of caspase-3 and caspase-6. Exendin-4, a long-acting analog of GLP-1, protected the neurons from apoptosis induced by Abeta oligomers. Exendin-4 stimulated cyclic AMP response element binding protein phosphorylation, a regulatory step in its activation. A transient transfection assay showed induction of a reporter linked to CRE site-containing human brain-derived neurotrophic factor promoter IV, by the growth factor through multiple signaling pathways. The anti-apoptotic action of exendin-4 was lost following down-regulation of cAMP response element binding protein. Withdrawal of neurotrophins resulted in the loss of neuronal phenotype of differentiated neuroprogenitor cells, which was prevented by incubation in the presence of exendin-4. Diabetes is a risk factor in the pathogenesis of Alzheimer's disease. Our findings suggest that GLP-1-based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population. CI - Published 2012. This article is a US Government work and is in the public domain in the USA. FAU - Velmurugan, Kalpana AU - Velmurugan K AD - Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado 80045, USA. FAU - Bouchard, Ron AU - Bouchard R FAU - Mahaffey, Gregory AU - Mahaffey G FAU - Pugazhenthi, Subbiah AU - Pugazhenthi S LA - eng GR - I01 BX001837/BX/BLRD VA/United States GR - I01 BX004480/BX/BLRD VA/United States PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20121025 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (CREB1 protein, human) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Brain-Derived Neurotrophic Factor/biosynthesis/genetics MH - Cell Differentiation/*physiology MH - Cells, Cultured MH - Cyclic AMP Response Element-Binding Protein/physiology MH - Gene Expression Regulation/physiology MH - Glucagon-Like Peptide 1/metabolism/*physiology MH - Humans MH - Neural Pathways/physiology MH - Neural Stem Cells/*cytology/metabolism MH - Neuroprotective Agents/*pharmacology MH - Promoter Regions, Genetic MH - Signal Transduction/genetics MH - Stem Cells/*cytology/metabolism EDAT- 2012/10/02 06:00 MHDA- 2013/02/15 06:00 CRDT- 2012/10/02 06:00 PHST- 2012/07/28 00:00 [received] PHST- 2012/09/21 00:00 [revised] PHST- 2012/09/24 00:00 [accepted] PHST- 2012/10/02 06:00 [entrez] PHST- 2012/10/02 06:00 [pubmed] PHST- 2013/02/15 06:00 [medline] AID - 10.1111/jnc.12036 [doi] PST - ppublish SO - J Neurochem. 2012 Dec;123(6):919-31. doi: 10.1111/jnc.12036. Epub 2012 Oct 25. PMID- 23011726 OWN - NLM STAT- MEDLINE DCOM- 20130829 LR - 20211021 IS - 1559-1174 (Electronic) IS - 1535-1084 (Linking) VI - 15 IP - 1 DP - 2013 Mar TI - The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-beta plaque and glial pathology in a mouse model of Alzheimer's disease. PG - 102-14 LID - 10.1007/s12017-012-8199-5 [doi] AB - Alzheimer's disease (AD) has been shown to involve desensitised insulin receptor (IR) signalling. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-beta plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. Altered IR status in APPSWE/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS(616) levels detected within neurons and neurites. The IR and IRS-1 pS(616) changes occur in the vicinity of all plaques in the APPSWE/PS1dE9 brain, and a significant upregulation of astrocytes and microglia surround this pathology. We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). Liraglutide also induces a highly significant reduction in astrocytosis and microglial number associated with both plaques and IR pathology. The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD. FAU - Long-Smith, Caitriona M AU - Long-Smith CM AD - Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland. FAU - Manning, Sean AU - Manning S FAU - McClean, Paula L AU - McClean PL FAU - Coakley, Meghan F AU - Coakley MF FAU - O'Halloran, Domhnall J AU - O'Halloran DJ FAU - Holscher, Christian AU - Holscher C FAU - O'Neill, Cora AU - O'Neill C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120921 PL - United States TA - Neuromolecular Med JT - Neuromolecular medicine JID - 101135365 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, mouse) RN - 0 (Neuroprotective Agents) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.10.1 (Receptor, Insulin) SB - IM MH - Alzheimer Disease/genetics/metabolism/*prevention & control MH - Amyloid beta-Peptides/*metabolism MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Astrocytes/drug effects/pathology MH - Disease Models, Animal MH - Female MH - Frontal Lobe/pathology MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology/physiology/therapeutic use MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Insulin Receptor Substrate Proteins/metabolism MH - Insulin Resistance MH - Liraglutide MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Microglia/drug effects/pathology MH - Mutation, Missense MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Phosphorylation/drug effects MH - Plaque, Amyloid/*prevention & control MH - Presenilin-1/genetics MH - Protein Processing, Post-Translational/drug effects MH - Protein Transport/drug effects MH - Receptor, Insulin/metabolism/*physiology MH - Signal Transduction/drug effects EDAT- 2012/09/27 06:00 MHDA- 2013/08/30 06:00 CRDT- 2012/09/27 06:00 PHST- 2012/03/22 00:00 [received] PHST- 2012/09/07 00:00 [accepted] PHST- 2012/09/27 06:00 [entrez] PHST- 2012/09/27 06:00 [pubmed] PHST- 2013/08/30 06:00 [medline] AID - 10.1007/s12017-012-8199-5 [doi] PST - ppublish SO - Neuromolecular Med. 2013 Mar;15(1):102-14. doi: 10.1007/s12017-012-8199-5. Epub 2012 Sep 21. PMID- 23000536 OWN - NLM STAT- MEDLINE DCOM- 20130426 LR - 20121116 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 237 DP - 2013 Jan 15 TI - The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. PG - 164-71 LID - S0166-4328(12)00607-9 [pii] LID - 10.1016/j.bbr.2012.09.021 [doi] AB - Incretins are a group of gastrointestinal hormones detected both peripherally and in the central nervous system (CNS). Recent studies have documented multiple effects of incretins on brain structure and function. Research into the neurological effects of incretins has primarily focused on animal models of neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's and Parkinson's diseases). Mood disorders (e.g. bipolar disorder (BD), major depressive disorder (MDD)) are associated with similar alterations in brain structure and function, as well as a range of cognitive deficits (e.g. memory, learning, executive function). Brain abnormalities and cognitive deficits are also found in populations with metabolic disorders (e.g., diabetes mellitus Type 2). In addition, individuals with mood disorders often have co-morbid metabolic conditions, thus treatment strategies which can effectively treat both cognitive deficits and metabolic abnormalities represent a possible integrated treatment avenue. In particular, glucagon-like peptide-1 (GLP-1) and its more stable, longer-lasting analogues have been demonstrated to exert neuroprotective and anti-apoptotic effects, reduce beta-amyloid (Abeta) plaque accumulation, modulate long-term potentiation and synaptic plasticity, and promote differentiation of neuronal progenitor cells. In animal models of behaviour, treatment with GLP-1 receptor agonists has been demonstrated to improve measures of cognitive function including learning and memory, as well as reduce depressive behaviour. Available GLP-1 treatments also have a favourable metabolic profile which includes weight loss and reduced risk for hypoglycemia. Systematic evaluation of the effects of GLP-1 treatment in psychiatric populations who evince cognitive deficits represents a promising treatment avenue. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - McIntyre, Roger S AU - McIntyre RS AD - Department of Psychiatry, University of Toronto, Toronto, ON, Canada. roger.mcintyre@uhn.on.ca FAU - Powell, Alissa M AU - Powell AM FAU - Kaidanovich-Beilin, Oksana AU - Kaidanovich-Beilin O FAU - Soczynska, Joanna K AU - Soczynska JK FAU - Alsuwaidan, Mohammad AU - Alsuwaidan M FAU - Woldeyohannes, Hanna O AU - Woldeyohannes HO FAU - Kim, Ashley S AU - Kim AS FAU - Gallaugher, L Ashley AU - Gallaugher LA LA - eng PT - Journal Article PT - Review DEP - 20120920 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Cognition Disorders/*drug therapy/*etiology MH - Glucagon-Like Peptide 1/*therapeutic use MH - Humans MH - Mood Disorders/*complications MH - Neuroprotective Agents/*therapeutic use EDAT- 2012/09/25 06:00 MHDA- 2013/04/27 06:00 CRDT- 2012/09/25 06:00 PHST- 2012/04/30 00:00 [received] PHST- 2012/09/10 00:00 [revised] PHST- 2012/09/14 00:00 [accepted] PHST- 2012/09/25 06:00 [entrez] PHST- 2012/09/25 06:00 [pubmed] PHST- 2013/04/27 06:00 [medline] AID - S0166-4328(12)00607-9 [pii] AID - 10.1016/j.bbr.2012.09.021 [doi] PST - ppublish SO - Behav Brain Res. 2013 Jan 15;237:164-71. doi: 10.1016/j.bbr.2012.09.021. Epub 2012 Sep 20. PMID- 22938097 OWN - NLM STAT- MEDLINE DCOM- 20130214 LR - 20220716 IS - 1179-1934 (Electronic) IS - 1172-7047 (Linking) VI - 26 IP - 10 DP - 2012 Oct 1 TI - Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. PG - 871-82 LID - 10.2165/11635890-000000000-00000 [doi] AB - The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza((R)); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta((R)); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK. c.holscher@ulster.ac.uk LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Clinical Trials, Phase II as Topic MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Neurodegenerative Diseases/*drug therapy/*metabolism MH - Neuroprotective Agents/*pharmacology/*therapeutic use MH - Randomized Controlled Trials as Topic MH - Risk Factors EDAT- 2012/09/04 06:00 MHDA- 2013/02/15 06:00 CRDT- 2012/09/04 06:00 PHST- 2012/09/04 06:00 [entrez] PHST- 2012/09/04 06:00 [pubmed] PHST- 2013/02/15 06:00 [medline] AID - 10.2165/11635890-000000000-00000 [doi] PST - ppublish SO - CNS Drugs. 2012 Oct 1;26(10):871-82. doi: 10.2165/11635890-000000000-00000. PMID- 22929437 OWN - NLM STAT- MEDLINE DCOM- 20130201 LR - 20211021 IS - 1559-7016 (Electronic) IS - 0271-678X (Print) IS - 0271-678X (Linking) VI - 32 IP - 12 DP - 2012 Dec TI - Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. PG - 2146-52 LID - 10.1038/jcbfm.2012.118 [doi] AB - Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with (18)fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia. FAU - Gejl, Michael AU - Gejl M AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. FAU - Egefjord, Laerke AU - Egefjord L FAU - Lerche, Susanne AU - Lerche S FAU - Vang, Kim AU - Vang K FAU - Bibby, Bo Martin AU - Bibby BM FAU - Holst, Jens Juul AU - Holst JJ FAU - Mengel, Annette AU - Mengel A FAU - Moller, Niels AU - Moller N FAU - Rungby, Jorgen AU - Rungby J FAU - Brock, Birgitte AU - Brock B FAU - Gjedde, Albert AU - Gjedde A LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20120829 PL - United States TA - J Cereb Blood Flow Metab JT - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JID - 8112566 RN - 0 (Glucose Transporter Type 1) RN - 0 (Radiopharmaceuticals) RN - 0 (SLC2A1 protein, human) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.1.1 (Hexokinase) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adult MH - Alzheimer Disease/diagnostic imaging/metabolism/physiopathology MH - Biological Transport MH - Blood-Brain Barrier/diagnostic imaging/*metabolism/physiopathology MH - Brain Chemistry MH - Brain Ischemia/diagnostic imaging/metabolism/physiopathology MH - Cross-Over Studies MH - Diabetes Mellitus, Type 2/diagnostic imaging/metabolism/physiopathology MH - Double-Blind Method MH - Fluorodeoxyglucose F18/administration & dosage MH - Glucagon-Like Peptide 1/*metabolism MH - Glucose/*metabolism MH - Glucose Clamp Technique MH - Glucose Transporter Type 1/metabolism MH - Hexokinase/*metabolism MH - Humans MH - Hyperglycemia/diagnostic imaging/*metabolism/physiopathology MH - Male MH - Positron-Emission Tomography MH - Radiography MH - Radiopharmaceuticals/administration & dosage MH - Stroke/diagnostic imaging/metabolism/physiopathology PMC - PMC3519409 EDAT- 2012/08/30 06:00 MHDA- 2013/02/05 06:00 PMCR- 2013/12/01 CRDT- 2012/08/30 06:00 PHST- 2012/08/30 06:00 [entrez] PHST- 2012/08/30 06:00 [pubmed] PHST- 2013/02/05 06:00 [medline] PHST- 2013/12/01 00:00 [pmc-release] AID - jcbfm2012118 [pii] AID - 10.1038/jcbfm.2012.118 [doi] PST - ppublish SO - J Cereb Blood Flow Metab. 2012 Dec;32(12):2146-52. doi: 10.1038/jcbfm.2012.118. Epub 2012 Aug 29. PMID- 22892942 OWN - NLM STAT- MEDLINE DCOM- 20140520 LR - 20211021 IS - 1574-4647 (Electronic) IS - 0161-9152 (Print) IS - 0161-9152 (Linking) VI - 35 IP - 5 DP - 2013 Oct TI - Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. PG - 1621-36 LID - 10.1007/s11357-012-9464-0 [doi] AB - Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment. FAU - Rachmany, Lital AU - Rachmany L AD - Department of Anatomy and Anthropology, Sackler School of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. FAU - Tweedie, David AU - Tweedie D FAU - Li, Yazhou AU - Li Y FAU - Rubovitch, Vardit AU - Rubovitch V FAU - Holloway, Harold W AU - Holloway HW FAU - Miller, Jonathan AU - Miller J FAU - Hoffer, Barry J AU - Hoffer BJ FAU - Greig, Nigel H AU - Greig NH FAU - Pick, Chaim G AU - Pick CG LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20120815 PL - Netherlands TA - Age (Dordr) JT - Age (Dordrecht, Netherlands) JID - 101250497 RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 0 (Glp1r protein, rat) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Receptors, Glucagon) RN - 0 (Venoms) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Alzheimer Disease/etiology/*prevention & control/psychology MH - Animals MH - Behavior, Animal/*drug effects MH - Brain/drug effects/metabolism MH - Brain Injuries/complications/*genetics/metabolism MH - Cell Line MH - Disease Models, Animal MH - Exenatide MH - Glucagon-Like Peptide 1 MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Incretins/pharmacology MH - Male MH - Memory/*physiology MH - Mice MH - Neuroprotective Agents/pharmacology MH - Oxidative Stress MH - Peptides/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Glucagon/*drug effects/metabolism MH - Recognition, Psychology/*drug effects MH - Trauma Severity Indices MH - Venoms/*pharmacology PMC - PMC3776106 EDAT- 2012/08/16 06:00 MHDA- 2014/05/21 06:00 PMCR- 2014/10/01 CRDT- 2012/08/16 06:00 PHST- 2012/05/24 00:00 [received] PHST- 2012/07/30 00:00 [accepted] PHST- 2012/08/16 06:00 [entrez] PHST- 2012/08/16 06:00 [pubmed] PHST- 2014/05/21 06:00 [medline] PHST- 2014/10/01 00:00 [pmc-release] AID - 9464 [pii] AID - 10.1007/s11357-012-9464-0 [doi] PST - ppublish SO - Age (Dordr). 2013 Oct;35(5):1621-36. doi: 10.1007/s11357-012-9464-0. Epub 2012 Aug 15. PMID- 22891821 OWN - NLM STAT- MEDLINE DCOM- 20130603 LR - 20211021 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 10 DP - 2012 Aug 15 TI - Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits. PG - 92 LID - 10.1186/1741-7015-10-92 [doi] AB - BACKGROUND: Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia.Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. DISCUSSION: Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. CONCLUSIONS: We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted. FAU - Ebdrup, Bjorn H AU - Ebdrup BH AD - Center for Neuropsychiatric Schizophrenia Research, CNSR and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Psychiatric Center Glostrup, University of Copenhagen, DK-2600 Glostrup, Denmark. bebdrup@cnsr.dk FAU - Knop, Filip K AU - Knop FK FAU - Ishoy, Pelle L AU - Ishoy PL FAU - Rostrup, Egill AU - Rostrup E FAU - Fagerlund, Birgitte AU - Fagerlund B FAU - Lublin, Henrik AU - Lublin H FAU - Glenthoj, Birte AU - Glenthoj B LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120815 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (Antipsychotic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Antipsychotic Agents/*adverse effects MH - Glucagon-Like Peptide 1/*analogs & derivatives/*therapeutic use MH - Humans MH - Obesity/*chemically induced/*drug therapy MH - Schizophrenia/drug therapy MH - Weight Gain/*drug effects PMC - PMC3573939 EDAT- 2012/08/16 06:00 MHDA- 2013/06/05 06:00 PMCR- 2012/08/15 CRDT- 2012/08/16 06:00 PHST- 2012/03/28 00:00 [received] PHST- 2012/08/15 00:00 [accepted] PHST- 2012/08/16 06:00 [entrez] PHST- 2012/08/16 06:00 [pubmed] PHST- 2013/06/05 06:00 [medline] PHST- 2012/08/15 00:00 [pmc-release] AID - 1741-7015-10-92 [pii] AID - 10.1186/1741-7015-10-92 [doi] PST - epublish SO - BMC Med. 2012 Aug 15;10:92. doi: 10.1186/1741-7015-10-92. PMID- 22867941 OWN - NLM STAT- MEDLINE DCOM- 20130104 LR - 20120827 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1473 DP - 2012 Sep 14 TI - Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain. PG - 204-13 LID - 10.1016/j.brainres.2012.07.029 [doi] AB - Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - McGovern, Stephen F J AU - McGovern SF AD - School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK. FAU - Hunter, Kerry AU - Hunter K FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120731 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Peptide Fragments) RN - 0 (glucagon-like peptide 1 (7-36), Val(8)-) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Blood-Brain Barrier/drug effects MH - Brain/*drug effects MH - Cell Proliferation/drug effects MH - Enzyme-Linked Immunosorbent Assay MH - Glucagon-Like Peptide 1/*pharmacology MH - Immunohistochemistry MH - Learning/*drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neural Stem Cells/*drug effects MH - Neurogenesis/*drug effects MH - Peptide Fragments/*pharmacology MH - Rats MH - Rats, Sprague-Dawley EDAT- 2012/08/08 06:00 MHDA- 2013/01/05 06:00 CRDT- 2012/08/08 06:00 PHST- 2012/03/31 00:00 [received] PHST- 2012/07/12 00:00 [revised] PHST- 2012/07/16 00:00 [accepted] PHST- 2012/08/08 06:00 [entrez] PHST- 2012/08/08 06:00 [pubmed] PHST- 2013/01/05 06:00 [medline] AID - S0006-8993(12)01176-6 [pii] AID - 10.1016/j.brainres.2012.07.029 [doi] PST - ppublish SO - Brain Res. 2012 Sep 14;1473:204-13. doi: 10.1016/j.brainres.2012.07.029. Epub 2012 Jul 31. PMID- 22780564 OWN - NLM STAT- MEDLINE DCOM- 20121121 LR - 20240318 IS - 1467-789X (Electronic) IS - 1467-7881 (Print) IS - 1467-7881 (Linking) VI - 13 IP - 10 DP - 2012 Oct TI - Impact of postprandial glycaemia on health and prevention of disease. PG - 923-84 LID - 10.1111/j.1467-789X.2012.01011.x [doi] AB - Postprandial glucose, together with related hyperinsulinemia and lipidaemia, has been implicated in the development of chronic metabolic diseases like obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In this review, available evidence is discussed on postprandial glucose in relation to body weight control, the development of oxidative stress, T2DM, and CVD and in maintaining optimal exercise and cognitive performance. There is mechanistic evidence linking postprandial glycaemia or glycaemic variability to the development of these conditions or in the impairment in cognitive and exercise performance. Nevertheless, postprandial glycaemia is interrelated with many other (risk) factors as well as to fasting glucose. In many studies, meal-related glycaemic response is not sufficiently characterized, or the methodology with respect to the description of food or meal composition, or the duration of the measurement of postprandial glycaemia is limited. It is evident that more randomized controlled dietary intervention trials using effective low vs. high glucose response diets are necessary in order to draw more definite conclusions on the role of postprandial glycaemia in relation to health and disease. Also of importance is the evaluation of the potential role of the time course of postprandial glycaemia. CI - (c) 2012 ILSI Europe. obesity reviews (c) 2012 International Association for the Study of Obesity. FAU - Blaak, E E AU - Blaak EE AD - Department of Human Biology, School of Nutrition & Toxicology Research and Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands. FAU - Antoine, J-M AU - Antoine JM FAU - Benton, D AU - Benton D FAU - Bjorck, I AU - Bjorck I FAU - Bozzetto, L AU - Bozzetto L FAU - Brouns, F AU - Brouns F FAU - Diamant, M AU - Diamant M FAU - Dye, L AU - Dye L FAU - Hulshof, T AU - Hulshof T FAU - Holst, J J AU - Holst JJ FAU - Lamport, D J AU - Lamport DJ FAU - Laville, M AU - Laville M FAU - Lawton, C L AU - Lawton CL FAU - Meheust, A AU - Meheust A FAU - Nilson, A AU - Nilson A FAU - Normand, S AU - Normand S FAU - Rivellese, A A AU - Rivellese AA FAU - Theis, S AU - Theis S FAU - Torekov, S S AU - Torekov SS FAU - Vinoy, S AU - Vinoy S LA - eng PT - Journal Article PT - Review DEP - 20120711 PL - England TA - Obes Rev JT - Obesity reviews : an official journal of the International Association for the Study of Obesity JID - 100897395 RN - 0 (Blood Glucose) RN - 0 (Incretins) SB - IM MH - Blood Glucose/metabolism MH - Body Weight/*physiology MH - Chronic Disease/*epidemiology/prevention & control MH - Humans MH - Hyperglycemia/metabolism/*physiopathology MH - Incretins/metabolism MH - Obesity/*metabolism MH - Postprandial Period MH - Risk Factors PMC - PMC3494382 EDAT- 2012/07/12 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/07/12 06:00 PHST- 2012/07/12 06:00 [entrez] PHST- 2012/07/12 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - 10.1111/j.1467-789X.2012.01011.x [doi] PST - ppublish SO - Obes Rev. 2012 Oct;13(10):923-84. doi: 10.1111/j.1467-789X.2012.01011.x. Epub 2012 Jul 11. PMID- 22718609 OWN - NLM STAT- MEDLINE DCOM- 20120724 LR - 20120621 IS - 0334-1763 (Print) IS - 0334-1763 (Linking) VI - 23 IP - 1 DP - 2011 Dec 21 TI - GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. PG - 1-11 LID - /j/revneuro.2012.23.issue-1/rns.2011.061/rns.2011.061.xml [pii] LID - 10.1515/rns.2011.061 [doi] AB - As a constitutively active kinase, glycogen synthase kinase 3 (GSK3) is a kinase which regulates body metabolism by phosphorylation of glycogen synthase (GS) and other substrates. Considerable evidence suggests that GSK3 is involved in the common pathology underlying Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The overexpression or overactivation of GSK3 could induce a series of pathological changes, most of which are hallmarks of AD and T2DM. Therefore, GSK3 could be a novel target to treat these two age-dependent diseases. The inhibition of this kinase can prevent the aggregation of beta-amyloid (Abeta) and hyperphosphorylation of tau protein. GSK3 inhibition can also be a promising strategy to ameliorate neurodegenerative developments. Its potential association with memory formation has been shown in electrophysiological and behavioral experiments. The neuroprotective effects of novel drugs developed to treat T2DM, glucagon-like peptide 1 (GLP-1) and its long-lasting analogs, have a possible link to GSK3 modification. Recent investigations of the interaction between the phosphatidylinositol 3 kinase (PI3K) signaling pathway and the protective effect of novel GPL-1 receptor agonist geniposide on PC12 cells support this theory. FAU - Gao, Chong AU - Gao C AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. FAU - Holscher, Christian AU - Holscher C FAU - Liu, Yueze AU - Liu Y FAU - Li, Lin AU - Li L LA - eng PT - Journal Article PT - Review DEP - 20111221 PL - Germany TA - Rev Neurosci JT - Reviews in the neurosciences JID - 8711016 RN - 0 (Enzyme Inhibitors) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Alzheimer Disease/*drug therapy/enzymology MH - Animals MH - Diabetes Mellitus, Type 2/*drug therapy/enzymology MH - Enzyme Inhibitors/*therapeutic use MH - Glycogen Synthase Kinase 3/antagonists & inhibitors/*metabolism MH - Humans MH - Signal Transduction/drug effects EDAT- 2012/06/22 06:00 MHDA- 2012/07/25 06:00 CRDT- 2012/06/22 06:00 PHST- 2011/09/14 00:00 [received] PHST- 2011/12/21 00:00 [accepted] PHST- 2012/06/22 06:00 [entrez] PHST- 2012/06/22 06:00 [pubmed] PHST- 2012/07/25 06:00 [medline] AID - /j/revneuro.2012.23.issue-1/rns.2011.061/rns.2011.061.xml [pii] AID - 10.1515/rns.2011.061 [doi] PST - epublish SO - Rev Neurosci. 2011 Dec 21;23(1):1-11. doi: 10.1515/rns.2011.061. PMID- 22592020 OWN - NLM STAT- MEDLINE DCOM- 20130429 LR - 20151119 IS - 1558-1497 (Electronic) IS - 0197-4580 (Linking) VI - 34 IP - 2 DP - 2013 Feb TI - Liraglutide protects against amyloid-beta protein-induced impairment of spatial learning and memory in rats. PG - 576-88 LID - S0197-4580(12)00238-2 [pii] LID - 10.1016/j.neurobiolaging.2012.04.009 [doi] AB - Type 2 diabetes mellitus is a risk factor of Alzheimer's disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-beta protein (Abeta), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Abeta(25-35) resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Abeta(25-35)-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD. CI - Copyright (c) 2013 Elsevier Inc. All rights reserved. FAU - Han, Wei-Na AU - Han WN AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China. FAU - Holscher, Christian AU - Holscher C FAU - Yuan, Li AU - Yuan L FAU - Yang, Wei AU - Yang W FAU - Wang, Xiao-Hui AU - Wang XH FAU - Wu, Mei-Na AU - Wu MN FAU - Qi, Jin-Shun AU - Qi JS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120515 PL - United States TA - Neurobiol Aging JT - Neurobiology of aging JID - 8100437 RN - 0 (Amyloid beta-Peptides) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (25-35)) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - E0399OZS9N (Cyclic AMP) SB - IM MH - Amyloid beta-Peptides/*pharmacology MH - Animals MH - Cyclic AMP/metabolism MH - Excitatory Postsynaptic Potentials/drug effects MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology MH - Hippocampus/drug effects/metabolism MH - Liraglutide MH - Long-Term Potentiation/*drug effects MH - Male MH - Maze Learning/*drug effects MH - Memory/*drug effects MH - Peptide Fragments/*pharmacology MH - Rats MH - Rats, Sprague-Dawley EDAT- 2012/05/18 06:00 MHDA- 2013/04/30 06:00 CRDT- 2012/05/18 06:00 PHST- 2011/10/24 00:00 [received] PHST- 2012/03/24 00:00 [revised] PHST- 2012/04/17 00:00 [accepted] PHST- 2012/05/18 06:00 [entrez] PHST- 2012/05/18 06:00 [pubmed] PHST- 2013/04/30 06:00 [medline] AID - S0197-4580(12)00238-2 [pii] AID - 10.1016/j.neurobiolaging.2012.04.009 [doi] PST - ppublish SO - Neurobiol Aging. 2013 Feb;34(2):576-88. doi: 10.1016/j.neurobiolaging.2012.04.009. Epub 2012 May 15. PMID- 22519295 OWN - NLM STAT- MEDLINE DCOM- 20121030 LR - 20211021 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 166 IP - 5 DP - 2012 Jul TI - Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. PG - 1586-99 LID - 10.1111/j.1476-5381.2012.01971.x [doi] AB - Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders. CI - Published 2012. This article is a U.S. Government work and is in the public domain in the USA. FAU - Salcedo, Isidro AU - Salcedo I AD - Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. FAU - Tweedie, David AU - Tweedie D FAU - Li, Yazhou AU - Li Y FAU - Greig, Nigel H AU - Greig NH LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Review PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Brain/metabolism MH - Cerebrovascular Disorders/drug therapy MH - Glucagon-Like Peptide 1/analogs & derivatives/*pharmacology/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Neurodegenerative Diseases/drug therapy MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Receptors, Glucagon/*physiology PMC - PMC3419902 EDAT- 2012/04/24 06:00 MHDA- 2012/10/31 06:00 PMCR- 2013/07/01 CRDT- 2012/04/24 06:00 PHST- 2012/04/24 06:00 [entrez] PHST- 2012/04/24 06:00 [pubmed] PHST- 2012/10/31 06:00 [medline] PHST- 2013/07/01 00:00 [pmc-release] AID - 10.1111/j.1476-5381.2012.01971.x [doi] PST - ppublish SO - Br J Pharmacol. 2012 Jul;166(5):1586-99. doi: 10.1111/j.1476-5381.2012.01971.x. PMID- 22443187 OWN - NLM STAT- MEDLINE DCOM- 20120810 LR - 20261030 IS - 1471-2202 (Electronic) IS - 1471-2202 (Linking) VI - 13 DP - 2012 Mar 23 TI - Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. PG - 33 LID - 10.1186/1471-2202-13-33 [doi] AB - BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza) and exenatide (Byetta) are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R). Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. RESULTS: In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza) and lixisenatide (Lyxumia). We measured the kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. CONCLUSIONS: Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of neurodegenerative diseases. FAU - Hunter, Kerry AU - Hunter K AD - School of Biomedical Sciences, Ulster University, Coleraine, UK. FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120323 PL - England TA - BMC Neurosci JT - BMC neuroscience JID - 100966986 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 0 (Peptides) RN - 74O62BB01U (lixisenatide) RN - 0 (Glucagon-Like Peptide-2 Receptor) SB - IM ECI - BMC Neurosci. 2026 Oct 29;27(1):53. doi: 10.1186/s12868-026-01068-5. PMID: 42958044 MH - Animals MH - Blood-Brain Barrier/*drug effects/metabolism MH - Brain/drug effects/metabolism MH - Dose-Response Relationship, Drug MH - Female MH - Glucagon-Like Peptide 1/*analogs & derivatives/pharmacology MH - Hypoglycemic Agents/*pharmacology MH - Liraglutide MH - Mice MH - Neurogenesis/*drug effects MH - Neurons/drug effects/metabolism MH - Peptides/*pharmacology MH - Glucagon-Like Peptide-2 Receptor PMC - PMC3352246 EDAT- 2012/03/27 06:00 MHDA- 2012/08/11 06:00 PMCR- 2012/03/23 CRDT- 2012/03/27 06:00 PHST- 2011/12/07 00:00 [received] PHST- 2012/03/23 00:00 [accepted] PHST- 2012/03/27 06:00 [entrez] PHST- 2012/03/27 06:00 [pubmed] PHST- 2012/08/11 06:00 [medline] PHST- 2012/03/23 00:00 [pmc-release] AID - 1471-2202-13-33 [pii] AID - 10.1186/1471-2202-13-33 [doi] PST - epublish SO - BMC Neurosci. 2012 Mar 23;13:33. doi: 10.1186/1471-2202-13-33. PMID- 22344583 OWN - NLM STAT- MEDLINE DCOM- 20130410 LR - 20241219 IS - 1460-2156 (Electronic) IS - 0006-8950 (Linking) VI - 136 IP - Pt 2 DP - 2013 Feb TI - Parkinson's disease, insulin resistance and novel agents of neuroprotection. PG - 374-84 LID - 10.1093/brain/aws009 [doi] AB - Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between Parkinson's disease and type 2 diabetes mellitus. Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. This includes converging evidence identifying that peroxisome proliferator activated receptor gamma coactivator 1-alpha, a key regulator of enzymes involved in mitochondrial respiration and insulin resistance, is potentially pivotal in the pathogenesis of neurodegeneration in Parkinson's disease. This evidence supports further study of these pathways, most importantly to identify neuroprotective agents for Parkinson's disease, and/or establish more effective prevention or treatment for type 2 diabetes mellitus. In parallel with these advances, there are already randomized trials evaluating several established treatments for insulin resistance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinson's disease, with only preliminary insights regarding their mechanisms of action in neurodegeneration, which may be effective in both disease processes through an action on mitochondrial function. Furthermore, parallels are also emerging between these same pathways and neurodegeneration associated with Alzheimer's disease and Huntington's disease. Our aim is to highlight this converging evidence and stimulate further hypothesis-testing studies specifically with reference to the potential development of novel neuroprotective agents in Parkinson's disease. FAU - Aviles-Olmos, Iciar AU - Aviles-Olmos I AD - Sobell Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. FAU - Limousin, Patricia AU - Limousin P FAU - Lees, Andrew AU - Lees A FAU - Foltynie, Thomas AU - Foltynie T LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20120217 PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Neuroprotective Agents) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/epidemiology/metabolism/*prevention & control MH - Humans MH - Insulin Resistance/*physiology MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Parkinson Disease/*drug therapy/epidemiology/metabolism EDAT- 2012/02/22 06:00 MHDA- 2013/04/11 06:00 CRDT- 2012/02/21 06:00 PHST- 2012/02/21 06:00 [entrez] PHST- 2012/02/22 06:00 [pubmed] PHST- 2013/04/11 06:00 [medline] AID - aws009 [pii] AID - 10.1093/brain/aws009 [doi] PST - ppublish SO - Brain. 2013 Feb;136(Pt 2):374-84. doi: 10.1093/brain/aws009. Epub 2012 Feb 17. PMID- 22245388 OWN - NLM STAT- MEDLINE DCOM- 20121120 LR - 20151119 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 46 IP - 1 DP - 2012 Apr TI - Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures. PG - 52-8 LID - 10.1016/j.nbd.2011.12.043 [doi] AB - Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. In this context, anti-diabetic agents such as rosiglitazone and glucagon-like peptide (GLP)-1 have been reported to reduce pathologies associated with AD, including tau hyperphosphorylation, suggesting that such agents might be used to treat AD. One such anti-diabetic agent is sitagliptin, which acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels. Given this action, sitagliptin would be predicted to reduce AD pathology. Accordingly, we investigated whether sitagliptin is effective in attenuating AD pathologies, focusing on tau phosphorylation in the OLETF type 2 diabetic rat model. Unexpectedly, we found that sitagliptin was not effective against pathological tau phosphorylation in the hippocampus of OLETF type 2 diabetes rats, and instead aggravated it. This paradoxically increased tau phosphorylation was attributed to activation of the tau kinase, GSK3beta (glycogen synthase kinase 3beta). Sitagliptin also increased ser-616 phosphorylation of the insulin receptor substrate (IRS)-1, suggesting increased insulin resistance in the brain. These phenomena were recapitulated in primary rat cortical neurons treated with sitagliptin, further confirming sitagliptin's effects on AD-related pathologies in neurons. These results highlight the need for caution in considering the use of sitagliptin in AD therapy. CI - Copyright A(c) 2012 Elsevier Inc. All rights reserved. FAU - Kim, Dong-Hou AU - Kim DH AD - Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea. FAU - Huh, Jae-Wan AU - Huh JW FAU - Jang, Mi AU - Jang M FAU - Suh, Jung-Hyun AU - Suh JH FAU - Kim, Tae-Wan AU - Kim TW FAU - Park, Jeong-Su AU - Park JS FAU - Yoon, Seung-Yong AU - Yoon SY LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120108 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Pyrazines) RN - 0 (Triazoles) RN - 0 (tau Proteins) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - Alzheimer Disease/*chemically induced/*metabolism/pathology MH - Animals MH - Diabetes Complications/*chemically induced/*metabolism/pathology MH - Diabetes Mellitus, Type 2/complications/enzymology/*metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/toxicity MH - Hippocampus/drug effects/enzymology MH - Male MH - Neurons/drug effects/enzymology/pathology MH - Phosphorylation/drug effects MH - Primary Cell Culture MH - Pyrazines/*toxicity MH - Rats MH - Rats, Inbred OLETF MH - Rats, Long-Evans MH - Sitagliptin Phosphate MH - Triazoles/*toxicity MH - tau Proteins/*metabolism EDAT- 2012/01/17 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/01/17 06:00 PHST- 2011/10/15 00:00 [received] PHST- 2011/12/13 00:00 [revised] PHST- 2011/12/23 00:00 [accepted] PHST- 2012/01/17 06:00 [entrez] PHST- 2012/01/17 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - S0969-9961(11)00429-3 [pii] AID - 10.1016/j.nbd.2011.12.043 [doi] PST - ppublish SO - Neurobiol Dis. 2012 Apr;46(1):52-8. doi: 10.1016/j.nbd.2011.12.043. Epub 2012 Jan 8. PMID- 23446787 OWN - NLM STAT- MEDLINE DCOM- 20130814 LR - 20220316 IS - 1179-1942 (Electronic) IS - 0114-5916 (Linking) VI - 35 Suppl 1 DP - 2012 Jan TI - Frailty and safety: the example of diabetes. PG - 63-71 LID - 10.1007/BF03319104 [doi] AB - Frailty is considered a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia and disability. In addition, there is a close relationship between age-related metabolic changes and the occurrence of comorbidities that may in turn lead to frailty.Even though the downward spiral of frailty is activated more quickly in older persons with type 2 diabetes, it is reversible with appropriate interventions before reaching a high level of severity. The hazard for geriatric patients with type 2 diabetes is that frailty encompasses diverse complications already associated with or caused by diabetes. Frailty is also associated with cognitive impairment, reduced ability to perform activities of daily living and increased expression of inflammatory and coagulation markers that may contribute to the adverse microvascular effects of diabetes. Although glycaemic control remains the main targeting achievement in type 2 diabetes, especially in well-functioning older persons, this is not appropriate for those with frailty. Frail elderly people with type 2 diabetes are a specific group in need of treatment parameters for both initial and maintenance therapy with oral antidiabetic agents. Therefore, the prescription of an antidiabetic agent in such individuals must take into consideration not only the standard goal of lowering hyperglycaemic levels, but also improving the quality of life and life expectancy. The clinical management of this population is currently particularly demanding, requiring special considerations with good medical decision making. Clinical aspects complicating diabetes care in older people include cognitive decline, physical functional decline and frailty. Available oral antidiabetic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors, thiazolidinediones and inhibitors of glucagon-like peptide 1 (GLP-1) degrading enzyme dipeptidyl peptidase 4. In addition, we will discuss injection treatment with GLP-1 analogues. This review will underline the association between diabetes and some frailty components in old patients and how specific antidiabetic agents may play a specific role in improving outcomes. FAU - Abbatecola, Angela M AU - Abbatecola AM AD - Scientific Direction, Italian National Research Center on Aging (INRCA), Ancona, Italy. angela_abbatecola@yahoo.com FAU - Olivieri, Fabiola AU - Olivieri F FAU - Corsonello, Andrea AU - Corsonello A FAU - Strollo, Felice AU - Strollo F FAU - Fumagalli, Alessia AU - Fumagalli A FAU - Lattanzio, Fabrizia AU - Lattanzio F LA - eng PT - Journal Article PT - Review PL - New Zealand TA - Drug Saf JT - Drug safety JID - 9002928 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glycoside Hydrolase Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Aged MH - Aging MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/adverse effects/therapeutic use MH - *Frail Elderly MH - Glucagon-Like Peptide 1/analogs & derivatives MH - Glycoside Hydrolase Inhibitors MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Inflammation/complications MH - Insulin/metabolism MH - Insulin Secretion MH - Muscle, Skeletal/physiology EDAT- 2012/01/01 00:00 MHDA- 2013/08/15 06:00 CRDT- 2013/03/01 06:00 PHST- 2013/03/01 06:00 [entrez] PHST- 2012/01/01 00:00 [pubmed] PHST- 2013/08/15 06:00 [medline] AID - 10.1007/BF03319104 [doi] PST - ppublish SO - Drug Saf. 2012 Jan;35 Suppl 1:63-71. doi: 10.1007/BF03319104. PMID- 22115896 OWN - NLM STAT- MEDLINE DCOM- 20120503 LR - 20181024 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 674 IP - 2-3 DP - 2012 Jan 15 TI - Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice. PG - 294-306 LID - 10.1016/j.ejphar.2011.11.007 [doi] AB - Type 2 diabetes is a risk factor for Alzheimer's disease. Insulin receptor desensitisation has been found in Alzheimer brains, which may be the underlying link. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling in diabetes. GIP and the GIP receptors are widely expressed in the brain, and GIP has been shown to have growth factor and neuroprotective properties. Here we investigate the potential therapeutic properties of different doses of the protease resistant long-lasting GIP receptor agonist D-Ala2GIP and the antagonist (Pro3)GIP in C57Bl/6 mice. We found that after acute injection, D-Ala2GIP had few effects on general behaviour in the open field at any dose tested (2.5, 25, 100, or 250 nmol/kg i.p.). In memory tests, no change was observed, whilst (Pro3)GIP at 25 nmol/kg i.p. impaired memory formation. In a chronic study over 4 weeks, mice injected with D-Ala2GIP (2.5 or 25 nmol/kg i.p.) and (Pro3)GIP (25 nmol/kg i.p.) learned a water maze task and object recognition task without impairment. In LTP recording in area CA1, both (Pro3)GIP as well as D-Ala2GIP enhanced LTP formation. In addition, the proliferation of neuronal progenitor cells in the dentate gyrus was increased both by D-Ala2GIP and (Pro3)GIP. The results show that the antagonist (Pro3)GIP has agonistic effects in chronic use, and both (Pro3)GIP and the agonist D-Ala2GIP are safe to use in wt mice and induces no major behavioural side effects nor impairments in learning whilst enhancing LTP and neuronal progenitor cell proliferation, which may be useful in treating neurodegenerative diseases. CI - Copyright (c) 2011 Elsevier B.V. All rights reserved. FAU - Faivre, Emilie AU - Faivre E AD - School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom. FAU - Hamilton, Alison AU - Hamilton A FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20111112 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Receptors, Gastrointestinal Hormone) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) SB - IM MH - Animals MH - CA1 Region, Hippocampal/cytology/drug effects/physiology MH - Cell Proliferation/drug effects MH - Cognition/*drug effects MH - Dentate Gyrus/cytology/drug effects/physiology MH - Exploratory Behavior/drug effects MH - Gastric Inhibitory Polypeptide/administration & dosage/*analogs & derivatives/*pharmacology MH - Long-Term Potentiation/drug effects MH - Male MH - Memory/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects MH - Neural Stem Cells/cytology/drug effects MH - Neurogenesis/*drug effects MH - Neuronal Plasticity/*drug effects MH - Receptors, Gastrointestinal Hormone/agonists MH - Synapses/*drug effects/metabolism MH - Time Factors EDAT- 2011/11/26 06:00 MHDA- 2012/05/04 06:00 CRDT- 2011/11/26 06:00 PHST- 2011/05/14 00:00 [received] PHST- 2011/10/27 00:00 [revised] PHST- 2011/11/04 00:00 [accepted] PHST- 2011/11/26 06:00 [entrez] PHST- 2011/11/26 06:00 [pubmed] PHST- 2012/05/04 06:00 [medline] AID - S0014-2999(11)01440-3 [pii] AID - 10.1016/j.ejphar.2011.11.007 [doi] PST - ppublish SO - Eur J Pharmacol. 2012 Jan 15;674(2-3):294-306. doi: 10.1016/j.ejphar.2011.11.007. Epub 2011 Nov 12. PMID- 21901364 OWN - NLM STAT- MEDLINE DCOM- 20130312 LR - 20211020 IS - 1574-4647 (Electronic) IS - 0161-9152 (Print) IS - 0161-9152 (Linking) VI - 34 IP - 5 DP - 2012 Oct TI - Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4. PG - 1211-24 AB - Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with age-dependent Alzheimer's disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3beta activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD. FAU - Chen, Song AU - Chen S AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China. FAU - Liu, Ai-ran AU - Liu AR FAU - An, Feng-mao AU - An FM FAU - Yao, Wen-bing AU - Yao WB FAU - Gao, Xiang-dong AU - Gao XD LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110908 PL - Netherlands TA - Age (Dordr) JT - Age (Dordrecht, Netherlands) JID - 101250497 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Peptides) RN - 0 (Venoms) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Alzheimer Disease/complications/*drug therapy/pathology MH - Animals MH - Blood Glucose/metabolism MH - Cell Survival MH - Diabetes Mellitus, Experimental/*complications/drug therapy/metabolism MH - Exenatide MH - Glucagon-Like Peptide 1 MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hippocampus/drug effects/metabolism/*pathology MH - Hypoglycemic Agents/therapeutic use MH - Insulin/metabolism MH - Male MH - Nerve Degeneration/etiology/metabolism/*prevention & control MH - *Oxidative Stress MH - Peptides/*therapeutic use MH - Rats MH - Rats, Wistar MH - Venoms/*therapeutic use PMC - PMC3448986 EDAT- 2011/09/09 06:00 MHDA- 2013/03/13 06:00 PMCR- 2013/10/01 CRDT- 2011/09/09 06:00 PHST- 2011/02/18 00:00 [received] PHST- 2011/08/19 00:00 [accepted] PHST- 2011/09/09 06:00 [entrez] PHST- 2011/09/09 06:00 [pubmed] PHST- 2013/03/13 06:00 [medline] PHST- 2013/10/01 00:00 [pmc-release] AID - 9303 [pii] AID - 10.1007/s11357-011-9303-8 [doi] PST - ppublish SO - Age (Dordr). 2012 Oct;34(5):1211-24. doi: 10.1007/s11357-011-9303-8. Epub 2011 Sep 8. PMID- 21824270 OWN - NLM STAT- MEDLINE DCOM- 20111014 LR - 20151119 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 13 Suppl 1 DP - 2011 Oct TI - The future of incretin-based therapy: novel avenues--novel targets. PG - 158-66 LID - 10.1111/j.1463-1326.2011.01457.x [doi] AB - Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years. CI - (c) 2011 Blackwell Publishing Ltd. FAU - Ahren, B AU - Ahren B AD - Department of Clinical Sciences Lund, Lund University, Lund, Sweden. Bo.Ahren@med.lu.se LA - eng PT - Journal Article PT - Review PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Incretins) RN - 0 (Receptors, Glucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Diabetes Mellitus, Type 2/*drug therapy/physiopathology MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Glucagon-Like Peptide 1/pharmacology/*therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Incretins/*therapeutic use MH - Receptors, Glucagon/*agonists/drug effects EDAT- 2011/08/17 06:00 MHDA- 2011/10/15 06:00 CRDT- 2011/08/10 06:00 PHST- 2011/08/10 06:00 [entrez] PHST- 2011/08/17 06:00 [pubmed] PHST- 2011/10/15 06:00 [medline] AID - 10.1111/j.1463-1326.2011.01457.x [doi] PST - ppublish SO - Diabetes Obes Metab. 2011 Oct;13 Suppl 1:158-66. doi: 10.1111/j.1463-1326.2011.01457.x. PMID- 21787319 OWN - NLM STAT- MEDLINE DCOM- 20111115 LR - 20151119 IS - 1470-8752 (Electronic) IS - 0300-5127 (Linking) VI - 39 IP - 4 DP - 2011 Aug TI - Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. PG - 891-7 LID - 10.1042/BST0390891 [doi] AB - Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by beta-amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin-like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, UK. christian_holscher@mac.com LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Biochem Soc Trans JT - Biochemical Society transactions JID - 7506897 RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Insulin) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Glucagon) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/drug therapy/*etiology MH - Animals MH - Diabetes Mellitus, Type 2/*complications MH - Disease Models, Animal MH - Gastric Inhibitory Polypeptide/metabolism MH - Glucagon-Like Peptide 1/analogs & derivatives/metabolism/therapeutic use MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Insulin/*metabolism/therapeutic use MH - Intercellular Signaling Peptides and Proteins/therapeutic use MH - Mice MH - Mice, Transgenic MH - Neuroprotective Agents/therapeutic use MH - Receptors, Glucagon/agonists MH - *Signal Transduction EDAT- 2011/07/27 06:00 MHDA- 2011/11/16 06:00 CRDT- 2011/07/27 06:00 PHST- 2011/07/27 06:00 [entrez] PHST- 2011/07/27 06:00 [pubmed] PHST- 2011/11/16 06:00 [medline] AID - BST0390891 [pii] AID - 10.1042/BST0390891 [doi] PST - ppublish SO - Biochem Soc Trans. 2011 Aug;39(4):891-7. doi: 10.1042/BST0390891. PMID- 21749267 OWN - NLM STAT- MEDLINE DCOM- 20120105 LR - 20131106 IS - 1744-7631 (Electronic) IS - 1472-8222 (Linking) VI - 15 IP - 10 DP - 2011 Oct TI - Targeting amyloid-beta by glucagon-like peptide -1 (GLP-1) in Alzheimer's disease and diabetes. PG - 1153-62 LID - 10.1517/14728222.2011.600691 [doi] AB - INTRODUCTION: Epidemiological evidence suggests an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD), in that one disease increases the risk of the other. T2DM and AD share several molecular processes which underlie the tissue degeneration in either disease. Disturbances in insulin signaling may be the link between the two conditions. Drugs originally developed for T2DM are currently being considered as possible novel agents in the treatment of AD. AREAS COVERED: This review discusses the potential role of glucagon-like peptide -1 (GLP-1) treatment in AD. GLP-1 receptors are expressed in areas of the brain important to memory and learning, and GLP-1 has growth-factor-like properties similar to insulin. A key neuropathological feature of AD is the accumulation of amyloid-beta (Abeta). In preclinical studies, GLP-1 and longer lasting analogues have been shown to have both neuroprotective and neurotrophic effects, and to protect synaptic activity in the brain from Abeta toxicity. EXPERT OPINION: A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD. FAU - Bak, Ann Mosegaard AU - Bak AM AD - University Hospital of Aarhus , Department of Medical Endocrinology, MEA, Norrebrogade, Denmark. ann.m.bak@farm.au.dk FAU - Egefjord, Laerke AU - Egefjord L FAU - Gejl, Michael AU - Gejl M FAU - Steffensen, Charlotte AU - Steffensen C FAU - Stecher, Chalotte Willemann AU - Stecher CW FAU - Smidt, Kamille AU - Smidt K FAU - Brock, Birgitte AU - Brock B FAU - Rungby, Jorgen AU - Rungby J LA - eng PT - Journal Article PT - Review DEP - 20110712 PL - England TA - Expert Opin Ther Targets JT - Expert opinion on therapeutic targets JID - 101127833 RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*drug therapy/epidemiology/metabolism/physiopathology MH - Amyloid beta-Peptides/*drug effects/metabolism MH - Animals MH - Cognition MH - Diabetes Mellitus, Type 2/*drug therapy/epidemiology MH - Glucagon-Like Peptide 1/pharmacology/*therapeutic use MH - Humans MH - Learning MH - Memory MH - Neuroprotective Agents/pharmacology/therapeutic use MH - Rats EDAT- 2011/07/14 06:00 MHDA- 2012/01/06 06:00 CRDT- 2011/07/14 06:00 PHST- 2011/07/14 06:00 [entrez] PHST- 2011/07/14 06:00 [pubmed] PHST- 2012/01/06 06:00 [medline] AID - 10.1517/14728222.2011.600691 [doi] PST - ppublish SO - Expert Opin Ther Targets. 2011 Oct;15(10):1153-62. doi: 10.1517/14728222.2011.600691. Epub 2011 Jul 12. PMID- 21747826 OWN - NLM STAT- MEDLINE DCOM- 20111202 LR - 20220321 IS - 1687-5303 (Electronic) IS - 1687-5214 (Print) IS - 1687-5214 (Linking) VI - 2011 DP - 2011 TI - Glucagon-like peptide-1, diabetes, and cognitive decline: possible pathophysiological links and therapeutic opportunities. PG - 281674 LID - 10.1155/2011/281674 [doi] LID - 281674 AB - Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline. FAU - Mossello, Enrico AU - Mossello E AD - Unit of Gerontology and Geriatric Medicine, Department of Critical Care Medicine and Surgery, University of Florence and Careggi Teaching Hospital, 50121 Florence, Italy. enrico.mossello@unifi.it FAU - Ballini, Elena AU - Ballini E FAU - Boncinelli, Marta AU - Boncinelli M FAU - Monami, Matteo AU - Monami M FAU - Lonetto, Giuseppe AU - Lonetto G FAU - Mello, Anna Maria AU - Mello AM FAU - Tarantini, Francesca AU - Tarantini F FAU - Baldasseroni, Samuele AU - Baldasseroni S FAU - Mannucci, Edoardo AU - Mannucci E FAU - Marchionni, Niccolo AU - Marchionni N LA - eng PT - Journal Article PT - Review DEP - 20110601 PL - United States TA - Exp Diabetes Res JT - Experimental diabetes research JID - 101274844 RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Cognition Disorders/*etiology/metabolism/physiopathology/prevention & control MH - Diabetes Mellitus, Type 2/*complications/*drug therapy/metabolism/*physiopathology MH - Endocrinology/methods/trends MH - Glucagon-Like Peptide 1/deficiency/metabolism/*physiology/therapeutic use MH - Humans MH - Insulin Resistance/physiology MH - Nerve Degeneration/drug therapy/etiology/metabolism MH - Therapies, Investigational/methods/trends PMC - PMC3124026 EDAT- 2011/07/13 06:00 MHDA- 2011/12/13 00:00 PMCR- 2011/06/01 CRDT- 2011/07/13 06:00 PHST- 2011/02/25 00:00 [received] PHST- 2011/04/05 00:00 [accepted] PHST- 2011/07/13 06:00 [entrez] PHST- 2011/07/13 06:00 [pubmed] PHST- 2011/12/13 00:00 [medline] PHST- 2011/06/01 00:00 [pmc-release] AID - 10.1155/2011/281674 [doi] PST - ppublish SO - Exp Diabetes Res. 2011;2011:281674. doi: 10.1155/2011/281674. Epub 2011 Jun 1. PMID- 21525299 OWN - NLM STAT- MEDLINE DCOM- 20110624 LR - 20211020 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 31 IP - 17 DP - 2011 Apr 27 TI - The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. PG - 6587-94 LID - 10.1523/JNEUROSCI.0529-11.2011 [doi] AB - Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(DeltaE9) (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall beta-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease. FAU - McClean, Paula L AU - McClean PL AD - School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, Northern Ireland, United Kingdom. FAU - Parthsarathy, Vadivel AU - Parthsarathy V FAU - Faivre, Emilie AU - Faivre E FAU - Holscher, Christian AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Hypoglycemic Agents) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - 0 (Synaptophysin) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*complications/genetics/pathology MH - Amyloid beta-Peptides/metabolism MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Analysis of Variance MH - Animals MH - Blood-Brain Barrier/drug effects/physiopathology MH - Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay/methods MH - Female MH - Glucagon-Like Peptide 1/*analogs & derivatives/therapeutic use MH - Hippocampus/drug effects/physiopathology MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Liraglutide MH - Long-Term Potentiation/drug effects/physiology MH - Male MH - Maze Learning/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Nerve Degeneration/*etiology/*prevention & control MH - Presenilin-1/genetics MH - Recognition, Psychology/drug effects MH - Synaptophysin/metabolism PMC - PMC6622662 EDAT- 2011/04/29 06:00 MHDA- 2011/06/28 06:00 PMCR- 2011/10/27 CRDT- 2011/04/29 06:00 PHST- 2011/04/29 06:00 [entrez] PHST- 2011/04/29 06:00 [pubmed] PHST- 2011/06/28 06:00 [medline] PHST- 2011/10/27 00:00 [pmc-release] AID - 31/17/6587 [pii] AID - 3693171 [pii] AID - 10.1523/JNEUROSCI.0529-11.2011 [doi] PST - ppublish SO - J Neurosci. 2011 Apr 27;31(17):6587-94. doi: 10.1523/JNEUROSCI.0529-11.2011. PMID- 21312223 OWN - NLM STAT- MEDLINE DCOM- 20110610 LR - 20220321 IS - 1097-4547 (Electronic) IS - 0360-4012 (Linking) VI - 89 IP - 4 DP - 2011 Apr TI - Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. PG - 481-9 LID - 10.1002/jnr.22565 [doi] AB - One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP-1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis. CI - Copyright (c) 2011 Wiley-Liss, Inc. FAU - Hamilton, A AU - Hamilton A AD - School of Biomedical Science, University of Ulster, Coleraine, Northern Ireland, United Kingdom. FAU - Patterson, S AU - Patterson S FAU - Porter, D AU - Porter D FAU - Gault, V A AU - Gault VA FAU - Holscher, C AU - Holscher C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110110 PL - United States TA - J Neurosci Res JT - Journal of neuroscience research JID - 7600111 RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Animals MH - Brain/*drug effects MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Dentate Gyrus/*drug effects MH - Diabetes Mellitus, Type 2/*drug therapy MH - Disease Models, Animal MH - Exenatide MH - Glucagon-Like Peptide 1/agonists/*analogs & derivatives/pharmacology MH - Hypoglycemic Agents/*pharmacology MH - Immunohistochemistry MH - Liraglutide MH - Male MH - Mice MH - Neural Stem Cells/*drug effects MH - Neurogenesis/drug effects MH - Neurons/cytology/drug effects MH - Peptides/*pharmacology MH - Venoms/*pharmacology EDAT- 2011/02/12 06:00 MHDA- 2011/06/11 06:00 CRDT- 2011/02/12 06:00 PHST- 2010/10/25 00:00 [received] PHST- 2010/10/26 00:00 [accepted] PHST- 2011/02/12 06:00 [entrez] PHST- 2011/02/12 06:00 [pubmed] PHST- 2011/06/11 06:00 [medline] AID - 10.1002/jnr.22565 [doi] PST - ppublish SO - J Neurosci Res. 2011 Apr;89(4):481-9. doi: 10.1002/jnr.22565. Epub 2011 Jan 10. PMID- 21294236 OWN - NLM STAT- MEDLINE DCOM- 20110517 LR - 20110204 IS - 1520-7560 (Electronic) IS - 1520-7552 (Linking) VI - 27 IP - 2 DP - 2011 Feb TI - Peptide hormones regulating appetite--focus on neuroimaging studies in humans. PG - 104-12 LID - 10.1002/dmrr.1154 [doi] AB - In recent years, knowledge about hormonal feedback from the gastrointestinal tract and adipose tissue has increased tremendously. Peptide hormones modulating hunger have been intensively studied, mostly in animals but increasingly also in humans. The first therapeutic agents, such as GLP-1 analogues, are in successful clinical use for T2D and may beneficially affect hunger and reduce weight. Data from in vitro studies and animals provide detailed insight into regulatory mechanisms leading to peptide secretion and receptor bindings, as well as to the distribution of receptors involved in different parts of the body. With neuroimaging techniques human brain structures have been identified that play a role in hunger, satiety and eating behaviour. These include the primary gustatory (insular) and olfactory (pyriform) cortex and regions with a highly permeable blood-brain barrier (hypothalamus, brain stem), which facilitates humoral input via gut peptides and leptin. In addition, cerebral networks involved in higher cognitive functions, especially those relevant to reward, pleasure and also addiction (ventral and dorsal striatum, amygdala, orbitofrontal cortex (OFC), prefrontal cortex (PFC)) were shown to be involved. First indications of direct influences of peptide hormones on these networks have become available from neuroimaging studies administrating synthetic PYY, ghrelin and leptin. Insulin also appears to play an important role as a central satiety hormone, and evidence indicating the possibility of central insulin resistance in obesity is available. CI - Copyright (c) 2011 John Wiley & Sons, Ltd. FAU - Schloegl, Haiko AU - Schloegl H AD - Department of Medicine, University of Leipzig, Leipzig, Germany. FAU - Percik, Ruth AU - Percik R FAU - Horstmann, Annette AU - Horstmann A FAU - Villringer, Arno AU - Villringer A FAU - Stumvoll, Michael AU - Stumvoll M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - England TA - Diabetes Metab Res Rev JT - Diabetes/metabolism research and reviews JID - 100883450 RN - 0 (Peptide Hormones) SB - IM MH - Animals MH - Appetite Regulation/*physiology MH - Brain/*metabolism MH - *Diagnostic Imaging MH - Humans MH - Hunger/physiology MH - Peptide Hormones/*physiology EDAT- 2011/02/05 06:00 MHDA- 2011/05/18 06:00 CRDT- 2011/02/05 06:00 PHST- 2011/02/05 06:00 [entrez] PHST- 2011/02/05 06:00 [pubmed] PHST- 2011/05/18 06:00 [medline] AID - 10.1002/dmrr.1154 [doi] PST - ppublish SO - Diabetes Metab Res Rev. 2011 Feb;27(2):104-12. doi: 10.1002/dmrr.1154. PMID- 21251764 OWN - NLM STAT- MEDLINE DCOM- 20110630 LR - 20171116 IS - 1532-2777 (Electronic) IS - 0306-9877 (Linking) VI - 76 IP - 4 DP - 2011 Apr TI - Milk signalling in the pathogenesis of type 2 diabetes. PG - 553-9 LID - 10.1016/j.mehy.2010.12.017 [doi] AB - The presented hypothesis identifies milk consumption as an environmental risk factor of Western diet promoting type 2 diabetes (T2D). Milk, commonly regarded as a valuable nutrient, exerts important endocrine functions as an insulinotropic, anabolic and mitogenic signalling system supporting neonatal growth and development. The presented hypothesis substantiates milk's physiological role as a signalling system for pancreatic beta-cell proliferation by milk's ability to increase prolactin-, growth hormone and incretin-signalling. The proposed mechanism of milk-induced postnatal beta-cell mass expansion mimics the adaptive prolactin-dependent proliferative changes observed in pregnancy. Milk signalling down-regulates the key transcription factor FoxO1 leading to up-regulation of insulin promoter factor-1 which stimulates beta-cell proliferation, insulin secretion as well as coexpression of islet amyloid polypeptide (IAPP). The recent finding that adult rodent beta-cells only proliferate by self-duplication is of crucial importance, because permanent milk consumption beyond the weaning period may continuously over-stimulate beta-cell replication thereby accelerating the onset of replicative beta-cell senescence. The long-term use of milk may thus increase endoplasmic reticulum (ER) stress and toxic IAPP oligomer formation by overloading the ER with cytotoxic IAPPs thereby promoting beta-cell apoptosis. Both increased beta-cell proliferation and beta-cell apoptosis are hallmarks of T2D. This hypothesis gets support from clinical states of hyperprolactinaemia and progeria syndromes with early onset of cell senescence which are both associated with an increased incidence of T2D and share common features of milk signalling. Furthermore, the presented milk hypothesis of T2D is compatible with the concept of high ER stress in T2D and the toxic oligomer hypothesis of T2D and may explain the high association of T2D and Alzheimer disease. CI - Copyright (c) 2010 Elsevier Ltd. All rights reserved. FAU - Melnik, Bodo C AU - Melnik BC AD - Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabruck, Osnabruck, Germany. melnik@t-online.de LA - eng PT - Journal Article DEP - 20110119 PL - United States TA - Med Hypotheses JT - Medical hypotheses JID - 7505668 RN - 0 (FOXO1 protein, human) RN - 0 (Forkhead Box Protein O1) RN - 0 (Forkhead Transcription Factors) RN - 0 (Homeodomain Proteins) RN - 0 (Trans-Activators) RN - 0 (pancreatic and duodenal homeobox 1 protein) SB - IM MH - Alzheimer Disease/etiology/genetics/metabolism MH - Animals MH - Apoptosis MH - Cellular Senescence MH - Diabetes Mellitus, Type 2/*etiology/genetics/metabolism MH - *Diet MH - Forkhead Box Protein O1 MH - Forkhead Transcription Factors/metabolism MH - Homeodomain Proteins/genetics MH - Humans MH - Insulin-Secreting Cells/metabolism/pathology/*physiology MH - Milk/*adverse effects/*metabolism MH - Trans-Activators/genetics MH - Up-Regulation EDAT- 2011/01/22 06:00 MHDA- 2011/07/01 06:00 CRDT- 2011/01/22 06:00 PHST- 2010/07/25 00:00 [received] PHST- 2010/10/04 00:00 [revised] PHST- 2010/12/23 00:00 [accepted] PHST- 2011/01/22 06:00 [entrez] PHST- 2011/01/22 06:00 [pubmed] PHST- 2011/07/01 06:00 [medline] AID - S0306-9877(10)00539-6 [pii] AID - 10.1016/j.mehy.2010.12.017 [doi] PST - ppublish SO - Med Hypotheses. 2011 Apr;76(4):553-9. doi: 10.1016/j.mehy.2010.12.017. Epub 2011 Jan 19. PMID- 21222567 OWN - NLM STAT- MEDLINE DCOM- 20110614 LR - 20110215 IS - 1473-4877 (Electronic) IS - 0300-7995 (Linking) VI - 27 IP - 3 DP - 2011 Mar TI - Neuroprotective properties of GLP-1: theoretical and practical applications. PG - 547-58 LID - 10.1185/03007995.2010.549466 [doi] AB - In the past few years, the development of pharmaceutical agents that enhance the physiological effects of glucagon-like peptide-1 (GLP-1), either through GLP-1 receptor agonism (GLP-1 agonists) or by inhibiting GLP-1 degradation (dipeptidylpeptidase-4 inhibitors) has broadened the range of treatment options for individuals with type 2 diabetes. It has been recognized for some time that GLP-1 also has extra-pancreatic effects, notably targeting the brain, where it regulates appetite and satiety, as well as peripheral functions highly controlled by the autonomic nervous system, such as gastric emptying. Furthermore, data are beginning to emerge that indicate a potential role for GLP-1 in neuroprotection. The increased risk of Alzheimer's disease, Parkinson's disease and stroke in people with type 2 diabetes suggests that shared mechanisms/pathways of cell death, possibly related to insulin dysregulation, may underlie all of these disorders. Although the disease anatomy varies with each disorder, a wide range of genetic and environmental triggers result in activation of similar biochemical pathways in all of them, suggesting a complex network of biochemical events that feed in to a final common path towards cellular dysfunction and death. This article summarizes the evidence for neuronal activity of GLP-1 and examines the limited data that currently exist on the therapeutic potential of GLP-1 in specific neurological and neurodegenerative conditions, namely Alzheimer's disease, Parkinson's disease, Huntingdon's disease, stroke and peripheral sensory neuropathy. FAU - Holst, Jens Juul AU - Holst JJ AD - Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark. jjholst@sund.ku.dk FAU - Burcelin, Remy AU - Burcelin R FAU - Nathanson, Esther AU - Nathanson E LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20110112 PL - England TA - Curr Med Res Opin JT - Current medical research and opinion JID - 0351014 RN - 0 (Neuroprotective Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Diabetes Complications/drug therapy/etiology MH - Glucagon-Like Peptide 1/*pharmacology/*therapeutic use MH - Humans MH - Models, Biological MH - Models, Theoretical MH - Nervous System/*drug effects MH - Nervous System Diseases/drug therapy/etiology MH - Neuroprotective Agents/*pharmacology/*therapeutic use EDAT- 2011/01/13 06:00 MHDA- 2011/06/15 06:00 CRDT- 2011/01/13 06:00 PHST- 2011/01/13 06:00 [entrez] PHST- 2011/01/13 06:00 [pubmed] PHST- 2011/06/15 06:00 [medline] AID - 10.1185/03007995.2010.549466 [doi] PST - ppublish SO - Curr Med Res Opin. 2011 Mar;27(3):547-58. doi: 10.1185/03007995.2010.549466. Epub 2011 Jan 12. PMID- 21094907 OWN - NLM STAT- MEDLINE DCOM- 20110405 LR - 20101124 IS - 0083-6729 (Print) IS - 0083-6729 (Linking) VI - 84 DP - 2010 TI - The role of GLP-1 in neuronal activity and neurodegeneration. PG - 331-54 LID - 10.1016/B978-0-12-381517-0.00013-8 [doi] AB - Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). The underlying mechanism behind this unexpected link is most likely linked to the observed desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting, and differentiation. Several drugs have been developed to treat type 2 diabetes which re-synthesize insulin receptors and may be of use to prevent neurodegenerative developments in AD. The incretin glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor like properties as insulin, and has been shown to protect neurons from toxic effects. In preclinical studies, GLP-1 and longer lasting analogues reduce apoptosis, protect neurons from oxidative stress, induce neurite outgrowth, protect synaptic plasticity and memory formation from the detrimental effects of beta-amyloid, and reduce plaque formation and the inflammation response in the brains of mouse models of AD. An advantage of GLP-1 is that it does not affect blood sugar levels in nondiabetic people. Furthermore, recent research has shown that some GLP-1 analogues can cross the blood-brain barrier, including two that are on the market as a treatment for type 2 diabetes. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions. CI - Copyright (c) 2010 Elsevier Inc. All rights reserved. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Vitam Horm JT - Vitamins and hormones JID - 0413601 RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 2.7.10.1 (Receptor, Insulin) SB - IM MH - Alzheimer Disease/metabolism/pathology MH - Animals MH - Blood-Brain Barrier/physiology MH - Diabetes Mellitus, Type 2/metabolism/pathology MH - Glucagon-Like Peptide 1/analogs & derivatives/*physiology MH - Humans MH - Nerve Degeneration/*physiopathology MH - Receptor, Insulin/*physiology EDAT- 2010/11/26 06:00 MHDA- 2011/04/06 06:00 CRDT- 2010/11/25 06:00 PHST- 2010/11/25 06:00 [entrez] PHST- 2010/11/26 06:00 [pubmed] PHST- 2011/04/06 06:00 [medline] AID - B978-0-12-381517-0.00013-8 [pii] AID - 10.1016/B978-0-12-381517-0.00013-8 [doi] PST - ppublish SO - Vitam Horm. 2010;84:331-54. doi: 10.1016/B978-0-12-381517-0.00013-8. PMID- 20920042 OWN - NLM STAT- MEDLINE DCOM- 20110602 LR - 20220321 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 12 IP - 10 DP - 2010 Oct TI - Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. PG - 891-9 LID - 10.1111/j.1463-1326.2010.01259.x [doi] AB - AIM: Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood-brain barrier and may additionally act to improve brain function. The present study tested the hypothesis that, in addition to its antihyperglycaemic actions, peripheral administration of Liraglutide exerts positive actions on cognitive function in mice with high fat dietary-induced obesity and insulin resistance. METHODS: Young Swiss TO mice maintained on high fat diet for 20 weeks received twice-daily injections of Liraglutide (200 microg/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non-fasting plasma glucose and insulin concentrations were monitored at regular intervals. Glucose tolerance, open field assessment, object recognition testing and electrophysiological long-term potentiation (LTP) were performed at termination of the study. RESULTS: Liraglutide treatment resulted in significant time-dependent reduction in bodyweight and energy intake, whilst improving non-fasting glucose and normalizing glucose tolerance. Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase in recognition index (RI) during object recognition testing, indicative of enhanced learning and memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission following both chronic and direct intracerebroventricular (icv) administration. CONCLUSION: Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established. CI - (c) 2010 Blackwell Publishing Ltd. FAU - Porter, D W AU - Porter DW AD - The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. FAU - Kerr, B D AU - Kerr BD FAU - Flatt, P R AU - Flatt PR FAU - Holscher, C AU - Holscher C FAU - Gault, V A AU - Gault VA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Blood Glucose/*drug effects MH - Cognition/*drug effects/physiology MH - Diabetes Mellitus, Type 2 MH - Glucagon-Like Peptide 1/administration & dosage/*analogs & derivatives MH - Hypoglycemic Agents/*administration & dosage MH - Insulin Resistance/physiology MH - Liraglutide MH - Male MH - Memory/*drug effects/physiology MH - Mice MH - Obesity/*drug therapy EDAT- 2010/10/06 06:00 MHDA- 2011/06/03 06:00 CRDT- 2010/10/06 06:00 PHST- 2010/10/06 06:00 [entrez] PHST- 2010/10/06 06:00 [pubmed] PHST- 2011/06/03 06:00 [medline] AID - 10.1111/j.1463-1326.2010.01259.x [doi] PST - ppublish SO - Diabetes Obes Metab. 2010 Oct;12(10):891-9. doi: 10.1111/j.1463-1326.2010.01259.x. PMID- 20727946 OWN - NLM STAT- MEDLINE DCOM- 20110118 LR - 20101004 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 170 IP - 4 DP - 2010 Nov 10 TI - Val8-glucagon-like peptide-1 protects against Abeta1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats. PG - 1239-48 LID - 10.1016/j.neuroscience.2010.08.028 [doi] AB - Amyloid beta protein (Abeta) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin-release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Abeta-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val(8)-GLP-1(7-36) on the Abeta fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Abeta1-40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val(8)-GLP-1(7-36) (0.05 pmol) effectively prevented Abeta1-40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Abeta1-40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val(8)-GLP-1(7-36) effectively reversed the impairment of spatial learning and memory induced by Abeta1-40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the degenerative processes observed in AD. CI - Copyright (c) 2010 IBRO. All rights reserved. FAU - Wang, X H AU - Wang XH AD - Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, PR China. FAU - Li, L AU - Li L FAU - Holscher, C AU - Holscher C FAU - Pan, Y F AU - Pan YF FAU - Chen, X R AU - Chen XR FAU - Qi, J S AU - Qi JS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100819 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-40)) RN - 0 (glucagon-like peptide 1 (7-36), Val(8)-) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Amyloid beta-Peptides/*pharmacology MH - Animals MH - CA1 Region, Hippocampal/*drug effects/physiology MH - Excitatory Postsynaptic Potentials MH - Glucagon-Like Peptide 1/*pharmacology MH - Long-Term Potentiation/*drug effects MH - Male MH - Maze Learning/*drug effects MH - Memory/drug effects MH - Neuroprotective Agents/*pharmacology MH - Peptide Fragments/*pharmacology MH - Rats MH - Rats, Wistar MH - Swimming MH - Synaptic Transmission/drug effects MH - Vision, Ocular/drug effects EDAT- 2010/08/24 06:00 MHDA- 2011/01/19 06:00 CRDT- 2010/08/24 06:00 PHST- 2010/07/01 00:00 [received] PHST- 2010/08/13 00:00 [accepted] PHST- 2010/08/24 06:00 [entrez] PHST- 2010/08/24 06:00 [pubmed] PHST- 2011/01/19 06:00 [medline] AID - S0306-4522(10)01136-X [pii] AID - 10.1016/j.neuroscience.2010.08.028 [doi] PST - ppublish SO - Neuroscience. 2010 Nov 10;170(4):1239-48. doi: 10.1016/j.neuroscience.2010.08.028. Epub 2010 Aug 19. PMID- 20698813 OWN - NLM STAT- MEDLINE DCOM- 20110131 LR - 20181024 IS - 1744-7658 (Electronic) IS - 1354-3784 (Linking) VI - 19 IP - 9 DP - 2010 Sep TI - Therapeutic potential of the original incretin hormone glucose-dependent insulinotropic polypeptide: diabetes, obesity, osteoporosis and Alzheimer's disease? PG - 1039-48 LID - 10.1517/13543784.2010.513381 [doi] AB - IMPORTANCE TO THE FIELD: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that potentiates nutrient-induced insulin release. To date, the physiological importance of GIP has received much less attention than its younger sister incretin hormone glucagon-like peptide-1. Thus, it is worthwhile to refocus on this important and somewhat neglected incretin hormone. AREAS COVERED IN THIS REVIEW: The potential role of GIP as a treatment option for type 2 diabetes is highlighted. Furthermore, the use of GIP as a new therapeutic option for obesity, osteoporosis and cognitive impairment is also considered. WHAT THE READER WILL GAIN: Long-acting GIP receptor agonists offer a potential new class of antidiabetic drugs. Furthermore, recent observations suggest an as yet untapped potential for GIP agonists in the treatment of osteoporosis and cognitive impairment. In addition, GIP is known to play a role in lipid metabolism and fat deposition. Accordingly, both genetic and chemical ablation of GIP signalling in mice with obesity-diabetes can protect against, or reverse, many of the obesity-associated metabolic disturbances. This review focuses on preclinical data generated to date. TAKE HOME MESSAGE: GIP-based therapeutics have potential for the treatment of type 2 diabetes and obesity, with the possibility of further beneficial actions in osteoporosis and cognitive decline. FAU - Irwin, Nigel AU - Irwin N AD - SAAD Centre for Diabetes and Pharmacy, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, Northern Ireland, UK. n.irwin@ulster.ac.uk FAU - Gault, Victor AU - Gault V FAU - Flatt, Peter R AU - Flatt PR LA - eng PT - Journal Article PT - Review PL - England TA - Expert Opin Investig Drugs JT - Expert opinion on investigational drugs JID - 9434197 RN - 0 (Hypoglycemic Agents) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) SB - IM MH - *Alzheimer Disease/drug therapy/metabolism MH - Animals MH - Cell Line MH - *Diabetes Mellitus, Type 2/drug therapy/physiopathology MH - *Gastric Inhibitory Polypeptide/agonists/analogs & derivatives/metabolism/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - *Obesity/drug therapy/metabolism MH - *Osteoporosis/drug therapy/metabolism MH - Osteoporosis, Postmenopausal/drug therapy/metabolism MH - Receptors, Gastrointestinal Hormone/agonists/antagonists & inhibitors/metabolism EDAT- 2010/08/12 06:00 MHDA- 2011/02/01 06:00 CRDT- 2010/08/12 06:00 PHST- 2010/08/12 06:00 [entrez] PHST- 2010/08/12 06:00 [pubmed] PHST- 2011/02/01 06:00 [medline] AID - 10.1517/13543784.2010.513381 [doi] PST - ppublish SO - Expert Opin Investig Drugs. 2010 Sep;19(9):1039-48. doi: 10.1517/13543784.2010.513381. PMID- 20638440 OWN - NLM STAT- MEDLINE DCOM- 20110228 LR - 20101115 IS - 1873-5118 (Electronic) IS - 0301-0082 (Linking) VI - 92 IP - 3 DP - 2010 Nov TI - Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: role of peripherally secreted and centrally produced peptides. PG - 442-62 LID - 10.1016/j.pneurobio.2010.07.003 [doi] AB - The scientific understanding of preproglucagon derived peptides has provided people with type 2 diabetes with two novel classes of glucose lowering agents, the dipeptidyl peptidase IV (DPP-IV) inhibitors and GLP-1 receptor agonists. For the scientists, the novel GLP-1 agonists, and DPP-IV inhibitors have evolved as useful tools to understand the role of the preproglucagon derived peptides in normal physiology and disease. However, the overwhelming interest attracted by GLP-1 analogues as potent incretins has somewhat clouded the efforts to understand the importance of preproglucagon derived peptides in other physiological contexts. In particular, our neurobiological understanding of the preproglucagon expressing neuronal pathways in the central nervous system as well as the degree to which central GLP-1 receptors are targeted by peripherally administered GLP-1 receptor agonists is still fairly limited. The role of GLP-1 as an anorectic neurotransmitter is well recognized, but clarification of the neuronal targets and physiological basis of this response is further warranted, as is the mapping of GLP-1 sensitive neurons involved in a variety of neuroendocrine and behavioral responses. Further recent evidence points to GLP-1 as a central neuropeptide with neuroprotective capabilities potentially mitigating a wide array of neurodegenerative conditions. It is the aim of the present review to summarize our current understanding of preproglucagon derived peptides as neurotransmitters in the central nervous system. CI - Copyright (c) 2010 Elsevier Ltd. All rights reserved. FAU - Vrang, Niels AU - Vrang N AD - Gubra ApS, Ridebanevej 12, 1870 Frederiksberg, Denmark. niels@gubra.dk FAU - Larsen, Philip Just AU - Larsen PJ LA - eng PT - Journal Article PT - Review DEP - 20100716 PL - England TA - Prog Neurobiol JT - Progress in neurobiology JID - 0370121 RN - 0 (Glucagon-Like Peptide 2) RN - 0 (Neurotransmitter Agents) RN - 0 (Oxyntomodulin) RN - 55963-74-1 (Proglucagon) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Animals MH - Central Nervous System/anatomy & histology/*metabolism MH - Glucagon-Like Peptide 1/*metabolism MH - Glucagon-Like Peptide 2/*metabolism MH - Humans MH - Neural Pathways/anatomy & histology/metabolism MH - Neurons/cytology/metabolism MH - Neurotransmitter Agents/metabolism MH - Oxyntomodulin/*metabolism MH - Proglucagon/*metabolism EDAT- 2010/07/20 06:00 MHDA- 2011/03/01 06:00 CRDT- 2010/07/20 06:00 PHST- 2010/03/02 00:00 [received] PHST- 2010/07/01 00:00 [revised] PHST- 2010/07/10 00:00 [accepted] PHST- 2010/07/20 06:00 [entrez] PHST- 2010/07/20 06:00 [pubmed] PHST- 2011/03/01 06:00 [medline] AID - S0301-0082(10)00134-6 [pii] AID - 10.1016/j.pneurobio.2010.07.003 [doi] PST - ppublish SO - Prog Neurobiol. 2010 Nov;92(3):442-62. doi: 10.1016/j.pneurobio.2010.07.003. Epub 2010 Jul 16. PMID- 20496097 OWN - NLM STAT- MEDLINE DCOM- 20101116 LR - 20240525 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 67 IP - 21 DP - 2010 Nov TI - Differentiating effects of the glucagon-like peptide-1 analogue exendin-4 in a human neuronal cell model. PG - 3711-23 LID - 10.1007/s00018-010-0398-3 [doi] AB - Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide with neurotrophic properties, as assessed in animal cell models. Exendin-4, a GLP-1 analogue, has been recently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to morphologically, structurally, and functionally characterize the differentiating actions of exendin-4 using a human neuronal cell model (i.e., SH-SY5Y cells). We found that exendin-4 increased the number of neurites paralleled by dramatic changes in intracellular actin and tubulin distribution. Electrophysiological analyses showed an increase in cell membrane surface and in stretch-activated-channels sensitivity, an increased conductance of Na(+) channels and amplitude of Ca(++) currents (T- and L-type), typical of a more mature neuronal phenotype. To our knowledge, this is the first demonstration that exendin-4 promotes neuronal differentiation in human cells. Noteworthy, our data support the claimed favorable role of exendin-4 against diabetic neuropathy as well as against different neurodegenerative diseases. FAU - Luciani, Paola AU - Luciani P AD - Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Florence, Italy. FAU - Deledda, Cristiana AU - Deledda C FAU - Benvenuti, Susanna AU - Benvenuti S FAU - Cellai, Ilaria AU - Cellai I FAU - Squecco, Roberta AU - Squecco R FAU - Monici, Monica AU - Monici M FAU - Cialdai, Francesca AU - Cialdai F FAU - Luciani, Giorgia AU - Luciani G FAU - Danza, Giovanna AU - Danza G FAU - Di Stefano, Chiara AU - Di Stefano C FAU - Francini, Fabio AU - Francini F FAU - Peri, Alessandro AU - Peri A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100523 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - 0 (Actin Depolymerizing Factors) RN - 0 (Actins) RN - 0 (Ion Channels) RN - 0 (Peptides) RN - 0 (Tubulin) RN - 0 (Venoms) RN - 5688UTC01R (Tretinoin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) SB - IM MH - Actin Depolymerizing Factors/metabolism MH - Actins/ultrastructure MH - Cell Line MH - Cytoskeleton/ultrastructure MH - Exenatide MH - Gene Expression MH - Glucagon-Like Peptide 1/*analogs & derivatives/genetics/metabolism MH - Humans MH - Ion Channels/metabolism MH - Membrane Potentials/drug effects MH - Neurogenesis/*drug effects MH - Neurons/*cytology/drug effects/metabolism MH - Peptides/*pharmacology MH - Phosphorylation MH - Tretinoin/pharmacology MH - Tubulin/ultrastructure MH - Venoms/*pharmacology PMC - PMC11115565 EDAT- 2010/05/25 06:00 MHDA- 2010/11/17 06:00 PMCR- 2010/05/23 CRDT- 2010/05/25 06:00 PHST- 2010/01/26 00:00 [received] PHST- 2010/04/30 00:00 [accepted] PHST- 2010/03/31 00:00 [revised] PHST- 2010/05/25 06:00 [entrez] PHST- 2010/05/25 06:00 [pubmed] PHST- 2010/11/17 06:00 [medline] PHST- 2010/05/23 00:00 [pmc-release] AID - 398 [pii] AID - 10.1007/s00018-010-0398-3 [doi] PST - ppublish SO - Cell Mol Life Sci. 2010 Nov;67(21):3711-23. doi: 10.1007/s00018-010-0398-3. Epub 2010 May 23. PMID- 20374430 OWN - NLM STAT- MEDLINE DCOM- 20100806 LR - 20250529 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 113 IP - 6 DP - 2010 Jun TI - Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. PG - 1621-31 LID - 10.1111/j.1471-4159.2010.06731.x [doi] AB - Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (GLP-1R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 and the long-acting agonist exendin-4 stimulated cell proliferation and increased cell viability by 2-fold at 24 h at physiologically relevant concentrations. This GLP-1R-dependent action was mediated via the protein kinase A and phosphoinositide 3-kinase signaling pathways, with the MAPK pathway playing a minor role. GLP-1 and exendin-4 pretreatment dose-dependently protected SH-hGLP-1R#9 cells from hydrogen peroxide (H(2)O(2))- and 6-hydroxydopamine-induced cell death. This involved amelioration of elevated caspase 3 activity, down-regulation of pro-apoptotic Bax and up-regulation of anti-apoptotic Bcl-2 protein. In the presence of 6-hydroxydopamine, GLP-1's ability to lower caspase-3 activity was abolished with the phosphoinositide 3-kinase inhibitor, LY2940002, and partly reduced with the protein kinase A inhibitor, H89. Hence, GLP-1R mediated neurotrophic and anti-apoptotic actions co-contribute to the neuroprotective property of GLP-1 in neuronal cell cultures, and reinforce the potential therapeutic value of GLP-1R agonists in neurodegenerative disorders involving oxidative stress. FAU - Li, Yazhou AU - Li Y AD - Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. liyaz@grc.nia.nih.gov FAU - Tweedie, David AU - Tweedie D FAU - Mattson, Mark P AU - Mattson MP FAU - Holloway, Harold W AU - Holloway HW FAU - Greig, Nigel H AU - Greig NH LA - eng GR - Z01 AG000311/ImNIH/Intramural NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20100402 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Adrenergic Agents) RN - 0 (Butadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (GLP1R protein, human) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (Nitriles) RN - 0 (Oxidants) RN - 0 (Peptides) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (Receptors, Glucagon) RN - 0 (U 0126) RN - 0 (Venoms) RN - 0 (bcl-2-Associated X Protein) RN - 145891-90-3 (Activating Transcription Factor 4) RN - 1F7A44V6OU (Colforsin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 8HW4YBZ748 (Oxidopamine) RN - 9P1872D4OL (Exenatide) RN - BBX060AN9V (Hydrogen Peroxide) RN - E0399OZS9N (Cyclic AMP) RN - EC 3.4.22.- (Caspase 3) RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Activating Transcription Factor 4/metabolism MH - Adrenergic Agents/toxicity MH - Apoptosis/drug effects MH - Bromodeoxyuridine/metabolism MH - Butadienes/pharmacology MH - Caspase 3/metabolism MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - Cell Survival/drug effects/physiology MH - Colforsin/pharmacology MH - Cyclic AMP/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/pharmacology MH - Exenatide MH - Glucagon-Like Peptide 1/*pharmacology MH - Glucagon-Like Peptide-1 Receptor MH - Humans MH - Hydrogen Peroxide/toxicity MH - Hypoglycemic Agents/pharmacology MH - Neuroblastoma MH - Neuroprotective Agents/*pharmacology MH - Nitriles/pharmacology MH - Oxidants/toxicity MH - Oxidopamine/toxicity MH - Peptides/pharmacology MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Receptors, Glucagon/genetics/*metabolism MH - Signal Transduction/drug effects/*physiology MH - Time Factors MH - Transfection/methods MH - Venoms/pharmacology MH - bcl-2-Associated X Protein/metabolism PMC - PMC2912144 MID - NIHMS219576 EDAT- 2010/04/09 06:00 MHDA- 2010/08/07 06:00 PMCR- 2011/06/01 CRDT- 2010/04/09 06:00 PHST- 2010/04/09 06:00 [entrez] PHST- 2010/04/09 06:00 [pubmed] PHST- 2010/08/07 06:00 [medline] PHST- 2011/06/01 00:00 [pmc-release] AID - JNC6731 [pii] AID - 10.1111/j.1471-4159.2010.06731.x [doi] PST - ppublish SO - J Neurochem. 2010 Jun;113(6):1621-31. doi: 10.1111/j.1471-4159.2010.06731.x. Epub 2010 Apr 2. PMID- 20337586 OWN - NLM STAT- MEDLINE DCOM- 20100907 LR - 20220223 IS - 2212-3954 (Electronic) IS - 1574-8898 (Linking) VI - 5 IP - 2 DP - 2010 Jun TI - Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. PG - 109-17 AB - Analogues of the incretins Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) have been developed to treat type 2 diabetes mellitus. They are protease resistant and have a longer biological half life than the native peptides. Some of these novel analogues can cross the blood-brain barrier, have neuroprotective effects, activate neuronal stem cells in the brain, and can improve cognition. The receptors for GIP and GLP-1 are expressed in neurons, and both GIP and GLP-1 are expressed and released as transmitters by neurons. GIP analogues such as DAla(2)GIP and GLP-1 analogues such as liraglutide enhance synaptic plasticity in the brain and also reverse the betaamyloid induced impairment of synaptic plasticity. In mouse models of Alzheimer's disease, GLP-1 analogues Val(8)GLP-1 and liraglutide prevent memory impairment and the block of synaptic plasticity in the brain. Since two GLP- 1 analogues exendin-4 (Exenatide, Byetta) and liraglutide (Victoza) are already on the market as treatments for Type 2 diabetes, and others are in late stage clinical trials, these drugs show promise as treatments for neurodegenerative diseases such as Alzheimer's disease. Currently, there are three patents covering native GLP-1 and different GLP-1 analogues and one patent for the use of GIP and different GIP analogues for the treatment of neurodegenerative diseases. FAU - Holscher, Christian AU - Holscher C AD - School of Biomedical Sciences, Ulster University, Cromore road, Coleraine BT52 1SA, UK. c.holscher@ulster.ac.uk LA - eng PT - Journal Article PT - Review PL - United Arab Emirates TA - Recent Pat CNS Drug Discov JT - Recent patents on CNS drug discovery JID - 101265656 RN - 0 (Incretins) RN - 0 (Neuroprotective Agents) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM MH - Alzheimer Disease/*drug therapy MH - Amino Acid Sequence MH - Animals MH - Blood-Brain Barrier/metabolism MH - Diabetes Mellitus, Type 2/*drug therapy MH - Gastric Inhibitory Polypeptide/analogs & derivatives/pharmacology/*therapeutic use MH - Glucagon-Like Peptide 1/analogs & derivatives/pharmacology/*therapeutic use MH - Humans MH - Incretins/*therapeutic use MH - Models, Neurological MH - Molecular Sequence Data MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Patents as Topic RF - 105 EDAT- 2010/03/27 06:00 MHDA- 2010/09/08 06:00 CRDT- 2010/03/27 06:00 PHST- 2010/01/21 00:00 [received] PHST- 2010/02/24 00:00 [accepted] PHST- 2010/03/27 06:00 [entrez] PHST- 2010/03/27 06:00 [pubmed] PHST- 2010/09/08 06:00 [medline] AID - BSP/RPCN/E-Pub/000020 [pii] AID - 10.2174/157488910791213130 [doi] PST - ppublish SO - Recent Pat CNS Drug Discov. 2010 Jun;5(2):109-17. doi: 10.2174/157488910791213130. PMID- 20308787 OWN - NLM STAT- MEDLINE DCOM- 20100722 LR - 20250529 IS - 1875-8908 (Electronic) IS - 1387-2877 (Print) IS - 1387-2877 (Linking) VI - 19 IP - 4 DP - 2010 TI - GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. PG - 1205-19 LID - 10.3233/JAD-2010-1314 [doi] AB - Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-beta protein (Abeta) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Abeta and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Abeta protein precursor and Abeta, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance. FAU - Li, Yazhou AU - Li Y AD - Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD, USA. FAU - Duffy, Kara B AU - Duffy KB FAU - Ottinger, Mary Ann AU - Ottinger MA FAU - Ray, Balmiki AU - Ray B FAU - Bailey, Jason A AU - Bailey JA FAU - Holloway, Harold W AU - Holloway HW FAU - Tweedie, David AU - Tweedie D FAU - Perry, Tracyann AU - Perry T FAU - Mattson, Mark P AU - Mattson MP FAU - Kapogiannis, Dimitrios AU - Kapogiannis D FAU - Sambamurti, Kumar AU - Sambamurti K FAU - Lahiri, Debomoy K AU - Lahiri DK FAU - Greig, Nigel H AU - Greig NH LA - eng GR - R01 AG018884/AG/NIA NIH HHS/United States GR - R01 AG023055/AG/NIA NIH HHS/United States GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States GR - R01-AG18379/AG/NIA NIH HHS/United States GR - P30-AG10133/AG/NIA NIH HHS/United States GR - ZIA AG000975/ImNIH/Intramural NIH HHS/United States GR - R01 AG022103/AG/NIA NIH HHS/United States GR - AG023055/AG/NIA NIH HHS/United States GR - U01-AG21380-03/AG/NIA NIH HHS/United States GR - R01 AG018379/AG/NIA NIH HHS/United States GR - R01-AG18884/AG/NIA NIH HHS/United States GR - Z01 AG000311/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Alzheimers Dis JT - Journal of Alzheimer's disease : JAD JID - 9814863 RN - 0 (Amyloid beta-Peptides) RN - 0 (GLP1R protein, human) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Receptors, Glucagon) RN - 0 (tau Proteins) SB - IM MH - Alzheimer Disease/epidemiology/*metabolism/*pathology MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Brain/*metabolism/*pathology MH - Diabetes Mellitus, Type 2/epidemiology MH - Disease Models, Animal MH - Female MH - Glucagon-Like Peptide-1 Receptor MH - Mice MH - Mice, Transgenic MH - Oxidative Stress/physiology MH - Receptors, Glucagon/*metabolism MH - tau Proteins/metabolism PMC - PMC2948479 MID - NIHMS239199 EDAT- 2010/03/24 06:00 MHDA- 2010/07/23 06:00 PMCR- 2010/10/01 CRDT- 2010/03/24 06:00 PHST- 2010/03/24 06:00 [entrez] PHST- 2010/03/24 06:00 [pubmed] PHST- 2010/07/23 06:00 [medline] PHST- 2010/10/01 00:00 [pmc-release] AID - V2080257QU782299 [pii] AID - 10.3233/JAD-2010-1314 [doi] PST - ppublish SO - J Alzheimers Dis. 2010;19(4):1205-19. doi: 10.3233/JAD-2010-1314. PMID- 20136169 OWN - NLM STAT- MEDLINE DCOM- 20100708 LR - 20211020 IS - 1179-1969 (Electronic) IS - 1170-229X (Linking) VI - 26 Suppl 1 DP - 2009 Dec TI - Antidiabetic oral treatment in older people: does frailty matter? PG - 53-62 LID - 10.2165/11534660-000000000-00000 [doi] AB - Life expectancy has significantly increased over the past 30 years, with a greater prevalence of diverse disease states, especially type 2 diabetes mellitus. As older persons are a very heterogeneous group with an increased prevalence of comorbidities and a relative inability to tolerate the adverse effects of oral antidiabetic agents, the treatment of type 2 diabetes is particularly demanding. The principles of its management are similar to those in younger patients, but with special considerations linked to comorbidities and clinical status. The available oral antidiabetic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors, thiazolidinediones and newly introduced inhibitors of glucagon-like peptide 1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). In addition, clinical aspects complicate diabetes care in the elderly, including cognitive disorders, physical disability and geriatric syndromes, such as frailty. The European Diabetes Working Party for Older Persons has increased glycaemic recommendations for target haemoglobin A(1c) from <7% to