Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders DOI Creative Commons
Yazhou Li, Kelli L. Vaughan, Yun Wang

et al.

GeroScience, Journal Year: 2024, Volume and Issue: 46(5), P. 4397 - 4414

Published: March 27, 2024

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, anti-neuroinflammatory actions. dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of GLP-1 GIP, and, thereby, extends the circulation these protective peptides. current nonhuman primate (NHP) study evaluates whether human translational doses can elevate systemic central nervous system (CNS) levels GLP-1/GIP in naive, non-lesioned NHPs, line with our prior rodent studies that demonstrated efficacy preclinical models Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose treatment inadequate. Repositioning well-tolerated efficacious diabetes drug provides a rapid approach to add therapeutic armamentarium for PD. pharmacokinetics pharmacodynamics 3 oral (5, 20, 100 mg/kg), equivalent routine clinical dose, tolerated higher dose maximal monkey, were evaluated. Peak plasma aligned both reports humans administered those rodents demonstrating reduction associated neurodegeneration. Although CNS uptake was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), CSF concentrations elevated studies. Additional cellular evaluating SH-SY5Y primary rat ventral mesencephalic cultures challenged 6-hydroxydopamine, established PD, joint + GIP mitigated cell death, particularly when combined DPP-4 inhibition maintain incretin levels. In conclusion, this supportive step towards evaluation other disorders which aging, similarly, greatest risk factor.

Language: Английский

Contemporary medical, device, and surgical therapies for obesity in adults DOI
Carolina M. Perdomo, Ricardo V. Cohen, Priya Sumithran

et al.

The Lancet, Journal Year: 2023, Volume and Issue: 401(10382), P. 1116 - 1130

Published: Feb. 9, 2023

Language: Английский

Citations

374
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1 DOI
Rola Hammoud, Daniel J. Drucker

Nature Reviews Endocrinology, Journal Year: 2022, Volume and Issue: 19(4), P. 201 - 216

Published: Dec. 12, 2022

Language: Английский

Citations

133
Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy DOI Creative Commons
Cindy X. Cai, Michelle R. Hribar, Sally L. Baxter

et al.

JAMA Ophthalmology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Importance Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns the treatment type 2 diabetes (T2D). Objective To investigate potential association between semaglutide and NAION Observational Health Data Sciences Informatics (OHDSI) network. Design, Setting, Participants This was retrospective study across 14 databases (6 administrative claims 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non–GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to 31, 2023. The incidence proportion rate calculated. Association assessed using approaches: an active-comparator cohort design comparing new users those GLP-1RAs drugs, self-controlled case-series (SCCS) analysis compare individuals’ risks during exposure nonexposure periods for each drug. used propensity score–adjusted Cox proportional hazards models estimate hazard ratios (HRs). SCCS conditional Poisson regression (IRRs). Network-wide HR IRR estimates generated random-effects meta-analysis model. Exposures non–GLP-1RAs. Main Outcomes Measures under alternative definitions based on diagnosis codes: one more inclusive sensitive, restrictive specific. Results included 37.1 million individuals T2D, including 810 390 users. Of 43 620 Optum’s deidentified Clinformatics Mart Database, 24 473 (56%) aged 50 69 years, 26 699 (61%) female. 14.5 per 100 000 person-years among not different compared that non–GLP-1RAs sensitive definition—empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin 1.30; 0.56-3.01; .27), glipizide 1.23; 0.66-2.28; .25). risk higher only patients empagliflozin 2.27; 1.16-4.46; .02) specific definition. showed increased (meta-analysis IRR, 1.32; 1.14-1.54; < .001). Conclusions Relevance this suggest modest increase associated use, smaller than previously reported, warranting further investigation into clinical implications association.

Language: Английский

Citations

7
Diabetes and cognitive function: An evidence-based current perspective DOI Open Access

Meghna Julian Sebastian,

Shahanas K A Khan,

Joseph M Pappachan

et al.

World Journal of Diabetes, Journal Year: 2023, Volume and Issue: 14(2), P. 92 - 109

Published: Feb. 14, 2023

Several epidemiological studies have clearly identified diabetes mellitus (DM) as a major risk factor for cognitive dysfunction, and it is going to be public health issue in the coming years because of alarming rise prevalence across world. Brain neural tissues predominantly depend on glucose energy substrate hence, any alterations carbohydrate meta-bolism can directly impact cerebral functional output including cognition, executive capacity, memory. DM affects neuronal function mental capacity several ways, some which include hypoperfusion brain from cerebrovascular disease, diabetes-related transporters causing abnormalities uptake metabolism, local hyper- hypometabolism areas insulin resistance, recurrent hypoglycemic episodes inherent pharmacotherapy resulting damage. Cognitive decline further worsen care disease largely self-managed by patients. Therefore, crucial understand pathobiology dysfunction relation its management optimal long-term plan A thorough appraisal normal metabolic characteristics brain, how metabolism diagnostic algorithm patients with dementia, prognosis when they this dangerous combination illnesses imperative context. This evidence-based narrative back-up latest clinical trial reviews elaborates current understanding empower physicians manage their day-to-day practice.

Language: Английский

Citations

39
Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity DOI Creative Commons
Rafael Tamayo‐Trujillo, Viviana A. Ruiz‐Pozo, Santiago Cadena-Ullauri

et al.

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: April 29, 2024

Obesity, a chronic global health problem, is associated with an increase in various comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, hypertension, and certain types of cancer. The increasing prevalence obesity requires research into new therapeutic strategies. Glucagon-like peptide-1 receptor agonists, specifically semaglutide liraglutide, designed for mellitus treatment, have been explored drugs the treatment obesity. This minireview describes molecular mechanisms liraglutide different metabolic pathways, its mechanism action processes appetite regulation, insulin secretion, glucose homeostasis, energy expenditure, lipid metabolism. Finally, several clinical trial outcomes are described to show safety efficacy these management.

Language: Английский

Citations

14
Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study DOI Creative Commons
Nabeela Siddeeque,

Mohammad H. Hussein,

Ahmed Abd‐Elmaksoud

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113537 - 113537

Published: Nov. 1, 2024

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.

Language: Английский

Citations

11
The immunomodulatory effects of GLP-1 receptor agonists in neurogenerative diseases and ischemic stroke treatment DOI Creative Commons

Haohui Sun,

Yue Hao, Hao Liu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 11, 2025

Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated clinical studies for various indications, including type 2 diabetes obesity (accounts 70% of total studies), non-alcoholic steatohepatitis, Alzheimer's disease, Parkinson's disease. This review presented fundamental information regarding two categories agonists (GLP-1RAs): peptide-based small molecule compounds, elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, ultimately improving cognitive function neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has unique role concurrent risk stroke T2D patients. Given infiltration peripheral immune cells into brain tissue, particularly areas surrounding infarct lesion, we further regulatory mechanisms. could not only facilitate M2 polarization microglia through both direct indirect pathways, but also modulate quantity T cell subtypes, CD4, CD8, cells, resulting inhibition inflammatory responses promotion regeneration interleukin-10 secretion. Therefore, believe that "Tregs-microglia-neuron/neural precursor cells" axis instrumental mediating suppression neuroprotection context ischemic stroke. benefits rapid diffusion, favorable blood-brain barrier permeability versatile administration routes, these compounds will be one important candidates GLP-1RA. We look forward to evidence intervention or complicated

Language: Английский

Citations

1
Therapeutic application of GLP-1 and GIP receptor agonists in Parkinson’s disease DOI
Xiaoyan Yang,

Peng Feng,

Rong Ji

et al.

Expert Opinion on Therapeutic Targets, Journal Year: 2022, Volume and Issue: 26(5), P. 445 - 460

Published: May 4, 2022

Introduction Diabetes is a risk factor for Parkinson's disease (PD) and shares similar dysregulated insulin pathways. Glucagon-like peptide-1 (GLP-1) analogs originally designed to treat diabetes have shown potent neuroprotective activity in preclinical studies of PD. They are by inhibiting inflammation, improving neuronal survival, maintenance synapses, dopaminergic transmission the brain. Building on this, three clinical reported impressive effects patients with PD, testing exendin-4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) another hormone that has good animal models Novel dual GLP-1/GIP agonists been developed can penetrate blood–brain barrier (BBB) show superior compared GLP-1 drugs.Areas covered The review summarizes GLP-1R GLP-1/GIPR PD discusses possible mechanisms action.Expert opinion Current strategies lowering levels alpha-synuclein not trials. It time move from 'misfolding protein' hypothesis. Growth factors such as cross BBB already future drug discovery

Language: Английский

Citations

29
Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules DOI
Nassima Oumata,

Kui Lu,

Yuou Teng

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 240, P. 114578 - 114578

Published: July 9, 2022

Language: Английский

Citations

29
Semaglutide, a novel glucagon-like peptide-1 agonist, amends experimental autoimmune encephalomyelitis-induced multiple sclerosis in mice: Involvement of the PI3K/Akt/GSK-3β pathway DOI
Mohamed A. Sadek, Esraa A. Kandil, Nesrine S. El Sayed

et al.

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 115, P. 109647 - 109647

Published: Dec. 27, 2022

Language: Английский

Citations

26