Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

Frontiers in Endocrinology, Journal Year: 2018, Volume and Issue: 9

Published: Nov. 23, 2018

The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its 'incretin effect' in restoring glucose homeostasis diabetics, however, it now apparent that has a broader range of physiological effects the body. Both vitro and vivo studies have demonstrated GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression influence neuroprotective pathways. A substantial body evidence accumulated with respect to how analogues act restore maintain normal cellular functions. These findings prompted several clinical trials which reported improve cardiac function, lung function reduce mortality patients obstructive disease, blood pressure lipid storage, even prevent synaptic loss neurodegeneration. Mechanistically, elicits via acute elevation cAMP levels, subsequent protein kinase(s) activation, pathways well defined pancreatic β-cells insulin secretion conjunction elevated Ca2+ ATP. More recently, new shed light on additional downstream stimulated by chronic exposure, direct relevance our understanding potential therapeutic longer lasting recently developed use. In this review, we provide comprehensive description diverse roles across multiple tissues, describe discuss novel pleiotropic applications treatment human disease.

Language: Английский

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The ongoing pursuit of neuroprotective therapies in Parkinson disease

Nature Reviews Neurology, Journal Year: 2014, Volume and Issue: 11(1), P. 25 - 40

Published: Dec. 2, 2014

Language: Английский

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Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease

Neuroscience, Journal Year: 2015, Volume and Issue: 303, P. 42 - 50

Published: July 4, 2015

Language: Английский

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The Association Between Type 2 Diabetes Mellitus and Parkinson’s Disease

Journal of Parkinson s Disease, Journal Year: 2020, Volume and Issue: 10(3), P. 775 - 789

Published: April 24, 2020

In recent years, an emerging body of evidence has forged links between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). observational studies, those with T2DM appear to be at increased risk developing PD, as well experiencing faster progression a more severe phenotype the effects being potentially mediated by several common cellular pathways. The insulin signalling pathway, for example, may responsible neurodegeneration via dysregulation, aggregation amyloids, neuroinflammation, mitochondrial dysfunction altered synaptic plasticity. light these potential shared mechanisms, clinical trials are now investigating use established drugs targeting resistance in management PD. This review will discuss epidemiological assess relevant treatment options modification

Language: Английский

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Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease

Science Translational Medicine, Journal Year: 2016, Volume and Issue: 8(368)

Published: Dec. 7, 2016

Mitochondrial pyruvate carrier may be a therapeutic target in Parkinson’s disease.

Language: Английский

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Diabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes

Brain, Journal Year: 2020, Volume and Issue: 143(10), P. 3067 - 3076

Published: July 17, 2020

Abstract The elevated risk of Parkinson’s disease in patients with diabetes might be mitigated depending on the type drugs prescribed to treat diabetes. Population data for users newer types used are scarce. We compared exposed thiazolidinediones (glitazones), glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, any other oral glucose lowering drugs. A population-based, longitudinal, cohort study was conducted using historic primary care from Health Improvement Network. Patients a diagnosis minimum two prescriptions medications between January 2006 2019 were included our study. outcome first recording after index date, identified clinical records. individuals treated glitazones or DPP4 inhibitors and/or GLP-1 antidiabetic agents Cox regression inverse probability treatment weighting based propensity scores. Results analysed separately insulin users. Among 100 288 [mean age 62.8 years (standard deviation 12.6)], 329 (0.3%) diagnosed during median follow-up 3.33 years. incidence 8 per 10 000 person-years 21 175 glitazones, 5 36 897 684 mimetics, 6861 whom GTZ prior mimetics. Compared comparison group (10 person-years), adjusted results showed no evidence association use [incidence rate ratio (IRR) 1.17; 95% confidence interval (CI) 0.76–1.63; P = 0.467], but there strong an mimetics onset (IRR 0.64; CI 0.43–0.88; < 0.01 IRR 0.38; 0.17–0.60; 0.01, respectively). same direction, overall size this small. varies substantially received. is associated lower

Language: Английский

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Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment

Pharmacological Research, Journal Year: 2022, Volume and Issue: 186, P. 106550 - 106550

Published: Nov. 11, 2022

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for diseases. Interestingly, increased inflammation risk been associated with type 2 diabetes mellitus (T2DM) insulin resistance (IR), suggesting that mitigate T2DM pathology may successful treating well. Glucagon-like peptide-1 (GLP-1) an incretin hormone promotes healthy signaling, regulates blood sugar levels, suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs developed approved by the US Food Drug Administration (FDA) related global regulatory authorities treatment T2DM. Furthermore, GLP-1R anti-inflammatory, neurotrophic, neuroprotective properties disorder preclinical models, hence hold promise repurposing In this review, we discuss pathways, intersections between neuroinflammation, brain IR, diseases, focus on AD PD. We additionally overview current FDA-approved agents development, including unimolecular single, dual, triple agonists, highlight those trials treatment. propose already-approved agonists safe, efficacious, cost-effective strategy ameliorating PD quelling neuroinflammation.

Language: Английский

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The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Sept. 1, 2022

Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD PD) that includes the highly controversial approval of Aβ-targeting antibody aducanumab AD. Hence, still an unmet need a neuroprotective drug in both AD PD. Type 2 diabetes risk factor Glucagon-like peptide 1 (GLP-1) hormone growth has shown effects preclinical studies, success GLP-1 mimetics phase II clinical trials PD raised new hope. are currently on market as treatments type diabetes. analogs safe, well tolerated, resistant to desensitization characterized clinic. Herein, we review existing evidence illustrate pathways induced following GLP-1R activation neurons, microglia astrocytes. The latter include synaptic protection, improvements cognition, learning motor function, amyloid pathology-ameliorating properties (Aβ, Tau, α-synuclein), suppression Ca

Language: Английский

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Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 89, P. 101979 - 101979

Published: June 15, 2023

Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD), are characterized by several pathological features. In AD PD, there is an abnormal accumulation toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, astrocyte activation, perhaps a state insulin resistance. Epidemiological evidence has revealed link between AD/PD type 2 diabetes mellitus, with these sharing some commonalities. Such opened up promising avenue repurposing antidiabetic agents in treatment disorders. A successful therapeutic strategy would likely require single or which target separate processes disease. Targeting cerebral signalling produces numerous neuroprotective effects preclinical brain models. Clinical trials shown promise approved diabetic compounds improving motor symptoms PD preventing decline, further phase II III underway populations. Alongside signalling, targeting incretin receptors represents one most currently available AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists displayed impressive clinical potential early studies. GLP-1 agonist, liraglutide, been demonstrated improve glucose metabolism functional connectivity small-scale pilot trials. Whilst agonist exenatide effective restoring function cognition. reduces inhibits apoptosis, prevents protein aggregation, enhances long-term potentiation autophagy as well restores dysfunctional signalling. Support also increasing use additional treatments, intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear γ agonists, amylin analogs, tyrosine phosphatase 1B inhibitors investigation deployment treatment. As such, we provide comprehensive review anti-diabetic PD.

Language: Английский

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Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity

Diabetes Care, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

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 GLP-1RA in select patient populations. In ongoing trials investigators are interrogating efficacy these agents new indications, including metabolic liver disease, peripheral artery Parkinson Alzheimer disease. success GLP-1–based medicines has spurred molecular entities combinations with unique pharmacokinetic pharmacodynamic profiles, exemplified tirzepatide, a GIP-GLP-1 coagonist. Simultaneously, investigational molecules such as maritide block GIP activate GLP-1 receptor, whereas retatrutide survodutide enable simultaneous activation glucagon receptors. Here I highlight evidence medicines, while discussing that inform safety, focusing on muscle strength, bone density fractures, exercise capacity, gastrointestinal motility, retained gastric contents anesthesia, pancreatic biliary tract disorders, risk cancer. Rapid progress highly efficacious anticipated differentiation newer subsets will provide greater opportunities use personalized medicine approaches to improve health people living cardiometabolic disorders.

Language: Английский

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