Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological Pitfalls

Diabetes, Journal Year: 2013, Volume and Issue: 62(10), P. 3316 - 3323

Published: July 2, 2013

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, somatostatin to facilitate glucose disposal. The actions terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) through renal clearance. GLP-1 GIP promote β-cell proliferation survival in rodents. DPP-4 inhibitors expand mass, reduce α-cell inhibit glucagon preclinical studies; however, whether incretin-based therapies sustain functional mass human diabetic subjects remains unclear. exert their predominantly unique G protein-coupled receptors expressed on β-cells other pancreatic cell types. Accurate localization receptor expression ductal or acinar cells normal pancreas is challenging because antisera used for detection often neither sufficiently sensitive nor specific yield reliable data. This article reviews recent advances controversies hormone action contrasts established mechanisms with areas uncertainty. Furthermore, methodological challenges pitfalls highlighted key requiring additional scientific investigation outlined.

Language: Английский

---

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Journal of Diabetes Investigation, Journal Year: 2013, Volume and Issue: 4(2), P. 108 - 130

Published: March 1, 2013

Abstract Glucose‐dependent insulinotropic polypeptide ( GIP ) and glucagon‐like peptide‐1 GLP ‐1) are the two primary incretin hormones secreted from intestine on ingestion of various nutrients to stimulate insulin secretion pancreatic β‐cells glucose‐dependently. ‐1 undergo degradation by dipeptidyl peptidase‐4 DPP ‐4), rapidly lose their biological activities. The actions mediated specific receptors, receptor GIPR ‐1R), which expressed in β‐cells, as well tissues organs. A series investigations using mice lacking and/or ‐1R, ‐4, showed involvement divergent activities, some could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy neuropathy) macrovascular coronary artery disease, peripheral disease cerebrovascular disease), comorbidity obesity, non‐alcoholic fatty liver bone fracture cognitive dysfunction). Furthermore, recent studies incretin‐based drugs, such agonists, stably activate ‐1R signaling, ‐4 inhibitors, enhance both R that exert effects possibly linked prevention or treatment comorbidities independently hyperglycemia. We review findings extrapancreatic heart, brain, kidney, eye nerves, liver, fat several organs perspective comorbidities.

Language: Английский

---

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

---

Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(7), P. 463 - 474

Published: March 28, 2023

Language: Английский

---

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

Diabetes, Journal Year: 2015, Volume and Issue: 64(7), P. 2537 - 2549

Published: March 3, 2015

Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in IEL preparations copurified with markers Tαβ Tγδ IELs, the two main subsets IELs. Exendin-4 cAMP accumulation purified IELs reduced production cytokines from activated but not splenocytes ex vivo. These actions were mimicked forskolin, absent Glp1r−/− mice, attenuated GLP-1R agonist exendin (9-39) consistent GLP-1R–dependent mechanism action. Furthermore, mice exhibited dysregulated gene expression, an abnormal representation microbial species feces, enhanced sensitivity to injury following administration dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized multiple genes regulating function epithelial integrity recipient whereas acute exendin-4 robustly induced encoding chemokines normal injured intestine. Taken together, these findings define enteroendocrine-IEL axis linking energy availability, host responses,

Language: Английский

---