The evolving story of incretins (GIP and GLP‐1) in metabolic and cardiovascular disease: A pathophysiological update

Diabetes Obesity and Metabolism, Journal Year: 2021, Volume and Issue: 23(S3), P. 5 - 29

Published: July 26, 2021

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 nutrient-induced from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for maintenance of a normal glucose tolerance. This exemplified by effect (greater secretory response to oral as compared "isoglycaemic" intravenous administration due action hormones). GIP GLP-1 additive effects on secretion. Local production and/or islet α-cells (instead enteroendocrine K L cells) has been observed, its significance still unclear. suppresses, increases glucagon secretion, both manner. plays greater an incretin. In type 2-diabetic patients, reduced despite more or less GLP-1. While are only slightly impaired 2 diabetes, lost much acute activity largely unknown reasons. Besides homoeostasis, additional biological functions: at pharmacological concentrations reduces appetite, food intake, and-in long run-body weight, similar evolving GIP, least animal studies. Human studies, however, do not confirm these findings. but triglyceride storage white adipose tissue through stimulating also interacting with regional blood vessels receptors. lesser degree GLP-1, play bone remodelling. slows gastric emptying, which post-meal glycaemic increments. For beneficial cardiovascular complications neurodegenerative central nervous system (CNS) disorders pointing therapeutic potential over above improving diabetes complications. recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide superior efficacy selective agonists respect control well body weight renewed interest previously was thought be without any potential. One focus this research into long-term interaction signalling. antagonist (exendin [9-39]) and, recently, agonist (GIP [3-30] NH2 ) hopefully, longer-acting human use will helpful tools shed light open questions. detailed knowledge physiology pathophysiology prerequisite designing effective incretin-based drugs.

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

---

GLP-1 Receptor Expression Within the Human Heart

Endocrinology, Journal Year: 2018, Volume and Issue: 159(4), P. 1570 - 1584

Published: Feb. 12, 2018

Glucagonlike peptide-1 receptor (GLP-1R) agonists, which are used to treat type 2 diabetes and obesity, reduce the rates of myocardial infarction cardiovascular death. GLP-1R has been localized human sinoatrial node; however, its expression in ventricular tissue remains uncertain. Here we studied heart using GLP-1R–directed antisera, quantitative polymerase chain reaction (PCR), reverse transcription PCR detect full-length messenger RNA (mRNA) transcripts, situ hybridization (ISH). GLP1R mRNA encompassing entire open reading frame, were detected all four cardiac chambers from 15 hearts at levels approximating those pancreas. In contrast, GLP2R was relatively lower, GCGR sporadic not left ventricle. transcripts fibroblasts, coronary artery endothelial, or vascular smooth muscle cells. Human Brunner glands pancreatic islets exhibited immunopositivity abundant by ISH. also ISH node tissue. However, definitive cellular localization immunoreactive protein within cardiomyocytes blood vessels remained elusive. Moreover, validated antisera lacked sufficient sensitivity endogenous islet Western blotting. Hence, although ventricles express GLP1R, identity one more cell type(s) that a translated requires further clarification with highly sensitive methods detection.

Language: Английский

---

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

Diabetologia, Journal Year: 2016, Volume and Issue: 59(5), P. 954 - 965

Published: Feb. 1, 2016

Language: Английский

---

Targeting GLP-1 receptor trafficking to improve agonist efficacy

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: April 17, 2018

Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but functional therapeutic consequences of modulating endocytic trafficking have not been clearly defined. Here, we investigate a series biased agonists with variable propensities for internalization recycling. Compared to panel FDA-approved GLP-1 mimetics, compounds that retain at plasma membrane produce greater long-term release, which dependent on reduction β-arrestin recruitment faster agonist dissociation rates. Such molecules elicit glycemic benefits mice without concomitant increases signs nausea, common side effect therapies. Our study identifies set agents specific profiles potential efficacy tolerability as T2D treatments.

Language: Английский

---