Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function

Abstract

GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the β-cell to induce insulin secretion in a glucosedependent manner. GLP-1 also inhibits α-cell secretion of glucagon. As few, if any, GLP-1r are expressed on α-cells, indirect regulation, via β-or δ-cell products has been thought to be the primary mechanism by which GLP-1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP-1r on α-cells for direct regulation as well. Although the predominant source of circulating GLP-1 is the intestine, the α-cell becomes a source of GLP-1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP-1 is also be important in regulating nutrient-induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg-derived protein produced by the α-cell, in stimulating insulin secretion by acting on GLP-1r. Altogether, these data clearly demonstrate the important role of Gcg-derived peptides in regulating insulin secretion. Because of GLP-1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus.

GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

“…DART-Seq improves detection of low-abundance transcripts in human islets. A growing body of literature reports that turning on α cell GLP-1 production potently improves islet function and glucose homeostasis (10,16,17,24,30,31). PC1/3 expression is required for α cell GLP-1 production; however, the mechanisms regulating α cell PC1/3 expression are poorly defined.…”

An alternative pathway for sweet sensation: possible mechanisms and physiological relevance

“…Intestinal GLP-1 secretion is induced by duodenal gastric inhibitory polypeptide (GIP) and muscarinic vagal stimulation [191]. Its physiological roles comprise: controlling fasting plasma glucagon, potentiating pancreatic insulin release, influencing motoric mechanisms of gastric emptying, and inhibiting short-term food intake [262,278] (for review, [62]). Both, sweet-taste receptor-dependent and sweettaste receptor-independent mechanisms were proposed for GLP-1 release by L cells, depending on species, intestinal region, and site of application [35,268].…”

An Overview of Similarities and Differences in Metabolic Actions and Effects of Central Nervous System Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2is)

“…GLP-1RA may influence the activity of two opposite subgroup neurons within ARC, which are related to food intake and body weight, containing proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) and neuropeptide Y/agouti related peptide (NPY/AgRP) neurons; 137 , 157 In PVN, 158 , 159 GLP-1RA particularly, has been shown to interact with neuropeptides, such as AVP, oxytocin, and CRH release, thereby regulating eating and stress; BNST, 160 , 161 which is associated with suppression of food intake and stress response; LPB, 162 which reportedly mediates food intake and reward; hippocampus, 163 which influences cognition performance for food intake in rodents; NTS, 164 a major critical knot for afferent signals of gastro-intestine and satiety; VTA 165 , 166 and NAc, 167–169 which process reward for food and drug behavior; amygdala 170 , 171 that influences glucose homeostasis and food reward; as well as HPA-axis 172 , 173 which could affect stress and SNS. 174 Previous studies have reported the comprehensive effects of GLP-1RA on the CNS, which go beyond the levels of blood glucose modulation, but are associated with numerous metabolic aspects such as food intake and preference, 127 , 175 water intake, 176 energy expenditure, 177 body weight reduction, 178 pancreatic function, 132 , 179 , 180 hypertension, 181 stress, 182 addiction behaviors, 183 , 184 as well as neurodegenerative disorders, such as Alzheimer and Parkinson diseases. 185 These metabolic effects have proved versatile central actions of GLP-1RAs, and have been associated with direct or indirect potential secondary benefits like reduced risks of dyslipidemia, anti-atherosclerosis, modulation of cardiovascular activity, and proteinuria, as well as influencing clinical outcomes in T2D patients.…”