The Physiology of Glucagon-like Peptide 1

Abstract

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

Serotonin controlling feeding and satiety

“…Glucagon like Peptide-1 (GLP-1) is released in response to a meal from the small intestine [299] and reduces food-intake both in animals and humans [289, 300for review]. As a central site of action is possible [301][302][303], it is of interest that both GLP-1 and the GLP agonist exendin-4 stimulate 5-HT release from hypothalamic synaptosomes [304].…”

Obesity diabetes and the role of bile acids in metabolism

“…Katsuma et al [18] have shown that bile acids promote glucagon-like peptide-1 (GLP-1) secretion through the bile receptor GpBAR-1 in a murine entero-endocrine cell line. GLP1 agonists are used in the treatment of type 2 diabetes because of their insulin-stimulating effect on the pancreatic B Cell, the inhibition of gastric emptying and the central effect on apatite inhibition, resulting in weight loss [19] . GLP-1 is secreted by L cells that are found in the distal ileum, colon, and rectum.…”

Surgical control of obesity and diabetes: The role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis

“…In addition, the physiology of the digestive system and its role in glucose and energy homeostasis are complex and yet incompletely understood. Over the last decades the study of GI physiology has advanced at cellular and molecular levels revealing roles for several GI factors in the regulation of energy and glucose homeostasis including gut hormones (14)(15)(16) bile acids (17,18), miocrobiota (19,20), neural signals (21), and intestinal nutrient sensing (7). Paradoxically, however, the understanding of how anatomical segments of the GI tract contribute to metabolic regulation remains rudimentary.…”