Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for Type 2-diabetes

Abstract

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone in normal humans explaining in part the augmented insulin response after oral versus intravenous glucose administration. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, reduces food intake upon intracerebroventricular administration in animals, and may, in addition, enhance insulin sensitivity. Therefore, GLP-1, in many aspects, opposes the Type 2-diabetic phenotype characterized by disturbed glucose-induced insulin secretory capacity, hyperglucagonaemia, moderate insulin deficiency, accelerated gastric emptying, overeating (obesity) and insulin resistance. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in Type 2-diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in diet- and sulfonylurea-treated Type 2-diabetic patients and also in patients under insulin therapy long after sulfonylurea secondary failure. Exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological postprandial levels fully normalizes fasting hyperglycaemia in Type 2-diabetic patients. The half life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections. Current research activities aim at finding GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Another approach could be the augmentation of endogenous release of GLP-1, which is abundant in L cells of the lower small intestine and the colon. Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Enprostil, a prostaglandin E2 analogue, fully suppresses GIP responses, while only marginally affecting insulin secretion and glucose tolerance after oral glucose, suggesting compensatory hypersecretion of additional insulinotropic peptides, possibly including GLP-1. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1.

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

“…Because SGLT1 is abundantly expressed in the duodenum in patients with T2DM (Freitas et al, 2008;Gerich, 2010) and aGLP-1 increases nutrient-induced insulin release (Nauck et al, 1997;Gromada et al, 1998), we determined the potential of concomitant inhibition of SGLT1 and DPP4 in hyperglycemic animals. In ZDF rats, an animal model exhibiting progressive diabetes similar to human T2DM, Intestinal SGLT1 Inhibition Enhances GLP-1 Secretion In Vivo insulin resistance develops at 7 weeks of age and plasma glucose levels increase by 13 weeks of age (Szocs et al, 2008;Watanabe et al, 2015).…”

Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?

“…It has been estimated that the amount of GLP-1 secreted after ingestion of a single nutrient load (calculated as integrated incremental response multiplied by the known metabolic clearance rate for GLP-1) accounts for about 10 % of the GLP-1 content of jejunal L-cells [46]. A second argument in favour of direct stimulation of upper-gut L-cells is the observation that the release of GIP is closely related to that of GLP-1, even at an intra-individual level, indicating that some individuals have a poor response of GIP and GLP-1, and others have average or higher release of both incretin hormones [20].…”

The potential role of sphingolipid-mediated cell signaling in the interaction between hyperglycemia, acute myocardial infarction and heart failure

“…Glucagon-like peptide-1 also lowers glucagon concentrations and slows gastric emptying. In addition, it reduces food intake after intra-cerebroventricular administration in animals [59].…”