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

Summary

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone in normal humans explaining in part the augmented insulin response after oral versus intra- venous 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 deficiency, accelerated gastric emptying, overeating insulin secretory capacity, hyperglucagonaemia, moderate in- (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 ocglucosidase 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.

Key words

Incretin hormones - glucagon-like peptide 1 (GLP-1) - insulin - glucagon - new therapy