GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AS A NEW THERAPEUTIC APPROACH FOR TYPE-2-DIABETES

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 al so lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, reduces food intake upon intracerebroventri cular administration in animals, and may, in addition, enhance insulin sensitivity. Therefore, GLP-1, in many aspects, opposes the Type 2-di abetic phenotype characterized by disturbed glucose-induced insulin se cretory capacity, hyperglucagonaemia, moderate insulin deficiency, acc elerated gastric emptying, overeating (obesity) and insulin resistance . The other incretin hormone, gastric inhibitory polypeptide (GIP), ha s lost almost all its activity in Type 2-diabetic patients. In contras t, GLP-1 glucose-dependently stimulates insulin secretion in diet-and sulfonylurea-treated Type 2-diabetic patients and also in patients und er insulin therapy long after sulfonylurea secondary failure. Exogenou s administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological post pra ndial levels fully normalizes fasting hyperglycaemia in Type 2-diabeti c patients. The half life of GLP-1 is too short to maintain therapeuti c plasma levels for sufficient periods by subcutaneous injections. Cur rent research activities aim at finding GLP-1 analogues with more suit able pharmacokinetic properties than the original peptide. Another app roach could be the augmentation of endogenous release of GLP-1, which is abundant in L cells of the lower small intestine and the colon. Int erference with sucrose digestion using alpha-glucosidase inhibition mo ves nutrients into distal parts of the gastrointestinal tract and, the reby, prolongs and augments GLP-1 release. Enprostil, a prostaglandin E-2 analogue, fully suppresses GIP responses, while only marginally af fecting insulin secretion and glucose tolerance after oral glucose, su ggesting compensatory hypersecretion of additional insulinotropic pept ides, possibly including GLP-1. Given the large amount of GLP-1 presen t in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1.