The Incretin Approach for Diabetes Treatment Modulation of Islet Hormone Release by GLP-1 Agonism

Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and -cell growth. Together with the related hormone glucose-dependent insulinotropic polypeptide (GIP), it is re-sponsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typ-ically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous admin-istration greatly improved glucose profiles and lowered body weight and HbA1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and -cell performance was greatly improved. The nat-ural peptide is rapidly degraded by the enzyme dipepti-dyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies. Diabetes 53 (Suppl