Incretin-based Therapies for Type 2 Diabetes

There is a growing interest in developing therapeutic strategies for type 2 diabetes based on the actions of the hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are the major incretins released from the intestine in response to nutrient ingestion, and they stimulate insulin secretion in a glucose-dependent manner. Both peptides are degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), thus terminating their actions. Studies in animal models of diabetes have shown that the incretins also exert a number of additional actions that improve glucose disposal. GLP-1 reduces food intake and gastric emptying, as well as inhibiting glucagon secretion. Injectable formulations of DPP-4-resistant GLP-1-related peptides (incretin mimetics) that are now in clinical use (exenatide) or undergoing trials (e.g. liraglutide) have been shown to reduce fasting and postprandial glucose and glycosylated hemoglobin (A1C) levels and induce weight loss. Oral administration of DPP-4 inhibitors potentiates the actions of incretins released during a meal. Clinical trials have demonstrated that DPP-4 inhibitors are weight-neutral drugs that also effectively reduce plasma glucose and A1C levels. One inhibitor, sitagliptin, is now available in Canada and the United States, and another, vildagliptin, has recently been approved by the European Union. Other inhibitors are under development. Preclinical studies indicate that treatment with incretin mimetics or DPP-4 inhibitors also preserves beta cell mass by exerting mitogenetic and prosurvival effects. It is not known whether similar effects occur in humans.