Last update:
10-Dec-2008

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived incretin hormones that stimulate insulin and suppress glucagon secretion, inhibit gastric emptying, and reduce appetite and food intake. An additional action of GLP-1 is the in vitro inhibition of β-cell apoptosis. GLP-1 can significantly lower plasma glucose in the majority of patients with type 2 diabetes. GLP-1 is inactivated rapidly in vivo by dipeptidyl peptidase 4 (DPP-4) and thus does not appear to be useful as a therapeutic agent in the long-term treatment of diabetes. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists, and inhibitors of DPP-4 activity. Clinical trials with the incretin mimetic exenatide and liraglutide show reduction in fasting and postprandial glucose concentration, and HbA_1c, associated with weight loss, but also some nausea and, rarely, vomiting. The DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin) control elevated blood glucose by promoting pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and reducing glucose production by the liver. The DPP-4 inhibitors have shown clinically significant HbA_1c reduction with a low risk of hypoglycemia and no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic β-cells. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.

Key words: Dipeptidyl peptidase 4, Exenatide, Glucagon-like peptide, Ιncretin, Inhibitors.