Glucagon-like peptide 1 (GLP-1) and incretin mimetics for the treatment of diabetes

Abstract

Glucagon-like peptide 1 (GLP-1) was discovered as an insulinotropic ('incretin') hormone, suggesting a physiological role in the potentiation of insulin secretory responses after oral glucose or meals. The incretin effect (i.e. the phenomenon that more insulin is secreted in response to oral as compared to intravenous glucose) is reduced/lost in patients with type 2 diabetes. GLP-1 (a) stimulates insulin secretion in a glucose-dependent manner, (b) suppresses glucagon, (c) reduces appetite and food intake, (d) decelerates gastric emptying, (e) stimulates pancreatic β cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) inhibits β cell apoptosis in vitro. Intravenous GLP-1 normalises and subcutaneous GLP-1 significantly lowers plasma glucose in the majority of patients with type 2 diabetes. GLP-1 itself, however, is not useful for chronic antidiabetic treatment, because it is too rapidly inactivated by proteolysis (DPP-4) and eliminated from the circulation. Agents interacting with GLP-1 receptors in pancreatic islets or the (central) nervous system have been found (like exendin-4) or developed as 'incretin mimetics' (like liraglutide). Clinical trials with exenatide (two injections per day) and liraglutide (one injection per day) have shown reductions in glucose concentrations and HbA1c by approximately 1%, associated with moderate weight loss (2-3kg), but also some nausea and, rarely, vomiting. This new class of antidiabetic agents will be available for clinical use pending completion of phase 3 trials and/or approval by regulatory agencies after 2005 (USA) and 2007 (Europe). Copyright © 2005 John Wiley & Sons, Ltd.