Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus

Abstract

The 'incretin effect' describes the phenomenon of an enhanced insulin response following oral ingestion of glucose compared with that after intravenous administration of glucose, leading to identical postprandial plasma glucose excursions. It accounts for up to 60% of the postprandial insulin secretion, but is diminished in patients with type 2 diabetes mellitus. Gastrointestinal hormones that promote the incretin effect are called incretins. Glucagon-like peptide-1 (GLP-1) is an important incretin. Under hyperglycemic conditions in humans, it stimulates insulin secretion and normalizes blood glucose levels. GLP-1 does not stimulate insulin secretion at normal glucose levels; therefore, it does not cause hypoglycemia. Furthermore, it inhibits glucagon secretion and delays gastric emptying. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting the apoptosis of islet cells. The improvement of beta-cell function due to GLP-1 can be indirectly observed from the increased insulin secretory capacity of humans receiving such treatment. GLP-1 may represent an attractive therapeutic method for patients with type 2 diabetes because of its multiple effects, including the simulation of satiety in the CNS by acting as a transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. liraglutide) and exendin-4 (exenatide) that are resistant to degradation, called 'incretin mimetics', are being investigated in clinical trials. Dipeptidyl peptidase-IV inhibitors (e.g. vildagliptin, sitagliptin, and saxagliptin) that inhibit the enzyme responsible for incretin degradation are also being studied.