Review: Maximising the therapeutic potential of glucagon-like peptide-1 in type 2 diabetes

Abstract

Tight control of blood glucose levels is fundamental for delaying or preventing the progression of metabolic complications in type 2 diabetes. Glucagon-like peptide-1 (GLP-1), secreted from the L-cells of the distal small intestine and colon in response to feeding, promotes insulin production and secretion, reduces glucagon secretion, delays gastric emptying and induces satiety. However, native GLP-1 is rapidly degraded by dipeptidyl peptidase (DPP) 4 reducing its therapeutic utility. Two approaches have been adopted to extend duration of action, namely enzyme-resistant GLP-1 mimetics and DPP 4 inhibitors which additionally promote insulin release by GIP. Clinical trials of incretin-based therapies have shown good efficacy in improving glycaemic control in type 2 diabetes. These therapies can be added to metformin or thiazolidinediones in order to target efects of insulin secretion as well as insulin action. However, incretin therapies also show potential when combined with approaches that increase insulin by endogenous (via sulphonylureas) or exogenous routes. Synergistic actions of incretin therapies with sulphonylureas on pancreatic beta-cells are also potentially advantageous. Incretin therapies can reduce hypoglycaemia since GLP-1 increases glucose sensing of both insulin and glucagon-secreting cells. Br J Diabetes Vasc Dis 2009; 9: 44—52