Glucagon-like peptide 1 (GLP-1) and metabolic diseases

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, mainly secreted after meals, which enhances glucose-induced insulin secretion and induces satiety. It has been reported that GLP-1 levels after a mixed meal and after an oral glucose load are reduced in patients with Type 2 diabetes. The reduction of oral glucose-stimulated active GLP-1 levels in patients with Type 2 diabetes has also been observed during euglycemic iper-insulinemic clamp. The reduction of post-prandial circulating active GLP-1 in Type 2 diabetic subjects, as a consequence of chronic hyperglycemia, could contribute to the reduction of early post-prandial insulin secretion; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits both an impairment of meal-induced insulin secretion and an increase of post-prandial glycemia similar to that observed in Type 2 diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), an enzyme produced by endothelial cells in different districts and that circulates in plasma. It is still not clear whether the reduction of meal-or oral-glucose stimulated GLP-1 levels in Type 2 diabetic patients is due to impairment of secretion, increase of degradation, or both. The major limitation of using GLP-1 to treat diabetic patients is the short half-life of the native compound. There are now several compounds in various stages of pre-clinical or clinical development for the treatment of Type 2 diabetes that utilize the GLP-1 signaling pathway; these include GLP-1 receptor agonists with extended half-lives, and inhibitors of DPP-IV that increase circulating levels of endogenous, intact and bioactive GLP-1.