Incretin-based therapy of type 2 diabetes mellitus.

This review article focuses on the therapeutic potential of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in treating type 2 diabetes mellitus (T2DM). T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for T2DM are often unsatisfactory at getting patients to glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. Therefore, the actions of GLP-1 and GIP, which include potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new drug classes based on the actions of the incretin hormones have recently been approved for therapy of T2DM; injectable long-acting stable analogues of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation of GLP-1 and GIP), the so-called incretin enhancers. This review article focuses on these two new classes of antidiabetic agents and will outline the scientific basis for the development of incretin mimetics and incretin enhancers, review clinical experience gathered so far and discuss future expectations for incretin-based therapy.