Incretin-based therapy and type 2 diabetes.

This chapter focuses on the incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), and their therapeutic potential in treating patients with type 2 diabetes. Type 2 diabetes 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 type 2 diabetes 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 potentiation 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 been approved for therapy of type 2 diabetes: injectable long-acting stable analogs 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. In this chapter, we will describe the physiological effect of the incretin hormones--the incretin effect--in a historical perspective and focus on the 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.