TY - JOUR T1 - Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus JF - Cleveland Clinic Journal of Medicine JO - Cleve Clin J Med SP - S12 LP - S19 DO - 10.3949/ccjm.76.s5.03 VL - 76 IS - 12 suppl 5 AU - Laurence Kennedy AU - Jeffrey S. Freeman Y1 - 2009/12/01 UR - http://www.ccjm.org/content/76/12_suppl_5/S12.abstract N2 - Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase–4 (DPP-4). Exenatide, a DPP-4–resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies. ER -