Following a meal, gut-produced incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the circulation. Because GLP-1 and GIP mediate grossly 60% of the insulin-stimulatory action, the so-called incretin effect, both are crucial components of a natural endogenous system guaranteeing glucose homeostasis. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha-cells and delays nutrient delivery from the stomach by inhibiting gastric emptying. The rise in insulin concentration enhances glucose clearance in peripheral tissues such as muscle, and the lower glucagon concentration combined with the rise in insulin reduces hepatic glucose production. By enhancing glucose clearance and lowering hepatic glucose production, the post-meal glucose excursion is reduced.~Both GLP-1 and GIP are degraded by the enzyme dipeptidylpeptidase-4 (DPP-4). Inhibition of DPP-4 by the specific DPP-4 inhibitor Sitagliptin increases plasma levels of both GLP-1 and GIP, and reduces postprandial glycemia.~Although important in healthy subjects, the role of the incretin hormones in patients with T2DM is unclear. In T2DM the insulinotropic efficacy of GIP is reduced and the postprandial release of GLP-1 is diminished.~Therefore, the aim of this study in T2DM is to quantify the incretin effect with and without the DPP-4 inhibitor sitagliptin. The specific GLP-1 receptor antagonist exendin(9-39) will be used to quantify the contribution of both GLP-1 and GIP to the incretin effect in patients with T2DM.
The purpose of this study is to assess the effect of the DPP-4 inhibitor sitagliptin on the incretin effect in patients with type 2 diabetes mellitus.