Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice

Inhibitionofdipeptidyl peptidase-4 (DPP-4) activity improvesglucosehomeostasis throughamode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressedon the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemicDPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia inmice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r/ and Gipr/mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an iv infusion of the corresponding receptor antagonist exendin (9–39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitroon isolated islets.Wedemonstrate that very lowdoses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but no