Differential antidiabetic efficacy of incretin agonists versus DPP-4 inhibition in high fat-fed mice

OBJECTIVE—We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist D-Ala2-GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced com-parable antidiabetic actions in high fat–fed mice. RESEARCH DESIGN AND METHODS—High fat–fed mice were administered twice-daily injections of Ex-4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP-4i) in food to produce sustained inhibition of DPP-4 activity. RESULTS AND CONCLUSIONS—Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP-4i prevented weight gain. Although Ex-4 improved oral glucose tolerance and insulin-to-glucos