Antidiabetic effects of dipeptidyl peptidase–IV inhibitors and sulfonylureas in streptozotocin-nicotinamide–induced mildly diabetic mice

The present study investigated the antidiabetic effects of the dipeptidyl peptidase (DPP)–IV inhibitors ASP8497 and vildagliptin, and the sulfonylureas glibenclamide and gliclazide in streptozotocin-nicotinamide–induced mildly diabetic mice. A single administration of ASP8497 and vildagliptin significantly improved glucose tolerance by increasing plasma insulin and glucagon-like peptide–1 levels. In addition, a single administration of glibenclamide and gliclazide also caused significant improvement in glucose tolerance with an accompanying increase in the plasma insulin level. Subsequently, the effects of a 1-week chronic daily dosing of DPP-IV inhibitors and sulfonylureas were investigated. All drugs significantly improved glucose tolerance on day 1 of chronic daily dosing. After 1 week of chronic daily dosing, the DPP-IV inhibitors caused a significant improvement in glucose tolerance similar to those observed on day 1 by increasing the plasma insulin and glucagon-like peptide–1 levels. In contrast, the sulfonylureas had no significant improving or insulinotropic effect. Furthermore, ASP8497 also had an antihyperglycemic effect and improved pancreatic histopathologic lesions in a 4-week chronic daily dosing study. These results suggest that chronic daily dosing of sulfonylureas had virtually no antidiabetic effects because of marked attenuation of the insulinotropic action in streptozotocin-nicotinamide–induced mildly diabetic mice. In contrast, the antidiabetic efficacy of DPP-IV inhibitors, including ASP8497, did not change even after chronic daily dosing; therefore, DPP-IV inhibitors are useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes mellitus.