Impact of the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin on Glucose Tolerance and β-Cell Function and Mass in Insulin Receptor Substrate-2-Knockout Mice Fed a High-Fat Diet

Type 2 diabetes is characterized by diminished pancreatic beta-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of beta-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, beta-cell function, and beta-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the beta-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive beta-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the beta-cell mass by reducing beta-cell apoptosis in the Irs2-/- mice, and that the reduction of beta-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells. (Endocrinology 153: 1093-1102, 2012)