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Publication : 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.

First Author  Sato K Year  2012
Journal  Endocrinology Volume  153
Issue  3 Pages  1093-102
PubMed ID  22315446 Mgi Jnum  J:182520
Mgi Id  MGI:5315796 Doi  10.1210/en.2011-1712
Citation  Sato K, et al. (2012) Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance and beta-cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet. Endocrinology 153(3):1093-102
abstractText  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.
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