Exenatide Treatment Improves Processing of Pro-Islet Amyloid Poly peptide in Human and Mouse Islets during Culture

& 1929-P Impact of Vildagliptin on Glucose Tolerance, and beta Cell Mass in Insulin Receptor Substrate-2-Knockout Mice KOICHIRO SATO, AKINOBU NAKAMURA, JUN SHIRAKAWA, TOMONORI MURAOKA, YU TOGASHI, KAZUKI ORIME, YASUO TERAUCHI, Yokohama, Japan Loss of beta-cell mass underlies the development of diabetes and insulin receptor substrate-2 (Irs2) is critically required for beta cell growth and survival. GLP-1 reportedly increased islet proliferation and reduced apoptosis of beta-cells in rodents. In this study, we explored the chronic effect of dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin on glucose tolerance and beta-cell mass in Irs2-knockout (Irs2-/-) mice fed a high-fat diet for 20 weeks. Wild type (WT) mice and Irs2-/mice of the same genetic background were fed standard-chow until 8 weeks of age, and then given free access to high-fat diet for 20 weeks. Half of the animals in each genotype were given vildagliptin in the drinking water (0.3 mg/ml) and others were given tap water without vildagliptin. Whereas there were no differences in body weight or food intake, vildagliptin signifi cantly reduced fasting blood glucose in Irs2-/mice. In both genotypes of mice, vildagliptin signifi cantly decreased AUC0-120min blood glucose and signifi cantly increased the insulin response to glucose during oral glucose tolerance test (OGTT). To evaluate the chronic effect rather than the direct effect, we also performed OGTT one day after discontinuation of vildagliptin administration. AUC0-120min blood glucose was still signifi cantly decreased and the insulin response to glucose during OGTT was signifi cantly increased in Irs2-/mice treated with vildagliptin compared with those without vildagliptin. Histochemical analysis of pancreatic islets revealed that treatment with vildagliptin signifi cantly increased beta-cell mass (p<0.05) and proportion of beta-cells to islet cells (p<0.01) in Irs2-/mice. Vildagliptin decreased the proportion of TUNEL-positive beta-cells (p<0.05), but failed to increase the BrdU incorporation in Irs2-/mice. These results suggest that vildagliptin improved glucose tolerance and increased beta-cell mass by reducing apoptotic beta-cells in Irs2-/mice and that vildagliptin is able to reduce apoptotic beta-cells in Irs2-independent manner.