Molecular mechanism by which vildagliptin, a DPP-IV inhibitor, preserves pancreatic β cells: A comparative analysis between diabetic and non-diabetic mice*
We investigated the molecular mechanism by which vildagliptin, a DPP-IV inhibitor, preserves the pancreatic β cells in diabetic mice. Male diabetic KK-Ay/TaJcl (KKAy) mice and non-diabetic C57BL/6J (B6) mice, 8 weeks of age, received vildagliptin or were vehicle-treated for 4 weeks. In addition to the morphological and biochemical analysis of the islets, gene expression profiles in the core area of pancreatic islet were also analyzed at 12 weeks by using laser capture microdissection method. We did not find any differences in body weight, food intake, fasted blood glucose, insulin, glucagon, and basal active-GLP-1 levels between the control and vildagliptin-treated groups in both of KK-Ay and B6 mice. Vildagliptin decreased the plasma TG level and islet TG content only in KK-Ay. Insulin sensitivity assessed by an intraperitoneal insulin tolerance test significantly improved in KK-Ay when treated with vildagliptin, but did not in B6. Vildagliptin ameliorated glucose tolerance and induced significantly higher plasma insulin at nearly all of the observed points on OGTT in KK-Ay, but at only 15min on OGTT in B6 mice. Vildagliptin increased the pancreatic βcell mass, islet insulin content, and glucose-stimulated insulin secretion from isolated islets in both strains of mice. Genes involved in cellular differentiation and proliferation were up-regulated by vildagliptin in both mouse strains. Gene expressions related with apoptosis, endoplasmic reticulum stress and lipid synthesis were downregulated and antioxidative stress related gene expression was up-regulated only in KK-Ay mice treated with vildagliptin. Morphometric results for PCNA, 4HNE, CHOP and TUNEL corresponded with the data obtained in gene expression analysis. Vildagliptin increased the β cell mass not only by directly regulating cell kinetics but also by suppressing oxidative and/or ER stress, secondary to amelioration of glucolipotoxicity.
