The DPP-4 inhibitor MK0626 and exercise protect islet function in early pre-diabetic kkay mice

Dipeptidyl peptidase-4 (DPP-4) inhibitor and exercise have proven to be effective treatments for diabetes. However, the effects of these interventions in compensatory hyperinsulinemia prediabetic period are unknown. The purpose of this study was to determine if these interventions have protective effects on β-cell function and preventive effects on the onset of diabetes in prediabetic kkay mice. After 2 weeks of high-fat diet feeding, we treated 7-week-old mice with a normal diet, high-fat diet, exercise training, or the DPP-4 inhibitor for 8 weeks. C57BL/6J mice served as a normal control. Kkay mice without intervention developed diabetes at week 15, but no diabetic mice were observed in the DPP-4I or exercise groups as well as the normal control group. The DPP-4I and exercise groups showed improved body weight, blood glucose level, glucose tolerance, insulin sensitivity, islet area, and islet morphology. In addition, the proportion of Ki67-positive β-cells in the treatment groups was obviously higher than that in the untreated groups. MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homolog A) expression in the treated groups increased markedly. However PDX-1 (pancreatic and duodenal homeobox-1) expression did not differ significantly among the groups. The results show that exercise and DPP-4I treatment conducted during the hyperinsulinemic prediabetic stage contribute to the maintenance of β-cell function and morphology, enhance β-cell proliferation, extend the compensatory insulin hypersecretion period, and delay disease onset. The expression of PDX-1 was not altered significantly during the early stages of diabetes. However, the reduced expression of the insulin transcription factor MafA may play an important role in the development of prediabetes.