Regulation of MafA Expression in Pancreatic β-Cells in db/db Mice With Diabetes

OBJECTIVE-Islet beta-cells loose their ability to synthesize insulin under diabetic conditions, which is at least partially due to the decreased activity of insulin transcription factors such as MafA. Although an in vitro study showed that reactive oxygen species (ROS) decrease MafA expression, the underlying mechanism still remains unclear. In this study, we examined the effects of c-Jun, which is known to be upregulated by ROS, on the expression of MafA under diabetic conditions. RESEARCH DESIGN AND METHODS-To examine the protein levels of MafA and c-Jun, we performed histological analysis and Western blotting using diabetic db/db mice. In addition, to evaluate the possible effects of c-Jun on MafA expression, we performed adenoviral overexpression of c-Jun in the MING beta-cell line and freshly isolated islets. RESULTS-MafA expression was markedly decreased in the islets of db/db mice, while in contrast c-Jun expression was increased. Costaining of these factors in the islets of db/db mice clearly showed that MafA and insulin levels are decreased in c-Jun-positive cells. Consistent with these results, overexpression of c-Jun significantly decreased MafA expression, accompanied by suppression of insulin expression. Importantly, MafA overexpression restored the insulin promoter activity and protein levels that were suppressed by c-Jun. These results indicate that the decreased insulin biosynthesis induced by c-Jun is principally mediated by the suppression of MafA activity. CONCLUSIONS-It is likely that the augmented expression of c-Jun in diabetic islets decreases MafA expression and thereby reduces insulin biosynthesis, which is often observed in type 2 diabetes. Diabetes 59:1709-1720, 2010