2021 Volume 65 Issue 2 Pages 47-50
Chronic hyperglycemia causes impaired insulin secretion and suppression of insulin gene expression in pancreatic β-cells, referred to as glucotoxicity. However, the molecular mechanisms of glucotoxicity are still not fully understood. We attempted to elucidate signaling pathways for suppression of insulin gene expression in glucotoxicity by techniques using Multi-PK antibody and Microarray analysis. Using Multi-PK antibody, we found that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was decreased in rat pancreatic insulinoma INS-1 cells under glucotoxic conditions. The reduction of CaMKIV was induced by degradation with calpain. Furthermore, CaMKIV was reduced in pancreatic islets of diabetic OLETF (Otsuka Long-Evans Tokushima fatty) rats compared with nondiabetic LETO (Long-Evans Tokushima Otsuka) rats. Next, we performed Microarray and Real-time PCR analysis, resulting that nine protein kinases were affected by glucotoxic condition. Among them, candidate plasticity gene 16 (CPG16) was increased in INS-1 cells under glucotoxic conditions and suppressed insulin promoter activity in a kinase activity-dependent manner. In addition, CPG16 bound and phosphorylated jun dimerization protein 2 (JDP2). JDP2 bound to the G1 element of the insulin promoter and up-regulated insulin promoter activity. Furthermore, CPG16 suppressed the up-regulation of insulin promoter activity by JDP2 in a kinase activity-dependent manner. These results suggest that calpain-CaMKIV and CPG16-JDP2 pathways play important roles in the suppression of insulin gene expression in pancreatic β-cells under glucotoxic conditions.
