Abstract
Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications.