High Glucose And Palmitate-Induced Pancreatic β Cell Apoptosis Is Mediated By JNK Activation Via Inhibition Of Insulin Signaling

The pathogenesis of type 2 diabetes mellitus(T2DM) has a dense link with hyperglycemia and obesity. Chronic hyperglycemia and hyperlipidemia can induce endoplasmic reticulum(ER) stress and oxidative stress in pancreaticβcells and various peripheral tissues, leading to pancreaticβcell dysfunction and insulin resistance.βcell dysfunction is essential for T2DM development, and apoptosis ofβcells is mainly responsible for the absolute deficiency in insulin secretion. Thus,βcell apoptosis plays a major role in the pathogenesis of T2DM. Under diabetic conditions, ER stress and oxidative stress induced in various tissues can activate c-Jun N-terminal kinase(JNK) pathway, leading to suppression of insulin biosynthesis and insulin action. Thus, JNK has a central role inβcell dysfunction and insulin resistance. However, it remains unclear that by which mechanisms JNK induces apoptosis. In this study, we investigated whether and how JNK activation was involved in high concentrations of glucose and saturated fatty acid palmitate-induced apoptosis in Min6 cells and primary rat islets. The results show that high glucose and palmitate treatment of Min6 can activate JNK by induction of ER stress and ultimately lead to apoptosis. Furthermore, recent evidences indicated that JNK can inhibit insulin signaling in peripheral tissues such as liver and adipose by phosphorylating insulin receptor substrate-1(IRS-1) at Ser 307. However, it remains uncertain whether JNK exhibits the similar function in pancreaticβcells. To verify this question, we used Western Blot to demonstrate that high glucose and palmitate induced phosphorylation of insulin receptor substrate-1(IRS-1) at Ser307 in Min6 cells and primary rat islets, whereas JNK specific inhibitor SP600125 can efficiently inhibit the Ser phosphorylation of IRS-1. These results illustrate high glucose and palmitate IRS-1 phosphorylation in JNK-dependent manner, leading to inhibition of insulin signaling in pancreaticβcells. In another aspect, IRS-1 deficient mouse has been shown a dramatic decline in pancreaticβcell mass indicating that apoptosis may occur. Above all, we proposed that high glucose and palmitated-induced Min6 cell apoptosis is mediated by JNK activation through inhibition of insulin signaling.