Mitogen‐inducible gene 6 potentiates glucolipotoxicity‐induced pancreatic beta cell death

Abstract

Destruction of the pancreatic insulin‐secreting beta cells, triggered by endoplasmic reticulum (ER) stress and glucolipotoxicity (GLT), is a common feature of type 2 diabetes. We previously identified that the endogenous epidermal growth factor inhibitor mitogen‐inducible gene 6 (Mig6) is induced by ER stress to promote beta cell apoptosis. In this study, we examined: 1) whether GLT also stimulates Mig6 expression, and 2) the cellular signaling cascades that interplay with Mig6 to facilitate GLT‐induced beta cell death. Using INS‐1‐derived 832/13 beta cells, we discovered that glucose, but not palmitate, stimulates Mig6 expression in a dose‐ and time‐dependent manner. Utilizing adenoviral‐mediated delivery of Mig6 to 832/13 cells, we found that Mig6 exacerbated GLT‐induced pro‐apoptotic JNK activation and caspase 3 activation. Furthermore, Mig6 might promote beta cell death by blocking cellular pro‐survival signaling pathways, as we have demonstrated that Mig6 overexpression inhibits the Akt and Erk signaling pathways in 832/13 cells. In conclusion, high glucose induces Mig6 expression in the pancreatic beta cells, which might facilitate GLT‐induced cell death. Supported by NIH DK078732(To PTF)