Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death

There is a growing evidence of the role of autophagy in pancreatic beta cell homeostasis. During development of type 2 diabetes, beta cells are required to supply the increased demand of insulin. In such a stage, beta cells have to address high ER stress conditions that could lead to abnormal insulin secretion, and ultimately, beta cell death and overt diabetes. In this study, we used insulin secretion-deficient beta cells derived from fetal mice. These cells present an increased accumulation of polyubiquitinated protein aggregates and LC3B-positive puncta, when compared with insulinoma-derived beta cell lines. We found that insulin secretion deficiency renders these cells hypersensitive to endoplasmic reticulum (ER) stress-mediated cell death. Chemical or shRNA-mediated inhibition of autophagy increased beta cell death under ER stress. On the other hand, rapamycin treatment increased both autophagy and cell survival under ER stress. Insulin secretion-deficient beta cells showed a marked reduction of the antiapoptotic protein BCL2, together with increased BAX expression and ERN1 hyperactivation upon ER stress induction. These results showed how insulin secretion deficiency in beta cells may be contributing to ER stress-mediated cell death, and in this regard, we showed how the autophagic response plays a prosurvival role.