Causes and cures for endoplasmic reticulum stress in lipotoxic β‐cell dysfunction

Abstract

Pancreatic β‐cell dysfunction is central to the pathogenesis of type 2 diabetes, and the loss of functional β‐cell mass in type 2 diabetes is at least in part secondary to increased β‐cell apoptosis. Accumulating evidence suggests that endoplasmic reticulum (ER) stress is present in β‐cells in type 2 diabetes. Free fatty acids (FFAs) cause ER stress and are putative mediators of β‐cell dysfunction and death. In this review, we discuss the molecular mechanisms underlying ER stress induced by saturated and unsaturated FFAs. Oleate and palmitate trigger ER stress through ER Ca2+ depletion and build‐up of unfolded proteins in the secretory pathway. Saturated and unsaturated FFAs elicit a differential signal transduction in the three branches of the ER stress response, resulting in different survival/apoptosis outcomes. The protection of β‐cells against FFAs through the interference with ER stress signalling has opened novel therapeutic perspectives for type 2 diabetes. Chemical chaperones, salubrinal and glucagon‐like peptide‐1 (GLP‐1) analogues have been used to protect β‐cells from lipotoxic ER stress. Importantly, the pro‐ and antiapoptotic effects of these compounds are cell and context dependent.