Role of the Unfolded Protein Response inβCell Compensation and Failure during Diabetes

Abstract

Pancreaticβcell failure leads to diabetes development. During disease progression,βcells adapt their secretory capacity to compensate the elevated glycaemia and the peripheral insulin resistance. This compensatory mechanism involves a fine-tuned regulation to modulate the endoplasmic reticulum (ER) capacity and quality control to prevent unfolded proinsulin accumulation, a major protein synthetized within theβcell. These signalling pathways are collectively termed unfolded protein response (UPR). The UPR machinery is required to preserve ER homeostasis andβcell integrity. Moreover, UPR actors play a key role by regulating ER folding capacity, increasing the degradation of misfolded proteins, and limiting the mRNA translation rate. Recent genetic and biochemical studies on mouse models and human UPR sensor mutations demonstrate a clear requirement of the UPR machinery to preventβcell failure and increaseβcell mass and adaptation throughout the progression of diabetes. In this review we will highlight the specific role of UPR actors inβcell compensation and failure during diabetes.