Role of the Unfolded Protein Response in beta Cell Compensation and Failure during Diabetes

Pancreatic beta cell failure leads to diabetes development. During disease progression, beta cells 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 the beta cell. These signalling pathways are collectively termed unfolded protein response (UPR). The UPR machinery is required to preserve ER homeostasis and beta cell 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 prevent beta cell failure and increase beta cell mass and adaptation throughout the progression of diabetes. In this review we will highlight the specific role of UPR actors in beta cell compensation and failure during diabetes.