Role of the unfolded protein response in β cell compensation and failure during diabetes

Abstract

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

Figure 1

Physiological and physiopathological UPR activated pathways in β cells. (a) Under physiological conditions, increased proinsulin synthesis in response to postprandial glucose activates UPR to reduce ER stress and to promote β cell adaptation. The UPR triggers transcription of folding protein (BiP, GRP94,…), protein quality control (ERAD), UPR retrocontrol protein (GADD34), and attenuates protein translation (elF2α). Additionally, the UPR regulates calcium homeostasis via PERK, promotes proinsulin synthesis via IRE1α, and increases insulin secretion via a WFS1-AC8 pathway. (b) Under physiopathological conditions, the UPR is hyperactivated leading to IRE1α hyperphosphorylation, which in turn induces proinsulin mRNA degradation, JNK pathway activation, and XBP1 mRNA splicing. XBP1s alone or in synergy with ATF6 lead to expression of ER chaperon (Herp1, EDEM, HRD1, p58IPK, and ERAD) and subsequent ER expansion. Both ATF4 and sXBP1 increase CHOP mRNA expression. Under these conditions the UPR feedback is deregulated.