Role of the Unfolded Protein Response 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.
