Uncontrolled endoplasmic reticulum stress response leads to pancreatic beta cell death via JNK andp53

Endoplasmic reticulum (ER) stress is a cause of beta cell death in both T1D and T2D. However, no therapeutics to reduce beta cell death have been approved, in part because molecular mechanisms driving beta cell death during ER stress are insufficiently defined. GRP78, an ER chaperone, is the critical regulator of unfolded protein response (UPR) stress response pathways. GRP78 binds and suppresses UPR initiators during the unstressed state, releasing them to promote UPR activation during stress. To study pathways causing beta cell decompensation during active ER stress and the related stress response, we engineered mice genetically lacking GRP78 in pancreatic beta cells. GRP78 deletion caused acute insulin deficient diabetes in pups before weaning, with reduced beta cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses outline a pathway in which JNK activity downstream of IRE1 kinase leads to p53 activation to mediate beta cell death during ER stress. Remarkably, in vivo JNK inhibition reduced beta cell death in two distinct ER stress diabetes models. In human beta cells, inhibitors of JNK and of p53 were both effective to improve beta cell survival in the face of ER stress. Our findings provide insight into mechanisms causing beta cell death and outline possible therapeutic targets to preserve insulin secretory capacity in the face of ER stress.