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

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.