Sex-dependent diabetes impact of acute Grp78 deletion in beta cells of adult mice

GRP78/BiP/HSPA5 is a widely expressed endoplasmic reticulum (ER) chaperone that also performs the critical role of regulating the unfolded protein response (UPR), an adaptive mechanism that maintains ER homeostasis. As the exclusive source of circulating insulin, pancreatic beta cells are prone to ER stress due to proinsulin synthesis workload. GRP78 is important for the ER stress response, but it is unknown whether beta cells require GRP78 in the absence of metabolic stress. Here we report the impact of genetic deletion of GRP78 in beta cells of healthy adult mice during normal metabolic conditions. Glucose intolerance occurred in both sexes, mildly in females but profoundly in males, concomitant with weight loss. Islet size and beta cell mass were reduced only in males. Both sexes showed similar increases in beta cell death and residual alpha cell proportion, but females more robustly increased beta cell proliferation. Intriguingly, dedifferentiation was prominent in males, both in vivo and ex vivo, and male islet cells showed hyperactive induction of ATF6 target genes during ex vivo Grp78 deletion compared to female. We conclude that GRP78 is essential for beta cell health even in resting conditions and that sex differences exist in the beta cell ER stress response.