Sex-Dependent Diabetes Impact of Acute Grp78 Deletion in β-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, an adaptive mechanism that maintains ER homeostasis. As the exclusive source of circulating insulin, pancreatic β-cells are prone to ER stress due to proinsulin synthesis workload. GRP78 is important for the ER stress response, but it is unknown whether β-cells require GRP78 in the absence of metabolic stress. Here, we report the impact of genetic deletion of GRP78 in β-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 β-cell mass were reduced only in males. Both sexes showed similar increases in β-cell death and residual α-cell proportion, but females more robustly showed increased β-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 with female. We conclude that GRP78 is essential for β-cell health, even in resting conditions, and that sex differences exist in the β-cell ER stress response. ARTICLE HIGHLIGHTS: We investigated the consequence of reducing GRP78 abundance in pancreatic β-cells of adult mice in normal physiological conditions. Genetic Grp78 reduction caused β-cell failure and diabetes in male mice, with weight loss, hyperglycemia, glucose intolerance, β-cell mass reduction, and β-cell dedifferentiation. Male and female mice showed similar increases in β-cell death, but proliferation was more profoundly increased in females. Ex vivo Grp78 deletion led to hyperactivation of ATF6 target genes in male islet cells compared with female. Preserving β-cell GRP78 abundance may reduce the likelihood of diabetes, especially in males.