1713-P: Acute Beta Cell Deletion of Grp78 Causes Diabetes in Adult Male Mice

Introduction: GRP78 is a stress-inducible endoplasmic reticulum (ER) chaperone and a key regulator of the unfolded protein response (UPR). Pancreatic beta cells are particularly susceptible to ER stress in order to adapt to increased insulin demand. It is unknown whether mature beta cells require GRP78 function for basal homeostasis. In this study, we investigated the impact of reducing GRP78 abundance in beta cells of adult mice in unstressed conditions. We hypothesized that loss of GRP78 activity results in decompensation and beta cell failure.

Methods: MIP-CreERT mice were bred to mice harboring loxP sites flanking exons 5-7 of the Grp78 gene. Male and female adults, genotypes Cre+Grp78 +/+ ("+/+"), Cre+Grp78 f/+ (“f/+”), and Cre+Grp78 f/f (“f/f"), were administered five daily doses of tamoxifen by oral gavage. Metabolic parameters were assessed and mice were sacrificed 10 days after the last tamoxifen dose for pancreas histology.

Results: GRP78 protein abundance was reduced in f/f beta cells relative to f/+ and +/+ beta cells by immunofluorescence. Grp78 deletion increased random blood glucose in male and female f/f mice compared to f/+ and +/+ controls. Males were more severely affected than females; f/f males also had elevated fasting glucose, impaired glucose tolerance, and weight loss. Random plasma insulin levels were reduced in some but not all mice. Pancreas weight was unaffected by Grp78 deletion. Beta cell mass was reduced in male f/f mice, islet architecture and cellular composition were distorted, with reduced frequency of beta cells and increased relative frequency of alpha cells. Interestingly, beta cell proliferation and beta cell death death were both significantly increased by Grp78 deletion.

Conclusions: Acute deletion of Grp78 in beta cells rapidly induces beta cell loss and diabetes in adult male mice. Beta cell GRP78 is important for maintaining whole-body glucose homeostasis. Impairment in GRP78 abundance or function in beta cells may contribute to the pathogenesis of diabetes