Stromal Interaction Molecule 1 Maintains β Cell Identity and Function in Female Mice through Preservation of G Protein-Coupled Estrogen Receptor 1 Signaling

Loss of pancreatic {beta} cell mass, identity, and function contribute to the development of diabetes. Here, we show that the endoplasmic reticulum (ER) calcium sensor, stromal interaction molecule 1 (STIM1), is critical for the maintenance of {beta} cell function in female mice. When mice with {beta} cell-specific deletion of STIM1 (STIM1{Delta}{beta}) were challenged with high-fat diet, {beta} cell dysfunction was observed in female, but not male, mice. Impaired glucose tolerance was accompanied by reductions in {beta} cell mass, a concomitant increase in cell mass, and significant reductions in the expression of markers of {beta} cell maturity, including MafA and UCN3. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1{Delta}{beta} mice was due in part to loss of signaling through the noncanonical 17-{beta} estradiol receptor, GPER1. Together, these data suggest that STIM1 orchestrates pancreatic {beta} cell function and identity through GPER1-mediated estradiol signaling.