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

Summary Loss of pancreatic β 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 β cell function in female mice. When mice with β cell-specific deletion of STIM1 (STIM1Δβ) were challenged with high-fat diet, β cell dysfunction was observed in female, but not male, mice. Impaired glucose tolerance was accompanied by reductions in β cell mass, a concomitant increase in α cell mass, and significant reductions in the expression of markers of β cell maturity, including MafA and UCN3. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Δβ mice was due in part to loss of signaling through the noncanonical 17-β estradiol receptor, GPER1. Together, these data suggest that STIM1 orchestrates pancreatic β cell function and identity through GPER1-mediated estradiol signaling.