STIM1 INTERACTS WITH G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING TO MAINTAIN BETA CELL IDENTITY IN FEMALE MICE

Type 2 diabetes (T2D), a multi-factorial disease characterized by insulin resistance and pancreatic β cell dysfunction, accounts for 90% of all forms of diabetes. Recent studies identified β cell dedifferentiation as one mechanism leading to β cell failure in T2D, and this phenotype has been linked with loss of expression of cellular identity markers​. The molecular mechanisms leading to β cell dedifferentiation in T2D are not well defined and represent a key gap in our understanding of disease progression. Furthermore, sex-specific mechanisms contributing to β cell dysfunction remain unknown. We demonstrated that β cell-specific stromal interaction molecule 1 knockout (STIM1Δβ) leads to obesity-induced glucose intolerance and reduced expression of β cell identity genes in female but not male mice. Mechanistic studies identified reduced G-protein coupled estrogen receptor (GPER) expression in female STIM1Δβ islets, suggesting a novel connection between STIM1, GPER, and β cell identity. To determine how STIM1 and GPER interact to maintain β cell identity in females, we generated and characterized two mouse models: a surgical ovariectomy (OVX) model and a β cell-specific GPER knockout (GPERΔβ) model. Female high fat diet (HFD)-fed OVX mice showed glucose intolerance and loss of β cell identity gene expression, and ex vivo treatment of OVX islets with a GPER agonist rescued the loss of β cell identity. Additionally, HFD-fed GPERΔβ female mice had increased glucose excursions compared to controls. Our results highlight the critical role that estradiol signaling through GPER plays in the maintenance of β cell health and identity and the pathogenesis of T2D in females.