176-OR: STIM1 Deletion Leads to Loss of Beta-Cell Identity in High-Fat Diet-Fed Female Mice

STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that replenishes ER Ca2+ stores in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To this end, mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ) were generated by crossing STIM1flox/flox with Ins-Cre mice and fed a high fat diet (HFD) beginning at 8 wk of age. Male STIM1Δβ mice did not show changes in glucose tolerance or body composition. In contrast, female HFD-fed STIM1Δβ mice were heavier (25.1 vs. 28.3 g, p<0.05), had increased fat mass (4.9 vs. 8.2g, P<0.01), and exhibited significant glucose intolerance (AUC IPGTT 22461 vs. 29245 mg/dL*min; p<0.0001) with impaired insulin secretion by in-vivo GSIS (p<0.05) without differences insulin tolerance, energy expenditure or food intake. Bulk RNA-sequencing of wild-type and STIM1Δβ female islets revealed reduced expression of MafA, UCN3, and Ins1 and Ins2 in STIM1Δβ islets, indicating potential loss of β cell identity. Pathway analysis showed modulation of pathways related to 17-beta estradiol (E2) signaling, with downregulation of a G-protein coupled estrogen receptor 1 (GPER), while differentially expressed genes were enriched for functions related to apoptosis, lipid metabolism, and epithelial cell differentiation. Consistently, STIM1Δβ female mice had lower β cell mass (2.984 mg vs. 1.349 mg, p<0.05) and higher alpha cell mass (0.1822 mg vs. 0.4463 mg, p<0.05). Proteomics analysis performed in STIM1-deficient INS-1 cells revealed significantly increased glucagon expression. Further, lower mobilization of intracellular cAMP levels was noted in response to treatment with E2 or G1, an agonist of GPER. These findings suggest a role for STIM1 in the maintenance of pancreatic β cell identity and indicate a potential interaction between SOCE and E2 signaling in female mice.