Loss of STIM1 leads to pancreatic beta cell dysfunction and dedifferentiation in females via GPER downregulation

ABSTRACT: STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that serves to replenish ER Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai1 channels 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 test this, we generated mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ). Our results revealed a striking sexual dimorphism in metabolic phenotypes when STIM1Δβ mice were challenged with high fat diet for 8 weeks. Male STIM1Δβ mice showed no differences in total weight, lean or fat mass, or glucose tolerance compared to WT littermate controls. In contrast, female STIM1Δβ mice displayed significantly increased total body weight, fat mass, and reduced glucose tolerance, in vivo glucose-stimulated insulin secretion and β cell mass compared to WT littermate controls, while insulin sensitivity, food intake, and energy expenditure were unchanged. To investigate mechanisms underlying these findings, RNA sequencing was performed in isolated islets and revealed altered 17-beta estradiol (E2) signaling, lipid metabolism, epithelial cell differentiation and decreased noncanonical estradiol receptor GPER. Consistent with this, alpha cell mass was increased in female STIM1Δβ, while proteomics and immunoblot analysis of STIM1 knockout (STIM1KO) INS-1 beta cells revealed reduce insulin expression and increased glucagon expression, suggesting STIM1 may be required for the maintenance of β cell identity. To this end, we show that a reduction of a noncanonical estradiol receptor GPER in STIM1 deficient islets contributes to the marked sexual dimorphism observed during beta cell dysfunction in female STIM1Δβ mice. This present study delineates a sexually dimorphic regulation of STIM1 in the maintenance of pancreatic beta cell identity through GPER and may expand the field of therapeutic approaches to diabetes. Our findings demonstrate the importance of STIM1 and GPER expression stability in the anti-diabetogenic response from estradiol.

ORGANISM(S): Mus musculus

PROVIDER: GSE208135 | GEO | 2023/08/15

REPOSITORIES: GEO