| First Author | Sohn P | Year | 2023 |
| Journal | Diabetes | Volume | 72 |
| Issue | 10 | Pages | 1433-1445 |
| PubMed ID | 37478155 | Mgi Jnum | J:344265 |
| Mgi Id | MGI:7538791 | Doi | 10.2337/db22-0988 |
| Citation | Sohn P, et al. (2023) Stromal Interaction Molecule 1 Maintains beta-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling. Diabetes 72(10):1433-1445 |
| abstractText | Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with beta-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with beta-cell-specific STIM1 deletion (STIM1Deltabeta mice) were generated and challenged with high-fat diet. Interestingly, beta-cell dysfunction was observed in female, but not male, mice. Female STIM1Deltabeta mice displayed reductions in beta-cell mass, a concomitant increase in alpha-cell mass, and reduced expression of markers of beta-cell maturity, including MafA and UCN3. Consistent with these findings, STIM1 expression was inversely correlated with HbA1c levels in islets from female, but not male, human organ donors. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Deltabeta mice was due, in part, to loss of signaling through the noncanonical 17-beta estradiol receptor (GPER1), as GPER1 knockdown and inhibition led to a similar loss of expression of beta-cell maturity genes in INS-1 cells. Together, these data suggest that STIM1 orchestrates pancreatic beta-cell function and identity through GPER1-mediated estradiol signaling. ARTICLE HIGHLIGHTS: Store-operated Ca2+ entry replenishes endoplasmic reticulum (ER) Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). beta-Cell-specific deletion of STIM1 results in a sexually dimorphic phenotype, with beta-cell dysfunction and loss of identity in female but not male mice. Expression of the noncanonical 17-beta estradiol receptor (GPER1) is decreased in islets of female STIM1Deltabeta mice, and modulation of GPER1 levels leads to alterations in expression of beta-cell maturity genes in INS-1 cells. |
