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

Version 2 2023-08-18, 17:49
Version 1 2023-07-21, 17:29
posted on 2023-08-18, 17:49 authored by Paul Sohn, Madeline R. McLaughlin, Preethi Krishnan, Wenting Wu, Marjan Slak Rupnik, Akira Takasu, Toshiya Senda, Chih-Chun Lee, Tatsuyoshi Kono, Carmella Evans-Molina

Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β cell dysfunction and diabetes development. Store-operated Ca2+ entry (SOCE) replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). To characterize the in vivo impact of STIM1 loss, mice with a β cell-specific STIM1 deletion (STIM1Δβ mice) were generated and challenged with high-fat diet. Interestingly, β cell dysfunction was observed in female, but not male, mice. Female STIM1Δβ mice displayed reductions in β cell mass, a concomitant increase in α cell mass, and reduced expression of markers of β 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, organ donors. 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), as GPER1 knockdown and inhibition led to a similar loss of expression of β cell maturity genes in INS-1 cells. Together, these data suggest that STIM1 orchestrates pancreatic β cell function and identity through GPER1-mediated estradiol signaling. 



This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK093954, R01DK127236, U01DK127786, R01DK127308, UC4DK104166 (to C.E.-M.), and 5F30DK123996-03 (to P.S.), U.S. Department of Veterans Affairs Merit Award I01BX001733 (to C.E.-M.), and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, the George and Frances Ball Foundation (to C.E.-M.). W.W. was supported by NIH grant U24DK097771 as part of the NIDDK Information Network's (dkNET) New Investigator Pilot Program in Bioinformatics. This work was partly supported by the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED) under Grant No. JP23ama121001 (to T.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors acknowledge the support of the Islet and Physiology and Translation Cores of the Indiana Diabetes Research Center (P30-DK-097512).


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