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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.

Authors :
Sohn P
McLaughlin MR
Krishnan P
Wu W
Slak Rupnik M
Takasu A
Senda T
Lee CC
Kono T
Evans-Molina C
Source :
Diabetes [Diabetes] 2023 Oct 01; Vol. 72 (10), pp. 1433-1445.
Publication Year :
2023

Abstract

Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β-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 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, human 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.<br />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). β-Cell-specific deletion of STIM1 results in a sexually dimorphic phenotype, with β-cell dysfunction and loss of identity in female but not male mice. Expression of the noncanonical 17-β estradiol receptor (GPER1) is decreased in islets of female STIM1Δβ mice, and modulation of GPER1 levels leads to alterations in expression of β-cell maturity genes in INS-1 cells.<br /> (© 2023 by the American Diabetes Association.)

Details

Language :
English
ISSN :
1939-327X
Volume :
72
Issue :
10
Database :
MEDLINE
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
37478155
Full Text :
https://doi.org/10.2337/db22-0988