McLaughlin, M. R. | Search bioRxiv

bioRxiv2022

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

Loss of pancreatic {beta} cell mass, identity, and function contribute to the development of diabetes. Here, we show that the endoplasmic reticulum (ER) calcium sensor, stromal interaction molecule 1 (STIM1), is critical for the maintenance of {beta} cell function in female mice. When mice with {beta} cell-specific deletion of STIM1 (STIM1{Delta}{beta}) were challenged with high-fat diet, {beta} cell dysfunction was observed in female, but not male, mice. Impaired glucose tolerance was accompanied by reductions in {beta} cell mass, a concomitant increase in cell mass, and significant reductions in the expression of markers of {beta} cell maturity, including MafA and UCN3. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1{Delta}{beta} mice was due in part to loss of signaling through the noncanonical 17-{beta} estradiol receptor, GPER1. Together, these data suggest that STIM1 orchestrates pancreatic {beta} cell function and identity through GPER1-mediated estradiol signaling.

cell biology↗

bioRxiv2021

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

BackgroundActivation of stress pathways intrinsic to the {beta} cell are thought to both accelerate {beta} cell death and increase {beta} cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. MethodsTo identify temporal and disease-related changes in islet {beta} cell protein expression, data independent acquisition-mass spectrometry was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. FindingsIn islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of {beta} cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, {beta} cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. InterpretationWe identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of {beta} cell stress in T1D.

physiology↗