36-OR: Sex-Based Molecular Architecture of Estrogen Receptor Actions in Human Islet Cells

Introduction and Objective: The main estrogen (17β-estradiol, E2) enhances insulin biosynthesis and secretion, protecting both female (F) and male (M) β-cells from metabolic stresses via the estrogen receptor-α (ERα). E2 activates unfolded protein degradation pathways, mitigating endoplasmic reticulum (EndRet) stress in human and mouse islets. However, the FDA-approved selective estrogen receptor modulator (SERM) bazedoxifene (BZA) protects F but not M β-cells. The mechanisms underlying these sexually dimorphic effects remain unclear. Methods: We treated human islets (3 F and 3 M donors) with vehicle, E2 or BZA, performing scRNAseq and snATACseq (~140,000 cells). Results: E2 increased gene pathways involved in mitochondrial function/respiration and antioxidant protection in β-cells and endothelial cells in both sexes. E2 also increased genes involved in unfolded protein response (UPR) in β-cells and angiogenesis in endothelial cells in both sexes. E2 increased genes in translation in F β-cells and lipid transport in F endothelial cells BZA increased cholesterol/lipid transport and metabolism genes in β-cell and endothelial cells as well as translation genes in β-cells of F. However, BZA increased genes in translation but downregulated genes in mitochondrial function/respiration in β-cells and endothelial cells. Conclusion: In summary, E2 promotes mitochondrial function and stress resilience as well as angiogenesis in both sexes. In contrast, BZA exhibits sexually dimorphic effects, suppressing mitochondrial activity in M cells while supporting lipid metabolism and cholesterol synthesis in F cells. These data highlight the importance of single cell transcriptomics for sex-based precision medicine. Disclosure M. Qadir: None. S. Haque: None. F. Mauvais-Jarvis: None. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (FMJ) (DK074970); NIH National Institute of General Medical Sciences (FMJ) (P20GM152305); U.S. Department of Veterans Affairs Merit Award (FMJ) (BX005812); NIH National Institute of Diabetes and Digestive and Kidney Diseases (IIDP) (2UC4DK098085); NIH NIDDK (1K99DK140067)