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Diabetes and Vascular Disease

ORF14-02 - Sex Differences in Islet-Intrinsic Inflammatory Signaling Contribute to Autoimmune Diabetes Susceptibility

Saturday, June 13, 2026
1:50 PM - 1:55 PM CT
Location: Room W181AB
Disclosure(s):
Sarah A. Tersey, PhD: No financial relationships to disclose
Ernesto S. Nakayasu, PhD: No financial relationships to disclose
Carmella Evans-Molina, MD, PhD: Astellas Pharmaceuticals: Grant Recipient (); Bristol Myers Squibb: In-Kind research support (); DiogenyX: Advisory Board (); Excalibur: Honorarium Recipient (); Isla Technologies: Advisory Board (); Lilly Pharmaceuticals: Grant Recipient (); Neurodon: Advisory Board (); Patent 16/291,668) Extracellular Vesicle Ribonucleic Acid (RNA) Cargo as a Biomarker of Hyperglycemia and Type 1 Diabetes : Patent (); Provisional Patent (63/285,765) Biomarker for Type 1 Diabetes (PDIA1 as a biomarker of β cell stress) : Provisional patent (); Sanofi: Advisory Board ()

Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, implicating sex hormones in disease modification. Because pancreatic β cells actively shape local immune responses, we hypothesized that sex-specific β-cell responses to inflammatory stress contribute to this disparity. To test this, we performed transcriptomic and proteomic profiling of human islets from male and female donors treated with a proinflammatory cytokine cocktail (PIC: IL-1β and IFN-γ), modeling early inflammatory stress in T1D. Analyses were conducted in both a public discovery cohort and a newly generated validation cohort. Despite differences in donor backgrounds and sequencing platforms, both datasets showed strong concordance in sexually dimorphic inflammatory responses. Male islets mounted a broader proinflammatory program characterized by increased interferon-stimulated genes, chemokines, and antigen presentation pathways, findings that were corroborated at the proteomic level by elevated IFN-responsive proteins and MHC class I components. In contrast, female islets were enriched for estrogen-responsive and developmental pathways, including EMT and Wnt signaling, which have been linked to β-cell plasticity and immune evasion. To assess the functional relevance of estrogen signaling, we treated human islets and mouse β-cell lines with 17β-estradiol (E2) in vitro, which suppressed inflammatory signaling, chemokine production, and markers of β-cell maturity. In vivo, chronic E2 treatment significantly reduced diabetes incidence and delayed insulitis in NOD mice. Single-cell RNA sequencing of islets from E2-treated NOD mice revealed reduced β-cell expression of interferon signaling genes, antigen processing pathways, and inflammatory chemokines. To determine whether E2 alters islet immunogenicity, E2-pretreated mouse islets were co-cultured with BDC2.5 splenocytes, resulting in reduced T cell proliferation and IFN-γ production. Finally, in an adoptive transfer model using BDC2.5 CD4⁺ T cells, E2-treated NOD/SCID recipients exhibited delayed diabetes onset and lower blood glucose levels, indicating partial islet-intrinsic protection. Together, these findings demonstrate that sex-specific β-cell inflammatory programs shape T1D risk and identify estradiol as a protective factor that reduces β-cell immunogenicity and enhances stress resilience. By identifying E2 signaling as a protective axis, this work advances understanding of β-cell-immune interactions and provides new insight for the broader diabetes field into strategies that may preserve β-cell survival and function.