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

Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet β cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibited a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse β cells with the sex hormone 17β-estradiol (E2) suppressed inflammatory signaling and markers of β-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduced diabetes incidence and limited progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppressed interferon signaling, chemokine production, and antigen presentation in β cells, while reducing activation and cytotoxicity pathways in immune cells. In an aggressive adoptive transfer model, E2 pretreatment of the recipient mice attenuated hyperglycemia. These findings support a model in which estradiol-mediated β-cell reprogramming reduces β-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.