GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310965/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310965GEOGSEfalseIslet-Intrinsic Sex Differences in Inflammatory Signaling Contribute to Autoimmune Diabetes SusceptibilityWhereas 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.2026/05/17GSE310965GSM9313358GSM9313357GSM9313359GSM9313398GSM9313354GSM9313353GSM9313397GSM9313356GSM9313355GSM9313350GSM9313394GSM9313393GSM9313352GSM9313396GSM9313395GSM9313351GSM9313390GSM9313392GSM9313391GSM9313369GSM9313368GSM9313365GSM9313364GSM9313367GSM9313366GSM9313361GSM9313360GSM9313363GSM9313362GSM9313339GSM9313379GSM9313376GSM9313375GSM9313378GSM9313377GSM9313372GSM9313371GSM9313374GSM9313373GSM9313370GSM9313347GSM9313346GSM9313349GSM9313348GSM9313343GSM9313387GSM9313386GSM9313342GSM9313389GSM9313345GSM9313388GSM9313344GSM9313383GSM9313382GSM9313341GSM9313385GSM9313384GSM9313340GSM9313381GSM931338034281310965Homo sapiens