McLaughlin Madeline R, Krishnan Preethi, Wu Wenting, Rostron Cameron, Orr Kara, Udari Lata, Del Carmen Aquino Jacqueline, Fisher Amanda, Kono Tatsuyoshi, Kua Kok Lim, Evans-Molina Carmella
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202.
Department of Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202.
bioRxiv. 2025 May 15:2025.05.12.652914. doi: 10.1101/2025.05.12.652914.
Type 2 diabetes (T2D) arises in the context of obesity and overnutrition; however, additional demographic features including age and biological sex contribute to T2D risk. Estradiol (E2) is thought to play a protective metabolic role that may govern sex differences in the development of T2D. The mechanisms by which E2 exerts these effects and the impact of reduced E2 signaling in β cells during menopause remain incompletely understood. We analyzed publicly available whole islet transcriptome datasets from female and male cadaveric donors and showed significant age-related modulation of gene expression, including changes in pathways related to β cell function, in islets from female donors. Importantly, these patterns were not observed in islets from male donors. To test the relationship between E2 signaling and β cell function, 10-week-old female C57BL6/J mice underwent an ovariectomy (OVX) or sham (CTR) surgery, followed by 4 weeks of high-fat diet (HFD) treatment. HFD-OVX mice exhibited obesity-induced glucose intolerance, increased α cell mass, and reduced expression of β cell identity markers. Furthermore, treatment of islets with the G protein coupled estrogen receptor (GPER)-specific agonist G-1 restored β cell identity gene expression. Together, these data identify a novel connection between GPER signaling and β cell identity and suggest that menopausal loss of E2 signaling through GPER may be linked with loss of β cell identity.
2型糖尿病（T2D）在肥胖和营养过剩的背景下出现；然而，包括年龄和生物性别在内的其他人口统计学特征也会增加T2D风险。雌二醇（E2）被认为具有保护性代谢作用，可能在T2D发展过程中决定性别差异。E2发挥这些作用的机制以及绝经期间β细胞中E2信号减少的影响仍未完全了解。我们分析了来自女性和男性尸体捐赠者的公开全胰岛转录组数据集，发现女性捐赠者的胰岛中存在与年龄相关的显著基因表达调节，包括与β细胞功能相关途径的变化。重要的是，在男性捐赠者的胰岛中未观察到这些模式。为了测试E2信号与β细胞功能之间的关系，对10周龄的雌性C57BL6/J小鼠进行卵巢切除术（OVX）或假手术（CTR），然后进行4周的高脂饮食（HFD）治疗。HFD-OVX小鼠表现出肥胖诱导的葡萄糖不耐受、α细胞质量增加以及β细胞身份标志物表达降低。此外，用G蛋白偶联雌激素受体（GPER）特异性激动剂G-1处理胰岛可恢复β细胞身份基因表达。总之，这些数据确定了GPER信号与β细胞身份之间的新联系，并表明绝经期间通过GPER导致的E2信号丧失可能与β细胞身份丧失有关。
