De Paoli Monica, Patel Zinal, Fang Susanna, Werstuck Geoff H
Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada L8L 2X2.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8S 4K1.
J Endocr Soc. 2025 Mar 15;9(5):bvaf048. doi: 10.1210/jendso/bvaf048. eCollection 2025 May.
The global incidence of diabetes mellitus is increasing, causing a heavy burden on health care management and costs. Sex differences in the incidence and prevalence of diabetes mellitus do exist, with premenopausal women being protected from developing this disease, compared to men or postmenopausal women. The mechanisms underlying these differences are not yet known and experimental animal models can significantly advance our understanding of these processes. In this study we characterized a mouse model of polygenic type 2 diabetes, the TALLYHO/JngJ mouse, which shows sexual dimorphism in blood glucose regulation. Male TALLYHO/JngJ mice develop chronic hyperglycemia by 5 weeks of age, while females remain normoglycemic. We analyzed the role of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) in the development of hyperglycemia in this mouse model. Additionally, we evaluated the effect of estrogen depletion in female TALLYHO/JngJ mice through ovariectomies. Ovariectomized female mice and males become chronically hyperglycemic (fasting blood glucose threshold >15 mM) and show significantly increased expression of GRP78/GRP94, markers of the adaptive unfolded protein response (UPR). GADD153/CHOP, a marker of the apoptotic UPR, is significantly increased in ovariectomized female mice. Treatment with a chemical chaperone 4-PBA, an ER stress alleviator, improves but does not normalize blood glucose levels in male and ovariectomized female TALLYHO/JngJ mice. Together, these findings support a protective role for estrogen and identify the UPR as a pathway through which estrogen may maintain pancreatic beta cell health.
全球糖尿病发病率呈上升趋势，给医疗管理和成本带来了沉重负担。糖尿病的发病率和患病率确实存在性别差异，与男性或绝经后女性相比，绝经前女性患这种疾病的风险较低。这些差异背后的机制尚不清楚，实验动物模型可以显著增进我们对这些过程的理解。在本研究中，我们对一种多基因2型糖尿病小鼠模型——TALLYHO/JngJ小鼠进行了表征，该模型在血糖调节方面表现出性别二态性。雄性TALLYHO/JngJ小鼠在5周龄时出现慢性高血糖，而雌性小鼠血糖仍保持正常。我们分析了内质网（ER）应激和未折叠蛋白反应（UPR）激活在该小鼠模型高血糖发展中的作用。此外，我们通过卵巢切除术评估了雌性TALLYHO/JngJ小鼠雌激素耗竭的影响。卵巢切除的雌性小鼠和雄性小鼠都会出现慢性高血糖（空腹血糖阈值>15 mM），并显示出适应性未折叠蛋白反应（UPR）标志物GRP78/GRP94的表达显著增加。凋亡性UPR的标志物GADD153/CHOP在卵巢切除的雌性小鼠中显著增加。用化学伴侣4-PBA（一种内质网应激缓解剂）治疗可改善雄性和卵巢切除雌性TALLYHO/JngJ小鼠的血糖水平，但不能使其恢复正常。总之，这些发现支持了雌激素的保护作用，并确定UPR是雌激素维持胰腺β细胞健康的一条途径。
