Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, Canada.
Thrombosis and Atherosclerosis Research Institute, 237 Barton Street E, Hamilton, ON L8L 2X2, Canada.
Int J Mol Sci. 2024 Feb 2;25(3):1816. doi: 10.3390/ijms25031816.
Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE:Ins2 mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE:Ins2 mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE:Ins2 mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE:Ins2 mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.
糖尿病在临床上被定义为慢性高血糖症。糖尿病的表现和结果存在性别差异，与男性相比，绝经前女性发生糖尿病的风险降低，而绝经后女性则如此。越来越多的证据表明雌激素，特别是 17-β雌二醇，在维持胰腺β细胞健康方面具有保护作用;然而，这种保护的机制尚不清楚。为了阐明这些潜在的机制，我们使用了一种胰腺β细胞系 (BTC6) 和一种高血糖诱导的动脉粥样硬化的小鼠模型，即 ApoE:Ins2 小鼠，其葡萄糖调节存在性别二态性。在这项研究中，我们假设 17-β雌二醇通过调节内质网 (ER) 应激反应中的未折叠蛋白反应 (UPR) 来保护胰腺β细胞。我们观察到，去卵巢的雌性和雄性 ApoE:Ins2 小鼠表现出明显增加的凋亡 UPR 标志物表达。与未补充的去卵巢雌性 ApoE:Ins2 小鼠相比，接受外源性 17-β雌二醇补充的假手术雌性和去卵巢雌性 ApoE:Ins2 小鼠增加了适应性 UPR 标志物的表达。这些发现与在培养的 BTC6 细胞中观察到的结果一致，表明 17-β雌二醇可能通过抑制凋亡 UPR 并增强胰腺 ER 应激反应中的适应性 UPR 激活来保护胰腺β细胞。
