Abstract：
Pancreatic β cell damage is the primary contributor to type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains nebulous. This study explored the role of ferroptosis in pancreatic β cell damage and the protective effects of grape seed proanthocyanidin extract (GSPE). In T2DM model rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of the T2DM model. MIN6 mouse insulinoma β cells were cultured in high glucose and sodium palmitate conditions to obtain a glycolipid damage model, which was administered with GSPE, ferrostatin-1 (Fer-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. GSPE and Fer-1 treatment significantly improved pancreatic β-cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved iron metabolism. Furthermore, the treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing β-cell damage and dysfunction in T2DM. Therefore, GSPE is a potential treatment strategy against T2DM.
摘要：
胰腺β细胞损伤是2型糖尿病(T2DM)的主要原因;然而,潜在的机制仍然模糊。本研究探讨铁凋亡在胰岛β细胞损伤中的作用及葡萄籽原花青素提取物(GSPE)的保护作用。在T2DM模型大鼠中,血糖，取水,尿量,HbA1c,稳态模型评估-胰岛素抵抗显著增加，体重和胰岛素水平显着下降，表明T2DM模型的成功建立。将MIN6小鼠胰岛素瘤β细胞在高糖和棕榈酸钠条件下培养，获得糖脂损伤模型，用GSPE给药，Fer-1(Fer-1)，或核因子红系2相关因子2（Nrf2）小干扰（si）RNA。GSPE和Fer-1治疗显着改善胰腺β细胞功能障碍并防止细胞死亡。两种处理都增加了超氧化物歧化酶和谷胱甘肽的活性，降低丙二醛和活性氧的水平，和改善铁代谢。此外，这些治疗逆转了糖脂毒性引起的铁凋亡标志物半胱氨酸/谷氨酸转运蛋白（XCT）和谷胱甘肽过氧化物酶4（GPX4）的表达。GSPE处理激活了Nrf2和相关蛋白的表达。当与si-Nrf2共转染时,这些作用被逆转。GSPE通过激活Nrf2信号通路抑制铁凋亡，从而减轻2型糖尿病患者的β细胞损伤和功能障碍。因此,GSPE是针对T2DM的潜在治疗策略。
