糖尿病(DM),一个重要的公共卫生问题,加剧了全球经济负担。糖尿病脑病(DE)是DM的中枢神经系统严重并发症。二甲双胍已被证明可以改善DE。然而,机制尚不清楚。在这项研究中,db/db鼠标,用于DE的通用模型,探讨和研究二甲双胍的神经保护作用及相关机制。行为测试表明,二甲双胍(100或200mg/kg/天)可以显着改善db/db小鼠的学习和记忆能力。口服葡萄糖耐量试验(OGTT)和胰岛素耐量试验(ITT)的结果表明,二甲双胍可有效调节db/db小鼠的葡萄糖和胰岛素信号通路。体重和血脂面板的结果(总胆固醇,甘油三酯,高密度脂蛋白胆固醇,低密度脂蛋白胆固醇)表明二甲双胍促进db/db小鼠的脂质代谢水平。此外,来自氧化应激测定的数据,测量丙二醛的水平,超氧化物歧化酶,过氧化氢酶,和谷胱甘肽过氧化物酶,提示二甲双胍抑制db/db小鼠氧化应激诱导的脑损伤。此外,westernblot,尼氏染色,免疫荧光结果显示,二甲双胍可增加神经生长因子的表达和突触后密度95,修复神经元结构损伤。对于机理研究,二甲双胍激活SIRT1并抑制NLRP3炎性体的表达(NLRP3,ASC,caspase-1,IL-1β,和IL-18)和炎性细胞因子(TNFα和IL-6)。总之,二甲双胍可通过SIRT1/NLRP3途径改善认知功能障碍,这可能是一种有希望的DE治疗机制。
Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system.
Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of
metformin and related mechanisms. Behavioral tests indicated that
metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study,
metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1β, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion,
metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.