中文摘要：

二甲双胍是一个一线抗糖尿病药物,然而其详细作用机制仍在研究中。Nrf2信号在保护细胞免受氧化性损伤中起着重要作用,近年来也成为干预糖尿病及其相关并发症的重要药物靶标。本研究在体内外实验中检测了二甲双胍对Nrf2信号的影响,并探究了其可能的机制。首先,二甲双胍激活AMPK和Nrf2信号,并以类似的浓度-和时间-依赖方式在小鼠骨骼肌细胞C2C12中诱导抗氧化基因NQO1和γ-GCSm的表达。其次,过表达AMPK会显著提高基础的和二甲双胍诱导的ARE–萤光素酶报告基因的活性,说明AMPK参与了二甲双胍对Nrf2信号的激活。最后,二甲双胍激活小鼠肝脏和骨骼肌组织中的Nrf2信号,诱导抗氧化基因HO-1和SOD的表达,导致GSH水平的增加。总之,我们的结果说明二甲双胍可以激活Nrf2信号和增强组织的抗氧化能力,并提供了二甲双胍作用的新机制。

英文摘要：

As a first line anti-diabetes drug, the molecular mechanisms by which metformin exerts its pharmacological activities are still under extensive investigations. The Nrf2 signaling plays a crucial role in protecting cells from oxidative damages, and has emerged as a promising target for treatment of diabetes and related complexes in recent years. In the present study, the effect of metformin on Nrf2 signaling was tested in vitro and in vivo, and the possible mechanism was explored. Metformin activated AMPK and Nrf2 signaling and induced the expression of antioxidant genes NQO1 and y-GCSm in C2C12 mouse myoblast cells in a similar concentration- and time-dependent manner. Moreover, overexpression of AMPK significantly elevated the basal and metformin-induced ARE-driven luciferase reporter activities, suggesting the involvement of AMPK in metformin-activated Nrf2 signaling. Finally, metformin activated Nrf2 signaling and induced the expression of antioxidant genes such as HO-1 and SOD, and resulted in increased GSH level in mouse liver and skeletal muscle tissues. Take together, our results clearly demonstrated that metformin activated Nrf2 signaling and enhanced the tissue antioxidant capacity, and provide a new molecular mechanism of action of metformin.