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.
