Figure 3: Metformin. Metformin inhibits complex I of the electron transport chain , leading to a rise in intracellular AMP and activation of AMPK [131,132]. AMPK activation can inhibit mTORC1 activity via phosphorylation of TSC2 [136] and Raptor [137] but metformin also independently inhibits the Rag family of GTPases that regulate mTORC1 localization [139]. Notably, the suppression of hepatic glucose output by metformin was recently shown to be dependent on reduced energy charge, but independent of AMPK [133]. Metformin further enhances insulin sensitivity directly at the level of the insulin receptor [128] and likely has indirect effects through mTORC1 by regulating the stability of IRS1/2 and Grb10.