Blocking the renin-angiotensin system (RAS) can reduce the risk of diabetes. Meanwhile, the angiotensin (Ang)-converting enzyme-2 (ACE2)/Ang-(1-7)/Mas axis has recently been proposed to function as a negative regulator of the RAS. In previous studies, we first demonstrated that ACE2 knockout (ACE2(-/y)) mice exhibit impaired glucose tolerance or diabetes. However the precise roles of ACE2 on glucose metabolism are unknown. Here we show that the ACE2/Ang-(1-7)/Mas axis can ameliorate insulin resistance in the liver. Activation of the ACE2/Ang-(1-7)/Mas axis increases glucose uptake and decreases glycogen synthesis in the liver accompanied by increased expression of glucose transporters, insulin receptor substrates and decreased expression of enzymes for glycogen synthesis. ACE2 knockout mice displayed elevated levels of oxidative stress and exposure to Ang-(1-7) reduced the stress in hepatic cells. As a consequence of anti-oxidative stress, activation of the ACE2/Ang-(1-7)/Mas axis led to improved hepatic insulin resistance through the Akt/PI3K/IRS-1/JNK insulin signaling pathway. This is the first time documented that the ACE2/Ang-(1-7)/Mas axis can ameliorate insulin resistance in the liver. As insulin resistance in the liver is considered to be the primary cause of the development of type 2 diabetes, this axis may serve as a new diabetes target. (C) 2014 Elsevier Ireland Ltd. All rights reserved.