title: The ACE2/Ang-(1-7)/Mas axis can inhibit hepatic insulin resistance.
abstract: 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.
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China; Beijng Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China; Beijng Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China; Beijng Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xin
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China; Beijng Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Xie
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China; Beijng Key Laboratory of Diabetes Research and Care, Beijing 100730, China. Electronic address: jinkui.yang@gmail.com.
authors.forename: Jin-Kui
authors.initials: JK
authors.lastname: Yang
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000809:Angiotensins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000809:Angiotensins; D017382:Reactive Oxygen Species; D048670:MAP Kinase Kinase 4; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE2; Angiotensin-(1–7); Insulin resistance; Mas; Renin-angiotensin system