title: Glutaredoxins concomitant with optimal ROS activate AMPK through S-glutathionylation to improve glucose metabolism in type 2 diabetes.
abstract: AMPK dysregulation contributes to the onset and development of type 2 diabetes (T2DM). AMPK is known to be activated by reactive oxygen species (ROS) and antioxidant interference. However the mechanism by which redox state mediates such contradictory result remains largely unknown. Here we used streptozotocin-high fat diet （STZ-HFD） induced-type 2 diabetic rats and cells lines (L02 and HEK 293) to explore the mechanism of redox-mediated AMPK activation. We show glutaredoxins (Grxs) concomitant with optimal ROS act as an essential mediator for AMPK activation. ROS level results in different mechanisms for AMPK activation. Under low ROS microenvironment, Grxs-mediated S-glutathionylation on AMPK-α catalytic subunit activates AMPK to improve glucose transportation and degradation while inhibiting glycogen synthesis and keeping redox balance. While, under high ROS microenvironment, AMPK is activated by an AMP-dependent mechanism, however sustained high level ROS also causes loss of AMPK protein. This finding provides evidence for a new approach to diabetes treatment by individual doses of ROS or antioxidant calibrated against the actual redox level in vivo. Moreover, the novel function of Grxs in promoting glucose metabolism may provide new target for T2DM treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Kelei
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors.forename: Liang-Jun
authors.initials: LJ
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, People's Republic of China. Electronic address: dyshi@fudan.edu.cn.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Shi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D054477:Glutaredoxins / Q000235:genetics* / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: D054477:Glutaredoxins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D013311:Streptozocin; D006003:Glycogen; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat; D005947:Glucose
keywords: AMPK; Glucose metabolism; Glutaredoxins; Glutathionylation; ROS; Type 2 diabetes