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Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

¹ Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, Victoria, Australia
² St. Vincent’s Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria, Australia
³ Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies, Parkville, Victoria, Australia
⁴ Molecular Endocrinology Laboratory, Baker Heart Research Institute, Melbourne, Australia
⁵ Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
⁶ The Centre for Inflammation and Metabolism, Department of Infectious Diseases and The Copenhagen Muscle Research Centre, Rigshospitalet University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark

Address correspondence and reprint requests to Mark A. Febbraio, PhD, Baker Heart Research Institute, P.O. Box 6492 St. Kilda Rd., Central Vic 8008, Australia. E-mail: mark.febbraio{at}baker.edu.au

Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; DG, deoxyglucose; EGP, endogenous glucose production; FFA, free fatty acid; GIR, glucose infusion rate; IL-6, interleukin-6; IRS, insulin receptor substrate; PI3-K, phosphatidylinositol 3-kinase; rhIL-6, recombinant human IL-6; rmIL-6, recombinant mouse IL-6; SOCS, suppressor of cytokine signaling; TNF-, tumor necrosis factor-

Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK -subunit. The effects described above were abrogated in AMPK dominant-negative–infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK.

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