Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 10; pp. 2939 - 2945
• Main Authors: Plomgaard, Peter, Bouzakri, Karim, Krogh-Madsen, Rikke, Mittendorfer, Bettina, Zierath, Juleen R., Pedersen, Bente K.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2005
• Subjects: Adult; Biological and medical sciences; Care and treatment; Deuterium; Diabetes. Impaired glucose tolerance; Drug Resistance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucose - biosynthesis; Glucose - metabolism; Glucose Clamp Technique; GTPase-Activating Proteins - metabolism; Health aspects; Humans; Insulin - blood; Insulin - pharmacology; Insulin resistance; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Muscle, Skeletal - drug effects; Obesity; Phosphorylation; Placebos; Recombinant Proteins; Risk factors; Signal Transduction - drug effects; Striated muscle. Tendons; Tumor necrosis factor; Tumor Necrosis Factor-alpha - analysis; Tumor Necrosis Factor-alpha - pharmacology; Vertebrates: osteoarticular system, musculoskeletal system; United Kingdom; Endocrinopathy; Human; Phosphorylation; Diabetes mellitus; Cytokine; Insulin resistance; Inhibition; Striated muscle; Tumor necrosis factor α
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.10.2939

Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation Peter Plomgaard 1 , Karim Bouzakri 2 , Rikke Krogh-Madsen 1 , Bettina Mittendorfer 3 , Juleen R. Zierath 2 and Bente K. Pedersen 1 1 Department of Infectious Diseases and the Copenhagen Muscle Research Centre, The Centre of Inflammation and Metabolism, Rigshospitalet University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark 2 Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden 3 Washington University, School of Medicine, St. Louis, Missouri Address correspondence and reprint requests to Bente Klarlund Pedersen, Rigshopitalet 7641, Blegdamsvej 9, DK-2200 Copenhagen N, Denmark. E-mail: bkp{at}rh.dk . Correspondencereprint requests may also be sent to Juleen R. Zierath, Karolinska Institutet, Department of Surgical Sciences, Section of Integrative Physiology, von Eulers väg 4, 4th floor S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}fyfa.ki.se Abstract Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-α (TNF-α) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-α infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-α directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-α infusion increases phosphorylation of p70 S6 kinase, extracellular signal–regulated kinase-1/2, and c-Jun NH 2 -terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-α negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome. AS160, Akt substrate 160 ERK, extracellular signal–regulated kinase IL, interleukin IRS, insulin receptor substrate JNK, c-Jun NH2-terminal kinase S6K, p70 S6 kinase TNF-α, tumor necrosis factor-α Footnotes P.P. and K.B. contributed equally to this work. Accepted June 23, 2005. Received April 5, 2005. DIABETES