Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation
Open Access
- 1 October 2005
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 54 (10), 2939-2945
- https://doi.org/10.2337/diabetes.54.10.2939
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 NH2-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.Keywords
This publication has 46 references indexed in Scilit:
- Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser473 of AktAmerican Journal of Physiology-Endocrinology and Metabolism, 2005
- TNF-α, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissueJournal of Applied Physiology, 2005
- The anti-inflammatory effect of exerciseJournal of Applied Physiology, 2005
- Insulin Stimulation of GLUT4 Exocytosis, but Not Its Inhibition of Endocytosis, Is Dependent on RabGAP AS160Molecular Biology of the Cell, 2004
- Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivityNature, 2004
- A Method to Identify Serine Kinase SubstratesJournal of Biological Chemistry, 2002
- Effects of tumour necrosis factor-α and inhibition of protein kinase C on glucose uptake in L6 myoblastsClinical Science, 2000
- IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin ResistanceScience, 1996
- Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.JCI Insight, 1995
- Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.JCI Insight, 1994