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

• DOI: 10.2337/db05-1404
• Publication Date: 2006-09-26T19:57:52Z
• Authors: Andrew L. Carey; Gregory R. Steinberg; S. Lance Macaulay; Walter G. Thomas; Anna G. Holmes; Georg Ramm; Oja Prelovsek; Cordula Hohnen-Be...; Matthew J. Watt; David E. James; Bruce E. Kemp; Bente K. Pedersen; Mark A. Febbraio
• Keywords: Adult; Male; 0301 basic medicine; 571; 060110 Receptors and Membrane Biology; 110903 Central Nervous System; AMP-Activated Protein Kinases; 060199 Biochemistry and Cell Biology not elsewhere classified; Cell Line; Myoblasts; Endocrinology & Metabolism; Mice; 03 medical and health sciences; Multienzyme Complexes; 3T3-L1 Cells; Hyperinsulinism; Animals; Humans; Insulin; 110201 Cardiology (incl. Cardiovascular Diseases); 060108 Protein Trafficking; Mice, Knockout; Glucose Transporter Type 4; Interleukin-6; Cell Membrane; Fatty Acids; Aminoimidazole Carboxamide; 060111 Signal Transduction; Glucose; Glucose Clamp Technique; 060602 Animal Physiology - Cell

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 α-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.