title: Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase.
abstract: 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 alpha-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.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Australia.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Carey
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.forename: S Lance
authors.initials: SL
authors.lastname: Macaulay
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.forename: Anna G
authors.initials: AG
authors.lastname: Holmes
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.forename: Oja
authors.initials: O
authors.lastname: Prelovsek
authors.forename: Cordula
authors.initials: C
authors.lastname: Hohnen-Behrens
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D032446:Myoblasts; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; D015850:Interleukin-6; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D012265:Ribonucleotides; D050796:STAT3 Transcription Factor; C495694:Slc2a4 protein, rat; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose