Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Plomgaard, P.
Right arrow Articles by Pedersen, B. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Plomgaard, P.
Right arrow Articles by Pedersen, B. K.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Diabetes 54:2939-2945, 2005
© 2005 by the American Diabetes Association, Inc.

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

Peter Plomgaard1, Karim Bouzakri2, Rikke Krogh-Madsen1, Bettina Mittendorfer3, Juleen R. Zierath2, and Bente K. Pedersen1

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

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-{alpha} (TNF-{alpha}) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-{alpha} 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-{alpha} directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-{alpha} 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-{alpha} 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.

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

Abbreviations: 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-{alpha}, tumor necrosis factor-{alpha}


Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 DiabetesHome page
R. L. Austin, A. Rune, K. Bouzakri, J. R. Zierath, and A. Krook
siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-{kappa}B Kinase Prevents Tumor Necrosis Factor-{alpha}-Induced Insulin Resistance in Human Skeletal Muscle
Diabetes, August 1, 2008; 57(8): 2066 - 2073.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
B. K. Pedersen, T. C. A. Akerstrom, A. R. Nielsen, and C. P. Fischer
Role of myokines in exercise and metabolism
J Appl Physiol, September 1, 2007; 103(3): 1093 - 1098.
[Abstract] [Full Text] [PDF]

Home page
 AMERICAN JOURNAL OF LIFESTYLE MEDICINEHome page
B. K. Pedersen
State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation
American Journal of Lifestyle Medicine, August 1, 2007; 1(4): 289 - 298.
[Abstract] [PDF]

Home page
 Endocr. Rev.Home page
R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon
Cardiovascular Actions of Insulin
Endocr. Rev., August 1, 2007; 28(5): 463 - 491.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
B. Lindegaard, C. Frosig, A. M. W. Petersen, P. Plomgaard, S. Ditlevsen, B. Mittendorfer, G. Van Hall, J. F.P. Wojtaszewski, and B. K. Pedersen
Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy
Diabetes, August 1, 2007; 56(8): 2070 - 2077.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. J. Tesz, A. Guilherme, K. V. P. Guntur, A. C. Hubbard, X. Tang, A. Chawla, and M. P. Czech
Tumor Necrosis Factor {alpha} (TNF{alpha}) Stimulates Map4k4 Expression through TNF{alpha} Receptor 1 Signaling to c-Jun and Activating Transcription Factor 2
J. Biol. Chem., July 6, 2007; 282(27): 19302 - 19312.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
Y.-S. Kim, R. Krogh-Madsen, P. Rasmussen, P. Plomgaard, S. Ogoh, N. H. Secher, and J. J. van Lieshout
Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H467 - H473.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
K. F. Howlett, K. Sakamoto, A. Garnham, D. Cameron-Smith, and M. Hargreaves
Resistance Exercise and Insulin Regulate AS160 and Interaction With 14-3-3 in Human Skeletal Muscle
Diabetes, June 1, 2007; 56(6): 1608 - 1614.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. C. Gormsen, N. Jessen, J. Gjedsted, S. Gjedde, H. Norrelund, S. Lund, J. S. Christiansen, S. Nielsen, O. Schmitz, and N. Moller
Dose-Response Effects of Free Fatty Acids on Glucose and Lipid Metabolism during Somatostatin Blockade of Growth Hormone and Insulin in Humans
J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1834 - 1842.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Bouzakri and J. R. Zierath
MAP4K4 Gene Silencing in Human Skeletal Muscle Prevents Tumor Necrosis Factor-{alpha}-induced Insulin Resistance
J. Biol. Chem., March 16, 2007; 282(11): 7783 - 7789.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
B. K. Pedersen, M. A. Febbraio, and R. A. Mooney
Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis
J Appl Physiol, February 1, 2007; 102(2): 814 - 816.
[Full Text] [PDF]

Home page
 DiabetesHome page
I. Nieto-Vazquez, S. Fernandez-Veledo, C. de Alvaro, C. M. Rondinone, A. M. Valverde, and M. Lorenzo
Protein-Tyrosine Phosphatase 1B-Deficient Myocytes Show Increased Insulin Sensitivity and Protection Against Tumor Necrosis Factor-{alpha}-Induced Insulin Resistance
Diabetes, February 1, 2007; 56(2): 404 - 413.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
F. S.L. Thong, P. J. Bilan, and A. Klip
The Rab GTPase-Activating Protein AS160 Integrates Akt, Protein Kinase C, and AMP-Activated Protein Kinase Signals Regulating GLUT4 Traffic
Diabetes, February 1, 2007; 56(2): 414 - 423.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Jager, T. Gremeaux, M. Cormont, Y. Le Marchand-Brustel, and J.-F. Tanti
Interleukin-1{beta}-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression
Endocrinology, January 1, 2007; 148(1): 241 - 251.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
S. Lambin, R. van Bree,, I. Vergote, and J. Verhaeghe
Chronic Tumor Necrosis Factor-{alpha} Infusion in Gravid C57BL6/J Mice Accelerates Adipose Tissue Development in Female Offspring
Reproductive Sciences, December 1, 2006; 13(8): 558 - 565.
[Abstract] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
E. P Weiss, S. B Racette, D. T Villareal, L. Fontana, K. Steger-May, K. B Schechtman, S. Klein, J. O Holloszy, and and the Washington University School of Medicine C
Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial.
Am. J. Clinical Nutrition, November 1, 2006; 84(5): 1033 - 1042.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Peters
The energy request of inflammation.
Endocrinology, October 1, 2006; 147(10): 4550 - 4552.
[Full Text] [PDF]

Home page
 DiabetesHome page
A. L. Carey, G. R. Steinberg, S. L. Macaulay, W. G. Thomas, A. G. Holmes, G. Ramm, O. Prelovsek, C. Hohnen-Behrens, M. J. Watt, D. E. James, et al.
Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase.
Diabetes, October 1, 2006; 55(10): 2688 - 2697.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. A. M. den Boer, P. J. Voshol, J. P. Schroder-van der Elst, E. Korsheninnikova, D. M. Ouwens, F. Kuipers, L. M. Havekes, and J. A. Romijn
Endogenous Interleukin-10 Protects against Hepatic Steatosis but Does Not Improve Insulin Sensitivity during High-Fat Feeding in Mice
Endocrinology, October 1, 2006; 147(10): 4553 - 4558.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J. T. Treebak, S. Glund, A. Deshmukh, D. K. Klein, Y. C. Long, T. E. Jensen, S. B. Jorgensen, B. Viollet, L. Andersson, D. Neumann, et al.
AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits.
Diabetes, July 1, 2006; 55(7): 2051 - 2058.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
R. Krogh-Madsen, P. Plomgaard, K. Moller, B. Mittendorfer, and B. K. Pedersen
Influence of TNF-{alpha} and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans
Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E108 - E114.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
H. K.R. Karlsson, M. Ahlsen, J. R. Zierath, H. Wallberg-Henriksson, and H. A. Koistinen
Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients.
Diabetes, May 1, 2006; 55(5): 1283 - 1288.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.