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Science 31 August 2001:
Vol. 293. no. 5535, pp. 1673 - 1677
DOI: 10.1126/science.1061620
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Reports

Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkbeta

Minsheng Yuan,1* Nicky Konstantopoulos,1* Jongsoon Lee,1* Lone Hansen,1 Zhi-Wei Li,2 Michael Karin,2 Steven E. Shoelson1dagger

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the Ikappa B kinase beta  (IKKbeta ) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta , rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta +/-) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.

1 Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
2 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Steven.Shoelson{at}Joslin.Harvard.edu

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Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy.
M. F. McCarty and K. I. Block (2006)
Integr Cancer Ther 5, 252-268
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Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1.
S.-Y. Park, Y.-R. Cho, H.-J. Kim, E.-G. Hong, T. Higashimori, S. J. Lee, I. J. Goldberg, G. I. Shulman, S. M. Najjar, and J. K. Kim (2006)
Am J Physiol Endocrinol Metab 291, E517-E524
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Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin..
B. Draznin (2006)
Diabetes 55, 2392-2397
   Abstract »    Full Text »    PDF »
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance.
G. Tuncman, J. Hirosumi, G. Solinas, L. Chang, M. Karin, and G. S. Hotamisligil (2006)
PNAS 103, 10741-10746
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Kinome Analysis Reveals Nongenomic Glucocorticoid Receptor-Dependent Inhibition of Insulin Signaling.
M. Lowenberg, J. Tuynman, M. Scheffer, A. Verhaar, L. Vermeulen, S. van Deventer, D. Hommes, and M. Peppelenbosch (2006)
Endocrinology 147, 3555-3562
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Myosin motor Myo1c and its receptor NEMO/IKK-{gamma} promote TNF-{alpha}-induced serine307 phosphorylation of IRS-1.
Y. Nakamori, M. Emoto, N. Fukuda, A. Taguchi, S. Okuya, M. Tajiri, M. Miyagishi, K. Taira, Y. Wada, and Y. Tanizawa (2006)
J. Cell Biol. 173, 665-671
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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms.
J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon (2006)
Circulation 113, 1888-1904
   Abstract »    Full Text »    PDF »
Review: Aspirin and diabetes.
R. P Raghavan, D. W Laight, K. M Shaw, and M. H Cummings (2006)
The British Journal of Diabetes & Vascular Disease 6, 74-82
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Acetylsalicylic Acid Improves Lipid-Induced Insulin Resistance in Healthy Men.
M. Mohlig, M. Freudenberg, T. Bobbert, M. Ristow, H. Rochlitz, M. O. Weickert, A. F. H. Pfeiffer, and J. Spranger (2006)
J. Clin. Endocrinol. Metab. 91, 964-967
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Reduced Skeletal Muscle Inhibitor of {kappa}B{beta} Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes: Reversal by Exercise Training.
A. Sriwijitkamol, C. Christ-Roberts, R. Berria, P. Eagan, T. Pratipanawatr, R. A. DeFronzo, L. J. Mandarino, and N. Musi (2006)
Diabetes 55, 760-767
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An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPAR{gamma}, adipogenesis, and insulin-responsive hexose transport.
X. Tang, A. Guilherme, A. Chakladar, A. M. Powelka, S. Konda, J. V. Virbasius, S. M. C. Nicoloro, J. Straubhaar, and M. P. Czech (2006)
PNAS 103, 2087-2092
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Autoamplification of Tumor Necrosis Factor-{alpha}: A Potential Mechanism for the Maintenance of Elevated Tumor Necrosis Factor-{alpha} in Male but Not Female Obese Mice.
J. G. Neels, M. Pandey, G. S. Hotamisligil, and F. Samad (2006)
Am. J. Pathol. 168, 435-444
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STEATOSIS IN CHRONIC HEPATITIS C: WHY DOES IT REALLY MATTER?.
T Asselah, L Rubbia-Brandt, P Marcellin, and F Negro (2006)
Gut 55, 123-130
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Palmitate Induces Tumor Necrosis Factor-{alpha} Expression in C2C12 Skeletal Muscle Cells by a Mechanism Involving Protein Kinase C and Nuclear Factor-{kappa}B Activation.
M. Jove, A. Planavila, R. M. Sanchez, M. Merlos, J. C. Laguna, and M. Vazquez-Carrera (2006)
Endocrinology 147, 552-561
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Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes.
F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh (2006)
Arterioscler Thromb Vasc Biol 26, 28-40
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Diet-induced obesity and acute hyperlipidemia reduce I{kappa}B{alpha} levels in rat skeletal muscle in a fiber-type dependent manner.
B. A. Bhatt, J. J. Dube, N. Dedousis, J. A. Reider, and R. M. O'Doherty (2006)
Am J Physiol Regulatory Integrative Comp Physiol 290, R233-R240
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Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non-Platelet-Mediated Effects.
W. Sun, C. Gerhardinger, Z. Dagher, T. Hoehn, and M. Lorenzi (2005)
Diabetes 54, 3418-3426
   Abstract »    Full Text »    PDF »


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