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PMID: 11533494 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.

Science (New York, N.Y.) ·Vol. 293 ·No. 5535 ·2001-08-31 ·Pages 1673-7

Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE

Abstract

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB 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 Lep(ob/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.

MeSH Terms

Animals Anti-Inflammatory Agents, Non-Steroidal/pharmacology Aspirin/administration & dosage,pharmacology Blood Glucose/metabolism Cell Line Dietary Fats/administration & dosage Gene Deletion Gene Targeting Glucose Tolerance Test I-kappa B Kinase Insulin/administration & dosage,blood,metabolism,pharmacology Insulin Resistance Lipids/blood Liver/metabolism Male Mice Mice, Obese Muscles/metabolism Obesity/metabolism,physiopathology Phosphorylation Prostaglandin-Endoperoxide Synthases/genetics,metabolism Protein Serine-Threonine Kinases/antagonists & inhibitors,genetics,metabolism Rats Rats, Zucker Receptor, Insulin/metabolism Signal Transduction Sodium Salicylate/administration & dosage,pharmacology Tumor Necrosis Factor-alpha/pharmacology

Chemicals

Anti-Inflammatory Agents, Non-Steroidal Blood Glucose Dietary Fats Insulin Lipids Tumor Necrosis Factor-alpha Prostaglandin-Endoperoxide Synthases Receptor, Insulin Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse Aspirin Sodium Salicylate

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Yuan M

Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

Konstantopoulos N

Lee J

Hansen L

Li Z W

Karin M

Shoelson S E

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

0036-8075

DOI

10.1126/science.1061620

Published

2001-08-31

Pages

1673-7

Language

English

Region

United States

NLM ID

0404511

Subset

Grants

NIAID NIH HHS · AI43477 · United States

NIDDK NIH HHS · DK45493 · United States

NIDDK NIH HHS · DK51729 · United States

Corrections

ErratumIn

External Links

PubMed source DOI: 10.1126/science.1061620 View journal details

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Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.

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