Cited by 738Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and Lipoproteins

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Prevention of fat-induced insulin resistance by salicylate

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Kim, Jason K., Kim, Yoon-Jung, Fillmore, Jonathan J., Chen, Yan, Moore, Irene, Lee, Jongsoon, Yuan, Minsheng, Li, Zhi Wei, Karin, Michael, Perret, Pascale, Shoelson, Steven E., Shulman, Gerald I.·2001·Journal of Clinical Investigation

DOI 10.1172/jci11559PMC PMC209353

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Abstract

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-(3)H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-(14)C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.

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Authors: Kim, J. K., Kim, Y.-J., Fillmore, J. J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z. W., Karin, M., Perret, P., Shoelson, S. E., & Shulman, G. I.
Affiliations: Howard Hughes Medical Institute (US)
Yale University (US)
Joslin Diabetes Center (US)
University of California San Diego (US)
Harvard University (US)
Corresponding author: Shulman, Gerald I.
ORCID: Kim, Jason K.
Lee, Jongsoon
Li, Zhi Wei
Karin, Michael
Perret, Pascale
Shoelson, Steven E.
Shulman, Gerald I.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2001-08-01
Volume: 108
Issue: 3
Pages: 437-446
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci11559
PMC: PMC209353
OpenAlex: W2097838137
Cited by: 737
References: 55
Citations by year: 2026: 3 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 11 · 2021: 11 · 2020: 12 · 2019: 15 · 2018: 26 · 2017: 23 · 2016: 29 · 2015: 23 · 2014: 26 · 2013: 30 · 2012: 52
FWCI: 14.68
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
U.S. Public Health Service (P30 DK45735, R01 DK-40936)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, P30DK045735, DK 51729, U24DK059635, U24DK59635, R01 DK-45493, R01 DK051729, R01DK040936, R01 DK-59635)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: insulin resistance, salicylates, IKKβ, type 2 diabetes, lipid infusion, skeletal muscle glucose uptake, IRS-1, PI3-kinase, insulin signaling, hyperinsulinemic-euglycemic clamp
MeSH terms: Animals, Diabetes Mellitus, Type 2, Dietary Fats, Enzyme Inhibitors, Glucose, Infusions, Intravenous, Insulin Resistance, Lipids, Male, Glucose Clamp Technique, Signal Transduction, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Salicylic Acid, Rats, I-kappa B Kinase

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Prevention of fat-induced insulin resistance by salicylate

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