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

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 +4 more·2001·Journal of Clinical Investigation

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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  • There is substantial local production of inflammatory mediators in organs affected by insulin resistance.

    “As described above, there is substantial local production of inflammatory mediators in organs affected by insulin resistance.”
  • Reduced secretion of pro-inflammatory mediators from adipocytes or adipose tissue macrophages likely contributes to the effect of weight loss.

    “On the other hand, it seems likely that reduced secretion of pro-inflammatory mediators from adipocytes or activated macrophages of adipose tissue contributes to the effect of weight loss (31,36,65,67,142) .”
  • Salicylates protected against insulin resistance in rodents after acute lipid infusion.

    “Moreover, the insulin resistance was ameliorated with salicylates, which also protected against insulin resistance in rodents after acute lipid infusion,127 and reversed insulin resistance in people with type 2 diabetes mellitus.128”

    From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [127]

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  1. 10.1210/en.141.6.1930 · DOI

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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.
Venue
Journal of Clinical Investigation
Published
2001-08-01
Volume
108
Issue
3
Pages
437-446
ISSN
0021-9738 (ISSN-L)
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
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 › Epidemiology › 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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