Prevention of fat-induced insulin resistance by salicylate

J Clin Invest. 2001 Aug;108(3):437-46. doi: 10.1172/JCI11559.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / prevention & control
  • Dietary Fats / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Glucose / metabolism
  • Glucose Clamp Technique
  • I-kappa B Kinase
  • Infusions, Intravenous
  • Insulin Resistance*
  • Lipids / administration & dosage
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Salicylic Acid / administration & dosage
  • Salicylic Acid / pharmacology*
  • Signal Transduction / drug effects

Substances

  • Dietary Fats
  • Enzyme Inhibitors
  • Lipids
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Glucose
  • Salicylic Acid