title: Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase.
abstract: OBJECTIVE
  Oxidative stress is associated with diabetes, hypertension and atherosclerosis. Insulin resistance is implicated in the development of these disorders. We tested the hypothesis that oxidative stress induces insulin resistance in rats, and endeavoured to identify mechanisms linking the two.
  
  
  METHODS
  Buthionine sulfoximine (BSO), an inhibitor of glutathione synthase, was administered to Sprague-Dawley rats and 3T3-L1 adipocytes. Glucose metabolism and insulin signalling both in vivo and in 3T3-L1 adipocytes were examined. In 3T3-L1 adipocytes, the effects of overexpression of a dominant negative mutant of inhibitory kappa B (I kappa B), one role of which is to block oxidative-stress-induced nuclear factor (NF)-kappa B activation, were investigated.
  
  
  RESULTS
  In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress. A hyperinsulinaemic-euglycaemic clamp study and a glucose transport assay using isolated muscle and adipocytes revealed insulin resistance in BSO-treated rats. BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes. In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted. BSO-induced impairments of insulin action and insulin signalling were reversed by overexpressing the dominant negative mutant of I kappa B, thereby suppressing NF-kappa B activation.
  
  
  CONCLUSIONS
  Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-kappa B activation is likely to be involved in this process.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogihara
authors.forename: T
authors.initials: T
authors.lastname: Asano
authors.forename: H
authors.initials: H
authors.lastname: Katagiri
authors.forename: H
authors.initials: H
authors.lastname: Sakoda
authors.forename: M
authors.initials: M
authors.lastname: Anai
authors.forename: N
authors.initials: N
authors.lastname: Shojima
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: M
authors.initials: M
authors.lastname: Fujishiro
authors.forename: A
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Fukushima
authors.forename: M
authors.initials: M
authors.lastname: Kikuchi
authors.forename: N
authors.initials: N
authors.lastname: Noguchi
authors.forename: H
authors.initials: H
authors.lastname: Aburatani
authors.forename: Y
authors.initials: Y
authors.lastname: Gotoh
authors.forename: I
authors.initials: I
authors.lastname: Komuro
authors.forename: T
authors.initials: T
authors.lastname: Fujita
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000097:blood; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D016328:NF-kappa B; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose