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Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase.

Abstract：

AIMS/HYPOTHESIS: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/INTERPRETATION: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.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Ogihara T,Asano T,Katagiri H,Sakoda H,Anai M,Shojima N,Ono H,Fujishiro M,Kushiyama A,Fukushima Y,Kikuchi M,Noguchi N,Aburatani H,Gotoh Y,Komuro I,Fujita T

doi

10.1007/s00125-004-1391-x

subject

Has Abstract

pub_date

2004-05-01 00:00:00

pages

794-805

issue

eissn

0012-186X

issn

1432-0428

journal_volume

pub_type

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Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase.