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

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

Research output: Contribution to journalArticle

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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 κB (IκB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-κB 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 IκB, thereby suppressing NF-κB activation. Conclusions/interpretation. Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-κB activation is likely to be involved in this process.

Original languageEnglish
Pages (from-to)794-805
Number of pages12
JournalDiabetologia
Volume47
Issue number5
DOIs
Publication statusPublished - 2004 May
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Buthionine Sulfoximine
Normal Distribution
Adipocytes
Insulin Resistance
Oxidative Stress
Insulin
Microsomes
Glucose
Glutathione Synthase
Phosphorylation
Muscles
Glucose Clamp Technique
Lipid Peroxides
Cytosol
Sprague Dawley Rats
Adipose Tissue
Atherosclerosis
Hypertension

Keywords

  • Buthionine sulfoximine
  • Glutathione
  • Hyperinsulinaemic-euglycaemic clamp
  • Inhibitory κB
  • Insulin resistance
  • IRS
  • Nuclear factor-κB
  • Oxidative stress
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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

In: Diabetologia, Vol. 47, No. 5, 05.2004, p. 794-805.

Research output: Contribution to journalArticle

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 2004, 'Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase', Diabetologia, vol. 47, no. 5, pp. 794-805. https://doi.org/10.1007/s00125-004-1391-x
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. / Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. In: Diabetologia. 2004 ; Vol. 47, No. 5. pp. 794-805.
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T1 - Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase

AU - Ogihara, T.

AU - Asano, T.

AU - Katagiri, H.

AU - Sakoda, H.

AU - Anai, M.

AU - Shojima, N.

AU - Ono, H.

AU - Fujishiro, M.

AU - Kushiyama, A.

AU - Fukushima, Y.

AU - Kikuchi, M.

AU - Noguchi, N.

AU - Aburatani, H.

AU - Gotoh, Y.

AU - Komuro, I.

AU - Fujita, T.

PY - 2004/5

Y1 - 2004/5

N2 - 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 κB (IκB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-κB 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 IκB, thereby suppressing NF-κB activation. Conclusions/interpretation. Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-κB activation is likely to be involved in this process.

AB - 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 κB (IκB), one role of which is to block oxidative-stress-induced nuclear factor (NF)-κB 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 IκB, thereby suppressing NF-κB activation. Conclusions/interpretation. Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-κB activation is likely to be involved in this process.

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KW - Inhibitory κB

KW - Insulin resistance

KW - IRS

KW - Nuclear factor-κB

KW - Oxidative stress

KW - Phosphatidylinositol 3-kinase

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