To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. In addition, we demonstrated that the expressions of p85α and p55α regulatory subunits of PI 3-kinase were reduced (p85α, 67%; p55α, 54%), and that the p50α regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110α and p110β. These alterations may reflect the obesity-related insulin resistance commonly observed in human NIDDM.
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Metabolism and Signal Transduction|
January 01 1998
Altered Expression Levels and Impaired Steps in the Pathway to Phosphatidylinositol 3-Kinase Activation via Insulin Receptor Substrates 1 and 2 in Zucker Fatty Rats
Motonobu Anai;
Motonobu Anai
Institute for Adult Diseases, Yamaguchi University School of Medicine, Asahi Life Foundation
Tokyo
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Makoto Funaki;
Makoto Funaki
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Takehide Ogihara;
Takehide Ogihara
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Jungo Terasaki;
Jungo Terasaki
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Kouichi Inukai;
Kouichi Inukai
Institute for Adult Diseases, Yamaguchi University School of Medicine, Asahi Life Foundation
Tokyo
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Hideki Katagiri;
Hideki Katagiri
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Yasushi Fukushima;
Yasushi Fukushima
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Yoshio Yazaki;
Yoshio Yazaki
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Masatoshi Kikuchi;
Masatoshi Kikuchi
Institute for Adult Diseases, Yamaguchi University School of Medicine, Asahi Life Foundation
Tokyo
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Yoshitomo Oka;
Yoshitomo Oka
Department of Internal Medicine , Yamaguchi University School of Medicine
Yamaguchi, Japan
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Tomoichiro Asano
Tomoichiro Asano
Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo
Tokyo
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Address correspondence and reprint requests to Dr. Tomoichiro Asano, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113, Japan. E-mail: [email protected]
Diabetes 1998;47(1):13–23
Article history
Received:
February 21 1997
Revision Received:
September 11 1997
Accepted:
September 11 1997
PubMed:
9421369
Citation
Motonobu Anai, Makoto Funaki, Takehide Ogihara, Jungo Terasaki, Kouichi Inukai, Hideki Katagiri, Yasushi Fukushima, Yoshio Yazaki, Masatoshi Kikuchi, Yoshitomo Oka, Tomoichiro Asano; Altered Expression Levels and Impaired Steps in the Pathway to Phosphatidylinositol 3-Kinase Activation via Insulin Receptor Substrates 1 and 2 in Zucker Fatty Rats. Diabetes 1 January 1998; 47 (1): 13–23. https://doi.org/10.2337/diab.47.1.13
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