Affiliation:
1. Institute for Adult Diseases, Yamaguchi University School of Medicine, Asahi Life Foundation Tokyo
2. Department of Internal Medicine, Yamaguchi University School of Medicine, Faculty of Medicine, University of Tokyo Tokyo
3. Department of Internal Medicine , Yamaguchi University School of Medicine Yamaguchi, Japan
Abstract
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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
88 articles.
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