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, Makoto Funaki, Takehide Ogihara, Jungo Terasaki, Kouichi Inukai, Hideki Katagiri, Yasushi Fukushima, Yoshio Yazaki, Masatoshi Kikuchi, Yoshitomo Oka, Tomoichiro Asano

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170 Citations (Scopus)

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 1 and 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.

Original languageEnglish
Pages (from-to)13-23
Number of pages11
JournalDiabetes
Volume47
Issue number1
DOIs
Publication statusPublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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