Regulation of Phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus

Franco Folli, Mario J.A. Saad, Jonathan M. Backer, C. Ronald Kahn

Research output: Contribution to journalArticlepeer-review

215 Scopus citations

Abstract

Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). In the present study, we have examined these processes in animal models of insulin-resistant and insulin-deficient diabetes mellitus. After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob / ob mouse. There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. Insulin-stimulated total PI 3-kinase activity was also absent in both tissues of the ob / ob mouse. By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resis tant diabetic states, such as that seen in the ob / ob mouse.

Original languageEnglish (US)
Pages (from-to)1787-1794
Number of pages8
JournalJournal of Clinical Investigation
Volume92
Issue number4
DOIs
StatePublished - 1993

Keywords

  • Diabetes
  • Insulin receptor kinase
  • Insulin receptor substrate
  • Insulin resistance
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Medicine(all)

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