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 journalArticle

214 Citations (Scopus)

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
StatePublished - 1993
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Insulin Receptor Substrate Proteins
Diabetes Mellitus
Animal Models
Insulin
Muscles
Liver
Phosphorylation
Streptozocin
Tyrosine

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Regulation of Phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. / Folli, Franco; Saad, Mario J A; Backer, Jonathan M.; Ronald Kahn, C.

In: Journal of Clinical Investigation, Vol. 92, No. 4, 1993, p. 1787-1794.

Research output: Contribution to journalArticle

@article{be049e80340544a085e62810a32e63ae,
title = "Regulation of Phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus",
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.",
keywords = "Diabetes, Insulin receptor kinase, Insulin receptor substrate, Insulin resistance, Phosphatidylinositol 3-kinase",
author = "Franco Folli and Saad, {Mario J A} and Backer, {Jonathan M.} and {Ronald Kahn}, C.",
year = "1993",
language = "English (US)",
volume = "92",
pages = "1787--1794",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - Regulation of Phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus

AU - Folli, Franco

AU - Saad, Mario J A

AU - Backer, Jonathan M.

AU - Ronald Kahn, C.

PY - 1993

Y1 - 1993

N2 - 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.

AB - 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.

KW - Diabetes

KW - Insulin receptor kinase

KW - Insulin receptor substrate

KW - Insulin resistance

KW - Phosphatidylinositol 3-kinase

UR - http://www.scopus.com/inward/record.url?scp=0027484001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027484001&partnerID=8YFLogxK

M3 - Article

VL - 92

SP - 1787

EP - 1794

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -