Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors

J Clin Invest. 1997 May 15;99(10):2538-44. doi: 10.1172/JCI119438.


We have investigated the metabolic actions of recombinant human IGF-1 in mice genetically deficient of insulin receptors (IR-/-). After intraperitoneal administration, IGF-1 caused a prompt and sustained decrease of plasma glucose levels in IR-/- mice. Plasma free fatty acid concentrations were unaffected. Interestingly, the effects of IGF-1 were identical in normal mice (IR+/+) and in IR-/- mice. Despite decreased glucose levels, IR-/- mice treated with IGF-1 died within 2-3 d of birth, like sham-treated IR-/- controls. In skeletal muscle, IGF-1 treatment caused phosphorylation of IGF-1 receptors and increased the levels of the phosphatidylinositol-3-kinase p85 subunit detected in antiphosphotyrosine immunoprecipitates, consistent with the possibility that IGF-1 stimulates glucose uptake in a phosphatidylinositol-3-kinase-dependent manner. IGF-1 receptor phosphorylation and coimmunoprecipitation of phosphatidylinositol3-kinase by antiphosphotyrosine antibodies was also observed in liver, and was associated with a decrease in mRNA levels of the key gluconeogenetic enzyme phosphoenolpyruvate carboxykinase. Thus, the effect of IGF-1 on plasma glucose levels may be accounted for by increased peripheral glucose use and by inhibition of hepatic gluconeogenesis. These data indicate that IGF-1 can mimic insulin's effects on glucose metabolism by acting through its own receptor. The failure of IGF-1 to rescue the lethal phenotype due to lack of insulin receptors suggests that IGF-1 receptors cannot effectively mediate all the metabolic actions of insulin receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Cell Transformation, Viral
  • Cells, Cultured
  • Exons
  • Fatty Acids, Nonesterified / blood
  • Heterozygote
  • Humans
  • Hypoglycemia / chemically induced*
  • Injections, Intraperitoneal
  • Insulin-Like Growth Factor I / administration & dosage
  • Insulin-Like Growth Factor I / pharmacology*
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Phosphorylation
  • Polymerase Chain Reaction
  • Receptor, IGF Type 1 / biosynthesis
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / biosynthesis
  • Receptor, Insulin / deficiency*
  • Receptor, Insulin / genetics
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Simian virus 40


  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Recombinant Proteins
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin