Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level

Mol Cell Endocrinol. 2008 Dec 16;296(1-2):58-63. doi: 10.1016/j.mce.2008.07.012. Epub 2008 Jul 30.

Abstract

Human microvascular endothelial cells (HMVEC) are sensitive to IGF-I but insulin resistant and express several times more IGF-I receptors (IGF-IR) than insulin receptors (IR). Our aim was to investigate the mechanism of this insulin resistance in cultured HMVEC by studying receptor activation and signal propagation downstream. The IGF-IR beta-subunit and the IR beta-subunit were detected and found to co-precipitate. IRA was the major IR isoform expressed in HMVEC. IGF-I 10(-9) to 10(-8)M phosphorylated its cognate receptor beta-subunit. IGF-I also phosphorylated the IR beta-subunit at 10(-9)M. Phosphorylation of insulin receptor substrate 1 was obtained by IGF-I 10(-9) to 10(-8)M. Akt was phosphorylated by IGF-I at 10(-8) to 10(-7)M and by insulin 10(-7)M. IGF-I at 10(-8) to 10(-6)M significantly increased DNA-synthesis. We conclude that microvascular endothelial cells are sensitive to IGF-I but resistant to insulin due to a preponderance of IGF-I receptors and sequestration of insulin receptors into insulin/IGF-I hybrid receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Drug Resistance / genetics*
  • Drug Resistance / physiology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology*
  • Microcirculation / drug effects
  • Phosphorylation
  • Protein Binding
  • Protein Isoforms / metabolism
  • Protein Kinases / metabolism
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism

Substances

  • Insulin
  • Protein Isoforms
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Protein Kinases
  • Receptor, IGF Type 1
  • Receptor, Insulin