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

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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.