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 β-subunit and the IR β-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 β-subunit. IGF-I also phosphorylated the IR β-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.