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.
Johansson
G S
GS
Linköping University, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping, Sweden. git.johansson@ibk.liu.se
Chisalita
S I
SI
Arnqvist
H J
HJ
D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics* / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D020033:Protein Isoforms; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin