Insulin and insulin-like growth factor-I receptors differentially mediate insulin-stimulated adhesion molecule production by endothelial cells.
Patients with type 2 diabetes are hyperinsulinemic and insulin resistant and develop premature atherosclerosis. High concentrations of insulin stimulate the production of adhesion molecules by endothelial cells (ECs). ECs express abundant IGF-I receptors as well as insulin receptors. Whether IGF-I receptors contribute to insulin-induced endothelial production of adhesion molecules is unknown. Bovine aortic ECs (BAECs) were incubated with insulin (100 nm) for 24 h. The cellular content of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was measured, and monocyte adhesion to ECs was quantified. Insulin increased both VCAM-1 (P < 0.001) and ICAM-1 (P < 0.0002) content, which was accompanied by an increased number of monocytes adherent to BAECs (P = 0.0001). Inhibition of either MAPK kinase-1 or p38 MAPK but not phosphatidylinositol 3-kinase abolished insulin-mediated production of adhesion molecules. Insulin receptor small interfering RNA knockdown abolished insulin-stimulated increases of ICAM-1 but not VCAM-1. Conversely, IGF-I receptor blockade with either a neutralizing antibody or specific small interfering RNA eliminated insulin-induced VCAM-1 but not ICAM-1 production. Blockade of signaling via either the insulin or IGF-I receptors decreased monocyte adherence to BAECs (P < 0.01 for each). We conclude that insulin and IGF-I receptors differentially mediate the production of adhesion molecules by ECs and monocyte adhesion onto the vascular endothelium in response to the hyperinsulinemic state. Dual-receptor activation may most effectively contribute to the pathogenesis of atherosclerotic disease in diabetes.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908-1410, USA.
Guolian
G
Li
Eugene J
EJ
Barrett
Seung-Hyun
SH
Ko
Wenhong
W
Cao
Zhenqi
Z
Liu
D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D007004:Hypoglycemic Agents; D007328:Insulin; D018799:Intercellular Adhesion Molecule-1; D048369:MAP Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019010:Vascular Cell Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases