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Endocrinology. 2009 Aug;150(8):3475-82. doi: 10.1210/en.2009-0172. Epub 2009 May 7.

Insulin and insulin-like growth factor-I receptors differentially mediate insulin-stimulated adhesion molecule production by endothelial cells.

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Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908-1410, USA.


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.

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