, Volume 47, Issue 3, pp 532-536
Date: 05 Feb 2004

Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase



Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mechanisms are poorly understood. We tested the hypothesis that insulin increases monocyte-endothelial interactions, which are implicated in atherosclerosis.


We treated human umbilical vein endothelial cells with insulin (10−10 to 10−7 mol/l) for 0 to 24 h. To dissect potentially implicated signal transduction pathways, we treated endothelial cells with known pharmacological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3′-kinase (PI3′-kinase) inhibitor wortmannin (3×10−8 to 10−6 mol/l), involved in insulin-induced endothelial nitric oxide synthase stimulation, and the p38 mitogen-activated protein (p38MAP) kinase inhibitor SB-203580 (10−7 to 2×10−6 mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays.


At pathophysiological concentrations (10−9 to 10−7 mol/l), insulin concentration-dependently induced vascular cell adhesion molecule (VCAM)-1 (average increase: 1.8-fold) peaking at 16 h. By contrast, the expression of intercellular adhesion molecule-1 and E-selectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the absence of cytotoxicity, wortmannin significantly potentiated the effect of insulin alone on VCAM-1 surface expression and monocytoid cell adhesion, whereas SB-203580 (10−6 mol/l) completely abolished such effects.


These observations indicate that insulin promotes VCAM-1 expression in endothelial cells through a p38MAP-kinase pathway, amplified by the PI3′-kinase blockage. This could contribute to explaining the increased atherosclerosis occurring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3′-kinase pathway.