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

Diabetologia. 2004 Mar;47(3):532-536. doi: 10.1007/s00125-004-1330-x. Epub 2004 Feb 5.


Aims/hypothesis: 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.

Methods: 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 x 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 x 10(-6) mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays.

Results: 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.

Conclusions/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Arteriosclerosis
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Imidazoles / pharmacology
  • Insulin / pharmacology*
  • Intercellular Adhesion Molecule-1 / genetics*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines / pharmacology
  • Signal Transduction
  • Umbilical Veins
  • Wortmannin
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Androstadienes
  • Enzyme Inhibitors
  • Imidazoles
  • Insulin
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Intercellular Adhesion Molecule-1
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • Wortmannin