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The risk of cardiovascular diseases in diabetic patients and even in those with IGT are associated with insulin resistance, two-to threefold higher than that in control subjects [1]. The United Kingdom Prospective Diabetes Study (UKPDS) and other similar studies indicated that intensive control of blood glucose in diabetic patients prevents and slows the progression of microvascular complications, but has little effect on the prevention of macrovascular complications i. e. acute myocardial infarction (AMI) [2]. Excessive macrovascular diseases in diabetes have thus been considered to be due to insulin resistance and/or hyperinsulinaemia.A recent study has shown that vascular inflammation with atherosclerosis is responsible for the onset of AMI [3]. Adhesion of leukocytes to the endothelium, which is regulated by several endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin, is the first and crucial step in both atherosclerosis and vascular inflammation. Whereas endothelial dysfunction induced by insulin resistance and/or hyperinsulin- AbstractAims/hypothesis. The association of insulin resistance and compensatory hyperinsulinaemia with increased coronary events in diabetic patients is poorly understood. There are few publications about the direct atherogenic actions of insulin on the endothelium compared with those on vascular smooth muscle cells. The aim of this study was to elucidate whether high insulin directly affects neutrophil-endothelial cell adhesion and surface expression of endothelial adhesion molecules. We also examined what intracellular mechanisms are involved in these events. Methods. Studies of adhesion between neutrophils from healthy volunteers and human umbilical vein endothelial cells incubated in insulin-rich medium were carried out. Adhered neutrophils were quantified by measuring their myeloperoxidase activities and surface expression of endothelial adhesion molecules was examined using an enzyme immunoassay. Results. High insulin enhanced neutrophil-endothelial cell adhesion with an increase in the expression of intercellular adhesion molecule-1 but not E-selectin or P-selectin. Both phenomena were attenuated by pretreatment with protein kinase C inhibitors and a mitogen activated protein kinase inhibitor. Conclusions/interpretation. These results suggest that hyperinsulinaemia causes vascular injury by directly exacerbating neutrophil-endothelial cell adhesion through increasing endothelial expression of intercellular adhesion molecule-1 via activation of protein kinase and mitogen activated protein kinase pathways. [Diabetologia (2002) 45:556±559]

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