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Aims/hypothesis. There is increasing evidence that hyperinsulinaemia is linked with the development of atherosclerosis in patients with diabetes. However, the mechanisms by which hyperinsulinaemia causes accelerated atherosclerosis, especially with respect to leukocytes transendothelial migration, are poorly understood. We examined whether hyperinsulinaemia directly affects neutrophil transendothelial migration and surface expression of related endothelial adhesion molecules. Methods. Experiments on the transmigration of neutrophils from healthy volunteers and from patients with Type II (non-insulin-dependent) diabetes mellitus across human umbilical vein endothelial cells cultured in insulin-rich medium using cell-culture inserts were carried out. Migrated neutrophils were quantified by measuring their myeloperoxidase activities, and the surface expression of endothelial adhesion molecules was examined using an enzyme immunoassay. Results. High insulin (over 50 µU/ml for 24 h) enhanced neutrophil transendothelial migration in a dose-dependent manner. This was associated with increased expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) but not of intercellular adhesion molecule-1 (ICAM-1), P-selectin or E-selectin. Both phenomena were attenuated by pretreatment with a tyrosine kinase inhibitor, especially a mitogenactivated protein kinase inhibitor, but not by inhibitors of other second messengers. In addition, a mitogenactivated protein kinase activator, anisomycin, by itself enhanced both neutrophil transendothelial migration and PECAM-1 expression within 3 h in a dosedependent manner. Pretreatment with nitric oxide synthase inhibitors had no effect on these events. Conclusion/interpretation. These results suggest that hyperinsulinaemia could accelerate atherosclerosis by directly enhancing neutrophil transendothelial migration through increasing endothelial PECAM-1 expression via mitogen-activated protein kinase activation.

A sandwich enzyme immunoassay (ELISA) system for mouse epidermal growth factor (EGF), which has a high sensitivity (500 fg/tube), has been established. It makes it possible to measure minute amounts of immunoreactive EGF in various mouse tissue without pretreatment. The immunoreactive EGF concentrations in digestive tissues of adult mice were much lower than previously reported. A significant sex difference was detected not only in the submandibular gland, but also in the oesophagus and forestomach. Although sialoadenectomy decreased the immunoreactive EGF contents in the alimentary tract to 4.2\p=n-\23.8% of the pre-operative levels, the duodenal immunoreactive EGF was unaffected. Positive immunostaining was observed in the submandibular and sublingual gland, but not in the other digestive tissues, including the duodenum. These data implied that most of the EGF in the digestive tissues was derived mainly from the saliva and that a small amount of endogenous EGF existed in the duodenum. The physiological role of exogenous salivary EGF in the alimentary tract and the origin of endogenous duodenal EGF are discussed.