High insulin exacerbates neutrophil-endothelial cell adhesion through endothelial surface expression of intercellular adhesion molecule-1 via activation of protein kinase C and mitogen-activated protein kinase.
OBJECTIVE
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
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.
Okouchi
M
M
First Department of Internal Medicine, Nagoya City University Medical School, Nagoya Japan. okochi@med.nagoya-cu.ac.jp
Okayama
N
N
Shimizu
M
M
Omi
H
H
Fukutomi
T
T
Itoh
M
M
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014471:Umbilical Veins
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007328:Insulin; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one