['Platelet hyperreactivity contributes to adverse vascular events in diabetes mellitus. It is unclear whether platelet hyperreactivity is due to impaired insulin effects directly on platelets and /or originates from endothelial cells. Here, acute effects of insulin on platelet activation and platelet-endothelial cell interactions were analyzed.', 'Washed human platelets were treated with insulin alone or in combinations with thrombin, collagen and ADP. Insulin signaling was analyzed by intracellular phosphorylation markers of platelet activation (ERK, p38 MAPK, PKB) or inhibition (VASP), platelet aggregation, intracellular Ca(2+) levels, and platelet adhesion to collagen coated surfaces and endothelial cells under flow. Insulin up to 100 nm for 5 min did not change phosphorylation status of VASP, p38, ERK or PKB in platelets. Integrin alpha(IIb)beta(3) activation, P-selectin expression, aggregation, and platelet adhesion to collagen coated surfaces and endothelial cells under flow were not altered by insulin. An insulin receptor was detected on endothelial cells but not on human platelets. Insulin treatment decreased platelet adhesion to endothelial cells through insulin stimulation of endothelial NO production and NOS inhibition interfered with this process.'] Is insulin inhibition of platelet-endothelial interaction mediated by insulin effects on endothelial cells without direct effects on platelets?