Atherothrombotic diseases are the main cause of mortality in long-term diabetes mellitus. Diabetic vessels are characterized by both a pro-oxidant and a pro-inflammatory status. Hyperglycemia is acknowledged as a main risk factor for developing diabetes-associated vasculopathy. We investigated whether high concentrations of D-glucose can directly trigger pro-inflammatory mechanisms in human vascular cells. In cultured human aortic smooth muscle cells (HASMC), increasing extracellular D-glucose from 5.5 to 22 mM had no effect on inducible nitric oxide synthase (iNOS) levels or extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor (NF)-kappaB activities, as determined by Western blotting and transient tranfection, respectively. However, high D-glucose (22 mM) increased iNOS expression, as well as both ERK 1/2 and (NF)-kappaB activation, triggered by the pro-inflammatory cytokine interleukin (IL)- 1beta (10 ng/ml). Furthermore, in human umbilical vein endothelial cells (HUVEC), high D-glucose enhanced the expression of the adhesion molecules ICAM-1 and VCAM-1 elicited by IL-1beta, as measured by flow cytometry. High D-glucose also potentiated the IL-1beta-induced adhesion of leukocytes to the endothelium, both in vivo and in vitro, as determined using flow chamber assays or intra-vital microscopy in non-diabetic Sprague-Dawley rats, respectively. High D-glucose alone failed to modify the endotelial expression of cell adhesion molecules or leukocyte-endothelium interactions. Therefore, D-glucose at high concentrations exacerbates the pro-inflammatory effects of IL-1beta. We suggest that the observed association between inflammation and diabetes is the result of elevated D-glucose enhancing a pre-existing inflammatory condition, rather than a direct effect of D-glucose on the production of inflammatory mediators.