OBJECTIVE: To examine whether and how improvement of glycemic control by long-term insulin therapy decreases endothelial activation as measured by serum levels of the soluble adhesion molecules sE-selectin and vascular cell adhesion molecule (VCAM-1) and whether the drug used to lower blood glucose in addition to insulin influences such a response. RESEARCH DESIGN AND METHODS: Circulating adhesion molecules were measured before and after 3 and 12 months of therapy in 81 patients with type 2 diabetes and 41 subjects without diabetes. The patients were treated with bedtime administration of NPH insulin combined with either glibenclamide (n = 19), metformin (n = 17), glibenclamide and metformin (n = 17), or morning administration of NPH insulin (n = 23). RESULTS: Before insulin therapy, serum sE-selectin level was 71% higher in the patients with type 2 diabetes (77 +/- 4 ng/ml) than in the normal subjects (45 +/- 3 ng/ml, P < 0.001), whereas levels of sVCAM-1 were comparable (420 +/- 25 vs. 400 +/- 11 ng/ml, respectively). Glycemic control in all patients improved as judged from a decrease in HbA1c from 9.7 +/- 0.2 to 7.6 +/- 0.1% (P < 0.001). sE-selectin decreased to 67 +/- 4 ng/ml by 3 months (P < 0.001 vs. 0 months) and then remained unchanged until 12 months (70 +/- 4 ng/ml P < 0.001 vs 0 months). sVCnM-1 levels at 12 months was similar to those at 0 months (416 +/- 25 ng/ml). The change in glycemic control, measured by HbA1c, but not in other parameters, was correlated with the change of sE-selectin (r = 0.41, P < 0.001) within the patients with type 2 diabetes. The decreases in sE-selectin were not different between the various treatment groups. CONCLUSIONS: We conclude that improvement in glycemic control by administration of insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the degree of improvement in glycemia. These data suggest that sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation.