Background. Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. Methods. Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). Results. 51 subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p = 0.004 and p = 0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p < 0.001) and HbA1c (rho 0.433, p = 0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p = 0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p = 0.022) and HbA1c (rho 0.319, p = 0.023). Conclusions. These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions. (C)) 2015 Elsevier Inc. All rights reserved.