The present study investigates the role of hyperglycemia on leukocyte recruitment and function in an acute model of inflammation, in addition to a clinically relevant model of bacterial infection. To exclude the possibility that the observed increased leukocyte recruitment in diabetic mice was caused by change of the total number and/or proportion of immune cells in the alloxan-treated hyperglycemic model, total white blood cells and a differential count was performed. To exclude that the impaired bacterial clearance observed in diabetic mice was not due to decreased leukocyte recruitment at later time points, the cremaster muscle of mice hyperglycemic for 8 days was superfused with MIP-2. The present study investigates a common complication to diabetes, impaired bacterial clearance, using in vivo models of longitudinal visualization of subcutaneous infection, leukocyte recruitment in single venules and leukocyte phagocytic ability. Increased leukocyte recruitment was observed during basal conditions as well as during acute inflammation in mice with alloxan- or diet-induced diabetes, i.e. animals with severe or moderate hyperglycemia. To understand how this correlates to difficulties in clearing bacterial infections, alloxan-induced diabetic mice were challenged by Staphylococcus aureus. Interestingly, despite increased numbers of recruited leukocytes, diabetic mice remained infected for a longer time period compared to control mice, which correlated to a 50% decreased phagocytic ability of diabetic leukocytes. Type 1 and type 2 diabetes are both associated with altered immune responses to bacterial infections. This is believed to be caused in part by impaired peripheral blood circulation which develops with time of fluctuating and uncontrolled plasma glucose levels. The effect of hyperglycemia per se on leukocyte recruitment to inflamed muscle was in the present study investigated by intravital microscopy of single venules. We found that during basal conditions prior to addition of chemokines, an increased number of leukocytes were recruited into muscle in long-term but not acutely hyperglycemic mice. This might reflect that prolonged hyperglycemia induces expression of adhesion molecules on muscle venular endothelium and/or circulating leukocytes. Still more leukocytes were recruited during inflammation in the alloxan-induced, type 1 diabetes model, and a similar trend was seen also in the type 2 diabetes model. However, no effects were seen after an acutely induced hyperglycemia. Thus, our results show that hyperglycemic mice with time develop a more activated immune system during both non-inflammatory as well as inflammatory conditions. These effects correlate with LDK378 levels of hyperglycemia, as they were more profound in the model of severe hyperglycemia even though the absence of anti-inflammatory insulin in the alloxan-treated model might contribute to this observation.