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Vascular endothelial growth factor (VEGF) is known to be up-regulated by hypoxia, hyperglycemia, and hypoglycemia in vitro. In contrast, it has been found in healthy humans that plasma concentrations of VEGF decrease upon hypoxia under in vivo conditions, indicating that systemic VEGF concentration may be differently regulated than cellular expression. To test the effect of blood glucose levels on VEGF concentrations in vivo, we examined plasma VEGF changes upon brief hyper- and hypoglycemia in healthy male subjects. We rapidly induced in a crossover design hypoglycemia by insulin bolus application of 0.1 U/kg or hyperglycemia by dextrose infusion in 24 healthy young men. Plasma VEGF concentrations were measured at baseline, at the target glucose concentration of <2.2 mmol/L or >10 mmol/L, and after further 5 and 10 minutes. Plasma VEGF concentrations decreased upon hyperglycemia as compared with euglycemic baseline (P = .027), whereas during hypoglycemic condition, there was a trend for an increase (P = .091). Analysis for repeated measurements including both conditions revealed a differential regulation of plasma VEGF levels upon glycemic condition (P = .035). Our results are consistent with the hypothesis that systemic VEGF concentration may be differentially regulated than expression on cellular basis. Because VEGF is a candidate hormone for regulating glucose passage across the blood-brain barrier under critical conditions, it possibly acts as a neuroprotective controller for constant cerebral glucose supply. This may be of relevance for the understanding of VEGF alterations in different pathological states such as diabetes mellitus.