Glucose, the most important fuel for the brain, is supplied by the actions of counterregulatory hormones and the sympathetic nervous system. Yet to obtain access to the brain, glucose must pass the blood-brain barrier. Here we show that vascular endothelial growth factor (VEGF), a potent regulator of blood vessel function, is a candidate hormone for facilitating glucose passage across the blood-brain barrier under critical conditions. In 16 healthy men, VEGF serum concentrations increased under 6 h of insulin-induced hypoglycemic conditions from 86.1 +/- 13.4 to 211.6 +/- 40.8 pg/ml (P = 0.002), whereas in the hyperinsulinemic euglycemic control condition, no change was observed. During hypoglycemia serum VEGF, but no other counterregulatory hormone, was associated with preserved neurocognitive function, as measured with a memory test (r = 0.539; P = 0.031) and the Stroop interference task (r = 0.569; P = 0.021). Findings show that acute hypoglycemia is accompanied by a brisk increase in circulating VEGF concentration and that VEGF could mediate rapid adaptation of the brain to neuroglycopenia.