Recent in vitro studies suggest that lactate, rather than glucose, may be the preferred fuel for neuronal metabolism. The authors examined the effect of lactate on global brain glucose uptake in euglycemic human subjects using 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET). Eight healthy men, aged 40 to 54 years, underwent a 60-minute FDG-PET scan on two occasions in random order. On one occasion, 6.72% sodium lactate was infused at a rate of 50 micro mol. kg-1. min-1 for 20 minutes and then reduced to 30 micro mol. kg-1. min-1; 1.4% sodium bicarbonate was infused as a control on the other occasion. Plasma glucose levels were not different between the two groups (5.3 +/- 0.23 and 5.3 +/- 0.24 mmol/L, P = 0.55). Plasma lactate was significantly elevated by lactate infusion (4.08 +/- 0.35 vs. 0.63 +/- 0.22 mmol/L, P < 0.0005. The whole-brain rate of glucose uptake was significantly reduced by approximately 17% during lactate infusion (0.195 +/- 0.022 vs. 0.234 +/- 0.020 micro mol. g-1. min-1, P = 0.001). The authors conclude that, in vivo in humans, circulating lactate is used by the brain at euglycemia, with sparing of glucose.