AIM: This study evaluated if the fatigue and apathy arising during exercise with hypoglycaemia could relate to a lowering of the cerebral metabolic rates of glucose and oxygen. METHODS AND RESULTS: Six males completed 3 h of cycling with or without glucose supplementation in random order. Cerebral blood flow, metabolism and interleukin-6 (IL-6) release were evaluated with the Kety-Schmidt technique. Blood glucose was maintained during the glucose trial, while it decreased from 5.2 +/- 0.1 to 2.9 +/- 0.3 mmol L-1 (mean +/- SE) after 180 min of exercise in the placebo trial with a concomitant increase in perceived exertion (P < 0.05). During hypoglycaemia, the cerebral glucose uptake was reduced from 0.34 +/- 0.05 to 0.28 +/- 0.04 micromol g(-1) min(-1), while the cerebral uptake of beta-hydroxybutyrate increased to 5 +/- 1 pmol g(-1) min(-1) (P < 0.05). The reduced glucose uptake was accompanied by a lowering of the cerebral metabolic rate of oxygen from 1.84 +/- 0.19 mmol g(-1) min(-)1 during exercise with glucose supplementation to 1.60 +/- 0.16 mmol g(-1) min(-1) during hypoglycaemia (P < 0.05). In addition, the cerebral IL-6 release was reduced from 0.4 +/- 0.1 to 0.0 +/- 0.1 pg g(-1) min(-1) (P < 0.05). CONCLUSIONS: Exercise-induced hypoglycaemia limits the cerebral uptake of glucose, exacerbates exercise, reduces the cerebral metabolic rate of oxygen and attenuates the release of IL-6 from the brain.