To determine whether acute hyperglycemia changes the hyperemic response to functional activation of brain, the area and magnitude of the activation were measured in healthy volunteers maintained at euglycemia and then at hyperglycemia using the hyperglycemic clamp technique. Activation of the visual cortex (8-16 Hz) was assessed by functional MRI with blood oxygenation level dependent (BOLD) contrast using a 4 Tesla magnet and a multi-slice echo-planar imaging sequence (TE = 30 msec, TR = 1.5 sec). At euglycemia (4.8 +/- 0.2 mM, mean +/- SEM, n = 6), the number of activated pixels in the occipital lobe was 79 +/- 10 and the intensity of activation was 4.5 +/- 0.5%. During hyperglycemia (plasma glucose 300% of control), the number of activated pixels was 90 +/- 20% of control and the BOLD activation was 3.5 +/- 0.3%, respectively. The change in BOLD signal was below 0.2%/mM plasma glucose. This study demonstrates that acute hyperglycemia is without substantial effect on the size and intensity of activation of the occipital cortex. The results further suggest that fluctuations in blood glucose within the physiologic range are without effect on the functional activation of the cerebral cortex measured by BOLD fMRI.