Recent 13 C NMR studies in rat models have shown that the glutamate͞glutamine cycle is highly active in the cerebral cortex and is coupled to incremental glucose oxidation in an Ϸ1:1 stoichiometry. To determine whether a high level of glutamatergic activity is present in human cortex, the rates of the tricarboxylic acid cycle, glutamine synthesis, and the glutamate͞glutamine cycle were determined in the human occipital͞parietal lobe at rest. During an infusion of [1-13 C]-glucose, in vivo 13 C NMR spectra were obtained of the time courses of label incorporation into [4-13 C]-glutamate and [4-13 C]-glutamine. Using a metabolic model we have validated in the rat, we calculated a total tricarboxylic acid cycle rate of 0.77 ؎ 0.07 mol͞min͞g (mean ؎ SD, n ‫؍‬ 6), a glucose oxidation rate of 0.39 ؎ 0.04 mol͞min͞g, and a glutamate͞ glutamine cycle rate of 0.32 ؎ 0.05 mol͞min͞g (mean ؎ SD, n ‫؍‬ 6). In agreement with studies in rat cerebral cortex, the glutamate͞glutamine cycle is a major metabolic f lux in the resting human brain with a rate Ϸ80% of glucose oxidation.The regulation of the release and re-uptake of the excitatory neurotransmitter glutamate is critical for mammalian brain function (1, 2). Glutamate released from the neuron may be cleared from the synaptic cleft through uptake by neuronal or glial glutamate transporters (3, 4). Recent studies have supported the glia as the major pathway of glutamate clearance (3). Neurons lack the enzymes necessary to perform net glutamate synthesis and depend on the glia to supply precursors. One of the pathways proposed for neuronal glutamate repletion is the glutamate͞glutamine cycle (5-8). In this pathway, glutamate taken up by the glia is converted to glutamine by glutamine synthetase (9-11). Glutamine then is released to the extracellular fluid, where it is taken up by neurons and is converted back to glutamate by the action of phosphate-activated glutaminase (12).The rate of the glutamate͞glutamine cycle has been controversial because of difficulties in performing measurements in the living brain. The prevailing belief has been that the glutamate͞glutamine cycle is a minor metabolic flux relative to total cellular glutamate metabolism. This view is largely based on the small size of the vesicular glutamate pool compared with other cellular glutamate pools (13,14). Additional evidence comes from the low flux of isotope from [1-13 C] glucose into glutamine in studies of brain slices (15).We have demonstrated that in vivo 13 C NMR may be used to measure the rate of glutamine labeling (16, 17) from [1-13 C] glucose in human occipital͞parietal cortex. These and subsequent studies (18) demonstrated that, in contrast with results from nonactivated brain slices (15), glutamine labeling is rapid. However, the rate of the glutamate͞glutamine cycle was not uniquely determined from these first experiments because of the inability to distinguish the glutamate͞glutamine cycle from other sources of glutamine labeling. The major alternate pathway of brain glutamine metaboli...

DMI shows metabolism of acetate and glucose in the brain and liver and reveals the Warburg effect in patients with brain tumors.