Why glucose transport in the brain matters for PET

Neuronal activity is fueled by glucose metabolism, a phenomenon exploited in basic research and clinical diagnosis using fluorodeoxyglucose positron emission tomography (FDG-PET). According to the current view, glucose transport into the brain is not rate-limiting; thus, it cannot exert control over metabolism. This article challenges such a view by showing that basal transport hovers near its maximum, making metabolic activation unable to increase flux on its own. In the light of recent evidence on the identity of the cell type that preferentially breaks down glucose, we suggest that FDG-PET reports the synergistic activation of glucose transport and metabolism in astrocytes, rather than in neurons.

[1]  G. S. Wilson,et al.  A Temporary Local Energy Pool Coupled to Neuronal Activity: Fluctuations of Extracellular Lactate Levels in Rat Brain Monitored with Rapid‐Response Enzyme‐Based Sensor , 1997, Journal of neurochemistry.

[2]  S. Laughlin,et al.  An Energy Budget for Signaling in the Grey Matter of the Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  A. McCall,et al.  Coupled Glucose Transport and Metabolism in Cultured Neuronal Cells: Determination of the Rate-Limiting Step , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  I. Simpson,et al.  Substrate specificity and kinetic parameters of GLUT3 in rat cerebellar granule neurons. , 1996, The Biochemical journal.

[5]  P. Magistretti,et al.  Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[6]  L. Sokoloff Energetics of Functional Activation in Neural Tissues , 1999, Neurochemical Research.

[7]  E. Welker,et al.  Glial Glutamate Transporters Mediate a Functional Metabolic Crosstalk between Neurons and Astrocytes in the Mouse Developing Cortex , 2003, Neuron.

[8]  R. M. Krupka,et al.  A general kinetic analysis of transport. Tests of the carrier model based on predicted relations among experimental parameters. , 1979, Biochimica et biophysica acta.

[9]  R. V. Van Heertum,et al.  Imaging the metabolic footprint of Glut1 deficiency on the brain , 2002, Annals of neurology.

[10]  M. Fillenz,et al.  Extracellular glucose turnover in the striatum of unanaesthetized rats measured by quantitative microdialysis , 1997, The Journal of physiology.

[11]  W. Webb,et al.  Neural Activity Triggers Neuronal Oxidative Metabolism Followed by Astrocytic Glycolysis , 2004, Science.

[12]  M. Fillenz,et al.  Continuous Monitoring of Extracellular Glucose Concentrations in the Striatum of Freely Moving Rats with an Implanted Glucose Biosensor , 1998, Journal of neurochemistry.

[13]  G. Rebec,et al.  Characterization of striatal activity in conscious rats: Contribution of NMDA and AMPA/kainate receptors to both spontaneous and glutamate‐driven firing , 2003, Synapse.

[14]  R. Gruetter,et al.  Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. E. Gold,et al.  Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux: effects of microdialysis flow rate, strain, and age. , 1999, Journal of neurochemistry.

[16]  Peter Lipton,et al.  Do active cerebral neurons really use lactate rather than glucose? , 2001, Trends in Neurosciences.

[17]  O. Porras,et al.  Glutamate Triggers Rapid Glucose Transport Stimulation in Astrocytes as Evidenced by Real-Time Confocal Microscopy , 2003, The Journal of Neuroscience.

[18]  P. Magistretti,et al.  Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[19]  L. Felipe Barros,et al.  Glutamate Mediates Acute Glucose Transport Inhibition in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[20]  R G Shulman,et al.  Cerebral energetics and the glycogen shunt: Neurochemical basis of functional imaging , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Uğurbil,et al.  Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain , 1998, Journal of neurochemistry.

[22]  R. Gruetter,et al.  Effect of Deep Pentobarbital Anesthesia on Neurotransmitter Metabolism in Vivo: On the Correlation of Total Glucose Consumption with Glutamatergic Action , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  S. Vannucci,et al.  Glucose transporter proteins in brain: Delivery of glucose to neurons and glia , 1997, Glia.

[24]  R Gruetter,et al.  Extracellular–Intracellular Distribution of Glucose and Lactate in the Rat Brain Assessed Noninvasively by Diffusion-Weighted 1H Nuclear Magnetic Resonance Spectroscopy In Vivo , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  John Eric Wilson Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function , 2003, Journal of Experimental Biology.