Differentiation of Glucose Transport in Human Brain Gray and White Matter

Graaf, Robin A. de; Pan, Jullie W.; Telang, Frank; Lee, Jing Huei; Brown, Peter B.; Novotny, Edward J.; Hetherington, Hoby P.; Rothman, Douglas L.

doi:10.1097/00004647-200105000-00002

Cited by 97 publications

(110 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such a model has been proposed, 21,128 and it was shown that one implication of the reversible model of brain glucose transport is that the relationship between brain and plasma glucose is linear. 21 Many measurements of brain glucose content as a function of plasma glucose have in the meantime corroborated the observation that brain glucose concentrations are a linear function of plasma glucose, 24,115,129,130 and such a case is illustrated for two different anesthetic regimes, -chloralose and pentobarbital in Fig. 11(A).…”

Section: Glucose Transportmentioning

confidence: 83%

See 1 more Smart Citation

Localized in vivo¹³C NMR spectroscopy of the brain

et al. 2003

View full text Add to dashboard Cite

Localized 13C NMR spectroscopy provides a new investigative tool for studying cerebral metabolism. The application of 13 C NMR spectroscopy to living intact humans and animals presents the investigator with a number of unique challenges. This review provides in the first part a tutorial insight into the ingredients required for achieving a successful implementation of localized 13 C NMR spectroscopy. The difficulties in establishing 13 C NMR are the need for decoupling of the one-bond 13 C-1 H heteronuclear J coupling, the large chemical shift range, the low sensitivity and the need for localization of the signals. The methodological consequences of these technical problems are discussed, particularly with respect to (a) RF front-end considerations, (b) localization methods, (c) the low sensitivity, and (d) quantification methods. Lastly, some achievements of in vivo localized 13 C NMR spectroscopy of the brain are reviewed, such as: (a) the measurement of brain glutamine synthesis and the feasibility of quantifying glutamatergic action in the brain; (b) the demonstration of significant anaplerotic fluxes in the brain; (c) the demonstration of a highly regulated malate-aspartate shuttle in brain energy metabolism and isotope flux; (d) quantification of neuronal and glial energy metabolism; and (e) brain glycogen metabolism in hypoglycemia in rats and humans. We conclude that the unique and novel insights provided by 13 19-24 Most of these studies have involved the administration of a 13 C-enriched precursor. When the enriched 13 C label is transferred to molecules in the metabolic pathway, sensitivity can not only be increased, but important information on metabolic pathways can also be obtained. For example, recent studies showed that the information content of 13 C NMR spectroscopy can be amplified considerably, such as the resolved observation of GABA labeling in the human brain, as well as the first detection of lactate labeling in normal human brain. 8 In addition to its importance in assessing metabolism in intact brain, 13 C NMR spectroscopy has become an important and useful tool in assessing compartmentation of metabolism in brain cells using extracts. 25,26 In addition to its low sensitivity, 13 C NMR spectroscopy is methodologically more challenging than 1 H or even 31 P NMR spectroscopy. However, 13C NMR provides its own unique insight and advantages over 1 H NMR spectroscopy. The uniqueness of 13 C NMR stems mainly from its increased chemical shift dispersion, which can, for example, be used in two-dimensional NMR to increase spectral resolution following specific labeling of the protein. 27 As shall be elaborated further below, 13 C NMR spectroscopy in living tissue provides a unique window on in vivo metabolism as it occurs. In the

show abstract

Section: Glucose Transportmentioning

confidence: 83%

“…21,22,115,129,130 A recent study extended the brain glucose concentrations measurements to hypoglycemia using 13 C NMR spectroscopy. 24 The concentrations measured by 13 C NMR were found to be in excellent agreement with those predicted by the reversible MichaelisMenten model as well as those measured by 1 H NMR spectroscopy [ Fig.…”

Section: Glucose Transportmentioning

confidence: 99%

Localized in vivo¹³C NMR spectroscopy of the brain

et al. 2003

View full text Add to dashboard Cite

show abstract

Section: Kinetics Of Glucose Transportmentioning

confidence: 99%

“…However, these transporters catalyze bi-directional fluxes, and the presence of intracellular and/or extracellular glucose alters the kinetics of transport both in and out of the cell. This bidirectional transport must be actively considered when modeling the flow of glucose from blood to the individual types of neural cells, primarily neurons and glial cells (see below Blomqvist et al, 1991;Carruthers, 1990;Choi et al, 2001;Cloherty et al, 1996;de Graaf et al, 2001; Gjedde, 1980; Gruetter et al, 1998; Hebert and Carruthers, 1991;Qutub and Hunt, 2005).The capacity for glucose transport depends on the concentration of the transporter proteins as well as their intrinsic catalytic turnover activity or number of transport cycles catalyzed per transporter per sec (k cat ) within the respective cellular compartments. It is relatively easy to determine the total concentration of GLUTs in brain microvessels, as these vessels can be readily isolated from whole brain (Vannucci, 1994).…”

mentioning

confidence: 99%

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Simpson

Carruthers

Vannucci

2007

J Cereb Blood Flow Metab

702

749

View full text Add to dashboard Cite

Glucose is the obligate energetic fuel for the mammalian brain, and most studies of cerebral energy metabolism assume that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter (GLUT) proteins deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood-brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters (MCT): MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, that is capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and -3 in BBB endothelial cells, astrocytes, and neurons, along with the corresponding kinetic properties of the MCTs, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed on neuronal activation. Keywords: glucose and lactate; glucose transporter proteins; mathematical modeling; monocarboxylate transporters; neurons and astrocytes; substrate delivery and metabolism IntroductionThe central dogma of cerebral energy metabolism is that glucose is the obligate energetic fuel of the mammalian brain and the only substrate able to completely sustain neural activity (Siesjo, 1978). Furthermore, it has traditionally been assumed that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state (Sokoloff et al, 1977). Rates of cerebral blood flow directly relate to measurements of cerebral oxygen consumption, generating the concept of the 'flow-metabolism couple' (Sokoloff, 1976;Sokoloff et al, 1977). The introduction of neuroimaging techniques to study cerebral metabolism revealed an 'uncoupling' between cerebral oxygen consumption, blood flow, and glucose utilization during brain activation (Fox and Raichle, 1986; Fox et al, 1988), with the suggestion of regional stimulation of oxidative glycolysis during neuronal activation. The temporal relationship between the release of lactate and the onset of neuronal activation, the source of the lactate, that is neuronal or glial, and its subsequent diffusion and disposal are all matters of considerable debate. Initial studies by Prichard et al (1991) assu...

show abstract

“…However, in order to take into account the different concentrations of metabolites in GM and WM, the two compartments were assigned different concentrations of glutamate (Glu), glutamine (Gln), aspartate (Asp), and lactate (Lac). The ratio [Glu] WM /[Glu] GM was set to ϳ0.5 according to human data (33,34) Metabolic fluxes and glutamate ADC in GM and WM were adjusted by minimizing the difference between the four measured and simulated time-courses for glutamate Ci enrichment (with i ϭ 3 and 4). At each step of the minimization procedure, Ci enrichment time-courses in GM and WM were generated for the tested values of V TCA GM , V X GM , V TCA WM , and V X WM by solving differential equations describing 13 C incorporation.…”

Section: Gm-wm Metabolic Modeling Including Diffusion Weightingmentioning

confidence: 99%

Diffusion‐weighted NMR spectroscopy allows probing of ¹³C labeling of glutamate inside distinct metabolic compartments in the brain

Valette

Chaumeil

Guillermier

et al. 2008

Magnetic Resonance in Med

View full text Add to dashboard Cite

In the present work, diffusion-weighted (DW)-NMR spectroscopy of glutamate was performed during a 13 C-labeled glucose infusion in monkey brain (six experiments). It is shown that glutamate 13 C labeling occurs significantly faster at higher diffusion weightings-slightly for glutamate in position C4, and more markedly for glutamate in position C3. This demonstrates the existence of different diffusion compartments for glutamate, associated with different metabolic rates. Metabolic modeling of 13 C enrichment time-courses suggests that these compartments might be gray and white matter, each having a specific oxidative metabolism rate possibly paralleled by a specific glutamate diffusion coefficient. Given its sensitivity to the molecular diffusion of metabolites, diffusion-weighted (DW)-NMR spectroscopy is generally accepted to be a valuable tool for probing various cellular compartments in vivo (for review, see Ref. 1). Indeed, the apparent diffusion coefficient (ADC) as measured by DW-NMR potentially depends on a wide variety of parameters that might be characteristic of different compartments, such as intracellular viscosity and tortuosity, restriction by or exchange through membranes, vesicle diffusions, or even cytoplasmic streaming. This expected sensitivity to cellular and subcellular properties has motivated various studies aimed at measuring metabolite ADC in the normal brain (2-10) or under perturbative conditions such as ischemia (11-16), excitotoxic injury (13), tumor (16), or variation of the anesthesia level (17). However, although there is little doubt about the actual existence in the brain of compartments with different diffusion properties, they have not been clearly identified, and the extent to which DW spectroscopy effectively allows them to be probed in vivo remains to be explored experimentally.A comparison of ADC values measured in the monkey brain and the rat brain led us to hypothesize that the molecular diffusion of metabolites, and particularly glutamate, could occur faster in white matter (WM) as compared to gray matter (GM) (6). A recent study in which the ADC was measured for NAA, creatine, and choline in different regions of the human brain seemed to confirm this trend (8), although the origin of the GM-WM discrepancy is unclear. We recently proposed that the ADC may also reflect subcellular compartmentation (in the cytoplasm and the different organelles [17]). In the end, regardless of the level at which diffusion properties vary, diffusion compartments are likely to match anatomical/functional compartments. It is therefore legitimate to expect some metabolic difference associated with these various diffusion compartments, which might give new insights into cellular compartmentation in the brain.13 C-NMR spectroscopy is a powerful tool for assessing oxidative metabolism in vivo. The measurement relies on the dynamic detection, during a 13 C-labeled glucose infusion, of 13 C incorporation into the concentrated aminoacid glutamate (for review see Refs. 18 and 19). Combining oxidativ...

show abstract

Differentiation of Glucose Transport in Human Brain Gray and White Matter

Cited by 97 publications

References 36 publications

Localized in vivo¹³C NMR spectroscopy of the brain

Localized in vivo¹³C NMR spectroscopy of the brain

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Diffusion‐weighted NMR spectroscopy allows probing of ¹³C labeling of glutamate inside distinct metabolic compartments in the brain

Contact Info

Product

Resources

About

Differentiation of Glucose Transport in Human Brain Gray and White Matter

Cited by 97 publications

References 36 publications

Localized in vivo13C NMR spectroscopy of the brain

Localized in vivo13C NMR spectroscopy of the brain

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Diffusion‐weighted NMR spectroscopy allows probing of 13C labeling of glutamate inside distinct metabolic compartments in the brain

Contact Info

Product

Resources

About

Localized in vivo¹³C NMR spectroscopy of the brain

Localized in vivo¹³C NMR spectroscopy of the brain

Diffusion‐weighted NMR spectroscopy allows probing of ¹³C labeling of glutamate inside distinct metabolic compartments in the brain