Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

Blomqvist, G.; Gjedde, Albert; Gutniak, M.; Grill, Valdemar; Widén, L.; Stone‐Elander, Sharon; Hellstrand, E.

doi:10.1007/bf00175064

Cited by 46 publications

(22 citation statements)

References 9 publications

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“…The increased fractional extraction was most likely secondary to the low blood glucose concentration and the unchanged fuel requirement of the brain. Accordingly, an increased clearance of glucose across the blood-brain barrier measured by the positron emission tomography technique has been reported during short-term hypoglycaemia in healthy subjects [25], but the mechanism for this is not clearly defined. Induction of the specific brain capillary endothelial glucose transporter (GLUT 1) has been shown in rats as an adaptation to chronic hypoglycaemia [26,27].…”

Section: Discussionmentioning

confidence: 99%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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It is now clearly established that tight blood glucose control substantially reduces or delays most of the chronic complications in patients with Type I (insulin-dependent) diabetes mellitus [1]. A tight blood glucose control, however, is accompanied by increased hypoglycaemic episodes [1]. These recurrent hypoglycaemic episodes are major impediments in achieving ideal blood glucose control in a substantial number of Type I diabetic patients. In studies where alternative fuels, such as b-hydroxybutyrate and lactate [2] were provided in attempts to alleviate hypoglycaemic symptoms, the response of the autonomic system to hypoglycaemia was diminished or prevented [3]. Based on this indirect evidence, it was concluded that the brain uses these alternative fuels during hypoglycaemia. The brain contains the enzyme systems that are required for the metabolism of a range of different carbohydrate and lipid substrates [4]. There is thus, no immediate reason why the brain Diabetologia (1999) AbstractAims/hypothesis. Our study was undertaken to examine directly the utilisation of glucose and alternative substrates, in particular amino acids, during hypoglycaemia.Methods. Catheters were positioned in the jugular venous bulb and an artery in six healthy subjects in the overnight fasted state. Arterio-venous differences for glucose, amino acids, lactate and pyruvate were measured in the basal state, during hyperinsulinaemic euglycaemia and during hyperinsulinaemic hypoglycaemia. The subjects were studied on two different occasions, once during intravenous infusion of amino acids and once during infusion of saline.Results. In the basal state the fractional extraction of glucose across the brain was 10 ± 2 %, glucose uptake accounted for 106 ± 5 % of the brain's oxidative metabolism. There was a small release of lactate and pyruvate. During hyperinsulinaemia glucose uptake continued to account for the entire fuel requirement

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Section: Discussionmentioning

confidence: 99%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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“…Localized glucose transport kinetic measurements in human brain (Brooks et al, i986;Feinendegen et al, 1986;Blomqvist et al, 1991;Gruetter et a!., 1992a, l996c) have so far been highly consistent, with a Michaelis-Menten constant K, of 4-5 mM for transport and an average maximal transport rate, Tmax, of '--~1 pmol/g/min (for reviews, see Gjedde, 1992;Gruetter et al, 1996 c). These kinetic constants of the standard Michaelis-Menten model predicted that brain glucose content should be <5~zmol/g when plasma glucose content is <30 mM.…”

Section: R Grue1ter Et Almentioning

confidence: 97%

“…Noteworthy is the observation that in the studies in the erythrocyte, which is a system of high purity and great simplicity, the Michaelis-Menten constants also appear to diverge substantially. Some of the discrepancy has been attributed to methodological inadequacies, and some may potentially be explained by differences in species-specific expression of i996).Localized glucose transport kinetic measurements in human brain (Brooks et al, i986;Feinendegen et al, 1986;Blomqvist et al, 1991; Gruetter et a!., 1992a, l996c) have so far been highly consistent, with a Michaelis-Menten constant K, of 4-5 mM for transport and an average maximal transport rate, Tmax, of '--~1 pmol/g/min (for reviews, see Gjedde, 1992; Gruetter et al, 1996 c). These kinetic constants of the standard Michaelis-Menten model predicted that brain glucose content should be <5~zmol/g when plasma glucose content is <30 mM.…”

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confidence: 99%

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

Gruetter¹,

Uğurbil

Seaquist³

1998

Journal of Neurochemistry

233

280

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Understanding the mechanism of brain glucose transport across the blood-brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport have been generally described using standard Michaelis-Menten kinetics. These models predict that the steady-state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, K~. In experiments where steady-state plasma glucose content was varied from 4 to 30 mM, the brain glucose level was a linear function of plasma glucose concentration. At plasma concentrations nearing 30 mM, the brain glucose level approached 9 mM, which was significantly higher than predicted from the previously reported Kõf --'4 mM (p < 0.05). The high brain glucose concentration measured in the human brain suggests that ablumenal brain glucose may compete with lumenal glucose for transport. We developed a model based on a reversible MichaelisMenten kinetic formulation of unidirectional transport rates. Fitting this model to brain glucose level as a function of plasma glucose level gave a substantially lower Kõ f 0.6 ±2.0 mM, which was consistent with the previously reported millimolar Km of GLUT-i in erythrocyte model systems. Previously reported and reanalyzed quantification provided consistent kinetic parameters. We conclude that cerebral glucose transport is most consistently described when using reversible Michaelis-Men±en kinetics. Key Words: NMR-Glucose transport-ln vivo studies-Spectroscopy-Human. J. Neurochem. 70, 397-408 (1998).Knowledge of the specific mechanism of glucose transport across the blood-brain barrier is important for understanding cerebral carbohydrate metabolism, which is the major source of energy for ATP production. Glucose transport across the blood-brain barrier occurs by facilitated diffusion mediated by specific transporter proteins. Glucose extraction is a saturable process in the brain/ (Crone, 1965) and erythrocytes (Le Fevre, 1961)atid is mediated by facilitated diffusion that has been well-established to be stereospecific and substrate-specific. Standard Michaelis-Menten models for glucose transport kinetics have since been used almost exclusively in most studies of the brain (for reviews, see, e.g., Lund-Andersen, 1979;Pardridge, 1983;Gjedde, 1992), with one exception .Many elegant techniques have been applied to study brain glucose uptake. The indicator-dilution techniques sample tracer extraction with a single pass across the capillary bed at a very high time resolution but with a somewhat limited spatial resolution (Knudsen et al., 1990). On the other hand, state-of-the art tracer techniques, such as positron emission tomography (PET), can provide a high spatial resolution (Svarer et al., 1996). However, the information on cerebral glucose content is indirect because the active metabolism of labeled glucose implies substantial label accumulation in metabolic products that cannot be distinguished fr...

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“…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).…”

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confidence: 99%

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

Simpson

Carruthers

Vannucci

2007

J Cereb Blood Flow Metab

703

749

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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...

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Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

Cited by 46 publications

References 9 publications

Brain substrate utilisation during acute hypoglycaemia

Brain substrate utilisation during acute hypoglycaemia

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

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

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