Brain Glucose Concentrations Research Articles

The neuroendocrine control of glucose allocation.

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.

3,4-Methylenedioxymethamphetamine produces glycogenolysis and increases the extracellular concentration of glucose in the rat brain.

Oxidative and/or bioenergetic stress is thought to contribute to the mechanism of neurotoxicity of amphetamine derivatives, e.g., 3,4-methylenedioxymethamphetamine (MDMA). In the present study, the effect of MDMA on brain energy regulation was investigated by examining the effect of MDMA on brain glycogen and glucose. A single injection of MDMA (10-40 mg/kg, s.c.) produced a dose-dependent decrease (40%) in brain glycogen, which persisted for at least 1 h. MDMA (10 and 40 mg/kg, s.c.) also produced a significant and sustained increase in the extracellular concentration of glucose in the striatum. Subjecting rats to a cool ambient temperature of 17 degrees C significantly attenuated MDMA-induced hyperthermia and glycogenolysis. MDMA-induced glycogenolysis also was prevented by treatment of rats with the 5-hydroxytryptamine(2) (5-HT(2)) antagonists 6-methyl-1-(1-methylethyl)-ergoline-8 beta-carboxylic acid 2-hydroxy-1 methylprophyl ester maleate (LY-53,857; 3 mg/kg i.p.), desipramine (10 mg/kg i.p.), and iprindole (10 mg/kg i.p.). LY-53,857 also attenuated the MDMA-induced increase in the extracellular concentration of glucose as well as MDMA-induced hyperthermia. Amphetamine analogs (e.g., methamphetamine and parachloroamphetamine) that produce hyperthermia also produced glycogenolysis, whereas fenfluramine, which does not produce hyperthermia, did not alter brain glycogen content. These results support the conclusion that MDMA induces glycogenolysis and that the process involves 5-HT(2) receptor activation. These results are supportive of the view that MDMA promotes energy dysregulation and that hyperthermia may play an important role in MDMA-induced alterations in cellular energetics.

Effect of α-Phenyl-N-tert-Butylnitrone on Brain Cell Membrane Function and Energy Metabolism in Experimental Escherichia coli Meningitis in the Newborn Piglet

We evaluated the efficacy of alpha-phenyl-N-tertbutylnitrone as an adjunctive therapy in experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10(8) colony-forming units of Escherichia coli in 100 microl of saline. Alpha-Phenyl-N-tert-butylnitrone 100 mg/kg was given as a bolus intravenous injection 30 min before induction of meningitis. Although it completely abolished the elevated CSF tumor necrosis factor-a level observed in the meningitis group, alpha-phenyl-N-tert-butylnitrone did not down-modulate parameters of inflammatory responses such as increased intracranial pressure, hypoglycorrhachia, elevated CSF lactate level, and CSF leukocytosis observed in this group. However, alpha-phenyl-N-tert-butylnitrone treatment mitigated alterations in brain cell membrane structure and function during meningitis, evidenced by amelioration of increased brain cell membrane lipid peroxidation products (conjugated dienes) and decreased Na+, K+-ATPase activity. Reduced mean arterial blood pressure, cerebral perfusion pressure, brain glucose concentration, and cerebral energy stores and marginally increased brain lactate level observed in the meningitis group were also ameliorated. These results suggest that although it failed to attenuate the inflammatory responses, alpha-phenyl-N-tert-butylnitrone was effective in ameliorating brain injury in neonatal bacterial meningitis.

In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia.

Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in alpha-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma glucose, which is consistent with the reversible Michaelis-Menten model. When the model was fitted to the brain glucose measurements, the apparent Michaelis-Menten constant, Kt, was 3.3 +/- 1.0 mmol/L, and the ratio of the maximal transport rate relative to CMRglc, Tmax/CMRglc, was 2.7 +/- 0.1. This Kt is comparable to the authors' previous human data, suggesting that glucose transport kinetics in humans and rats are similar. Cerebral blood flow (CBF) was simultaneously assessed and constant above 2 mmol/L plasma glucose at 73 +/- 6 mL 100 g(-1) min(-1). Extrapolation of the reversible Michaelis-Menten model to hypoglycemia correctly predicted the plasma glucose concentration (2.1 +/- 0.6 mmol/L) at which brain glucose concentrations approached zero. At this point, CBF increased sharply by 57% +/- 22%, suggesting that brain glucose concentration is the signal that triggers defense mechanisms aimed at improving glucose delivery to the brain during hypoglycemia.

Fluctuations in Brain Glucose Concentration during Behavioral Testing: Dissociations between Brain Areas and between Brain and Blood

Traditional beliefs about two aspects of glucose regulation in the brain have been challenged by recent findings. First, the absolute level of glucose in the brain's extracellular fluid appears to be lower than previously thought. Second, the level of glucose in brain extracellular fluid is less stable than previously believed. In vivo brain microdialysis was used, according to the method of zero net flux, to determine the basal concentration of glucose in the extracellular fluid of the striatum in awake, freely moving rats for comparison with recent hippocampal measurements. In addition, extracellular glucose levels in both the hippocampus and the striatum were measured before, during, and after behavioral testing in a hippocampus-dependent spontaneous alternation task. In the striatum, the resting extracellular glucose level was 0.71 mM, approximately 70% of the concentration measured previously in the hippocampus. Consistent with past findings, the hippocampal extracellular glucose level decreased by up to 30 ± 4% during testing; no decrease, and in fact a small increase (9 ± 3%), was seen in the striatum. Blood glucose measurements obtained during the same testing procedure and following administration of systemic glucose at a dose known to enhance memory in this task revealed a dissociation in glucose level fluctuations between the blood and both striatal and hippocampal extracellular fluid. These findings suggest, first, that glucose is compartmentalized within the brain and, second, that one mechanism by which administration of glucose enhances memory performance is via provision of increased glucose supply from the blood specifically to those brain areas involved in mediating that performance.

Differentiation of glucose transport in human brain gray and white matter.

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

The Role of Cerebral Microdialysis in Predicting the Outcome after Experimental Hypothermic Circulatory Arrest

Objective –To evaluate whether and which of the cerebral microdialysis parameters are predictive of postoperative outcome after an experimental 75-min period of hypothermic circulatory arrest (HCA) in a chronic porcine model. Design –Seventy-four juvenile female pigs underwent a 75-min period of HCA at 20°C. A microdialysis catheter was placed into the cortex gray matter and brain extracellular concentrations of glucose, lactate, glycerol and glutamate were measured throughout the experiment by enzymatic methods using a microdialysis analyzer. Surviving animals were sacrificed on the 7th postoperative day and histopathological examination of the brain was performed. Results –Brain glucose concentrations were higher in animals that survived ( p = 0.017), especially from the 90-min until the 7-h interval after the start of rewarming. The blood venous concentrations of glucose were also higher among survivors, and correlated significantly with the brain glucose levels at 2-h and 4-h intervals after the start of rewarming. Higher concentrations of brain lactate, glycerol and glutamate were observed throughout the study among animals that died postoperatively. Brain glutamate and glycerol concentrations were significantly, negatively correlated with brain glucose concentrations. The lactate/glucose ratio was significantly lower among survivors during the postoperative period ( p = 0.014). Furthermore, brain glucose concentrations were higher and brain glycerol concentrations lower among the animals that did not develop brain infarction, but such differences did not reach statistical significance. Conclusion –Cerebral microdialysis is a useful tool for cerebral monitoring during experimental HCA. Low brain glucose concentrations and high brain lactate/glucose ratios after HCA are strong predictors of postoperative death. Brain glucose concentrations are negatively correlated with brain glycerol and glutamate concentrations.

The effect of chronic dexamethasone-induced hyperglycemia and its acute treatment with insulin on brain glucose and glycogen concentrations in rats.

In the rat model of forebrain ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic functional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data. Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were administered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16). Of the rats treated with dexamethasone for 4 days, one half (N = 8) were administered an insulin-containing saline infusion subsequently to restore normoglycemia short-term. All other rats (N = 50) were administered an infusion of saline without insulin. Plasma glucose was quantified, and brains were excised after in situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses. After 4 days of dexamethasone treatment, plasma glucose was 159% greater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 micromol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations increased parallel to plasma glucose. An insulin infusion for 27 +/- 5 min restored normoglycemia but resulted in a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01). Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentrations. In a nonischemic rat model, dexamethasone alone had no independent effect on the brain-to-plasma glucose ratio. However, short-term insulin therapy caused a dysequilibrium between plasma and brain glucose, resulting in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of glucose reduction. The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury completely in a previous report that used the rat model of forebrain ischemia.

The Efficacy of Pentoxifylline as an Anti-Inflammatory Agent in Experimental Escherichia coli Meningitis in the Newborn Piglet

This study was done to evaluate the anti-inflammatory effect and the ensuing neuroprotective effect of pentoxifylline in neonatal experimental bacterial meningitis. Newborn piglets were divided into three groups: 10 in the control group (CG), 13 in the meningitis group (MG), and 13 in the meningitis with pentoxifylline group (PG). Meningitis was induced by intracisternal injection of 10⁸ colony-forming units of Escherichia coli in 100 μl of saline. In PG, 20 mg/kg of pentoxifylline was given as a bolus intravenous injection 30 min before induction of meningitis and 6 mg/kg/h was given continuously throughout the experiment. In PG, the increase of CSF TNF-α level observed in MG was abolished. Reduced brain glucose and ATP concentrations observed in MG were significantly increased in PG. However, other parameters of inflammatory responses such as increased intracranial pressure, reduced glucose and increased lactate concentrations in the CSF observed in MG were not significantly down-modulated. The extent of CSF leukocytosis was even higher in PG than in MG. Increased cerebral cortical cell membrane lipid peroxidation products and decreased Na⁺,K⁺-ATPase activity observed in MG, indicative of meningitis-induced brain cell membrane dysfunction, tended to improve without statistical significance in PG. In summary, although some anti-inflammatory effects have been observed, the overall anti-inflammatory effects of pentoxifylline was very weak, and it failed to significantly reduce the brain damage in experimental neonatal bacterial meningitis.

902 Effect of Dexamethasone-Induced Hyperglycemia, and its Acute Treatment with Insulin, on Brain Glucose Concentrations in Rats

902 Effect of Dexamethasone-Induced Hyperglycemia, and its Acute Treatment with Insulin, on Brain Glucose Concentrations in Rats

Cardiovascular function and brain metabolites in normal weight and intrauterine growth restricted newborn piglets — Effect of mild hypoxia

In order to clarify the influence of intrauterine growth restriction on systemic hemodynamics, catecholamine response, and regional distribution of brain energy metabolites per se and during mild hypoxic episodes a study was performed in thirty newborns with a well-characterized state of intrauterine and intra-natal development. Thirty animals were divided into fifteen normal weight piglets (NW) and fifteen intrauterine growth restricted (IUGR) piglets according to their birth weight. Category "NW" covered animals with a birth weight of > 40th percentile; IUGR category covered animals with a birth weight of > 5th and < 10th percentiles. Animals were anesthetized with halothane in 70% nitrous oxide and 30% oxygen and after immobilization artificially ventilated. The acid-base balance and blood gas values at baseline conditions were similar within the different groups investigated and consistent with other data obtained from anesthetized and artificially ventilated newborn piglets. Mild hypoxic hypoxia which was induced by lowering the FiO2 from 0.35 to 0.15 resulted in reduced arterial pO2 (NW: from 115 +/- 37 mmHg to 39 +/- 7 mmHg; IUGR: from 117 +/- 23 mmHg to 39 +/- 3 mmHg; p < 0.05), but arterial pH and pCO2 remained unchanged. Under baseline conditions arterial blood pressure, cardiac output, and myocardial contractility, expressed as dp/dt(max) and plasma catecholamine values were similar in all groups studied. Heart rate was slightly increased in IUGR (p < 0.05). Mild hypoxia led to a strong increase of myocardial contractility in NW as well as IUGR piglets to 2.4 and 2.7 fold and remained increased during recovery (p < 0.05). Moreover, total peripheral resistance was enhanced at the end of recovery period in IUGR animals (p < 0.05). There was a significant increase of epinephrine (E) in NW animals in comparison to sham-operated animals (p < 0.05). Interestingly, during reoxygenation the further increase in E and norepinephrine (NE) levels were enhanced in the animals which suffered from mild hypoxia (p < 0.05). Regional distribution of brain tissue metabolites was partly affected by intrauterine growth restriction. In particular, brain tissue glucose content was strongly reduced by 65 to 72 per cent in all brain regions investigated. Mild hypoxia led to an increase of about 30 percent in NW animals (p < 0.05). In IUGR piglets the percentage increase of brain glucose content was on an average more pronounced but with considerably higher variance. Also, a strong increase of brain lactate content appeared here (p < 0.05). In contrast, brain tissue ATP was quite similar in all groups studied, but brain creatine phosphate was significantly reduced in some forebrain structures of IUGR piglets after mild hypoxia (figure 2, p < 0.05). In summary, this investigation provides information on cardiovascular functions and brain metabolites of normal weight and naturally occurring growth restricted newborn piglets. Mild hypoxemia was well-tolerated from both animal groups. It is suggested that lactate may play a significant role as a source for brain energy production in the newborn IUGR piglets.

The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose.

The effect of hyperglycaemia on regional cerebral glucose utilization was studied in five healthy males fasted over-night using positron emission tomography. Selectively labelled glucose, [1-11C]-D-glucose, was used as a tracer. After correction for the small loss of [11C]CO2 from the tissue, this tracer measures the rate of glucose oxidation rather than the total rate of glucose metabolism. Each subject was investigated twice: during normoglycaemia (plasma glucose 5.3 +/- 0.3 mumol mL-1) and at the end of a 2-h period of hyperglycaemia (plasma glucose 13.8 +/- 0.7 mumol mL-1). Assuming unchanged rate constant for loss of labelled CO2 at normo- and hyperglycaemia the oxidative metabolic rate of glucose was found to be slightly larger at combined hyperglycaemia and hypersulinemia (0.30 +/- 0.01 mmol mL-1 min-1) than at normal glucose and insulin levels (0.25 +/- 0.01 mmol mL-1 min-1). This suggests that the process of glucose phosphorylation might not be fully saturated in the human brain or, alternatively, that the glycogen deposition increases during short-term hyperglycaemia. The relative increase of oxidative metabolic rate was considerably larger (approximately 50%) in white matter than in the brain as a whole (20%). The brain glucose content was found to increase non-linearly with increasing plasma glucose. Together with data from previous studies these results suggest that the free glucose in the human brain is close to zero when the plasma glucose is below 2 mumol mL-1.

The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose

The effect of hyperglycaemia on regional cerebral glucose utilization was studied in five healthy males fasted over-night using positron emission tomography. Selectively labelled glucose, [1–11C]-D-glucose, was used as a tracer. After correction for the small loss of [11C]CO2 from the tissue, this tracer measures the rate of glucose oxidation rather than the total rate of glucose metabolism. Each subject was investigated twice: during normoglycaemia (plasma glucose 5.3 ± 0.3 μmol mL−1) and at the end of a 2-h period of hyperglycaemia (plasma glucose 13.8 ± 0.7 μmol mL−1). Assuming unchanged rate constant for loss of labelled CO2 at normo- and hyperglycaemia the oxidative metabolic rate of glucose was found to be slightly larger at combined hyperglycaemia and hypersulinemia (0.30 ± 0.01 mmol mL−1 min−1) than at normal glucose and insulin levels (0.25 ± 0.01 mmol mL−1 min−1). This suggests that the process of glucose phosphorylation might not be fully saturated in the human brain or, alternatively, that the glycogen deposition increases during short-term hyperglycaemia. The relative increase of oxidative metabolic rate was considerably larger (≈50%) in white matter than in the brain as a whole (20%). The brain glucose content was found to increase non-linearly with increasing plasma glucose. Together with data from previous studies these results suggest that the free glucose in the human brain is close to zero when the plasma glucose is below 2 μmol mL−1.

Effect of induced hyperglycemia on brain cell membrane function and energy metabolism during the early phase of experimental meningitis in newborn piglets

This study was done to elucidate the mechanism of hypoglycorrhachia and elevated lactate concentrations leading to neuronal dysfunction in neonatal meningitis, and to determine the effects of induced hyperglycemia on these disturbances. Thirty-eight newborn piglets were divided into three groups: 12 in the control group (CG), 12 in the normoglycemic meningitis group (NG), and 14 in the hyperglycemic meningitis group (HG). Meningitis was induced by intracisternal injection of 108 cfu of Escherichia coli. Hyperglycemia (blood glucose 300–400 mg dl −1) was induced and maintained for 60 min before induction of meningitis and throughout the experiment using modified glucose clamp technique. CSF-to-blood glucose ratio decreased significantly in NG. In HG, baseline CSF-to-blood glucose ratio was lower than two other groups, but increased at 1 h after induction of meningitis. CSF lactate concentration was increased progressively in both meningitis groups, and positively correlated with CSF leukocyte numbers ( r=0.41, p<0.001) and TNF- α level ( r=0.43, p<0.001). Brain glucose concentration was significantly increased in HG and showed inverse correlation with CSF leukocyte numbers ( r=−0.59, p<0.01). Brain lactate concentration was not significantly different among three groups and positively correlated with the CSF TNF- α level ( r=0.51, p<0.05). Lipid peroxidation products were increased in NG. Na +,K +-ATPase activity, ATP/PCr concentrations were not different among three groups. Increased intracranial pressure, CSF pleocytosis (214±59 vs. 437±214/mm 3, p<0.02) and increased lipid peroxidation products observed in NG were reduced in HG. These results suggest that hypoglycorrhachia and elevated lactate concentration in the CSF during meningitis originates primarily from the increased anaerobic glycolysis in the subarachnoid space, induced by TNF- α and leukocytes. Induced hyperglycemia attenuates the inflammatory responses of meningitis and might be beneficial by providing an increased glucose delivery to meet its increased demand in meningitis.

Steady-state cerebral glucose concentrations and transport in the human brain.

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, Kt. 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 Kt of approximately 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 Michaelis-Menten kinetic formulation of unidirectional transport rates. Fitting this model to brain glucose level as a function of plasma glucose level gave a substantially lower Kt of 0.6 +/- 2.0 mM, which was consistent with the previously reported millimolar Km of GLUT-1 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-Menten kinetics.

Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat.

We previously have demonstrated that hypocapnia aggravates and hypercapnia protects the immature rat from hypoxic-ischemic brain damage. To ascertain cerebral blood flow (CBF) and metabolic correlates, 7-d postnatal rats were subjected to hypoxia-ischemia during which they were rendered either hypo-(3.5 kPa), normo- (5.1 kPa), or hypercapnic (7.3 kPa) by the inhalation of either 0, 3, or 6% CO2, 8% O2, balance N2. CBF during hypoxia-ischemia was better preserved in the normo- and hypercapnic rat pups; these animals also exhibited a stimulation of cerebral glucose utilization. Brain glucose concentrations were higher and lactate lower in the normo- and hypercapnic animals, indicating that glucose was consumed oxidatively in these groups rather than by anaerobic glycolysis, as apparently occurred in the hypocapnic animals. ATP and phosphocreatine were better preserved in the normo- and hypercapnic rats compared with the hypocapnic animals. Cerebrospinal fluid glutamate, as a reflection of the brain extracellular fluid concentration, was lowest in the hypercapnic rats at 2 h of hypoxia-ischemia. The data indicate that during hypoxia-ischemia in the immature rat, CBF is better preserved during normo- and hypercapnia; the greater oxygen delivery promotes cerebral glucose utilization and oxidative metabolism for optimal maintenance of tissue high energy phosphate reserves. An inhibition of glutamate secretion into the synaptic cleft and its attenuation of N-methyl-D-aspartate receptor activation would further protect the hypercapnic animal from hypoxic-ischemic brain damage.

1H NMR Studies of Glucose Transport in the Human Brain

The difference between 1H nuclear magnetic resonance (NMR) spectra obtained from the human brain during euglycemia and during hyperglycemia is depicted as well-resolved glucose peaks. The time course of these brain glucose changes during a rapid increase in plasma glucose was measured in four healthy subjects, aged 18-22 years, in five studies. Results demonstrated a significant lag in the rise of glucose with respect to plasma glucose. The fit of the integrated symmetric Michaelis-Menten model to the time course of relative glucose signals yielded an estimated plasma glucose concentration for half maximal transport, Kt, of 4.8 +/- 2.4 mM (mean +/- SD), a maximal transport rate, Tmax, of 0.80 +/- 0.45 micromol g-1 min-1, and a cerebral metabolic glucose consumption rate (CMR)glc of 0.32 +/- 0.16 micromol g-1 min-1. Assuming cerebral glucose concentration to be 1.0 micromol/g at euglycemia as measured by 13CMR, the fit of the same model to the time course of brain glucose concentrations resulted in Kt = 3.9 +/- 0.82 mM, Tmax = 1.16 +/- 0.29 micromol g-1 min-1, and CMRglc = 0.35 +/- 0.10 micromol g-1 min-1. In both cases, the resulting time course equaled that predicted from the determination of the steady-state glucose concentration by 13C NMR spectroscopy within the experimental scatter. The agreement between the two methods of determining transport kinetics suggests that glucose is distributed throughout the entire aqueous phase of the human brain, implying substantial intracellular concentration.

Brain glucose metabolism in hypobaric hypoxia.

Hypobaric hypoxia at one-half atmospheric pressure for 3 wk was reported to increase the brain capillary density and glucose transport at the blood-brain barrier in the adult rat. We examined the metabolic concomitants of these alterations in rats subjected to the same hypoxic insult. Hypoxic rats increased brain glucose and lactate concentrations and decreased brain glycogen. However, hypoxia had no significant effects on regional brain levels of ATP and phosphocreatine or on intracellular pH, indicating successful adaptation to the hypoxic insult. 2-Deoxyglucose studies showed that hypoxia increased the regional metabolic rate for glucose by 10-40%. These results indicate increased glycolysis in the hypoxic rat brain, which probably underlies the increased density of glucose transporters in brain microvessels and the increased blood-to-brain glucose influx in hypoxia.

The effect of acute hypoglycemia on the cerebral NMDA receptor in newborn piglets

The effects of acute insulin-induced hypoglycemia on the cerebral NMDA receptor in the newborn were examined by determining [ 3H]MK-801 binding as an index of NMDA receptor function in 6 control and 7 hypoglycemic piglets. In hypoglycemic animals, the glucose clamp technique with constant insulin infusion was used to maintain a blood glucose concentration of 1.2 mmol/l for 120 min before obtaining cerebral cortex for further analysis; controls received a saline infusion. Concentrations of glucose, lactate, ATP, and PCr were measured in cortex, and Na +,K +-ATPase activity was determined in a brain cell membrane preparation. [ 3H]MK-801 binding was evaluated by: (1) saturation binding assays over the range of 0.5–50 nM [ 3H]MK-801 in the presence of 100 μM glutamate and glycine; and (2) binding assays at 10 nM [ 3H]MK-801 in the presence of glutamate and/or glycine at 0, 10, or 100 μM. Blood and brain glucose concentrations were significantly lower in hypoglycemic animals than controls. There was no change in brain ATP with hypoglycemia, but PCr was decreased 80% compared to control ( P < 0.05). Na +,K +-ATPase activity was 13% lower in hypoglycemic animals ( P < 0.05). Based on saturation binding data, hypoglycemia had no effect on the number of functional receptors ( B max), but the apparent affinity was significantly increased, as indicated by a decrease in the K d (dissociation constant) from the control value of 8.1 ± 1.6 nM to 5.5 ± 2.1 nM ( P < 0.05). Augmentation of [ 3H]MK-801 binding by glutamate and glycine alone or in combination was also significantly greater in the hypoglycemic animals. These data suggest that acute hypoglycemia may enhance the excitotoxic effects of glutamate in the newborn.

Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals

The concentration of extracellular glucose in anesthetized rat brain was measured continuously with two types of substrate-specific microelectrodes in a number of physiological and pathological conditions. Extracellular glucose level increased in hyperglycemia and decreased in hypoglycemia, paralleling the changes in blood sugar. Increased neuronal activity and in particular spreading depression, evoked triphasic alterations in extracellular glucose concentration: an initial rapid fall was followed by an equally swift overshoot above the baseline and a subsequent return to it. Limitation in O2 supply led to a decline in extracellular content of glucose: respiration with 5% O2 reduced the level by 7-20% and that with 3% O2 by 75-85%. Decreases to undetectable concentrations were seen in ischemia despite the use of an oxygen-insensitive microglucose sensor. Restoration of oxygen supply to the brain was accompanied by increases in extracellular glucose content above the original normoxic level, which returned to baseline values after 10-15 min. In hyperglycemic animals ischemia-induced leakage of K+ was delayed while the rate of recovery to control levels after restitution of blood flow was enhanced. It is concluded that continuous monitoring of glucose with glucose-specific microelectrodes provides a new and important insight into brain energy metabolism.