Regional Cerebral Glucose Utilization During Insulin-Induced Hypoglycemia in Unanesthetized Rats

Regional cerebral glucose utilization (rCMRgl) was studied during insulin-induced hypoglycemia in unanesthetized rats. Rats were surgically prepared using halothane and nitrous oxide anesthesia and allowed 5 h to recover from the anesthesia before rCMRgl was measured. The rCMRgl was measured using [6-14C]glucose in a normoglycemic control group and two hypoglycemic groups, A (30 min after insulin injection) and B (2 h after insulin injection). The mean plasma glucose level was 7.03 mumol/ml in the normoglycemic group, 1.96 mumol/ml in hypoglycemic group A, and 1.40 mumol/ml in hypoglycemic group B. The rCMRgl in hypoglycemic group A decreased 8-18% in 17 brain regions measured; five changes were statistically significant. The rCMRgl in hypoglycemic group B decreased significantly in all but one of the brain regions measured; the decrease ranged from 15% in the pyramidal tract to 36% in the motor and auditory cortices. The rCMRgl in every brain region decreased when the plasma glucose level fell below 1.5-2.5 mumol/ml. No brain region could maintain rCMRgl at plasma glucose concentrations lower than predicted by regional glucose influx described in previous studies. Glucose utilization in all brain regions appears to be limited by the influx of glucose.     

Vascular Perfusion and Blood-Brain Glucose Transport in Acute and Chronic Hyperglycemia

We studied the effects of acute and streptozotocin-induced chronic hyperglycemia on regional brain blood flow and perfusion characteristics, and on the regional transport of glucose across the blood-brain barrier in awake rats. We found (1) a generalized decrease in regional brain blood flow in both acute and chronic hyperglycemia; (2) that chronic, but not acute, hyperglycemia is associated with a marked and diffuse decrease in brain L-glucose space; and (3) that chronic hyperglycemia does not alter blood-to-brain glucose transport. Taken together, these results suggest that in streptozotocin-induced chronic hyperglycemia, there is a reduction in the proportion of perfused brain capillaries and/or an alteration in brain endothelial membrane properties resulting in decreased noncarrier diffusion of glucose.     

Decreased cerebral blood flow and hemodynamic parameters during acute hyperglycemia in mice model observed by dual‐wavelength speckle imaging

In this study, we use dual‐wavelength optical imaging‐based laser speckle technique to assess cerebral blood flow and metabolic parameters in a mouse model of acute hyperglycemia (high blood glucose). The effect of acute glucose levels on physiological processes has been extensively described in multiple organ systems such as retina, kidney, and others. We postulated that hyperglycemia also alters brain function, which in turn can be monitored optically using dual‐wavelength laser speckle imaging (DW‐LSI) platform. DW‐LSI is a wide‐field, noncontact optical imaging modality that integrates the principles of laser flowmetry and oximetry to obtain macroscopic information such as hemoglobin concentration and blood flow. A total of eight mice (C57/BL6) were used, randomized into two groups of normoglycemia (control, n = 3) and hyperglycemia (n = 5). Hyperglycemia was induced by intraperitoneal injection of a commonly used anesthetic drug combining ketamine and xylazine (KX combo). We found that this KX combo increases blood glucose (BG) levels from 150 to 350 mg/dL, approximately, when measured 18 minutes post‐administration. BG continues to increase throughout the test period, with BG reaching an average of 463 ± 20.34 mg/dL within 60 minutes. BG levels were measured every 10 minutes from tail blood using commercially available glucometer. Experimental results demonstrated reductions in cerebral blood flow (CBF) by 55%, tissue oxygen saturation (SO₂) by 15%, and cerebral metabolic rate of oxygen (CMRO₂) by 75% following acute hyperglycemia. The observed decrease in these parameters was consistent with results reported in the literature, measured by a variety of experimental techniques. Measurements with laser Doppler flowmetry (LDF) were also performed which confirmed a reduction in CBF following acute hyperglycemia. In summary, our findings indicate that acute hyperglycemia modified brain hemodynamic response and induced significant changes in blood flow and metabolism. As far as we are aware, the implementation of the DW‐LSI to monitor brain hemodynamic and metabolic response to acute hyperglycemia in intact mouse brain has not been previously reported.      

Hyperbaric Oxygen Reduces Cerebral Blood Flow by Inactivating Nitric Oxide

Based on recent evidence that nitric oxide (NO(.)) is involved in hyperoxic vasoconstriction, we tested the hypothesis that decreases in NO(.) availability in brain tissue during hyperbaric oxygen (HBO(2)) exposure contribute to decreases in regional cerebral blood flow (rCBF). rCBF was measured in rats exposed to HBO(2) at 5 atmospheres (ATA) and correlated with interstitial brain levels of NO(.) metabolites (NO(X)) and production of hydroxyl radical ((.)OH). Changes in rCBF were also correlated with the effects of NO(.) synthase inhibitor (l-NAME), NO(.) donor PAPANONOate, and intravascular superoxide dismutase (MnSOD) during HBO(2). After 30 min of O(2) exposure at 5 ATA, rCBF had decreased in the substantia nigra, caudate putamen, hippocampus, and parietal cortex by 23 to 37%. These reductions in rCBF were not augmented by exposure to HBO(2) in animals pre-treated with l-NAME. After 30 min at 5 ATA, brain NO(X) levels had decreased by 31 +/- 9% and correlated with the decrease in rCBF, while estimated (.)OH production increased by 56 +/- 8%. The decrease in rCBF at 5 ATA was completely abolished by MnSOD administration into the circulation before HBO(2) exposure. Doses of NO(.) donor that significantly increased rCBF in animals breathing air had no effect at 5 ATA of HBO(2). These results indicate that decreases in rCBF with HBO(2) are associated with a decrease in effective NO(.) concentration and an increase in ROS production in the brain. The data support the hypothesis that inactivation of NO(.) antagonizes basal relaxation of cerebral vessels during HBO(2) exposure, although an effect of HBO(2) on NO(.) synthesis has not been excluded.     

Regional cerebral blood flow response during and after acute asphyxia in newborn piglets

The hemodynamic response during and after acute asphyxia was studied in 14 newborn piglets. An apnea-like asphyxial insult was produced in paralyzed mechanically ventilated piglets by discontinuing ventilation until the piglets became bradycardic (heart rate less than 80 beats/min). Seven piglets had organ blood flow measured by microspheres at control, during asphyxia (PO2 = 16 +/- 11 Torr, pH = 7.31 +/- 0.07, PCO2 = 47 +/- 9 Torr), and during recovery from asphyxia. During acute asphyxia, rapid organ blood flow redistribution occurred, producing decreased renal and skeletal muscle blood flow, while coronary blood flow increased. Although total brain blood flow changed little during asphyxia, regional cerebral blood flow (rCBF) analysis revealed significant nonhomogeneous blood flow distribution within the brain during asphyxia, with decreases to the cerebral gray and white matter and the choroid plexus, whereas brain stem structures had increased flow. During recovery with reventilation, total brain blood flow increased 24% above control, with a more uniform distribution and increased flow to all brain regions. The time course of rCBF changes during acute asphyxia was then determined in seven additional piglets with CBF measurements made sequentially at 30-60 s, 60-120 s, and 120-180 s of asphyxia. The vasoconstriction seen in cortical structures, concurrent with the reduction in skeletal and kidney blood flow, known to be sympathetically mediated, suggest a selective reflex effect in this brain region. The more gradual and progressive vasodilation in brain stem regions during asphyxia is consistent with chemical control. These findings demonstrate significant regional heterogeneity in CBF regulation in newborn piglets.     

Effects of acute and chronic hyperglycemia on the neurochemical profiles in the rat brain with streptozotocin-induced diabetes detected using in vivo ¹H MR spectroscopy at 9.4 T

Chronic hyperglycemia could lead to cerebral metabolic alterations and CNS injury. However, findings of metabolic alterations in poorly managed diabetes in humans and animal models are rather inconsistent. We have characterized the cerebral metabolic consequences of untreated hyperglycemia from the onset to the chronic stage in a streptozotocin-induced rat model of diabetes. In vivo 1H magnetic resonance spectroscopy was used to measure over 20 neurochemicals longitudinally. Upon the onset of hyperglycemia (acute state), increases in brain glucose levels were accompanied by increases in osmolytes and ketone bodies, all of which remained consistently high through the chronic state of over 10 weeks of hyperglycemia. Only after over 4 weeks of hyperglycemia, the levels of other neurochemicals including N-acetylaspartate and glutathione were significantly reduced and these alterations persisted into the chronic stage. However, glucose transport was not altered in chronic hyperglycemia of over 10 weeks. When glucose levels were acutely restored to euglycemia, some neurochemical changes were irreversible, indicating the impact of prolonged uncontrolled hyperglycemia on the CNS. Furthermore, progressive changes in neurochemical levels from control to acute and chronic conditions demonstrated the utility of 1H magnetic resonance spectroscopy as a non-invasive tool in monitoring the disease progression in diabetes.     

Chloramphenicol decreases brain glucose utilization and modifies the sleep-wake cycle architecture in rats

We studied the effects of chloramphenicol on brain glucose utilization and sleep-wake cycles in rat. After slightly anaesthetized animals were injected with [18F]fluoro-2-deoxy-D-glucose, we acquired time-concentration curves from three radiosensitive beta microprobes inserted into the right and left frontal cortices and the cerebellum, and applied a three-compartment model to calculate the cerebral metabolic rates for glucose. The sleep-wake cycle architecture was analysed in anaesthetic-free rats by recording electroencephalographic and electromyographic signals. Although chloramphenicol is a well-established inhibitor of oxidative phosphorylation, no compensatory increase in glucose utilization was detected in frontal cortex. Instead, chloramphenicol induced a significant 23% decrease in the regional cerebral metabolic rate for glucose. Such a metabolic response indicates a potential mismatch between energy supply and neuronal activity induced by chloramphenicol administration. Regarding sleep-wake states, chloramphenicol treatment was followed by a 64% increase in waking, a 20% decrease in slow-wave sleep, and a marked 59% loss in paradoxical sleep. Spectral analysis of the electroencephalogram indicates that chloramphenicol induces long-lasting modifications of delta-band power during slow-wave sleep.     

Haloperidol and Cerebral Metabolism in the Conscious Rat: Relation to Pharmacokinetics

The time course and distribution of alterations in cerebral metabolic activity after haloperidol administration were evaluated in relation to the pharmacokinetics of haloperidol and the topography of the dopaminergic system in the brain. Local cerebral glucose utilization was measured, using the 2-deoxyglucose technique, in awake rats after i.p. administration of the dopamine antagonist haloperidol (0.5 or 1 mg/kg). Haloperidol significantly reduced glucose utilization in 60% of 59 brain regions examined, but produced a large increase in the lateral habenula. The regional distribution of changes in glucose utilization was not closely related to the known anatomy of the brain dopaminergic system. The time course of the effect of haloperidol on cerebral metabolism was different for the two doses studied (0.5 and 1 mg/kg), and was not simply related to estimated brain concentrations of haloperidol. However, a linear relation between the metabolic effect and the time-integrated brain concentration was demonstrated. These results show that haloperidol has an effect on CNS metabolic activity that is more widespread than would be predicted from the topography of the dopaminergic system; this may be due to indirect propagation of the primary effects of haloperidol. The metabolic response to haloperidol depends on brain concentration and duration of exposure to the drug.     

Changes in the Redox State in the Retina and Brain During the Onset of Diabetes in Rats

Diabetic retinopathy is thought to result from chronic changes in the metabolic pathways of the retina. Hyperglycemia leads to increased intracellular glucose concentrations, alterations in glucose degradation and an increase in lactate/pyruvate ratio. We measured lactate content in retina and other ocular and non-ocular tissues from normal and diabetic rats in the early stages of streptozotocin-induced diabetes. The intracellular redox state was calculated from the cytoplasmic [lactate]/[pyruvate] ratio.Elevated lactate concentration were found in retina and cerebral cortex from diabetic rats. These concentrations led to a significant and progressive decrease in the NAD⁺/NADH ratio, suggesting that altered glucose metabolism is an initial step of retinopathy. It is thus possible that tissues such as cerebral cortex have mechanisms that prevent the damaging effect of lactate produced by hyperglycemia and/or alterations of the intracellular redox state     

The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans.

PACAP (10 pmol kg^− 1 min^− 1) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and ¹³³Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO₂ (P_etCO₂) and vital parameters were recorded throughout the 2 hour study period.

PACAP38 decreased rCBF in all regions of interest (ROIs) by  3–10%, though not uniformly significant. P_etCO₂ decreased significantly during PACAP38 infusion compared to placebo (P = 0.032), peak decrease was 8.9 ± 3.8%. After correction for P_etCO₂, rCBF remained unchanged in most ROIs. Heart rate increased 61.9 ± 22.4% (P < 0.0001 vs. placebo).

These findings suggest that PACAP38 has no major direct effect on rCBF in healthy volunteers. The marked increase in heart rate and the reduction in rCBF caused by decreased P_etCO₂ are important dose-limiting factors to consider in future clinical studies.     

In vivo tracer studies of glucose metabolism,cerebral blood flow,and protein synthesis in naloxone precipitated morphine withdrawal

Quantitative autoradiography of [¹⁴C]deoxyglucose, [¹⁴C]iodoantipyrine, and [¹⁴C]leucine was used to estimate regional cerebral glucose metabolism, cerebral blood flow, and cerebral protein synthesis, respectively, in rats during morphine dependence and withdrawal. Glucose metabolism was elevated in 19 of 26 selected brain regions; the elevations in glucose metabolism were similar when data were expressed as either optical density ratios or as calculated rate values of mol/100 gm/min. Restraining the rats produced heterogeneous effects on glucose metabolism during morphine withdrawal (MW). Neither estimated cerebral blood flow nor cerebral protein synthesis were affected by morphine and/or naloxone treatments in either naive or morphine-dependent rats. The data demonstrate that changes in regional cerebral glucose utilization occur independently of blood flow changes and exclude the possibility that regional changes in glucose utilization occur as a consequence of large regional changes in protein synthesis rates in brain. These data confirm the utility of 2-deoxyglucose measures of MW as objective biochemical indices of opiate agonist and antagonist effects in vivo.     

Tissue glucose utilization during epinephrine-induced hyperglycemia

The aim of this study was to investigate glucose utilization by individual tissues during epinephrine infusion. First, the applicability of the 2-deoxyglucose (2-DG) tracer technique during in vivo hyperglycemia was investigated in model systems in vitro. Epitrochlearis muscle and spleen cells were incubated with 1.25-20 mM glucose. The discrimination against 2-[14C]DG in glucose metabolic pathways, expressed by the lumped constant, remained unchanged over this wide range of glucose concentrations. It was concluded that in vivo hyperglycemia does not preclude the application of the 2-DG method. In a series of in vivo experiments, chronically catheterized conscious rats fasted for 24 h and were infused with epinephrine (0.2 microgram.kg-1.min-1), which produced a two-fold increase in plasma glucose concentration. 2-[14C]DG was injected 30 min after starting the epinephrine infusion and glucose utilization rates of individual tissues were calculated based on the concentration of phosphorylated 2-DG in samples excised at 70 min. The epinephrine infusion increased glucose utilization rates by 40-160% in hindlimb muscles, skin, ileum, liver, spleen, lung, epididymal fat, and kidney, although no change was found in the brain. Mass action of the increased plasma glucose is likely to play an important role in the enhanced rate of glucose utilization.     

Study of insulin response to oral glucose load after acute and chronic glycemic control in type 2 diabetic subjects

To investigate whether correction of fasting hyperglycemia per se improves the insulin secretion in type 2 diabetic subjects, plasma insulin response to 75 g oral glucose load has been studied after acute and chronic normalization of fasting plasma glucose levels in 7 overt type 2 diabetic subjects. For the acute normalization of elevated fasting plasma glucose levels, an artificial endocrine pancreas was employed. Although fasting plasma glucose concentrations were normalized before the oral glucose challenge, insulin response to oral glucose was not improved compared to those without normalization of fasting plasma glucose levels. After 1-3 month control of hyperglycemia, the insulin response to glucose in the subjects was significantly improved compared to those without treatments. Results indicate that chronic metabolic control is essential for the improvement of insulin response to glucose in type 2 diabetic subjects, and also suggest that the impaired insulin secretion in type 2 diabetes is not due to hyperglycemia per se, but due to the metabolic derangements which lead to chronic hyperglycemia.     

Regional Cerebral Glucose Metabolism and Blood Flow During the Silent Phase of Methylmercury Neurotoxicity in Rats

Methylmercuric chloride was given to rats in a neurotoxic dose regimen (six daily doses of 8 mg kg-1 p.o.). During the silent (asymptomatic) phase of intoxication, the rates of cerebral glucose influx and cerebral glucose phosphorylation were measured simultaneously using 2-deoxyglucose. Regional cerebral blood flow was also measured using iodoantipyrine. The unidirectional flux of glucose into brain was not affected by methylmercury, and differences in the rates of glucose phosphorylation from region to region remained coupled to the regional cerebral blood flow. However, the blood flow was reduced throughout the brain, an observation suggesting that the operational level of metabolically regulated blood flow had been reset. Thus, in spite of a generalised reduction in blood flow, there was no indication of impaired cerebral glucose supply or utilization during the silent phase of methylmercury intoxication.     

Simultaneous measurement of glucose transport and utilization in the human brain

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K(M)(t) and V(max)(t), in humans have so far been obtained by measuring steady-state brain glucose levels by proton ((1)H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMR(glc)) obtained from other tracer studies, such as (13)C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state (1)H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ～17 mmol/l for ～2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMR(glc), this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain.     

Extension of the 2-Deoxyglucose Method to the Fetus in Utero: Theory and Normal Values for the Cerebral Glucose Consumption in Fetal Guinea Pigs

Abstract: Fetal cerebral metabolism changes during development. The normal fetal metabolic rate must be known to evaluate pathophysiological changes. Therefore, we determined the regional cerebral glucose consumption in the fetal guinea pig. This required the application of the 2-deoxyglucose method to this species. We measured both the transfer coefficients of deoxyglucose and glucose between the maternal arterial plasma and the fetal brain and the lumped constant in chronically prepared undisturbed guinea pig dams using a three-compartment model. Furthermore, the ratio between the initial clearances of deoxyglucose and glucose between the maternal arterial plasma and the fetal brain and the ratio between the phosphorylation coefficients of these substrates in the fetal brain were determined. The total cerebral glucose consumption measured by the deoxyglucose method (10 ± 1.2 µmol/100 g/min) was similar to that calculated from the glucose concentration and the phosphorylation coefficient of glucose in the cerebrum (10 ± 0.4 µmol/100 g/min). We conclude that the 2-deoxyglucose method is applicable to the guinea pig, and we further conclude that in the fetal guinea pig cerebral glucose consumption is 10 times lower than that in the adult.     

Chronic hyperglycemia reduces substrate oxidation and impairs metabolic switching of human myotubes

Skeletal muscle of insulin resistant individuals is characterized by lower fasting lipid oxidation and reduced ability to switch between lipid and glucose oxidation. The purpose of the present study was to examine if chronic hyperglycemia would impair metabolic switching of myotubes. Human myotubes were treated with or without chronic hyperglycemia (20 mmol/l glucose for 4 days), and metabolism of [¹⁴C]oleic acid (OA) and [¹⁴C]glucose was studied. Myotubes exposed to chronic hyperglycemia showed a significantly reduced OA uptake and oxidation to CO₂, whereas acid-soluble metabolites were increased compared to normoglycemic cells (5.5 mmol/l glucose). Glucose suppressibility, the ability of acute glucose (5 mmol/l) to suppress lipid oxidation, was 50% in normoglycemic cells and reduced to 21% by hyperglycemia. Adaptability, the capacity to increase lipid oxidation with increasing fatty acid availability, was not affected by hyperglycemia. Glucose uptake and oxidation were reduced by about 40% after hyperglycemia, and oxidation of glucose in presence of mitochondrial uncouplers showed that net and maximal oxidative capacities were significantly reduced. Hyperglycemia also abolished insulin-stimulated glucose uptake. Moreover, ATP concentration was reduced by 25% after hyperglycemia. However, none of the measured mitochondrial genes were downregulated nor was mitochondrial DNA content. Microarray and real-time RT-PCR showed that no genes were significantly regulated by chronic hyperglycemia. Addition of chronic lactate reduced both glucose and OA oxidation to the same extent as hyperglycemia. In conclusion, chronic hyperglycemia reduced substrate oxidation in skeletal muscle cells and impaired metabolic switching. The effect is most likely due to an induced mitochondrial dysfunction.     

The effect of audiogenic seizures on regional CNS energy reserves, glycolysis and citric acid cycle flux

Selected energy reserves, glycolytic intermediates and citric acid cycle intermediates were measured in the cerebral cortex, thalamus, brain stem, cerebellum and spinal cord of susceptible mice during audiogenic seizures. Changes in energy reserves (ATP, phosphocreatine and glucose) differed strikingly in extent and temporal pattern from region to region. The audiogenic seizure produced a transient, large decrease in thalamic energy reserves during the early, pretonic phase of the seizure. Less extensive decreases were observed in brain stem and spinal cord; but in these latter regions the changes persisted throughout the pretonic and tonic phases of the seizures. In cerebellum there was a biphasic decrease in energy reserves; a small decrease was observed immediately after the sound stimulus and a second much greater decrease was observed during the tonic phase of the seizure. No change in energy reserves was observed in cerebral cortex. Changes in glycolytic intermediates (glucose 6-phosphate, fructose diphosphate, pyruvate and lactate) also varied from region to region in response to the decreases in energy reserves. In contrast, changes in the two citric acid cycle intermediates, α-oxoglutarate and malate, were essentially the same in all regions studied. α-Oxoglutarate decreased during the tonic phase of the seizure and rose during recovery. Malate remained at control levels throughout the seizure and then slowly increased. These findings are interpreted as indicating regional variations in nueronal activity during audiogenic seizures. During the period when clinical seizure activity is apparent neuronal activity increases in the subcortical regions. This is reflected by an increase in energy utilization and an increase in glycolytic flux in these areas. However, a concomitant increase in citric acid cycle flux does not seem to occur during this period. Citric acid cycle flux does appear to increase after the seizure is over.     

Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep

Brain uptake of substrates other than glucose has been demonstrated in neonatal but not fetal animals in vivo. This study was undertaken to investigate the ability of the fetal sheep brain to use potential alternative substrates when they were provided in increased amounts. Brain substrate uptake was measured in chronically catheterised fetal sheep during 2-h infusions of neutralised lactate (n = 12) or beta-hydroxybutyrate (n = 12). Despite large increases in fetal arterial lactate and beta-hydroxybutyrate during the respective infusions, no significant uptake of either substrate was demonstrated. However during both types of infusion, the brain arterio-venous difference for glucose decreased 30% (P less than 0.05). Since the brain arterio-venous difference for oxygen was unchanged, and blood flow to the cerebral hemispheres (measured in 11 studies) was also unchanged, the infusions appeared to cause a true decrease in brain glucose uptake. This decrease paralleled the rise in lactate concentration during lactate infusions, and the rise in lactate and butyrate concentrations during the butyrate infusions. Both substrates have metabolic actions that may inhibit brain glucose uptake. We speculate that the deleterious effects of high lactate and ketone states in the perinatal period may in part be due to inhibition of brain glucose uptake.     

Effect of chronic hypernatremic dehydration and rapid rehydration on brain carbohydrate, energy, and amino acid metabolism in weanling mice

Abstract: This is a study of the effects of chronic hypernatremic dehydration and rehydration on carbohydrate, energy, and amino acid metabolism in the brains of weanling mice. Chronic hypernatremic dehydration induced by 4 days of water deprivation and salt loading was associated with severe weight loss (no other observed clinical effects), increased brain Na⁺ levels, and a decreased brain water content. Changes in the concentrations of brain glucose, glycolytic and citric acid cycle metabolic intermediates, and phosphocreatine were compatible with reduced cerebral metabolic rate. In adaptation to chronic hypernatremia, there was a significant increase in the content of the measured brain amino acids. Rapid rehydration over a 4-h period with 2.5% dextrose in water returned plasma Na⁺ levels and brain Na⁺ and water contents to normal. After rehydration, metabolites were altered in a manner consistent with increased fluxes through the glycolytic pathway and citric acid cycle; the brain glycogen content almost tripled. Brain taurine and glutamine levels were not lowered by rehydration, and the total content of the measured amino acids in brain was still significantly higher than in controls. We speculate that these metabolic perturbations may relate to the development of cerebral edema and seizures or coma following rapid rehydration of humans with chronic hypernatremic dehydration.