Brain Glucose Concentrations Research Articles

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

Rates of glucose utilization (lCMRglc) in many structures of the brain of fed, portacaval-shunted rats, when assayed with the [14C]deoxyglucose (DG) method in our laboratory, were previously found to be unchanged (30 of 36 structures) or depressed (6 structures) during the first 4 weeks after shunting, but to rise progressively to higher than normal values in 25 of 36 structures from 4-12 weeks. In contrast, lCMRglc, when assayed with the [14C]glucose method in another laboratory, was depressed in most structures of brains of 4-8-week shunted rats that had relatively high brain ammonia levels. There was a possibility that the increases in lCMRglc obtained with the [14C]DG method may have been artifactual, due, in part, to a change in brain glucose content which could alter the value of the lumped constant of the DG method. Brain glucose levels of shunted rats were, therefore, assayed by both direct chemical measurement in freeze-blown samples and by determination of steady-state brain:plasma distribution ratios for [14C]methylglucose; the methylglucose distribution ratio varies as a function of plasma and tissue glucose contents. Within a week after shunting, ammonia levels in blood and brain rose to 0.25-0.30 mM and 0.35-0.70 mumol/g, respectively, and mean plasma glucose levels fell from 9-10 mM to 7.4-8.5 mM, and then remained nearly constant. Brains of fed-shunted rats had normal glycogen levels and stable but moderately reduced glucose contents between 1 and 12 weeks (i.e., 1.9-2.2 mumol/g). [14C]Methylglucose distribution ratios were essentially the same as those in controls in 22 brain structures at 2 and 8 weeks after shunting. Because brain glucose levels remained stable from 1 to 12 weeks after shunting, there is no evidence to support the hypothesis that the value of the lumped constant would have changed and caused an artifactual rise in lCMRglc.

Effects of acute treatments with haloperidol and sulpiride on extracellular glucose and lactate concentration in the rat brain

Effects of acute treatments with haloperidol and sulpiride on extracellular glucose and lactate concentration in the rat brain

Localized 1H NMR measurement of glucose consumption in the human brain during visual stimulation.

Spatially localized 1H NMR spectroscopy has been applied to measure changes in brain glucose concentration during 8-Hz photic stimulation. NMR spectroscopic measurements were made in a 12-cm3 volume centered on the calcarine fissure and encompassing the primary visual cortex. The average maximum change in glucose levels was 0.34 mumol.g-1 (n = 5) at 15 min; glucose level had turned toward resting level at 25 min. The glucose change was used to calculate the increase of glucose cerebral metabolic rate in the visual cortex region for individual subjects by using the Michaelis-Menten model of glucose transport on the assumption of constant transport kinetics. The glucose cerebral metabolic rate was calculated to increase over the nonstimulated rate by 22% during the first 15 min of photic stimulation. A model in which the glucose metabolic rate gradually decreases during stimulation was proposed as a possible explanation for the recovery of brain glucose and previously measured lactate concentrations to prestimulus values after 15 min.

Sympathetic Activity Enhances Glucose-related Ischemic Injury in the Rat

Studies have shown that increased sympathetic activity or increased blood and brain glucose concentration worsen postischemic brain damage. The authors evaluated the interaction of plasma glucose with epinephrine and norepinephrine during incomplete cerebral ischemia in the rat using ganglionic blockade. Rats were anesthetized with 25 micrograms.kg-1.h-1 fentanyl and 70% nitrous oxide in oxygen. Ganglionic blockade was produced in 30 rats using 8 mg/kg hexamethonium intravenously. Three plasma glucose ranges, low < 150 mg/dl, moderate = 150-300 mg/dl, and high > 300 mg/dl, were produced in each group. Ischemia was induced by unilateral carotid ligation and hemorrhagic hypotension to 30 mmHg for 30 min. Plasma norepinephrine and epinephrine were measured by radioimmunoassay. Neurologic outcome was evaluated daily for 3 days after ischemia. Ganglionic blockade decreased blood pressure before the start of ischemia and plasma epinephrine and norepinephrine during ischemia (P < 0.05). Neurologic outcome was significantly worse in rats with high glucose compared with low glucose concentrations with and without ganglionic blockade (P < 0.05). Neurologic outcome and stroke-related mortality were worse in rats with increased plasma epinephrine and norepinephrine compared with rats with ganglionic blockade when plasma glucose was less than 300 mg/dl (P < 0.05). These results indicate that increased concentration of catecholamines enhance glucose-related injury during incomplete ischemia in rats.

Nuclear magnetic resonance imaging and spectroscopy of human brain function.

The techniques of in vivo magnetic resonance (MR) imaging and spectroscopy have been established over the past two decades. Recent applications of these methods to study human brain function have become a rapidly growing area of research. The development of methods using standard MR contrast agents within the cerebral vasculature has allowed measurements of regional cerebral blood volume (rCBV), which are activity dependent. Subsequent investigations linked the MR relaxation properties of brain tissue to blood oxygenation levels which are also modulated by consumption and blood flow (rCBF). These methods have allowed mapping of brain activity in human visual and motor cortex as well as in areas of the frontal lobe involved in language. The methods have high enough spatial and temporal sensitivity to be used in individual subjects. MR spectroscopy of proton and carbon-13 nuclei has been used to measure rates of glucose transport and metabolism in the human brain. The steady-state measurements of brain glucose concentrations can be used to monitor the glycolytic flux, whereas subsequent glucose metabolism--i.e., the flux into the cerebral glutamate pool--can be used to measure tricarboxylic acid cycle flux. Under visual stimulation the concentration of lactate in the visual cortex has been shown to increase by MR spectroscopy. This increase is compatible with an increase of anaerobic glycolysis under these conditions as earlier proposed from positron emission tomography studies. It is shown how MR spectroscopy can extend this understanding of brain metabolism.

NMR-spectroscopic investigation of cerebral reanimation after prolonged ischemia.

The severity of brain injury following interruption of blood flow depends on a number of ischemic and post-ischemic variables. The most important ischemic variables are the duration of ischemia, the amount of residual blood flow, the type and depth of anesthesia, brain glucose content and temperature. Among the post-ischemic factors the no-reflow phenomenon, edema and a variety of biochemical disturbances are of particular importance. Due to the complex interaction of these factors irreversible brain injury usually occurs after less than 10 min cerebrocirculatory arrest in normothermia. However, the safe ischemia time of the brain can be substantially extended when appropriate therapeutic measures are used to alleviate post-ischemic injury. NMR-spectroscopy is particularly suited for the analysis of this process. Recording of 31P, 1H and 19F spectra allow the continuous non-invasive assessment of such basic parameters as brain energy state, tissue pH, the content of lactate and blood flow (using Freon-23 as an inert tracer). In addition, information is obtained about changes in the content of phosphomonoesters and -diesters, glutamate, glutamine, aspartate and N-acetyl aspartate. These measurements can be combined with in vivo electrophysiological and post-mortem biochemical investigations for the further refinement of functional/metabolic monitoring. We have used this approach to study the potentials of post-ischemic resuscitation after one hour complete ischemia of the normothermic cat brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct measurement of brain glucose concentrations in humans by 13 C NMR spectroscopy

Direct measurement of brain glucose concentrations in humans by ¹³ C NMR spectroscopy

Correction: Direct Measurement of Brain Glucose Concentrations in Humans by 13C NMR Spectroscopy

Correction: Direct Measurement of Brain Glucose Concentrations in Humans by 13C NMR Spectroscopy

Postischemic hyperglycemia is not protective to the neonatal rat brain.

Brain glucose concentration during and after hypoxia-ischemia may be one of the variables affecting outcome of asphyxial insults. Glucose given before global ischemic forebrain injury to adult rats increases morphologic brain damage, and postischemic insulin administration reduces selective neuronal necrosis and cortical infarction. Because glucose infusions are routinely used in the clinical management of perinatal asphyxia, we evaluated the role of glucose administration after ischemic neuronal damage to neonatal rat brain. Sprague-Dawley rat pups (postnatal d 7) were subjected to left common carotid artery ligation followed by 2.5 h of 8% oxygen (Levine procedure). The experimental group was subdivided so that pups received either systemic injections of glucose or saline immediately after the hypoxic insult. Animals were killed on postnatal d 12 and brain areas of ipsi- and contralateral cortex and caudate were calculated from camera lucida tracings. There was no significant difference in size of brain infarction between postischemic glucose-treated and post-ischemic saline-treated pups. However, hypoxic-ischemic brains did show more severe neuronal damage when hyperglycemia was induced after asphyxia. Because post-ischemic hyperglycemia does not attenuate and may exacerbate injury, we recommend careful monitoring of blood glucose so that hyperglycemia does not occur during resuscitation of asphyxiated infants.

In vivo identification and monitoring of changes in rat brain glucose by two-dimensional shift-correlated 1H NMR spectroscopy.

Intracerebral glucose resonance was directly detected and resolved in vivo by two-dimensional shift-correlated (COSY) 1H NMR spectroscopy in anesthetized rats (n = 4). The relative changes in brain glucose concentration were measured by volume integration of the alpha-D-glucose cross peak in the 2D COSY spectra. This report demonstrates the possibility of monitoring the variations in cerebral glucose following iv injection of glucose.

An Overview of Minimally Invasive Technologies

Self-measurement of blood glucose is an integral part of diabetes mellitus therapy. As many as 65% of diabetic people (4-5 million people) perform some degree of self-monitoring and approximately 20-30% do so frequently. Most patients consider this the most onerous part of their diabetes therapy. It requires obtaining blood, frequently in public, and is usually the most painful part of therapy, being significantly more painful than insulin self-administration. Patients therefore are anxious for a less-invasive method for glucose measurement. Methods exist or are being developed for minimally invasive glucose monitoring, which use body fluids other than blood (e.g., sweat and saliva), subcutaneous tissue, or blood measured less invasively. Sweat and saliva are relatively easily obtained but their glucose concentration lags significantly behind blood glucose. Methods to increase sweating have been developed and seem to increase the timeliness of the sweat glucose measurement. Subcutaneous glucose measurement seems to lag only a few minutes behind blood glucose and may actually be a better measurement of the critical values of glucose concentrations in brain, muscle, and other tissue. Glucose can be measured by noninvasive or minimally invasive methods, such as those making skin or mucous membranes permeable to glucose or those placing a reporter molecule in the subcutaneous tissue. Needle-type sensors have been improved in accuracy, size, and stability and can be placed into the subcutaneous tissue or peripheral veins to monitor blood glucose with miniature instruments.

Autoradiographic determination of glucose content and estimation of the lumped constant in intracerebral neuronal tissue transplants

The quasi-steady-state distribution volume of brain glucose was measured using3- O-[ 14C]methylglucose quantitative autoradiography in a group of rats ( n = 5) which 12–15 weeks previously had undergone unilateral ibotenic acid-induced lesion of the nucleus basalis magnocellularis, followed by implantation into ipsilateral neocortex of primordial basal forebrain cell suspensions. The effects of the lesion and the presence of transplanted tissue in neocortex were visualized by acetylcholinesterase histochemistry. The3- O-[ 14C]methylglucose tracer was distributed homogeneously throughout the host brain areas analysed, with no side-to-side differences, despite a marked unilateral depletion of acetylcholinesterase activity ipsilateral to the lesion site. Whilst the transplants were indistinguishable from the homogeneity of surrounding host frontal cortex, there was a 70% increase in the apparent distribution volume of methylglucose localized around the ibotenate injection site and associated needle tract. Brain glucose content is an important experimental variable affecting the lumped constant of the 2-deoxyglucose technique. There was no evidence of any significant difference in the lumped constant between transplant and host tissue which might compromise the validity of the 2-deoxyglucose technique when used together with intracerebral implantation of fetal neuronal cell suspensions.

Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy.

Glucose is the main fuel for energy metabolism in the normal human brain. It is generally assumed that glucose transport into the brain is not rate-limiting for metabolism. Since brain glucose concentrations cannot be determined directly by radiotracer techniques, we used 13C NMR spectroscopy after infusing enriched D-[1-13C]glucose to measure brain glucose concentrations at euglycemia and at hyperglycemia (range, 4.5-12.1 mM) in six healthy children (13-16 years old). Brain glucose concentrations averaged 1.0 +/- 0.1 mumol/ml at euglycemia (4.7 +/- 0.3 mM plasma) and 1.8-2.7 mumol/ml at hyperglycemia (7.3-12.1 mM plasma). Michaelis-Menten parameters of transport were calculated to be Kt = 6.2 +/- 1.7 mM and Tmax = 1.2 +/- 0.1 mumol/g.min from the relationship between plasma and brain glucose concentrations. The brain glucose concentrations and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels greater than 3 mM.

The Effects of Insulin Infusion on Plasma and Brain Glucose in Hyperglycemic Diabetic Rats A Comparison with Placebo-treated Diabetic and Nondiabetic Rats

Experimental and clinical studies have revealed a worsened neurologic outcome after cerebral ischemia in hyperglycemic subjects, including hyperglycemic diabetic subjects. A possible therapy to reduce the magnitude of ischemic brain injury in diabetic subjects would be to use an insulin infusion to reduce brain glucose concentrations to values found in those who are normoglycemic and non-diabetic. The present study, using hyperglycemic diabetic rats, examined the effect of an insulin infusion on plasma and brain glucose concentrations to determine their relationship while plasma glucose concentrations decreased. In addition, plasma and brain glucose concentrations were compared to those in diabetic and nondiabetic rats treated with saline. Saline had no effect on the plasma or brain glucose concentrations in the diabetic rats or nondiabetic rats. The saline-treated diabetic rats had increased plasma and brain glucose concentrations as well as an increased brain-to-plasma glucose ratio when compared to the saline-treated nondiabetic rats. When an insulin infusion was used in diabetic rats to decrease plasma glucose to nondiabetic levels over approximately 2 h, the brain glucose concentration decreased. However, the brain-to-plasma glucose ratio remained at the "diabetic" value, so that the brain glucose concentration tended to remain increased when compared to normoglycemic, nondiabetic rats. We conclude that if these results are applicable to humans, measurement of plasma glucose in diabetic patients will underestimate the amount of glucose in the brain and this relationship will not be influenced by acute insulin therapy.

Effects of Focal Cortical Freezing Lesion on Regional Energy Metabolism

Freezing lesions have been shown to cause a depression in glucose use, particularly in cortical areas of the brain ipsilateral to the lesion, and this effect was interpreted to be caused by a depressed functional activity in these regions. The metabolic status of the affected areas has not been previously examined and could be a factor in the observed changes in local CMRglc. In frozen-cut and dried sections taken from brains 3 days after freeze lesioning, discrete pieces of the median and lateral parietal cortex, striatum, hippocampus, and hypothalamus were dissected and analyzed for ATP, P-creatine, glucose, and lactate. CMRglc measurements were also made in the same animals. The concentrations of the four metabolites were significantly increased in the lesioned hemisphere, with the most predominant effects observed in the cortical areas that exhibited the greatest depression in CMRglc. The enriched metabolite profile, particularly in the cortical areas, is consistent with the hypothesis that decreased glucose use in the traumatized brain is caused by diminished need rather than by decreased supply of energy. Because the lumped constant in the operational equation of the deoxyglucose method for determination of CMRglc is a function of brain glucose content and decreases gradually in hyperglycemia, the degree of metabolic depression in cortical areas of lesioned hemisphere probably have been somewhat overestimated in this and previous publications. However, provisionally recalculated local CMRglc in the lesioned hemisphere remain significantly lower than in the contralateral hemisphere and in the normal brain.

One‐Line Monitoring of Extracellular Brain Glucose Using Microdialysis and a NADPH‐Linked Enzymatic Assay

A method to monitor extracellular glucose in freely moving rats, based on intracerebral microdialysis coupled to an enzyme reactor is described. The dialysate is continuously mixed with a solution containing the enzymes hexokinase and glucose-6-phosphate dehydrogenase, and the fluorescence of NADPH formed enables the on-line registration of extracellular glucose. The method is applied to monitor changes in extracellular brain glucose during the infusion of glucose, electrically induced seizure, immobilization stress, and repetitive hypoxia. After glucose loading or after seizure, hippocampus dialysate glucose concentration was increased transiently. During immobilization, there was a short-lasting decrease and, thereafter, an increase in the extracellular hippocampus glucose. During repetitive hypoxia in rats with a unilaterally occluded carotid artery, the content of glucose of striatal dialysates followed closely changes in blood pressure. These results illustrate the usefulness of the method in studying changes in brain glucose concentrations under pathological and physiological conditions.

Glucose transporter gene expression in rat brain: Pretranslational changes associated with chronic insulin-induced hypoglycemia, fasting, and diabetes

Steady-state levels of the major glucose transporter gene (GLUT-1) of the brain were evaluated under three conditions that induced chronic changes in plasma glucose and insulin in adult rats: (i) repeated injection of insulin for 5 days, resulting in plasma glucose levels of 60–70 mg/dl for at least 3 days; (ii) fasting for 3 days; and (iii) moderate streptozotocin-induced diabetes of 1 week duration. Brain GLUT-1 mRNA was measured by dot blot hybridization with a HepG2/erythrocyte (GLUT1) [32P]cRNA probe, and GLUT-1 protein by immunoblot analysis with a polyclonal antibody (11493). Insulin injection resulted in hypoglycemia, increased GLUT-1 mRNA (143 ± 15%, P < 0.05), and increased GLUT-1 protein (141 ± 6%, P < 0.05). The increase in GLUT-1 mRNA was specific for brain, as no change was observed in liver or kidney. Fasting resulted in mild hypoglycemia, lower plasma insulin, increased GLUT-1 mRNA (131 ± 17%, P < 0.05 vs control), and no change in GLUT-1 protein (125 ± 9%, N.S.). Mild streptozotocin diabetes resulted in hyperglycemia, undetectable plasma insulin, decreased GLUT-1 mRNA (65 ± 6%, P < 0.05 vs control), and no change in GLUT-1 protein (84 ± 9%, N.S.). A negative correlation (r = −0.61, P < .0001) between GLUT-1 mRNA levels in brain and plasma glucose concentrations was observed among the three experimental groups and control animals, suggesting that the plasma glucose concentration may be at least one determinant of GLUT-1 levels in rat brain. The importance of these results is the finding that GLUT-1 gene expression in rat brain is regulated in vivo by the nutritional and endocrine status of the animal.

Glucose concentrations in brain and blood: regulation by dopamine receptor subtypes

The stimulation of D 1 and D 2 dopamine (DA) receptors by selective agonists produced large increases in brain glucose concentrations. D 2 receptor stimulation also produced large increases in blood glucose. The D 1-induced increases were somewhat variable in normal animals, but were more reliably observed and greatly increased in animals with brain DA depletions. Blockade of D 1 receptors prevented these increases. Likewise, centrally acting D 2 antagonists, but not the peripheral D 2 antagonist domperidone, prevented D 2 agonist-induced increases in brain and blood glucose. These observations point to an important role for DA in the regulation of glucose homeostatis.

Effects of insulin on blood, plasma, and brain glucose in hyperglycemic diabetic rats.

This study, in biologically bred hyperglycemic diabetic rats, examined the effect of a intravenous insulin infusion (1.5 units.hr-1) on blood, plasma, and brain glucose concentrations to determine their relationship during decreasing blood and plasma glucose levels. The data were compared to saline-treated diabetic rats and saline-treated nondiabetic littermates. The volume and duration of the treatment infusion were similar in all groups. Insulin infusion in diabetic rats produced the expected reduction in blood and plasma glucose, and normoglycemia was produced within 78 +/- 37 minutes (mean +/- SD). However, once normoglycemia was achieved, brain glucose was still significantly greater by 44% than in nondiabetic rats (p = 0.015). Moreover, the ratio of brain to plasma glucose was more than 50% greater in diabetic than nondiabetic rats, irrespective of whether or not they received insulin (p less than 0.01). We conclude that measurement of blood or plasma glucose in diabetic subjects will tend to underestimate the amount of glucose in the brain and that this relationship is not influenced by acute insulin therapy.

Modeling the Dependence of Hexose Distribution Volumes in Brain on Plasma Glucose Concentration: Implications for Estimation of the Local 2-Deoxyglucose Lumped Constant

The steady-state distribution volumes of glucose, 3-O-methylglucose, and 2-deoxyglucose (2DG) are known to change as the concentration of glucose in plasma ranges from hypo- to hyperglycemic values. Model estimates of the three distribution volumes were compared with distribution volume values experimentally measured in the brains of conscious rats as the concentration of glucose in plasma was varied from 2 to 28 mM. The dependence on plasma glucose concentration of the 2DG lumped constant, the factor that relates the phosphorylation rate of 2DG to the net rate of glucose utilization at unit specific radioactivity in the plasma, had been determined previously in separate series of experiments. The model was extended to incorporate this dependence of the lumped constant. In the model both the transport and the phosphorylation barriers were assumed to be single and saturable. The values of their respective half-saturation concentrations and the ratio of the two maximum velocities for glucose were assumed to be invariant over the entire range of plasma glucose concentration. Good agreement between measured and estimated values for the distribution volumes and the lumped constant was attained over the full range of plasma glucose concentration. The model estimates reflected the progressive transport limitation of the brain glucose content as plasma glucose levels were reduced to hypoglycemic values. The results also indicated that these changes should be evident in the time course of 2DG in brain following administration by bolus or continuous infusion, and thus that indexes of local lumped constant change could be derived from the time course data.