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D L Rothman

Publications and source records attributed to D L Rothman.

At least 19 recordsLinked to original sources
PubMed1999

In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics.

In this article we review recent studies, primarily from our laboratory, using 13C NMR (nuclear magnetic resonance) to non-invasively measure the rate of the glutamate-glutamine neurotransmitter cycle in the cortex of rats and humans. In the glutamate-glutamine cycle, glutamate released from nerve terminals is taken up by surrounding glial cells and returned to the nerve terminals as glutamine. 13C NMR studies have shown that the rate of the glutamate-glutamine cycle is extremely high in both the rat and human cortex, and that it increases with brain activity in an approximately 1:1 molar ratio with oxidative glucose metabolism. The measured ratio, in combination with proposals based on isolated cell studies by P. J. Magistretti and co-workers, has led to the development of a model in which the majority of brain glucose oxidation is mechanistically coupled to the glutamate-glutamine cycle. This model provides the first testable mechanistic relationship between cortical glucose metabolism and a specific neuronal activity. We review here the experimental evidence for this model as well as implications for blood oxygenation level dependent magnetic resonance imaging and positron emission tomography functional imaging studies of brain function.

Ammonia↗
PubMed1999

Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes.

BACKGROUND: Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase activity and glucose transport have been implicated. METHODS: We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. RESULTS: The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism. CONCLUSIONS: Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.

Adult↗
PubMed1999

Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR.

Recent 13C NMR studies in rat models have shown that the glutamate/glutamine cycle is highly active in the cerebral cortex and is coupled to incremental glucose oxidation in an approximately 1:1 stoichiometry. To determine whether a high level of glutamatergic activity is present in human cortex, the rates of the tricarboxylic acid cycle, glutamine synthesis, and the glutamate/glutamine cycle were determined in the human occipital/parietal lobe at rest. During an infusion of [1-13C]-glucose, in vivo 13C NMR spectra were obtained of the time courses of label incorporation into [4-13C]-glutamate and [4-13C]-glutamine. Using a metabolic model we have validated in the rat, we calculated a total tricarboxylic acid cycle rate of 0.77 +/- 0.07 micromol/min/g (mean +/- SD, n = 6), a glucose oxidation rate of 0.39 +/- 0.04 micromol/min/g, and a glutamate/glutamine cycle rate of 0.32 +/- 0.05 micromol/min/g (mean +/- SD, n = 6). In agreement with studies in rat cerebral cortex, the glutamate/glutamine cycle is a major metabolic flux in the resting human brain with a rate approximately 80% of glucose oxidation.

Adult↗
PubMed1999

Stimulated changes in localized cerebral energy consumption under anesthesia.

Focal changes in the cerebral metabolic rate of glucose utilization (CMRglc) are small (10-40%) during sensory activation in awake humans, as well as in awake rodents and primates (20-50%). They are significantly larger (50-250%) in sensory activation studies of anesthetized rats and cats. Our data, in agreement with literature values, show that in the resting anesthetized state values of CMRglc are lower than in the resting nonanesthetized state whereas the final state values, reached upon activation, are similar for the anesthetized and nonanesthetized animals. The lower resting anesthetized state values of CMRglc explain why the increments upon activation from anesthesia are larger than when starting from the nonanesthetized conditions. Recent 13C NMR measurements in our laboratory have established a quantitative relationship between the energetics of glucose oxidation, CMRglc (oxidative), and the flux of the glutamate/gamma-aminobutyric acid/glutamine neurotransmitter cycle, Vcycle. In both the resting awake value of CMRglc(oxidative), and its increment upon stimulation, a large majority (approximately 80%) of the brain energy consumption is devoted to Vcycle. In the differencing methods of functional imaging, it is assumed that the incremental change in the measured signal represents the modular activity that supports the functional response. However, the same amount of activity must be present during the response to stimulation, irrespective of the initial basal state of the cortex. Thus, whereas the incremental signals of DeltaCMRglc can localize neurotransmitter activity, the magnitude of such activity during the response is represented by the total localized CMRglc, not the increment.

Anesthesia↗
PubMed1999

Energy on demand.

Explore the source record for details and available documents.

Adenosine Triphosphate↗
PubMed1999

In vivo chemical shift imaging of gamma-aminobutyric acid in the human brain.

A gradient-based multiple quantum filtering method is presented for in vivo chemical shift imaging of gamma-aminobutyric acid (GABA) in the human brain, which provides effective suppression of the overlapping creatine singlet with close to optimal detection efficiency. It is shown by product operator calculations and coherence pathway analysis that under conditions of no B1 and B0 inhomogeneity gradient filtering retains 75% of the two outer resonance lines of the GABA-4 triplet with no creatine contamination. A variation of the method with 100% retention of the GABA-4 outer resonance lines but higher sensitivity to B1 inhomogeneity is also discussed. By using a localized version of the sequence with an 8-cm surface coil for transmission and detection, it was found in phantom experiments at 2.1 T that a 69% signal retention of the two outer resonance lines of the GABA-4 triplet was achieved relative to a spin echo sequence with inhibition of GABA J modulation. A creatine suppression ratio of 2000:1 was measured. The use of the method for chemical shift imaging of GABA is demonstrated by coronal images obtained from phantoms and from the occipital lobe of a healthy volunteer.

Brain↗
PubMed1999

Localized 1H NMR measurements of 2-pyrrolidinone in human brain in vivo.

Localized 1H NMR homonuclear J editing spectroscopy was used to measure the concentration of 2-pyrrolidinone (PRDN) in the human occipital lobe of five normal and six epileptic subjects taking vigabatrin. PRDN is a lactam cyclization product of gamma-aminobutyric acid (GABA). From a localized volume of 13.5 cm3 in the occipital cortex, the concentration of PRDN ranged from 0.2 to 0.3 micromol/g in normal subjects, whereas in epileptic subjects on vigabatrin PRDN was elevated to 0.6 +/- 0.1 micromol/g. The elevated PRDN in patients on vigabatrin was in accord with raised GABA levels compared with normals. 1H NMR measurements of PRDN will be important in assessment of the role of this metabolite for improved seizure control.

Adult↗
PubMed1999

Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.

Recent muscle biopsy studies have shown a relation between intramuscular lipid content and insulin resistance. The aim of this study was to test this relation in humans by using a novel proton nuclear magnetic resonance (1H NMR) spectroscopy technique, which enables non-invasive and rapid (approximately 45 min) determination of intramyocellular lipid (IMCL) content. Normal weight non-diabetic adults (n = 23, age 29+/-2 years. BMI = 24.1+/-0.5 kg/m2) were studied using cross-sectional analysis. Insulin sensitivity was assessed by a 2-h hyperinsulinaemic (approximately 450 pmol/l)-euglycaemic (approximately 5 mmol/l) clamp test. Intramyocellular lipid concentrations were determined by using localized 1H NMR spectroscopy of soleus muscle. Simple linear regression analysis showed an inverse correlation (r = -0.579, p = 0.0037) [corrected] between intramyocellular lipid content and M-value (100-120 min of clamp) as well as between fasting plasma non-esterified fatty acid concentration and M-value (r = -0.54, p = 0.0267). Intramyocellular lipid content was not related to BMI, age and fasting plasma concentrations of triglycerides, non-esterified fatty acids, glucose or insulin. These results show that intramyocellular lipid concentration, as assessed non invasively by localized 1H NMR spectroscopy, is a good indicator of whole body insulin sensitivity in non-diabetic, non-obese humans.

Adult↗
PubMed1999

Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures.

Preclinical studies suggested valproate increased brain gamma-aminobutyric acid (GABA) with no major effects on brain glutamate or glutamine. Valproate increased human cerebrospinal fluid GABA and glutamine in some studies; others reported no effect. In vivo measurements of glutamate, glutamine, and GABA were made of a 14 cm3volume in the occipital cortex using a1H spectroscopy with a 2.1 Tesla magnetic resonance spectrometer and an 8 cm surface coil. Ten control subjects and 14 patients with refractory complex partial seizures were examined. Brain glutamine concentrations were above normal in three of five patients taking valproate and two of nine taking carbamazepine or phenytoin. Mean glutamine levels of patients taking valproate were higher than control subjects and patients taking carbamazepine or phenytoin. Brain glutamate concentrations were above normal in four of nine patients taking phenytoin or carbamazepine and two of five taking valproate. Brain GABA levels were below normal in four of nine patients taking carbamazepine or phenytoin and one of five taking valproate. Above normal glutamate or below normal GABA was present in nine of 14 patients and may contribute to their refractory epilepsy. Increased brain glutamine associated with valproate therapy may reflect mild hyperammonemia.

Adult↗
PubMed1999

GABA changes with vigabatrin in the developing human brain.

PURPOSE: Changes in gamma-aminobutyric acid (GABA) physiology are important in determining seizure susceptibility in the developing nervous system. Noninvasive measurements of brain GABA in adults with epilepsy have demonstrated important relations among seizure control, brain GABA levels, and changes in brain GABA with drugs designed to alter GABA metabolism. The purpose of this study was to demonstrate the changes in GABA in the occipital lobes of children with epilepsy after treatment with vigabatrin (VGB). METHODS: Ten proton nuclear magnetic resonance spectroscopic (NMRS) studies were obtained on four subjects with epilepsy. The subjects were between ages 1 and 5 years. Occipital lobe GABA levels were measured before and after treatment with VGB. RESULTS: Brain GABA levels increased significantly in these subjects after VGB treatment (p < 0.05, paired Student's t test). In one subject, brain GABA was decreased in the region of the epileptic focus compared with the homologous region of the opposite hemisphere. A nearly fivefold increase in GABA occurred in the epileptic region after VGB treatment in this subject. CONCLUSIONS: VGB increases brain GABA levels in children with epilepsy. NMRS can be used to monitor the response of brain GABA levels to drugs known to alter GABA physiology and serve as an important tool to understand the role of GABA-mediated inhibition in pediatric epilepsies.

Adult↗
PubMed1999

Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures.

PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and maintenance of VGB as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week.

Administration, Oral↗
PubMed1999

Effects of vigabatrin on the GABAergic system as determined by [123I]iomazenil SPECT and GABA MRS.

PURPOSE: To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. METHODS: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. RESULTS: Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. CONCLUSIONS: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.

Adult↗
PubMed1999

Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.

To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%-60% lower following the lipid infusion compared with the glycerol infusion and were associated with a approximately 90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated PI 3-kinase activity.

Adolescent↗
PubMed1999

Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients.

OBJECTIVE: The aim of the study was to compare levels of neuroactive amino acids in the cerebral cortex of healthy subjects, recently detoxified alcohol-dependent patients, and patients with hepatic encephalopathy. METHOD: Metabolite levels were measured in the occipital cortex by using spatially localized 1H-MRS. Five recently detoxified alcohol-dependent and five hepatic encephalopathy patients with alcohol and non-alcohol-related disease were compared with 10 healthy subjects. RESULTS: The combined level of gamma-aminobutyric acid (GABA) plus homocarnosine was lower in the alcohol-dependent and hepatic encephalopathy patients than in the healthy subjects. CONCLUSIONS: The findings suggest that GABA-ergic systems are altered in both alcohol-dependent and hepatic encephalopathy patients.

Adult↗
PubMed1999

Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy.

OBJECTIVE: To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy. BACKGROUND: Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects. RESULTS: Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.

Adolescent↗
PubMed1998

Interpreting functional imaging studies in terms of neurotransmitter cycling.

Functional imaging experiments, in particular positron-emission tomography and functional magnetic resonance imaging, can be analyzed either in psychological terms or on the basis of neuroscience. In the usual psychological interpretation, stimulations are designed to activate specific mental processes identified by cognitive psychology, which are then localized by the signals in functional imaging experiments. An alternate approach would be to analyze experiments in terms of the neurobiological processes responsible for the signals. Recent in vivo 13C NMR measurements of the glutamate-to-glutamine neurotransmitter cycling in rat and human brains facilitate a neuroscientific interpretation of functional imaging data in terms of neurobiological processes since incremental neurotransmitter flux showed a 1:1 stoichiometry with the incremental rate of glucose oxidation. Because functional imaging signals depend on brain energy consumption, a quantitative relationship can be established between the signal (S) and the specific neurochemical cerebral neurotransmitter activity (N) of glutamate-to-glutamine neurotransmitter cycling. The quantitation of neuronal activity proposed has implications for the psychological design and interpretation of functional imaging experiments. Measurements of the neurotransmitter cycling flux at rest in functional imaging experiments suggest that performing cognitive tasks and sensory stimulations increases neurotransmitter cycling by only 10-20%. Therefore it cannot be assumed that reference state activities are negligible, nor that they are constant during stimulation.

Animals↗
PubMed1998

Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans.

13C NMR spectroscopy was used to assess flux rates of hepatic glycogen synthase and phosphorylase in overnight-fasted subjects under one of four hypoglucagonemic conditions: protocol I, hyperglycemic (approximately 10 mM) -hypoinsulinemia (approximately 40 pM); protocol II, euglycemic (approximately 5 mM) -hyperinsulinemia (approximately 400 pM); protocol III, hyperglycemic (approximately 10 mM) -hyperinsulinemia (approximately 400 pM); and protocol IV; euglycemic (approximately 5 mM) -hypoinsulinemia (approximately 40 pM). Inhibition of net hepatic glycogenolysis occurred in both protocols I and II compared to protocol IV but via a different mechanism. Inhibition of net hepatic glycogenolysis occurred in protocol I mostly due to decreased glycogen phosphorylase flux, whereas in protocol II inhibition of net hepatic glycogenolysis occurred exclusively through the activation of glycogen synthase flux. Phosphorylase flux was unaltered, resulting in extensive glycogen cycling. Relatively high rates of net hepatic glycogen synthesis were observed in protocol III due to combined stimulation of glycogen synthase flux and inhibition of glycogen phosphorylase flux. In conclusion, under hypoglucagonemic conditions: (a) hyperglycemia, per se, inhibits net hepatic glycogenolysis primarily through inhibition of glycogen phosphorylase flux; (b) hyperinsulinemia, per se, inhibits net hepatic glycogenolysis primarily through stimulation of glycogen synthase flux; (c) inhibition of glycogen phosphorylase and the activation of glycogen synthase are not necessarily coupled and coordinated in a reciprocal fashion; and (d) promotion of hepatic glycogen cycling may be the principal mechanism by which insulin inhibits net hepatic glycogenolysis and endogenous glucose production in humans under euglycemic conditions.

Adult↗