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R G Shulman

Publications and source records attributed to R G Shulman.

At least 91 records · Page 5Linked to original sources
PubMed1992

Proton magnetic resonance spectroscopy of cerebral lactate and other metabolites in stroke patients.

BACKGROUND AND PURPOSE: Proton magnetic resonance spectroscopy can measure in vivo brain lactate and other metabolites noninvasively. We measured the biochemical changes accompanying stroke in 16 human subjects with cortical or deep cerebral infarcts within the first 3 weeks after symptom onset, and performed follow-up studies on six. METHODS: One-dimensional proton spectroscopic imaging encompassing the infarct region was performed with a 2.1-T whole-body magnet using the stimulated echo pulse sequence and an echo time of 270 msec. RESULTS: All but one of the cortical stroke patients had increased lactate within or near the infarct. Persistently elevated cerebral lactate was documented in five of six cases studied serially as long as 251 days after infarction. N-acetylaspartate levels were decreased in most cortical strokes. Elevated lactate, accompanied by minimal reduction in N-acetylaspartate, was recorded in two of four patients in the first week following a small subcortical infarct. CONCLUSIONS: Long-term elevation of lactate commonly occurs after stroke. This lactate may arise from ongoing ischemia or infiltrating leukocytes, or it may be a residual of the lactate formed during the initial insult. The ability to observe stroke-elevated lactate pools at any time after lesion onset provides an approach to distinguishing among these possibilities in the future.

Aspartic Acid↗
PubMed1992

31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus.

To assess the rate-limiting step in muscle glycogen synthesis in non-insulin-dependent diabetes mellitus (NIDDM), the concentration of glucose-6-phosphate (G6P) was measured by 31P nuclear magnetic resonance (NMR) during a hyperglycemic-hyperinsulinemic clamp. Six subjects with NIDDM and six age weight-matched controls were studied at similar steady-state plasma concentrations of insulin (approximately 450 pmol/liter) and glucose (11 mmol/liter). The concentration of G6P in the gastrocnemius muscle was measured by 31P NMR. Whole-body oxidative and nonoxidative glucose metabolism was determined by the insulin-glucose clamp technique in conjunction with indirect calorimetry. Nonoxidative glucose metabolism which under these conditions is a measure of muscle glycogen synthesis (1990. N. Engl. J. Med. 322:223-228), was 31 +/- 7 mumol/(kg body wt-min) in the normal subjects and 13 +/- 3 mumol/(kg body wt-min) in the NIDDM subjects (P less than 0.05). The concentration of G6P was higher (0.24 +/- 0.02 mmol/kg muscle) in the normal subjects than in the NIDDM subjects (0.17 +/- 0.02, P less than 0.01). Increasing insulin concentrations to insulin 8,500 pmol/liter in four NIDDM subjects restored the glucose uptake rate and G6P concentrations to normal levels. In conclusion, the lower concentration of G6P in the diabetic subjects despite a decreased rate of nonoxidative glucose metabolism is consistent with a defect in muscle glucose transport or phosphorylation reducing the rate of muscle glycogen synthesis.

Aged↗
PubMed1992

Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study.

UNLABELLED: To quantitate hepatic glycogenolysis, liver glycogen concentration was measured with 13C nuclear magnetic resonance spectroscopy in seven type II diabetic and five control subjects during 23 h of fasting. Net hepatic glycogenolysis was calculated by multiplying the rate of glycogen breakdown by the liver volume, determined from magnetic resonance images. Gluconeogenesis was calculated by subtracting the rate of hepatic glycogenolysis from the whole body glucose production rate, measured using [6-3H]glucose. Liver glycogen concentration 4 h after a meal was lower in the diabetics than in the controls; 131 +/- 20 versus 282 +/- 60 mmol/liter liver (P < 0.05). Net hepatic glycogenolysis was decreased in the diabetics, 1.3 +/- 0.2 as compared to 2.8 +/- 0.7 mumol/(kg body wt x min) in the controls (P < 0.05). Whole body glucose production was increased in the diabetics as compared to the controls, 11.1 +/- 0.6 versus 8.9 +/- 0.5 mumol/(kg body wt x min) (P < 0.05). Gluconeogenesis was consequently increased in the diabetics, 9.8 +/- 0.7 as compared to 6.1 +/- 0.5 mumol/(kg body wt x min) in the controls (P < 0.01), and accounted for 88 +/- 2% of total glucose production as compared with 70 +/- 6% in the controls (P < 0.05). IN CONCLUSION: increased gluconeogenesis is responsible for the increased whole body glucose production in type II diabetes mellitus after an overnight fast.

Aged↗
PubMed1992

Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes.

Previous studies of human stroke by 1H nuclear magnetic resonance spectroscopy have shown elevation of lactate lasting 3 to 6 months. Complete metabolic turnover of the elevated lactate pool has been demonstrated 5 weeks after a stroke. Its cellular localization is among the first questions requiring clarification. Information pertinent to this question came to us from a patient with a 2-week-old stroke by 1H nuclear magnetic resonance spectroscopic imaging 1 week before his death led to neuropathologic examination of the brain. 1H spectra from voxels including the infarcts showed increased lactate and decreased N-acetylaspartate. Histopathology showed sheets of foamy macrophages in the infarct, but few neurons. Macrophage density ranged from 196 cells/mm2 near the surface of the infarct to 788 near its medial margin. Glial density was 500 to 800 cells/mm2. Lactate concentration in voxels including portions of the infarct was estimated at 7 to 14 mM. Voxels showing low N-acetylaspartate and high lactate on spectroscopic imaging were associated with histopathologic sections containing foamy macrophages. Brain macrophages--which begin to appear 3 days after infarction and gradually disappear over several months--could be a major source of elevated lactate signals that persist for months after stroke.

Brain↗
PubMed1991

Assignment of the 1H chemical shifts of glycogen.

Assignments of nearly all the 1H chemical shifts of glycogen are made by 2-D 1H-1H homonuclear and 13C-1H heteronuclear COSY. We demonstrated that it is possible to obtain well-resolved 2-D n.m.r. spectra for a large molecule like glycogen. The seven nonequivalent protons of the glucose residues in the alpha-(1----4)-linked chains, and of those at the nonreducing ends, were completely assigned. Distinct chemical shifts for H-1 and H-2 immediately adjacent to the alpha-(1----6) bonds at the branch points were also determined. Several modifications of previous 13C chemical shift assignments were made from the heteronuclear 2-D n.m.r. data.

Animals↗
PubMed1991

Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR.

The rate of net hepatic glycogenolysis was assessed in humans by serially measuring hepatic glycogen concentration at 3- to 12-hour intervals during a 68-hour fast with 13C nuclear magnetic resonance spectroscopy. The net rate of gluconeogenesis was calculated by subtracting the rate of net hepatic glycogenolysis from the rate of glucose production in the whole body measured with tritiated glucose. Gluconeogenesis accounted for 64 +/- 5% (mean +/- standard error of the mean) of total glucose production during the first 22 hours of fasting. In the subsequent 14-hour and 18-hour periods of the fast, gluconeogenesis accounted for 82 +/- 5% and 96 +/- 1% of total glucose production, respectively. These data show that gluconeogenesis accounts for a substantial fraction of total glucose production even during the first 22 hours of a fast in humans.

Adult↗
PubMed1991

Quantitation of metabolites by 1H NMR.

In this report we describe the three factors that need to be measured when quantitating an edited resonance relative to an internal standard using a surface coil. These factors are necessary by virtue of the water, fat suppressing, and localization schemes used in studing a 1H metabolite. First, use of semi-selective pulses requires amplitude correction of the edited and reference resonances. Second, use of a single surface coil results in different sensitive volumes for different resonances due to the inhomogeneous B1 and therefore require separate acquisition of the resonances. Third, editing pulses alter the sensitive volumes and this correction must be made internally by applying the same editing pulse to the reference resonance. A rationalization of this correction is given in terms of rotation operators. We apply these corrections to quantitate edited lactate relative to total creatine in a MnCl2-doped phantom and find 91% rather than 145% of known concentration. In human skeletal muscle in vivo after exhaustive exercise, we measured the lactate after exercise and found it to be 27.2 mM in two experiments, in reasonable agreement with literature values for the given exercise protocol.

Adult↗
PubMed1991

Correlation of lactate and pH in human skeletal muscle after exercise by 1H NMR.

We have made in vivo 1H NMR measurements of the time course of pH and lactate in human skeletal muscle after exercise. Spectra were obtained in a 4.7-T 30-cm bore Bruker Biospec spectrometer with a 2.5-cm diameter single surface coil. pH was determined from the shift of the endogenous carnosine H-C2 peak while lactate concentrations were determined by comparison with endogenous total creatine, taken to be 28.5 mM/kg wet wt. Fitting the data shows that the exponential decay of lactate (-0.094 +/- 0.014 min-1. t1/2 = 10.6 min) is slower than that of pH (-0.147 +/- 0.015 min-1, t1/2 = 4.7 min), n = 7 with two different volunteers. These values are significantly different with P less than 0.0005. Relaxation times of lactate and creatine were also measured for lactate quantitation; creatine T1, 1.23 +/- 12 s, T2, 136.2 +/- 26.4 ms (both in resting human muscle); lactate T1 (in postmortem rabbit muscle), 1.0 +/- 11 s and T2, 80 ms (in postexercise human muscle). At the end of intense exercise, the lactate level reached was 25.3 +/- 4.0 mM and the average pH drop was 1.0 pH unit. We discuss the implications of these measurements in conjunction with existing data on other sources of H+ flux, phosphocreatine resynthesis, H+ transport, and contribution of inorganic phosphate to buffering.

Adult↗
PubMed1991

13C NMR visibility of rabbit muscle glycogen in vivo.

The integrated 13C NMR intensity of the glycogen C1 resonance was measured in skeletal muscle (biceps femoris region) of nine rabbits under in vivo conditions. Concurrent chemical determinations of glycogen content showed that the in vivo signal was 1.02 +/- 0.06 the intensity of analytical samples, where glycogen is known to be approximately 100% visible.

Animals↗
PubMed1991

Localized proton NMR observation of [3-13C]lactate in stroke after [1-13C]glucose infusion.

To assess whether elevated lactate in stable stroke is being actively produced from blood glucose localized 1H NMR stimulated echo spectra were obtained from a patient in the region of a 32-day-old cortical infarct before and 60-100 min after infusion of [1-13C]glucose. Prior to the infusion the spectrum from the region of the infarct contained an elevated resonance from C3 lactate and a greatly reduced resonance from N-acetyl groups relative to an unaffected contralateral region. After the infusion two additional resonances were observed at 62 and -64 Hz relative to the unlabeled resonance of C3 lactate which were assigned on the basis of chemical shift and relative intensity to [3-13C]lactate. The [3-13C]lactate fractional enrichment in the infarct region was measured to be 32% which is within error one-half the average [1-13C]plasma glucose enrichment during the postinfusion NMR measurement. The result suggests that the stroke lactate pool was completely derived from infused glucose.

Blood Glucose↗
PubMed1991

13C-NMR measurements of muscle glycogen during low-intensity exercise.

Glycogen metabolism in exercising gastrocnemius muscles was examined by natural abundance 13C nuclear magnetic resonance (NMR) spectroscopy. Five-minute 13C-NMR measurement of muscle glycogen had a reproducibility of +/- 6.5% (+/- 4.8 mM). Experiments were performed on healthy fed male and female subjects. Two protocols were followed. 1) Subjects performed plantar flexion from rest at 15, 20, or 25% of maximum voluntary contraction for up to 9 h. 2) Subjects predepleted gastrocnemius glycogen with heavy exercise and then either performed low-intensity exercise as before or rested. Gastrocnemius glycogen was measured by NMR at rest and after each hour of exercise. In some sessions, both the exercised leg and the nonexercised leg were monitored with 13C-NMR. In protocol 1, blood velocity in the femoral artery was similarly assessed with ultrasonography. During low-intensity exercise from rest (protocol 1) muscle glycogen fell to a new steady-state value after several hours and then remained constant despite continued exercise. Mean blood velocity increased ninefold within 2 min of onset of exercise and remained constant thereafter. After predepletion (protocol 2), muscle glycogen was repleted both during low-intensity exercise and at rest. After 1 h the amount of glycogen repletion was greater when coupled with light exercise [48.5 +/- 2.8 mM after 1 h of exercise, 39.7 +/- 1.1 mM after 1 h of rest (P less than 0.05)]. During subsequent light exercise, glycogen reached a steady-state value similar to that obtained in protocol 1, while in resting, recovery glycogen levels continued to increase (+2.7 mM/h) over a 7-h period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

13C NMR relaxation times of hepatic glycogen in vitro and in vivo.

The field dependence of relaxation times of the C-1 carbon of glycogen was studied in vitro by natural-abundance 13C NMR. T1 is strongly field dependent, while T2 does not change significantly with magnetic field. T1 and T2 were also measured for rat hepatic glycogen enriched with [1-13C]glucose in vivo at 4.7 T, and similar relaxation times were observed as those obtained in vitro at the same field. The in vitro values of T1 were 65 +/- 5 ms at 2.1 T, 142 +/- 10 ms at 4.7 T, and 300 +/- 10 ms at 8.4 T, while T2 values were 6.7 +/- 1 ms at 2.1 T, 9.4 +/- 1 ms at 4.7 T, and 9.5 +/- 1 ms at 8.4 T. Calculations based on the rigid-rotor nearest-neighbor model give qualitatively good agreement with the T1 field dependence with a best-fit correlation time of 6.4 X 10(-9) s, which is significantly smaller than tau M, the estimated overall correlation time for the glycogen molecule (ca. 10(-5) s). A more accurate fit of T1 data using a modified Lipari and Szabo approach indicates that internal fast motions dominate the T1 relaxation in glycogen. On the other hand, the T2 relaxation is dominated by the overall correlation time tau M while the internal motions are almost but not completely unrestricted.

Animals↗
PubMed1990

Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy.

To examine the extent to which the defect in insulin action in subjects with non-insulin-dependent diabetes mellitus (NIDDM) can be accounted for by impairment of muscle glycogen synthesis, we performed combined hyperglycemic-hyperinsulinemic clamp studies with [13C]glucose in five subjects with NIDDM and in six age- and weight-matched healthy subjects. The rate of incorporation of intravenously infused [1-13C]glucose into muscle glycogen was measured directly in the gastrocnemius muscle by means of a nuclear magnetic resonance (NMR) spectrometer with a 15.5-minute time resolution and a 13C surface coil. The steady-state plasma concentrations of insulin (approximately 400 pmol per liter) and glucose (approximately 10 mmol per liter) were similar in both study groups. The mean (+/- SE) rate of glycogen synthesis, as determined by 13C NMR, was 78 +/- 28 and 183 +/- 39 mumol-glucosyl units per kilogram of muscle tissue (wet weight) per minute in the diabetic and normal subjects, respectively (P less than 0.05). The mean glucose uptake was markedly reduced in the diabetic (30 +/- 4 mumol per kilogram per minute) as compared with the normal subjects (51 +/- 3 mumol per kilogram per minute; P less than 0.005). The mean rate of nonoxidative glucose metabolism was 22 +/- 4 mumol per kilogram per minute in the diabetic subjects and 42 +/- 4 mumol per kilogram per minute in the normal subjects (P less than 0.005). When these rates are extrapolated to apply to the whole body, the synthesis of muscle glycogen would account for most of the total-body glucose uptake and all of the nonoxidative glucose metabolism in both normal and diabetic subjects. We conclude that muscle glycogen synthesis is the principal pathway of glucose disposal in both normal and diabetic subjects and that defects in muscle glycogen synthesis have a dominant role in the insulin resistance that occurs in persons with NIDDM.

Blood Glucose↗
PubMed1990

Direct carbon versus proton heteronuclear editing of 2-13C ethanol in rabbit brain in vivo: a sensitivity comparison.

Proton NMR editing techniques were utilized to study the pharmacology of 13C-labeled ethanol in the cerebrum of the living rabbit at 4.7 T. The sensitivity of these proton spectroscopic methods was compared to direct carbon spectroscopy and a 14-fold improvement in sensitivity of 1H over 13C NMR spectroscopy was observed in vivo. This increase in sensitivity permitted the observation of the time course of the influx and afflux of this 13C-labeled compound with a time resolution of approximately 2 min per spectrum.

Animals↗