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 Vmax t, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) 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 13C 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 1H 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.

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Differentiation of Glucose Transport in Human Brain Gray and White Matter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200105000-00002 ◽

2001 ◽

Vol 21 (5) ◽

pp. 483-492 ◽

Cited By ~ 70

Author(s):

Robin A. de Graaf ◽

Jullie W. Pan ◽

Frank Telang ◽

Jing-Huei Lee ◽

Peter Brown ◽

...

Keyword(s):

Nuclear Magnetic Resonance ◽

Steady State ◽

White Matter ◽

Magnetic Resonance ◽

Human Brain ◽

Glucose Transport ◽

Gray Matter ◽

Transport Model ◽

Transport Activity ◽

Brain Glucose

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

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Placental glucose transport in heat-induced fetal growth retardation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.263.3.r578 ◽

1992 ◽

Vol 263 (3) ◽

pp. R578-R585 ◽

Cited By ~ 32

Author(s):

P. J. Thureen ◽

K. A. Trembler ◽

G. Meschia ◽

E. L. Makowski ◽

R. B. Wilkening

Keyword(s):

Glucose Transport ◽

Fetal Growth ◽

Plasma Glucose ◽

Growth Retardation ◽

Glucose Consumption ◽

Fetal Growth Retardation ◽

Transport Capacity ◽

Placental Perfusion ◽

Fetal Plasma ◽

Glucose Levels

In six ewes heat stressed from 39 to 125 days gestation and studied in a normothermic environment at 135 days, fetal and placental masses were less than in control sheep (1,645 vs. 3,112 and 149 vs. 356 g, respectively, P less than 0.01). Umbilical glucose uptakes (Rf,UP) were measured keeping maternal arterial plasma glucose at 70 mg/dl at spontaneously occurring fetal plasma glucose values (state A) and at two additional fetal glucose levels, to determine the transplacental glucose difference (delta) vs. Rf,UP relation. At normal delta of 49.2 mg/dl, Rf,UP was less in the experimental group (3.2 vs. 5.6 mg.min-1.kg fetus-1, P less than 0.05). Differences in placental perfusion and glucose consumption could not account for this result, thus indicating a reduced placental glucose transport capacity. In state A, fetal hypoglycemia enlarged significantly (P less than 0.01) the delta to 56.7 mg/dl and increased Rf,UP approximately 50% over the Rf,UP at a normal delta. In heat-induced fetal growth retardation, fetal hypoglycemia increases the flux of maternal glucose across a placenta with reduced glucose transport capacity.

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Early insulin sensitivity after restrictive bariatric surgery, inconsistency between HOMA-IR and steady-state plasma glucose levels

Surgery for Obesity and Related Diseases ◽

10.1016/j.soard.2009.11.011 ◽

2010 ◽

Vol 6 (4) ◽

pp. 340-344 ◽

Cited By ~ 9

Author(s):

Francois M.H. van Dielen ◽

Jeroen Nijhuis ◽

Sander S.M. Rensen ◽

Nicolaas C. Schaper ◽

Janneke Wiebolt ◽

...

Keyword(s):

Bariatric Surgery ◽

Steady State ◽

Insulin Sensitivity ◽

Plasma Glucose ◽

Glucose Levels ◽

Restrictive Bariatric Surgery ◽

State Plasma

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Counterregulatory hormones oscillate during steady-state hypoglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.275.5.e821 ◽

1998 ◽

Vol 275 (5) ◽

pp. E821-E829 ◽

Cited By ~ 2

Author(s):

Pauline Genter ◽

Nancy Berman ◽

Mary Jacob ◽

Eli Ipp

Keyword(s):

Steady State ◽

Plasma Glucose ◽

Cardiovascular Responses ◽

Large Magnitude ◽

Counterregulatory Hormones ◽

Glucose Levels ◽

Clinical Observations ◽

Serial Blood Sampling ◽

The Mean ◽

Glucose Reduction

During hypoglycemia, the magnitude of the counterregulatory response depends on the extent of plasma glucose reduction. However, our clinical observations during steady-state hypoglycemia indicate that symptom severity can change independently of plasma glucose concentrations, i.e., symptoms appeared to fluctuate despite stable glucose levels. This study was therefore designed to test the hypothesis that hormonal and symptomatic responses to hypoglycemia are pulsatile. Seven healthy subjects had serial blood sampling at 3-min intervals during 90 min of insulin-induced hypoglycemia. Mean ± SE plasma glucose levels plateaued at 62 ± 3 mg/dl. Counterregulatory hormones were significantly elevated ( P < 0.05–0.01, except norepinephrine) and strikingly pulsatile. Cluster analysis revealed pulses of large magnitude in plasma glucagon, epinephrine, and norepinephrine concentrations. Amplitudes were, respectively, 72 ± 4, 64 ± 8, and 48 ± 3% of the mean. Interpeak intervals were 27 ± 7, 19 ± 4, and 25 ± 5 min, respectively. Symptom score and cardiovascular responses were also pulsatile; their peaks were found to coincide with epinephrine peaks. We conclude that hormonal and symptomatic counterregulation in hypoglycemia, while critically driven by plasma glucose levels, is also influenced by an endogenous pulsatility that exists despite steady-state glucose concentrations.

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NMR Determination of Intracerebral Glucose Concentration and Transport Kinetics in Rat Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.62 ◽

1992 ◽

Vol 12 (3) ◽

pp. 448-455 ◽

Cited By ~ 82

Author(s):

Graeme F. Mason ◽

Kevin L. Behar ◽

Douglas L. Rothman ◽

Robert G. Shulman

Keyword(s):

Steady State ◽

Plasma Glucose ◽

Glucose Concentration ◽

Goodness Of Fit ◽

Glucose Consumption ◽

Plasma Glucose Concentration ◽

Transport Parameters ◽

Glucose Levels ◽

Normal Glucose ◽

Wet Weight

The concentration of intracerebral glucose as a function of plasma glucose concentration was measured in rats by 13C NMR spectroscopy. Measurements were made in 20–60 min periods during the infusion of [1-13C]d-glucose, when intracerebral and plasma glucose levels were at steady state. Intracerebral glucose was found to vary from 0.7 to 19 μmol g−1 wet weight as the steady-state plasma glucose concentration was varied from 3 to 62 m M. A symmetric Michaelis–Menten model was fit to the brain and plasma glucose data with and without an unsaturable component, yielding the transport parameters Km, Vmax, and Kd. If it is assumed that all transport is saturable ( Kd = 0), then Km = 13.9 ± 2.7 m M and Vmax/ Vgly = 5.8 ± 0.8, where Vgly is the rate of brain glucose consumption. If an unsaturable component of transport is included, the transport parameters are Km = 9.2 ± 4.7 m M, Vmax/ Vgly = 5.3 ± 1.5, and Kd/ Vgly = 0.0088 ± 0.0075 ml μmol−1. It was not possible to distinguish between the cases of Kd = 0 and Kd > 0, because the goodness of fit was similar for both. However, the results in both cases indicate that the unidirectional rate of glucose influx exceeds the glycolytic rate in the basal state by 2.4-fold and as a result should not be rate limiting for normal glucose utilization.

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Weight Reduction Increases Plasma Levels of an Adipose-Derived Anti-Inflammatory Protein, Adiponectin

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.8.7741 ◽

2001 ◽

Vol 86 (8) ◽

pp. 3815-3819 ◽

Cited By ~ 488

Author(s):

Wei-Shiung Yang ◽

Wei-Jei Lee ◽

Tohru Funahashi ◽

Sachiyo Tanaka ◽

Yuji Matsuzawa ◽

...

Keyword(s):

Body Mass Index ◽

Body Weight ◽

Steady State ◽

Body Mass ◽

Plasma Glucose ◽

Weight Reduction ◽

Plasma Levels ◽

Plasma Adiponectin ◽

Body Weight Reduction ◽

Glucose Levels

Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = −0.5, P = 0.01), waist (r = −0.4, P = 0.04) and hip (r =− 0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = −0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (β = −0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (β =− 0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.

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