Vol. 276, Issue 1, H129-H133, January 1999
Lumped constant for deoxyglucose is decreased when myocardial
glucose uptake is enhanced
Katsuji
Hashimoto1,
Tsunehiko
Nishimura1,
Ken-Ichi
Imahashi1,
Hitoshi
Yamaguchi1,
Masatsugu
Hori2, and
Hideo
Kusuoka1
1 Division of Tracer Kinetics,
Biomedical Research Center,
and 2 First Department of
Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan
 |
ABSTRACT |
Quantification of
myocardial glucose uptake by positron emission tomography with
[18F]fluorodeoxyglucose
(FDG) requires the "lumped constant" (LC), which corrects the
difference of affinity between glucose and FDG to glucose transporters
and phosphorylating system. Since LC was introduced, it has been
considered to be constant. However, this has recently been questioned.
To elucidate the constancy of LC by other than radioisotope techniques,
the accumulation rate of sugar phosphates
(d[SP]/dt) was measured
in isolated, perfused rat hearts by
31P NMR spectroscopy with
2-deoxyglucose (DG). We postulate 
as the affinity of DG to
transporters and the phosphorylating system relative to that of
glucose. Theoretically, is equivalent to LC. We determined by
measuring d[SP]/dt at DG
concentration ([DG]) = 10, 7, 5, and 3 mmol/l, keeping the
total of glucose concentration ([glucose]) and
[DG] to 10 mmol/l. When the glucose uptake was enhanced by
insulin (10 mU/ml) or stunning, calculated was reduced (insulin
stimulated, 0.15; stunning, 0.19) compared with the control (0.59).
These results indicate that LC can be evaluated by methods without
radiolabeled tracers and is smaller when glucose uptake is augmented.
insulin; myocardial stunning; nuclear magnetic resonance
spectroscopy
| |
INTRODUCTION |
THE TRACER
[18F]fluorodeoxyglucose
(FDG) has been used widely with positron emission tomography (PET) to
estimate glucose utilization in myocardium (2, 13, 17-19). To
quantify the myocardial glucose uptake with FDG, it is necessary to
introduce the "lumped constant" (LC) because the affinity of FDG
for glucose transporters and phosphorylation enzymes is different from
that of glucose. LC was initially defined by Sokoloff (21) using
2-deoxyglucose (DG) as follows
|
(1)
|
where
is the ratio of distribution volumes of DG and glucose, 
is
glucose-6-phosphatase activity,
Vm and
Km are the
maximal velocity and Michaelis-Menten constant of hexokinase to
glucose, respectively, and
and
are
Vm and
Km to DG. Because
LC was introduced on the basis of experiments using radioactive
tracers, some conceptual parameters such as distribution volumes are
required to describe and determine LC (21). Whether LC can be
determined by methods other than radioisotope technique has not been elucidated.
Since LC was introduced, it has been supposed to be constant. Actually,
it has been reported that LC did not change under physiological
conditions (8, 9, 15). Therefore, only one value (i.e., 0.6) has been
used in quantifying the glucose uptake in myocardium using FDG PET.
However, recent studies gave doubt about the constancy of LC (1, 5, 12,
16). This study aims to elucidate whether LC can be determined by a
method without radioactive tracers and whether LC is changeable when
myocardial glucose uptake is enhanced.
| |
METHODS |
The whole heart preparation was described previously (6). Briefly,
hearts were excised from male rats (Sprague-Dawley, body wt
400-450 g) anesthetized with pentobarbital sodium (50 mg/kg ip;
Abbott Laboratories, North Chicago, IL) and heparinized. After
excision, the aorta was cannulated, and the hearts were retrogradely
perfused with a modified HEPES buffer (standard perfusate; in mmol/l:
108 NaCl, 5 KCl, 1 MgCl2, 1.5 CaCl2, 5 HEPES, 10 glucose, and 20 Na-acetate) bubbled with 100% O2
at 37°C. Heart rate was maintained at 300 beats/min by right
ventricular pacing. A latex balloon tied to the end of a polyethylene
tube was passed into the left ventricle (LV) through the mitral valve
and connected to a pressure transducer (SPB-101, San-ei Electric,
Tokyo, Japan). The balloon was filled with 25 mmol/l magnesium
trimetaphosphate solution as a standard for
31P NMR spectroscopy (10). LV
end-diastolic pressure was set at 5-10 mmHg by adjusting the
balloon volume, and then the balloon was kept isovolumic throughout the
experiment. Aortic pressure was monitored at the cannulation point of
the aorta. LV pressure and aortic pressure were recorded with a
direct-writing recorder. Aortic pressure was adjusted to 70-80
mmHg by controlling the flow rate of the perfusion, and flow rate was
kept constant throughout the experiment except during ischemia.
The experiments reported herein were approved by the Animal Care and
Use Committee of Osaka University Medical School.
Determination of DG uptake rate in myocardium.
The uptake rate of DG in myocardium was determined as the accumulation
rate of sugar phosphates (SP) when glucose in the perfusate was
substituted by DG (6). Acetate (20 mmol/l) was always present in the
perfusate. The signal of phosphorylated DG appears at ~6 parts per
million in the spectrum as SP (see Fig. 1). The accumulation rate of SP
in myocardium (d[SP]/dt,
where [SP] is SP concentration) was calculated from the
slope of the regression line obtained from the data over 20 min after
the substitution of glucose by DG and is expressed in micromoles per
gram of wet weight per minute. If SP peak saturated within the initial
20 min, d[SP]/dt was
calculated during the initial 15 min.
The method to determine myocardial DG uptake rate using
31P NMR was described previously
(6). Briefly, the preparation was put into a 20-mm-diameter tube and
placed into the superconducting magnet at 9.4 T. 31P NMR spectra were obtained on
an NMR spectrometer (AMX-400wb, Bruker), for which the resonance
frequency for 31P equals 161.98 MHz. The free induction decays from the heart using 60-degree pulses
delivered at 2-s intervals were accumulated and processed. Each
spectrum was obtained with 144 pulses, resulting in a total acquisition
time of 5 min.
Intramyocardial amounts of metabolites were quantified as reported
previously (10). Briefly, the amounts of phosphorus compounds in the
myocardium were obtained by planimetry of the area under the
corresponding peak. The tissue contents were normalized by the peak for
the magnesium trimetaphosphate standard in the LV balloon. The
calculated amount was divided by the measured weight of each heart to
yield concentrations in micromoles per gram of wet weight.
Calculation of parameter.
Glucose and DG have different affinities to the glucose transporter
(GLUT)-hexokinase system. Therefore, it has been considered that
myocardial DG uptake is modified when glucose and DG are present
simultaneously in the perfusate and that these two substrates are in
competition to this system (21). To investigate the relative relation
between glucose and DG to the GLUT-hexokinase system, the effect of
coexisting glucose on myocardial DG uptake was evaluated in perfused
hearts. Hearts were perfused with the standard solution, and then
glucose in the perfusate was completely or partially replaced by DG but
the total of glucose concentration ([glucose]) and DG
concentration ([DG]) was kept to 10 mmol/l.
d[SP]/dt was measured in
the hearts perfused with solutions of the following [DG]
and [glucose]: 3:7, 5:5, 7:3, and 10:0 mmol/l.
To evaluate the relative relation between glucose and DG to the
GLUT-hexokinase system quantitatively, we introduced the following model. In this model, myocardial uptake of glucose and DG is considered to be determined by two factors: one is [glucose] and
[DG], and the other is the relative affinity of glucose and
DG to the GLUT-phosphorylation system. When [DG] in the
perfusate is supposed to be x mmol/l, [glucose] in the perfusate is (10 
x) mmol/l because the total of
[DG] and [glucose] is kept to 10 mmol/l in our
experiments. If affinity of DG to transporter and phosphorylation
system relative to that of glucose is postulated as , the ratio of
myocardial DG uptake to that of glucose is equal to
x:(10 x). The accumulation of SP is mainly
caused by the accumulation of deoxyglucose-6-phosphate. Therefore,
d[SP]/dt normalized by its
maximal value is expressed as
![&agr;<IT>x</IT>/[(10 − <IT>x</IT>) + &agr;<IT>x</IT>]](/content/vol276/issue1/fulltext/H129/img004.gif)
|
(2)
|
The
value of was determined by fitting data sets obtained with changing
[DG] to Eq. 2.
Statistical analysis.
Data are presented as means ± SE. Multiple comparison was performed
using ANOVA with Scheffé's test. A
P value <0.05 was considered as
significant. Curve fitting was performed with SigmaPlot version 2.01 (Jandel Scientific Software).
| |
RESULTS |
In control hearts.
Hearts were first perfused with the standard perfusate and allowed to
stabilize. Afterward, NMR spectra and mechanical function were measured
for 20 min as an initial control. Glucose in a perfusate was then
totally or partially replaced by DG. Figure
1 illustrates the changes in P NMR spectra
before and after the exposure to DG. SP was accumulated after the
perfusate was switched. Figure 2 summarizes
the changes of [SP] in different [DG]. When
[DG] was reduced from 10 to 3 mmol/l, keeping the total
concentration of DG and glucose to 10 mmol/l, the accumulation of SP
became slower and d[SP]/dt
was decreased (Table 1).
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Fig. 1.
Changes in sugar phosphate (SP) peak in
31P NMR spectra after substitution
of glucose (10 mmol/l) with 2-deoxyglucose (DG, 10 mmol/l).
A: spectrum obtained during control
perfusion, i.e., without DG. B:
spectrum obtained 10-15 min after switching from standard
perfusate to solution containing DG (10 mmol/l).
1, SP;
2, inorganic phosphate;
3, phosphocreatine;
4-6, 3 phosphates of ATP ( ,
, and  , respectively); 7,
magnesium trimetaphosphate (standard in left ventricular balloon).
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Fig. 2.
Changes in myocardial SP concentration ([SP]) in control
hearts perfused with solution containing different concentrations of DG
and glucose. Symbols represent hearts perfused with solution containing
following composition of DG and glucose (in mmol/l):  , 10:0;  ,
7:3;  , 5:5;  , 3:7. * P < 0.05, ** P < 0.01 vs. DG = 10 mmol/l.
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Table 1.
d[SP]/dt at different DG and glucose concentrations in control,
insulin-stimulated, and stunned myocardium
|
|
d[SP]/dt of the hearts
perfused with the solution in which glucose was totally replaced by DG
gave the maximal rate of the myocardial sugar uptake because there was
no competition between DG and glucose. Thus
d[SP]/dt at different
[DG] was normalized by
d[SP]/dt at
[DG] = 10 mmol/l and fitted to Eq. 2. The best fit was obtained when = 0.59 (Fig. 3).
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Fig. 3.
SP accumulation rate
(d[SP]/dt) normalized by
d[SP]/dt at
[DG] = 10 mmol/l. , control hearts; ,
insulin-stimulated hearts;  , stunned myocardium. Solid line, dashed
line, and dotted line indicate relation best fitted to equation
y = x /[(10 x) + x], where is affinity
of DG to transporters and phosphorylation system relative to that of
glucose, in control, insulin-stimulated, and stunned groups,
respectively. * P < 0.05, ** P < 0.01 vs. control
hearts.
|
|
In hearts enhanced in glucose uptake.
We also investigated the change in when glucose uptake was
enhanced. To enhance myocardial glucose uptake, we first added insulin
to the perfusate. In this group, the standard perfusate was switched to
that containing DG 10 min after the administration of insulin (regular
insulin, 10 mU/ml; Shimizu Pharmacy, Shizuoka, Japan). When compared in
the control hearts, insulin augmented d[SP]/dt at higher
concentrations of DG but not significantly at lower concentrations of
DG (Table 1). These results suggest that in insulin-stimulated
hearts is not equal to that in control hearts. The fitting revealed
that was equal to 0.15 (Fig. 3). We also used stunning to enhance
myocardial glucose uptake. As previously reported,
d[SP]/dt significantly
increases in stunned myocardium (6). To stun myocardium, we reperfused
hearts after 15-min global ischemia at 37°C. Hearts were
perfused with the standard solution before ischemia and
reperfused with the solution containing DG. In stunned hearts,
d[SP]/dt was significantly
increased at higher [DG] but not at lower [DG]
as was observed in insulin-stimulated hearts (Table 1). The fitting
revealed that was equal to 0.19 (Fig. 3).
| |
DISCUSSION |
Relation between and LC.
The LC was introduced by Sokoloff et al. (21) based on the
three-compartment model describing the dynamics of glucose and DG
(Fig. 4). On the basis of this
model, the glucose utilization rate,
Ri, is described by
Eq. 3, when substrate concentrations and rate constants are defined as in Fig. 4 (7, 14)
|
(3)
|
According
to the assumption of a steady state in myocardial sugar uptake and
metabolism, i.e.,
/dt = 0
|
(4)
|
Therefore
|
(5)
|
|
(6)
|
This
equation indicates that LC is equal to the ratio of the unit
utilization rate of DG
(
/
) to that of glucose
(Ri/CP).
The definition of LC in this manner is completely equivalent to the
definition of in our model. Actually, the estimated value of in
control hearts in our experiments was equal to 0.59 and agrees well
with the LC currently used for FDG (0.6) (8, 9, 15) or that measured
with DG in rat (5). Thus these results indicate that our method is a
new method to determine LC without radioactive tracers.
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Fig. 4.
Three-compartment model for kinetics of glucose and DG.
Left compartment represents
extracellular space for glucose and DG.
Middle compartment represents
intracellular space for free glucose and free DG.
Right compartment represents
intracellular space for glucose-6-phosphate and
deoxyglucose-6-phosphate. k and C are
rate constant and concentration, respectively, where subscripts P, E, M
indicate extracellular, intracellular free, and intracellular
phosphorylated, respectively. Quantities for DG and glucose are denoted
by symbols with and without asterisk, respectively. Modified from
Sokoloff et al. (21).
|
|
Radioactive tracer has a lot of advantages in measuring metabolic
states. However, as shown by the original definition of LC (21), many
assumptions with compartmental models are necessary to quantify
metabolic parameters. Recent studies adopted the direct comparison of
metabolic rates of FDG/DG and glucose (4, 5), and these methods are
close to our new method measuring DG accumulation directly. Our method
is equivalent to those with radioactive tracers and is preferable to
perform in those countries, including Japan, where the use of
radioisotopes in whole animals in vivo is difficult because of major
restriction by legal regulations.
Change in LC at enhanced glucose uptake rate.
Coupled with the previous discussion, our results indicate that LC
decreases when glucose uptake is enhanced. Ng et al. (12) reported that
10 mU/ml insulin decreased LC from 0.94 to 0.33 when
[glucose] was kept to 5 mmol/l. Recently, it is reported that myocardial glucose uptake measured with DG underestimates true
uptake in insulin-stimulated myocardium (5). The variability of LC,
depending on the condition to which hearts are exposed, is proposed as
the mechanism for the underestimation of glucose uptake. Changes in LC
measured by FDG PET were also reported (1); LC showed biphasic change,
that is, increased at lower serum level of insulin and decreased at
higher serum level of insulin.
Changes in LC were also suggested in reperfused myocardium. Doenst et
al. (3) showed that FDG retention in reperfused hearts was blunted
compared with that before ischemia and then gradually increased
during the reperfusion period. These results also suggest a change in
LC. Actually, the decrease in LC was reported in hearts reperfused
after low-flow ischemia (4). Glucose uptake rate in stunned
myocardium is enhanced just after reperfusion and gradually decreases
during reperfusion (6). Therefore, the time-dependent change in the FDG
retention pattern may be caused by the change in LC parallel to the
withdrawal of glucose uptake in reperfused myocardium.
Mechanism of changes in LC.
The mechanism for the change in LC has not been clarified. Ng et al.
(12) suggested that LC may be sensitive to [glucose] in the
perfusate and that LC rises with increase in [glucose] because glycolysis comes to be rate limiting. In fact, low
[glucose] increased LC in their experiments. This may be
caused by the limitation in the transport of glucose via GLUT, because
the influx of glucose is determined by the concentration gradient. In
contrast, the total sugar concentration in our experiments was kept to
10 mmol/l, which may be enough to saturate the GLUT. Thus the transport
step would not be the rate-limiting step in our experiments. Russell et
al. (16) reported that insulin increased hexokinase activity associated
with the mitochondrial fraction. Hexokinase bound to mitochondria
exhibited an 8.5-fold increase in
Km for DG
compared with that of hexokinase in the cytosol (16). Therefore,
insulin-dependent change in the relative affinity to hexokinase between
DG and glucose may play an important role in the change of LC.
GLUT4 and GLUT1 are the primary forms expressed in adult mammalian
heart muscle (22). Insulin increases the number of GLUT4 on the cell
surface (20, 23). Ischemia also translocates GLUT4 and GLUT 1 to the cell surface (23, 24). Therefore, the changes in the population
of GLUT on the cell surface may also be a mechanism.
Recently, Doenst and Taegtmeyer (4) showed a significant increase of
intracellular free glucose during reperfusion that accompanied the
decrease in LC, supporting the hypothesis that glucose influx exceeds
the ability of phosphorylation.
Limitations.
In this study, we determined the relative affinity of DG to glucose in
the GLUT-hexokinase system using NMR, not radioisotope. NMR cannot
detect the concentration of tracer. However, P NMR detects only the
phosphorylated form of DG within the cell. Therefore, we need not
discriminate and
by compartment analysis. Nevertheless, LC in control hearts determined by the NMR method was
equal to the value previously reported with the radioactive tracer
technique (8, 9, 15). Thus both methods can be considered to be
equivalent to measure LC.
Hexokinase phosphorylates DG and glucose with different preferences (4,
16), suggesting that our estimation for myocardial accumulation of
phosphorylated DG may overestimate the actual value even though
glucose-6-phosphate is metabolized further. However, we used the
accumulation rate of SP rather than the absolute amount of SP.
Furthermore, is postulated as the total affinity of DG to both the
transporter and phosphorylation system relative to that of glucose.
Thus the contamination of the signals from the metabolites of glucose
little affects the determination of .
It is well known that a high [DG] has deteriorating effects
on myocardial energy metabolism. As addressed previously (6), we
carefully used only the initial part of the NMR data after switching
glucose to DG in the perfusate to determine the myocardial accumulation
rate of DG. A similar concept is used to measure enzyme activity,
although the time span is different. The data used in the analysis were
obtained during the phase when the intervention induced minimal changes
in metabolism.
It might be possible that LC for FDG is different from that for DG. It
has been reported that LC in brain metabolism is not different between
FDG and DG. Recently, LC for FDG was reported to be higher than that
for DG in rabbit hearts (11). Nevertheless, the same report observed
that insulin decreased LC for FDG and DG in a parallel manner (11).
Thus the absolute value of LC may be different between LC and FDG, but
our conclusion about the effect of insulin on LC is consistent for both
FDG and DG.
In conclusion, the lumped constant can be evaluated by methods other
than those using radiolabeled tracers. Our data indicate that the
lumped constant is smaller in insulin-stimulated hearts or in stunned
myocardium compared with the control condition. These results suggest
that the lumped constant is changed depending on the metabolic state,
and careful quantification is necessary to estimate of myocardial
glucose utilization using FDG PET when myocardial glucose uptake is enhanced.
| |
ACKNOWLEDGEMENTS |
This work was partly supported by Grants-in-Aid for Scientific
Research (no. B 08457208 and University-to-University Cooperative Research no. 07045051 to H. Kusuoka) of the Ministry of Education, Science and Culture of Japan.
| |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: H. Kusuoka, Inst. for Clinical Research,
Osaka National Hosp. 2-1-14 Hoenzaka, Chuo Osaka 540-0006 Japan (E-mail: kusuoka{at}onh.go.jp).
Received 4 May 1998; accepted in final form 10 September 1998.
| |
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Am J Physiol Heart Circ Physiol 276(1):H129-H133
0002-9513/99 $5.00
Copyright © 1999 the American Physiological Society
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Abstract
Introduction
