(Circulation. 1999;99:578-588.)
© 1999 American Heart Association, Inc.
Current Perspective |
Glucose for the Heart
From the Department of Internal Medicine (C.D., H.T.), Division of Cardiology, University of Texas Houston Medical School; and Institute of Cellular and Molecular Pathology (C.D.) and Division of Cardiology (J.-L.J.V.), University of Louvain Medical School, Brussels, Belgium.
Key Words: metabolism • glucose • heart failure • ischemia • myocardium
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Introduction |
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 Top Introduction Regulation of Glucose Metabolism...Glucose Metabolism in the...Glucose and Insulin as...Unresolved IssuesReferences |
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The homeostasis of plasma glucose levels is essential for survival of the mammalian organism. Since blood glucose concentration is maintained within a narrow range, glucose is a most reliable substrate for energy production in the heart. The importance of glucose metabolism via glycolysis is well appreciated in ischemic and hypertrophied heart muscle,1 2 3 4 but aerobic glucose metabolism for support of normal contractile function has received less attention, mainly because of the well-known fact that fatty acids are normally the predominant fuel for cardiac energy production.2 5 6 We have drawn attention to the heart as a true "omnivore," ie, an organ that functions best when it oxidizes different substrates simultaneously.7 In light of this concept, we wish to reexamine myocardial glucose metabolism and its relevance to the human heart. In recent years, the tools of molecular and cellular biology have provided new insight into the mechanisms of glucose transport and phosphorylation. Glycogen metabolism has come into greater focus. The regulation of glycolysis is more accurately defined, and the effects of second messengers on myocardial glucose utilization are better known. In view of this background, 2 well-known clinical concepts of myocardial glucose metabolism require critical reevaluation: (1) the diagnostic concept of metabolic imaging with PET and the glucose tracer analogue 18F-2-deoxy-2-fluoro-D-glucose (FDG) and (2) the therapeutic concept of metabolic support for the postischemic heart with glucose, insulin, and K+ (GIK).
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Regulation of Glucose Metabolism in Normoxic Heart |
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TopIntroductionRegulation of Glucose Metabolism...Glucose Metabolism in the...Glucose and Insulin as...Unresolved IssuesReferences |
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The simple sugar D-glucose is the most abundant organic molecule in nature. Glucose for the heart is derived either from the bloodstream or from intracellular stores of glycogen (Figure 1
). The transport of glucose into the
cardiomyocyte occurs along a steep concentration gradient
and is regulated by specific transporters. Intracellular glucose is
rapidly phosphorylated and becomes a substrate for the
glycolytic pathway, glycogen synthesis, and ribose synthesis. After
entering the glycolytic pathway, glucose is ultimately broken down to
pyruvate (Figure 1), which, in turn, is a substrate for further
metabolic pathways. Glucose uptake, defined as glucose
transport and phosphorylation, is measured as the
product of glucose extraction (percentage)xarterial
concentration of glucosexflow. Measurements of net glucose uptake and
lactate release by the arteriovenous differences have been extensively
used in humans to assess glucose metabolism, but
measurements in vivo are not as precise as in isolated hearts. In the
latter, glucose metabolism can be directly assessed by
labeled tracers and analogues. For instance, glucose uptake may be
measured by the detrition rate of
[2-3H]glucose, and glycolytic flux may be
measured by the detrition rate of [3-3H]glucose
or [5-3H]glucose. Similarly, glucose oxidation
may be measured by the release of
14CO2 from
[14C]glucose. Glycogen may also be labeled with
the same tracers. Dual- or triple-labeling techniques allow precise
measurement of the relative amounts of glucose derived from glycogen
compared with glucose derived from extracellular
sources.8 The quantitative determination of
glucose uptake by the glucose tracer analogue 2-deoxyglucose or FDG is
based on the assumption that, unlike glucose 6-phosphate,
2-deoxyglucose 6-phosphate and FDG 6-phosphate are irreversibly trapped
in the tissue and are neither subject to further metabolism
nor subject to dephosphorylation. The 3-compartment
model of Sokoloff et al9 and the graphic
analysis of Patlak et al10 are commonly
used to quantify the rates of myocardial glucose uptake from dynamic
measurements of radioactivity in a region of
interest.11 Under steady-state conditions, the
accumulation of tracers is linear and follows zero-order
kinetics.12 Since the affinity of glucose
transport is higher and that of hexokinase is lower for deoxyglucose
than for glucose, Sokoloff et al introduced a lumped constant (LC) to
calculate rates of glucose uptake from tissue activity in the brain.
However, derivation of this formula for tracer kinetic analysis
of glucose uptake in the heart13 is flawed by a
trivial solution,14 and LC decreases
significantly with insulin or after addition of another substrate
together with glucose.15 Combining upper and
lower limits for LC with the ratio between unidirectional and
steady-state FDG uptake rates allows the prediction of individual LCs
and, hence, the quantification of myocardial glucose uptake by a simple
tracer kinetic model.16
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Regulatory Steps of Glucose Metabolism
Glucose Transport
The transporters regulating the uptake of glucose belong to the
GLUT family17 18 19 and constitute a system of
stereospecific and saturable transport/countertransport. The isoform
that is predominantly expressed at the surface of adult
cardiomyocytes is GLUT 4, the insulin-sensitive transporter
also found in adipose tissue.17 In addition, the
cardiomyocyte expresses the GLUT 1 transporter, which is
presumably independent of insulin action and predominant in fetal
myocardium.18 Both transporters have
a Km for glucose (ie, the concentration of
glucose at which the rate of transport is half-maximal) that is in the
range of plasma glucose concentrations under fasting
conditions.20 The normal heart also expresses a
low amount of GLUT 3, which has a Km below
the normal plasma glucose concentration.21
Stimulation of glucose transport is exerted by a recruitment of
transporters from intracellular stores to the plasma
membrane,17 18 19 resulting in an increased maximal
velocity of transport.
Hexokinase
Glucose phosphorylation by hexokinase is the first
regulatory step that commits glucose to further metabolism
(Figure 1
). Two different isozymes of hexokinase are present in the
heart, hexokinases I and II.22 Hexokinase I is
predominant in the fetal and newborn heart, whereas the
insulin-regulated hexokinase II is predominant in the adult heart. The
reasons for this genetic shift are not known. Hexokinase is present
in the cytosolic fraction of the cell but also binds to the outer
mitochondrial membrane.23 Binding lowers the
Km for glucose and increases hexokinase
activity,24 although the
Km for 2-deoxyglucose remains nearly
10-fold higher than that for glucose.24 This
attachment also suppresses inhibition of hexokinase by glucose
6-phosphate.23 Insulin shifts the control
strength of glucose uptake from glucose transport to
phosphorylation. Control strength is defined as the
ratio of the change in enzyme activity on the change in the pathway
flux.25
Glycogen Metabolism
Although the bulk of glucose 6-phosphate enters the glycolytic
pathway (Figure 1), glucose 6-phosphate is also a substrate for
glycogen synthesis. The dynamics of glycogen turnover have recently
been investigated, and cycling of glucose moieties in and out of
glycogen has been proposed as a control site for myocardial glucose
metabolism.7 Glycogen occupies about
2% of the cell volume of the adult and 30% of the cell volume of the
fetal and newborn cardiomyocyte.26
Unlike liver and skeletal muscle, heart muscle increases its glycogen
content with fasting.27 This observation is
consistent with the general principle that fatty acids, the
predominant fuel for the heart during fasting, inhibit glycolysis more
than glucose uptake, thereby rerouting glucose toward glycogen
synthesis. Glycogen stores are also increased by insulin, from the
simultaneous stimulation of glucose transport and glycogen
synthase activity.28 Net glycogen synthesis also
occurs when lactate is the predominant fuel for the
heart.29 30
A variable amount of exogenous glucose cycles through glycogen before entering the glycolytic pathway. The cycling of glucose through the glycogen pool is substrate dependent. In isolated working rat heart perfused with glucose as sole substrate, a small part of extracellular glucose taken up by the cell is incorporated into glycogen before entering the glycolytic pathway,31 whereas this incorporation rate is significantly greater in vivo, when hormones and competing substrates are present.32 At the other end of the spectrum, glycogen is rapidly broken down when glycogen phosphorylase is stimulated by epinephrine or glucagon.31 Glycogen phosphorylase is the main regulator of glycogenolysis and one of the best-studied enzymes. It is activated by phosphorylation, either by cAMP-dependent protein kinase or by Ca2+-activated phosphorylase kinase.33 Glycogen breakdown is also rapidly stimulated during sudden increases of heart work.34 35 Glucosyl moieties coming from glycogen breakdown are preferentially oxidized rather than converted to lactate.34 As a result, there is a dichotomy between glucosyl units coming from extracellular glucose, which are metabolized into lactate, and glucosyl units coming from glycogen, which are oxidized. After the addition of epinephrine (in the presence of physiological concentrations of fatty acids), the extra energy requirements are initially met by glycogenolysis and then by a sustained increase in the rate of glucose oxidation.36 37
6-Phosphofructo-1-Kinase
The first regulatory site that commits glucose to the glycolytic
pathway is at the level of 6-phosphofructo-1-kinase (PFK-1), catalyzing
the phosphorylation of fructose 6-phosphate to fructose
1,6-bisphosphate (Figure 1). Because of a complex allosteric
regulation,38 conversion of fructose 6-phosphate
into fructose 1,6-diphosphate is a rate-limiting step of glycolysis.
ATP, citrate, and protons are negative allosteric
effectors,38 39 whereas AMP and fructose
2,6-diphosphate are positive effectors.40 41
Fructose 2,6-diphosphate is the main activator of PFK-1 in
normoxic heart.42 The concentration of this
effector increases when glycolytic flux is stimulated and decreases
when the heart oxidizes competing
substrates.42 43 44
GAPDH catalyzes the transformation, by oxidation and phosphorylation, of glyceraldehyde 3-phosphate into 1,3-diphosphoglycerate. As is the case with most dehydrogenases, GAPDH is inhibited by high concentrations of NADH and protons.45
Pyruvate kinase catalyzes the transformation of phospho(enol)pyruvate into pyruvate. Pyruvate kinase, which constitutes an irreversible step of glycolysis in heart muscle, may increase glycolytic flux, because it is stimulated by fructose 1,6-diphosphate, the product of PFK-1.46 PFK-1 thus synchronizes several glycolytic reactions, allowing an acceleration of the glycolytic pathway without accumulation of the glycolytic intermediates.
Fate of Pyruvate
Pyruvate enters the mitochondria via a monocarboxylate
carrier.47 In the mitochondrial matrix, pyruvate
becomes an intermediate at a branch point for several
metabolic pathways (Figure 2). Most of pyruvate produced either from
glycolysis or from exogenous lactate is oxidized to acetyl coenzyme A
(acetyl-CoA) by the pyruvate dehydrogenase complex (PDC) and fed into
the Krebs cycle. Pyruvate can also replenish Krebs cycle intermediates
through its transformation into oxaloacetate by pyruvate carboxylase or
malic enzyme.48 49 50 This mechanism of
replenishment in a metabolic cycle is also termed
anaplerosis. Oxidative decarboxylation of pyruvate to acetyl-CoA by the
PDC commits pyruvate to oxidation. The PDC is a mitochondrial
multienzyme complex that is regulated by its substrates and
products and by
phosphorylation/dephosphorylation
(Figure 3). Pyruvate dehydrogenase (PDH)
kinase, which inhibits the PDC, is stimulated by acetyl-CoA and NADH
(produced mainly by fatty acid oxidation) and inhibited by pyruvate
(produced from glucose and lactate), whereas PDH phosphatase, which
activates the PDC, is mainly stimulated by
Ca2+.51 52 The activation
of the PDC observed in working hearts submitted to increased workload
or perfused with epinephrine appears to be the result of
increased mitochondrial Ca2+
entry.52
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Integrative Mechanisms Regulating Glucose Metabolism
Long-Chain Fatty Acid Metabolism
The inhibition of glucose oxidation by fatty acids is a well-known
phenomenon of mammalian metabolism. Its mechanisms were
defined in the isolated perfused heart, and the results gave rise to
the formulation of the "glucose–fatty acid
cycle."5 Glucose may also inhibit fatty acid
oxidation, as follows. The transfer of the fatty acyl moieties into
mitochondria, where ß-oxidation occurs, is catalyzed by carnitine
palmitoyltransferases (CPT-1 and CPT-2). The rate of fatty acid
oxidation is controlled by their rate of transfer into the mitochondria
through CPT-1 (Figure 4).6 This latter
step is inhibited by malonyl-CoA,53 formed from
acetyl-CoA by acetyl-CoA carboxylase (ACC).54 55
Conditions that increase the production of acetyl-CoA from
pyruvate (as an increased concentration of glucose or lactate or the
addition of insulin) stimulate the production of malonyl-CoA
and thereby inhibit the ß-oxidation. Such a mechanism leads to the
suppression of fatty acid oxidation by glucose or lactate and is
reinforced by the fact that high plasma levels of glucose and insulin
decrease the concentration of circulating fatty acids.
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The Krebs Cycle
The Krebs cycle is perhaps the best example for the paradigm of
efficient energy transfer through metabolic cycles, which
includes the recycling of CO2 and
H2O. Without the recycling of
H2O, ATP production by the Krebs cycle
would be 60% less than with recycling (6 versus 15 moles of ATP per
mole pyruvate oxidized).7 Under normoxic
conditions, pyruvate is not only decarboxylated but also carboxylated
to oxaloacetate and malate (Figure 2). This mechanism allows both a
"refeeding" of Krebs cycle intermediates and a recycling of
CO2 produced from the action of
dehydrogenases.48 Fixation of
CO2 is particularly important during prolonged
oxidation of fatty acids and ketone bodies, which can "unspan" the
Krebs cycle by the sequestration of coenzyme
A.56 The potential contribution of substrates to
anaplerosis has given rise to the distinction between glucose and
lactate, which produce both acetyl-CoA and oxaloacetate, and fatty
acids or ketone bodies, which produce only acetyl-CoA. The need for
anaplerosis may explain why glucose uptake is never completely
inhibited in hearts perfused with fatty acids.
Malate-Aspartate Shuttle
This shuttle, first discovered in the liver, is also of major
importance for the heart.57 Several of the
intermediates presented in Figure 4 participate in the transfer
of reducing equivalents from cytosol to mitochondrion. The
malate-aspartate shuttle operates through 2 carriers, the dicarboxylate
carrier, which exchanges malate and 2-oxoglutarate, and the
aspartate/glutamate shuttle, which exchanges these 2 amino acids. The
net effect of the malate-aspartate shuttle is the transfer of hydrogen
ions from the cytosol (where they are produced) into the mitochondrion
(where they are consumed by the electron transport chain for oxidative
phosphorylation). These carriers thus preserve the
ionic balance between the cytosol and mitochondria. Such a mechanism
may be of particular importance during postischemic
reperfusion, when protons produced by ATP breakdown need to be carried
into the mitochondria (see below).
Determinants of Myocardial Glucose Uptake
Substrate Supply
Quantity and quality of substrate supply to the heart are
determined by the dietary state and physical activity of the body as a
whole. Long-chain fatty acids are the major substrates for the heart.
With fasting, fatty acids and triglycerides are released
from the adipose tissue and enter the circulation. Fatty acids are
taken up by the cardiac cell to be degraded to acetyl-CoA. Oxidation of
acetyl-CoA begins with the formation of citrate, which is the first
intermediate of the citric acid cycle. By an allosteric feedback
mechanism, citrate inhibits glycolysis at the PFK-1
step.39 Inhibition of glucose
metabolism by fatty acid oxidation was first observed in
isolated perfused heart muscle5 and also occurs
in vivo.58 As already stated, fatty acids inhibit
glucose oxidation more than glycolysis and glycolysis more than glucose
uptake.44 59 Glucose becomes the main substrate
for oxidative metabolism of the heart when fatty acid
levels are low and when the concentrations of glucose and insulin are
high, as in the postprandial state.7 We have
already mentioned that glucose decreases rates of long-chain fatty acid
oxidation,60 most likely at the level of CPT-1
through the production of malonyl-CoA by
ACC.54 55 Other substrates are lactate and ketone
bodies. The uptake and utilization of these substrates by the heart is
a function of their blood concentration.7
Isotopic studies in vivo have shown that the heart takes up lactate in
spite of net lactate release.61 There are 2
separate nonexchanging pools of lactate in the isolated
glucose-perfused rat heart.62 Lactate contributes
significantly to the supply of carbons for the tricarboxylate cycle and
may replace all other substrates (including glucose), especially after
exercise.63 Ketone bodies are produced from the
catabolism of fatty acids in the liver, and their plasma concentration
rises mainly with starvation, in the last trimester of pregnancy, and
in diabetic ketoacidosis.64 Both lactate and
ketone bodies inhibit glycolytic flux through elevating the cytosolic
levels of citrate and NADH, by the same mechanism as for fatty
acids.29 44 Moreover, ketone bodies require
CoA-SH moieties to be activated. Because CoA-SH is also a
cosubstrate for the Krebs cycle enzyme 2-oxoglutarate dehydrogenase,
flux through the cycle is inhibited, and the heart cannot sustain its
contractile activity when oxidizing ketone bodies
only.64 Because glucose or pyruvate restore
normal function, this observation of reversible contractile dysfunction
due to the depletion and replenishment of the Krebs cycle caused us to
propose the concept of shared substrate supply.7
Hormonal Milieu
The hormonal regulation of glucose metabolism involves
catecholamines, insulin, glucagon, thyroid hormones, and
acetylcholine. It also includes paracrine molecules, such as
bradykinin, or cytokines, such as tumor necrosis factor-
.
Epinephrine increases glycogen breakdown and glucose uptake.
Its intracellular action is partly mediated by cAMP and the
cAMP-dependent protein kinase44 and partly by
increased Ca2+
transients.65 The stimulation of glycolysis by
insulin results from a control at different
levels,28 mainly a stimulation of glucose
transport66 67 and of
PFK-1.68 Chronic administration of thyroid
hormones also stimulates glucose transport and
glycolysis.69 Inversely, in hypothyroid rats,
both the expression of glucose transporters and the activity of PFK-1
are decreased.70 71 Acetylcholine may
downregulate glucose utilization by increasing the concentration of
cGMP (see below).
Cardiac Work
Tight coupling between cardiac work, coronary flow, and
substrate oxidation is a central feature of cardiac physiology.
Increased external work in working heart models modifies glucose uptake
in parallel72 73 through a recruitment of glucose
transporters to the plasma membrane.67 74 The
positive inotropic action of epinephrine also results in
increased heart work and a marked acceleration of glucose uptake and
oxidation.36 44 In both cases, the inciting
stimulus of increased transport and oxidation seems to be an increase
in Ca2+ concentration. The increased heart work
brought by systemic hypertension results in an enzymatic shift favoring
the oxidation of glucose over fatty acids,4 even
in the absence of hypertrophy.
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Glucose Metabolism in the Ischemic and Reperfused Heart |
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TopIntroductionRegulation of Glucose Metabolism...Glucose Metabolism in the...Glucose and Insulin as...Unresolved IssuesReferences |
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Glucose assumes a central role for energy production in the ischemic heart, when lack of oxygen induces a shift to anaerobic metabolism with rapid stimulation of glucose uptake, glycogenolysis, and glycolytic flux.75 76 The relative contribution of glucose to energy production is highly dependent on the severity of ischemia. In moderate ischemia (reduction of coronary flow by 75%), glucose uptake remains unchanged, while glucose extraction increases and metabolism of glucose is directed from oxidation to lactate production.77 In severe ischemia, myocardial glucose extraction is inversely related to coronary flow,78 until the degree of ischemia becomes so severe that glycolysis is inhibited by the accumulation of its products.79 Once glycolysis is inhibited, glucose uptake progressively decreases, while protons, Na+, and Ca2+ continue to accumulate.80 81 82 The decline of glucose uptake during prolonged severe ischemia may be attenuated by various interventions protecting the heart against ischemic injury, such as an increase of the extracellular glucose concentration or the addition of insulin.82 83 84 85 86 The stimulation of glucose uptake by moderate ischemia is additive to that induced by insulin.87 These interventions promote glucose uptake to meet the increased demand for glucose moieties as an energy source. These conditions also stimulate glycogen synthesis.81 88
The controversy over whether the effects of glucose during ischemia are beneficial or deleterious is most likely the result of the different models used to investigate glucose metabolism and the different parameters measured by the investigators. A clear distinction must be made between glucose uptake, glycolysis, proton production, and glucose oxidation, on one hand, and between the different models of ischemia, on the other hand. Two models are mainly used to investigate heart metabolism during ischemia/reperfusion, the model of no-flow ischemia and the model of low-flow ischemia. Both models are not fully representative of the situation in vivo. In the first model, the heart is usually perfused in a working mode, and coronary flow is commensurate with the work performed. With ischemia, the flow is totally interrupted, so that all the metabolic end products accumulate in the heart. In the model of low-flow ischemia, the heart is perfused at constant coronary flow. Ischemia is induced by decreasing the coronary flow to such a value that the heart cannot further sustain its contractile activity. During low-flow ischemia, residual flow thus allows for a washout of metabolic end products. In such a model, it is possible to impose longer periods of ischemia, so that the damage induced by ischemia is only partly irreversible.80 In the model of low-flow ischemia, glucose uptake and glycolysis are accelerated, and both lactate and protons may be extruded. In the model of no-flow ischemia, glucose uptake is interrupted, glycolytic flux is supported by glycogen breakdown, and metabolic end products accumulate in the cytosol, where they not only amplify ischemic injury but eventually also shut down glycolysis.89
Glucose Uptake
The mechanisms leading to the stimulation of glucose uptake in
ischemia have recently been reviewed.90
The induction of ischemia or hypoxia is rapidly
followed in various experimental models by a recruitment of both GLUT 4
and GLUT 1 transporters from intracellular stores to the plasma
membrane,91 92 93 94 and if oxygen
deprivation is prolonged, the transcription of glucose
transporters is also modified.95 96 97 In any
event, the net result is an increase in the maximal velocity of glucose
transport. Glucose uptake progressively and irreversibly decreases
during ischemia, despite a maintained substrate
supply.80 This "metabolic
exhaustion" of glucose uptake happens before irreversible
ischemic injury is observed in isolated heart
preparations98 and results from inhibition of
glycolytic activity by the combined effect of ionic
disturbances (such as accumulation of protons), the inability
to extrude the products of glycolysis (such as lactate), and the
damaging effects of oxygen-derived free radicals on enzymes and
membrane phospholipids. Also, cGMP increases in the ischemic
heart99 because of an activation of NO
synthase,100 the product of which stimulates
cGMP production. Addition of cGMP analogues or NO donors to
perfused hearts decreases glucose uptake and glycolytic
flux.101 Thus, cGMP probably downregulates
glucose uptake during ischemia, as the addition of NO synthase
inhibitors to ischemic heart stimulates glucose
metabolism and improves the resistance against
ischemia.83
Glycolytic Flux
Stimulation of glucose transport by ischemia is coupled to
accelerated glycolytic flux. Such acceleration is explained by a
reversal of Pasteur's effect, which is the inhibition of glycolysis by
ATP. The acceleration of glycolytic flux is attributed to an activation
of PFK-1 by both an increase of AMP, an activator of PFK-1,
and a decrease of ATP, an inhibitor of the enzyme. The
change in the ratio of these 2 nucleotides constitutes the
mechanism of PFK-1 activation by
ischemia,102 since no change of fructose
2,6-diphosphate and citrate concentration is observed in this
condition.42 Stimulation of glycolytic flux may
also be due to a translocation of hexokinase, but this possibility has
not yet been investigated. In no-flow ischemic conditions,
however, the overall glycolytic flux may be limited by GAPDH, through
an inhibition by the accumulation of lactate and protons, although no
allosteric control of GAPDH by lactate has been found in a purified
enzyme preparation.45 Glycolysis during
ischemia seems particularly important in providing a residual
production of ATP. Such production sustains the
activity of ATP-requiring enzymes, mainly the sarcolemmal
Na+,K+-ATPase103 104
and the sarcoendoplasmic Ca2+-ATPase.
Glycogen Metabolism
Glycogen breakdown during ischemia and the stimulation of
glycogen phosphorylase by cAMP are long recognized but
still incompletely understood. Several studies have postulated a
"toxic" effect of glycogen breakdown in ischemic heart that
is due to an accumulation of protons and lactate and have suggested the
beneficial consequences of depleting the glycogen stores before an
ischemic episode.79 Many other studies,
however, have shown that protection of the heart against
ischemic injury is related to glycogen
availability.73 81 105 106 107 108 109 The absolute amount
of glucose moieties arising from glycogen is not negligible at the
onset of ischemia. In isolated perfused hearts subjected to
low-flow ischemia, glycogen breakdown provides, during the
first 15 minutes, about 60 µmol glucose equivalents per gram dry
weight, whereas during the same period, glucose uptake offers about
35 µmol glucose per gram.83 In the same
model, ischemic contracture begins when glycogen breakdown
stops and, concomitantly, the rate of glucose uptake decreases.
Enhanced utilization of extracellular glucose during ischemia
does not increase the absolute rate of glycolytic flux but prevents the
participation of glycogen stores to this flux, thereby limiting
ischemic damage and contracture.110 These
data indicate that cellular homeostasis in the ischemic heart
is better preserved as long as glycogen is present and available
for energy production.111 The exact
mechanism by which glycogen protects the ischemic heart remains
to be determined.
Another intriguing characteristic of glycogen metabolism in ischemic heart disease is the accumulation of glycogen in hibernating heart. Hibernating myocardium represents a chronically dysfunctional myocardium that has most likely been subjected to repetitive episodes of ischemia but is still capable of improving contractile function after reperfusion.112 To prevent irreversible tissue damage, the myocardium adapts the ventricular performance to the reduction of oxygen delivery. Indirect evidence supports a deregulation of glycogen metabolism in the hibernating heart, and several groups of investigators have reported that glycogen content in this tissue is dramatically increased.3 112 113 114 Hibernating myocardium is also characterized at PET by an increased signal of FDG,115 corresponding to glycogen accumulation in the same regions.116 The increased FDG signal in hibernating myocardium could thus be related to a stimulation of glucose uptake for glycogen synthesis, although this remains to be demonstrated. Interestingly, the accumulation of glycogen and other morphological alterations seen in hibernating tissue are also found in unloaded myocardium and in fetal heart,117 118 suggesting that hibernation may induce a reliance on glucose for energy provision similar to that observed in fetal heart.
Glycogen and Ischemic Preconditioning
Although the exact mechanism of preconditioning is most probably
multifactorial, many studies have demonstrated an attenuation of
glycolytic activity in preconditioned hearts. Preconditioning decreases
glycogen breakdown as well as the accumulation of hexose 6-phosphates
and lactate during no-flow
ischemia.119 120 Because the duration of
protection by preconditioning is also related to the time course of
postischemic glycogen recovery,121
the data, when taken together, show that protection by ischemic
preconditioning reduces glycogen breakdown, therefore attenuating the
accumulation of metabolic end products and the
development of intracellular acidosis. The slower decline of both
pHi and high-energy phosphates in preconditioned
hearts during no-flow ischemia122 is in
agreement with this hypothesis. Most of the preconditioning protocols
are performed on models of no-flow ischemia; this further
illustrates the importance of limiting the accumulation of glycolytic
end products in the absence of residual coronary flow. The
controversies about preconditioning may in part result from the variety
of the models used and parameters measured. Because of the
incomplete understanding of the mechanisms underlying ischemic
preconditioning, it is quite impossible to gauge the relative
importance of glucose metabolism in this condition.
Glucose Metabolism at Reperfusion
Both severity and duration of ischemia determine not only
the extent of the metabolic and ionic derangements but also
the return of function at reperfusion. The biochemical features of the
postischemic heart are both similar and different from
those of the ischemic heart. As for the ischemic heart,
many uncertainties exist about the role of glucose as substrate during
reperfusion. Again, such uncertainties may result from the different
experimental models. The 2 models described above for the
ischemic heart (no-flow ischemia and low-flow
ischemia) are also those used to investigate the effects of
reperfusion. In the model of no-flow ischemia, the
ischemic episode is relatively short (
30 minutes), and the
functional recovery at reperfusion is mainly determined by both the
extent of accumulation of metabolic end products during
ischemia and the substrate availability at reperfusion. In the
model of low-flow ischemia, the ischemic damage
is partly irreversible because of the longer episode of
ischemia (usually 
1 hour). The functional recovery at
reperfusion is thus mainly determined by the extent of irreversible
ischemic damage. After brief episodes of ischemia (up
to 20 to 30 minutes), oxidative metabolism rapidly returns,
well before contractile activity is
restored.123 124 125 126 Stimulation of glucose
oxidation at the onset of reperfusion improves and accelerates
functional recovery, whereas inhibition of glucose utilization induces
a strong impairment of postischemic
contractility.127 128 129 When
glycolysis is stimulated in reperfused myocardium, the
cytosolic accumulation of Ca2+
decreases.128 Because pharmacological
interventions that prevent Ca2+ accumulation in
reperfused myocardium also decrease the severity of
stunning,130 it is reasonable to assume that ATP
produced from glycolysis is used preferentially to support the activity
of ion pumps. The efficiency of this ionic homeostasis is further
improved by stimulating the PDC,131 which reduces
the accumulation of protons brought by glycolysis during
ischemia. The breakdown of ATP produced from glycolysis induces
a net production of protons that are consumed by the PDC. When
glycolysis is not coupled to glucose oxidation, the resulting
accumulation of protons stimulates the
Na+-H+ exchanger at
reperfusion.132 As a result of the accumulation
of Na+, the
Na+-Ca2+ exchanger is
stimulated, eventually leading to Ca2+ overload
and reperfusion injury.133 By activating the PDC,
such accumulation can be limited, and functional recovery is
improved.89 Paradoxically, fatty acid oxidation
is favored at reperfusion by a decrease of malonyl-CoA, thus relieving
the inhibition of CPT-1.134 The decrease of
malonyl-CoA results from the inhibition of ACC by a specific
AMP-dependent protein kinase activated by the AMP accumulation
during ischemia.134 135 The beneficial
effect of pyruvate at reperfusion136 and the fact
that the utilization of fatty acids instead of glucose strongly impairs
the efficiency of the reperfused heart129 137
suggest that the anaplerotic pathway is also stimulated at reperfusion.
Finally, glucose at reperfusion is also required to rebuild glycogen.
The best protection to the reperfused heart should be brought by a
combination of stimulated glycolytic flux, activated PDC,
increased glycogen storage, and anaplerosis of the Krebs cycle. This
hypothesis has yet to be tested.
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Glucose and Insulin as Substrates for Postischemic Heart |
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Substrate metabolism and contractile function are inseparable features of normal cardiac physiology. Reperfusion of ischemic myocardium is accompanied by a separation of substrate oxidation and contractile function. Prominent among the derangements responsible for functional impairment of postischemic myocardium is cellular Ca2+ overload, and ATP derived from glycolysis appears to play an important role for the restoration of Ca2+ homeostasis. The effects of glucose and insulin on restoration of contractile function are not entirely surprising in light of earlier clinical and experimental findings. After the effects of glucose and insulin on the ECGs of acutely ischemic dog hearts had been determined, a clinical role for GIK as a therapeutic agent was proposed in the 1960s.138 The rationale was that such a "polarizing treatment" reverses loss of intracellular K+ during acute ischemia. Although the exact mechanisms for the effects of glucose and insulin in the ischemic myocardium are not known, it seems reasonable to assume that they enhance membrane stability.104 138 Shortly after, it was also observed that GIK decreases the infarct size after coronary artery ligation in dogs, lessens ultrastructural damage, and improves global contractile function of the heart.139 The infusion of GIK was shown to reduce the frequency and duration of ventricular arrhythmias and to improve the survival of patients after myocardial infarction.140 141 Similarly, beneficial effects on ejection fraction and survival were observed when GIK was administered in conjunction with a thrombolytic agent142 or when GIK was given to patients with myocardial infarction and non–insulin-dependent diabetes mellitus.143 Most recently, a meta-analysis of all placebo-controlled trials of GIK treatment in acute myocardial infarction has shown an overall mortality reduction of 28%.144 A large prospective, randomized study of GIK as an adjunctive therapy to thrombolysis and/or restoration of blood flow in acute myocardial infarction has not yet been undertaken, probably for the following reasons. First, it was pointed out that the phosphorylation of glucose in glucose 6-phosphate actually uses ATP and draws on an already limited supply of the high-energy phosphates.79 Second, it was suggested that depletion of glycogen before ischemia reduces lactate production and improves contractile function with reperfusion.79 Third, in the postischemic myocardium, there is an imbalance between glycolysis on the one hand and glucose oxidation on the other.131 It has been argued that postischemic contractile dysfunction is caused by impaired glucose oxidation and cytosolic proton accumulation, and agents that enhanced glucose oxidation in the postischemic heart also seem to improve contractile function.89 Although this line of reasoning seems of compelling logic, glycolysis is also an adaptive emergency mechanism that can prevent deleterious myocyte deenergization.127 145 Thus, the use of metabolic support during both ischemia and reperfusion should complement other pharmacological interventions aimed at the restoration of normal pump function of the myocardium. Moreover, the different experimental data summarized in the previous section have shown that fatty acid metabolism is stimulated at reperfusion. This may be harmful for the heart, because it decreases functional performance and alters membrane stability.137 One of the beneficial effects of the GIK solution is the reduction of circulating free fatty acids. We have proposed that such treatment also promotes glucose oxidation, thereby limiting proton accumulation by replenishing the tricarboxylate cycle.146
The short-term infusion of GIK (up to 48 hours) has been used very effectively in patients with refractory left ventricular failure after hypothermic ischemic arrest of the heart for revascularization surgery.147 148 In these patients, the administration of GIK (a solution of 50% D-glucose containing 80 U of regular insulin and 100 mEq KCl) lowered the plasma concentration of free fatty acids, decreased systemic vascular resistance, raised the cardiac index, and increased urine output. The need for inotropic drugs, the time on the intra-aortic balloon pump, and the stay in the intensive care unit were all significantly reduced. Most important, there was a significant decrease in both short-term and long-term mortality in patients receiving GIK. These results have recently been corroborated in a larger (but nonrandomized) group of 322 patients treated at the Texas Heart Institute (Houston, Tex) and in a smaller (but randomized) study at Boston University (Boston, Mass).149 150
The rationale for the use of glucose and insulin as therapeutic agents is based on the considerations described in the first part of this review. In the ischemic heart, a protection against ischemic damage can be afforded as long as ATP is produced and protons are eliminated. The GIK solutions increase glucose uptake in the ischemic heart and probably allow for a higher rate of ATP production from glycolysis. Such ATP production inhibits ATP-dependent K+ channels of the plasma membrane and prevents changes of membrane potential that could lead to severe arrhythmias.151 Glycogen synthesis is also stimulated by increasing the production of glucose 6-phosphate, leading to a "glycogen loading" similar to that described above in isolated heart preparations.146 Several clinical reports stress the importance of preoperative glycogen loading for improvement of myocardial protection during cold cardioplegia and reperfusion.152
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TopIntroductionRegulation of Glucose Metabolism...Glucose Metabolism in the...Glucose and Insulin as...Unresolved IssuesReferences |
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Many issues of glucose metabolism in the heart remain unresolved, especially with respect to the heart in vivo. Examples include the exact triggering mechanism inducing increased glucose extraction at the onset of ischemia. Although many effectors (ATP, phosphocreatine, Ca2+, AMP, and glucose 6-phosphate) have been implied, none of them seems to be the exact mechanism. Also, we have described above the ionic imbalance occurring during ischemia/reperfusion, but the real contribution of glycolysis in the production of protons remains to be measured. Experiments using NMR spectroscopy have provided tantalizing glimpses at changes in protons and Na+ and Ca2+ concentrations but yielded no quantitative measurements on the source and fate of these ions. If proton overload induces an accumulation of Na+, then a stimulation of the Na+,K+-ATPase during ischemia/reperfusion should prevent Ca2+ accumulation. The inhibition of GAPDH by protons and/or lactate is still controversial, because no clear conclusion could be made from experiments using purified enzyme preparations.45 The regulation of glucose transporters also remains largely unknown. Besides their recruitment to the plasma membrane, glucose transporters could also be regulated by covalent modifications, such as phosphorylation or binding of regulatory proteins. Moreover, their mechanism of trafficking between intracellular stores and plasma membrane is largely unknown. Another topic awaiting further resolution is the compartmentation of ATP. Because ATP is used for many purposes in the heart (eg, contraction, Ca2+ reuptake and other ionic pumps, protein phosphorylation, and glycolysis), it is possible that a real compartmentation of high-energy phosphates exists. Also of interest is the increasing awareness of the importance of phosphorylation signaling pathways, which are intimately intertwined with enzyme regulation. Proteins such as mitogen-activated protein kinases, AMP-dependent protein kinase, cAMP-dependent protein kinases, cGMP-dependent protein kinases, protein kinase C, Jun NH2-terminal kinase, and many others are now familiar terms, and the future will tell us more about the role of phosphoprotein phosphatases. Of growing interest is the study of intercellular communication, mainly that between the cardiomyocyte and the endothelial cell. Metabolic effects of many intercellular mediators, such as NO, cAMP, cGMP, adenosine, endothelin-1, bradykinin, and interleukins, are now under investigation. Last, the tools of molecular biology will help to define the long-term regulation of metabolism at the transcriptional level. It is very likely that clinical situations such as hibernation, heart failure, hypertrophy, chronic ischemic heart disease, and cardiomyopathies induce a shift in the genetic expression of metabolic enzymes, contractile proteins, and oncogenes. A better understanding of these alterations may help to prevent them and could provide potential targets for gene therapy.
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Acknowledgments |
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Dr Taegtmeyer was supported by grant RO1-HL-43133 from the US Public Health Service. Dr Depre was a fellow from the Belgian Fonds de Developpement Scientifique. We thank Dr Gary Goodwin for his critical comments and Dr Louis Hue for guidance. We thank the reviewers for constructive criticism.
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Footnotes |
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Reprint requests to Heinrich Taegtmeyer, MD, DPhil, Division of Cardiology, University of Texas Houston Medical School, 6431 Fannin, MSB 1.264, Houston, TX 77030.
Guest Editor for this article was Dr Lionel Opie, University of Cape Town Medical School, Cape Town, South Africa.
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H. B. van Wezel and S. W. M. d. Jong Clinical Use of Glucose-Insulin-Potassium in Cardiac Surgery andAcute Myocardial Infarction: An Overview Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2003; 7(1): 77 - 83. [PDF]
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I. Friehs and P. J. del Nido Increased susceptibility of hypertrophied hearts to ischemic injury Ann. Thorac. Surg., February 1, 2003; 75(2): S678 - 684. [Abstract] [Full Text] [PDF]
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M. Eynan, T. Knubuvetz, U. Meiri, G. Navon, G. Gerstenblith, Z. Bromberg, Y. Hasin, and M. Horowitz Heat acclimation-induced elevated glycogen, glycolysis, and low thyroxine improve heart ischemic tolerance J Appl Physiol, December 1, 2002; 93(6): 2095 - 2104. [Abstract] [Full Text] [PDF]
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P. Herrero, T. L. Sharp, C. Dence, B. M. Haraden, and R. J. Gropler Comparison of 1-11C-Glucose and 18F-FDG for Quantifying Myocardial Glucose Use with PET J. Nucl. Med., November 1, 2002; 43(11): 1530 - 1541. [Abstract] [Full Text] [PDF]
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S. L. Bacharach and S. K. Sundaram 18F-FDG in Cardiology and Oncology: The Bitter with the Sweet J. Nucl. Med., November 1, 2002; 43(11): 1542 - 1544. [Full Text] [PDF]
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S. D. Solomon, M. S. J. Sutton, G. A. Lamas, T. Plappert, J. L. Rouleau, H. Skali, L. Moye, E. Braunwald, M. A. Pfeffer, and for the Survival And Ventricular Enlargement (SAVE Ventricular Remodeling Does Not Accompany the Development of Heart Failure in Diabetic Patients After Myocardial Infarction Circulation, September 3, 2002; 106(10): 1251 - 1255. [Abstract] [Full Text] [PDF]
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A. M. Vogt, M. Poolman, C. Ackermann, M. Yildiz, W. Schoels, D. A. Fell, and W. Kubler Regulation of Glycolytic Flux in Ischemic Preconditioning. A STUDY EMPLOYING METABOLIC CONTROL ANALYSIS J. Biol. Chem., June 28, 2002; 277(27): 24411 - 24419. [Abstract] [Full Text] [PDF]
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H. Taegtmeyer, P. McNulty, and M. E. Young Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts Circulation, April 9, 2002; 105(14): 1727 - 1733. [Full Text] [PDF]
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Y. Cottin, I. Lhuillier, L. Gilson, M. Zeller, C. Bonnet, C. Toulouse, P. Louis, L. Rochette, C. Girard, and J.-E. Wolf Glucose insulin potassium infusion improves systolic function in patients with chronic ischemic cardiomyopathy Eur J Heart Fail, March 1, 2002; 4(2): 181 - 184. [Abstract] [Full Text] [PDF]
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C. P Lydell, A. Chan, R. B Wambolt, N. Sambandam, H. Parsons, G. P Bondy, B. Rodrigues, K. M Popov, R. A Harris, R. W Brownsey, et al. Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts Cardiovasc Res, March 1, 2002; 53(4): 841 - 851. [Abstract] [Full Text] [PDF]
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L. A Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P Shannon Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure Cardiovasc Res, February 1, 2002; 53(2): 392 - 404. [Abstract] [Full Text] [PDF]
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C. Korvald, O. P. Elvenes, E. Aghajani, E. S. P. Myhre, and T. Myrmel Postischemic mechanoenergetic inefficiency is related to contractile dysfunction and not altered metabolism Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2645 - H2653. [Abstract] [Full Text] [PDF]
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J. J. Krueger, X.-H. Ning, B. M. Argo, O. Hyyti, and M. A. Portman Triidothyronine and epinephrine rapidly modify myocardial substrate selection: a 13C isotopomer analysis Am J Physiol Endocrinol Metab, November 1, 2001; 281(5): E983 - E990. [Abstract] [Full Text] [PDF]
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C. Korvald, O. P. Elvenes, T. Myrmel, and D. G. Sorlie Cardiac dysfunction and inefficiency after substrate-enriched warm blood cardioplegia Eur. J. Cardiothorac. Surg., September 1, 2001; 20(3): 555 - 564. [Abstract] [Full Text] [PDF]
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J. Terrand, I. Papageorgiou, N. Rosenblatt-Velin, and R. Lerch Calcium-mediated activation of pyruvate dehydrogenase in severely injured postischemic myocardium Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H722 - H730. [Abstract] [Full Text] [PDF]
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R. Tian and E. D. Abel Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis Circulation, June 19, 2001; 103(24): 2961 - 2966. [Abstract] [Full Text] [PDF]
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D. Jagasia, J. M. Whiting, J. Concato, S. Pfau, and P. H. McNulty Effect of Non-Insulin-Dependent Diabetes Mellitus on Myocardial Insulin Responsiveness in Patients With Ischemic Heart Disease Circulation, April 3, 2001; 103(13): 1734 - 1739. [Abstract] [Full Text] [PDF]
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H. Taegtmeyer Metabolism--the lost child of cardiology J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1386 - 1388. [Full Text] [PDF]
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C. Ceconi, P. Bernocchi, A. Boraso, A. Cargnoni, P. Pepi, S. Curello, and R. Ferrari New insights on myocardial pyridine nucleotides and thiol redox state in ischemia and reperfusion damage Cardiovasc Res, August 18, 2000; 47(3): 586 - 594. [Abstract] [Full Text] [PDF]
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D Pagano, J N Townend, D V Parums, R S Bonser, and P G Camici Hibernating myocardium: morphological correlates of inotropic stimulation and glucose uptake Heart, April 1, 2000; 83(4): 456 - 461. [Abstract] [Full Text]
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C. Korvald, O. P. Elvenes, and T. Myrmel Myocardial substrate metabolism influences left ventricular energetics in vivo Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1345 - H1351. [Abstract] [Full Text] [PDF]
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P. Zhu, L. Lu, Y. Xu, C. Greyson, and G. G. Schwartz Glucose-insulin-potassium preserves systolic and diastolic function in ischemia and reperfusion in pigs Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H595 - H603. [Abstract] [Full Text] [PDF]
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]
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G. D. Dispersyn, M. Borgers, and W. Flameng Apoptosis in chronic hibernating myocardium: sleeping to death? Cardiovasc Res, February 1, 2000; 45(3): 696 - 703. [Abstract] [Full Text] [PDF]
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P. Iozzo, P. Chareonthaitawee, M. Di Terlizzi, D. J. Betteridge, E. Ferrannini, and P. G. Camici Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1163 - E1171. [Abstract] [Full Text] [PDF]
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