Glucose for the Heart
1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 4 Linguagem: Inglês
10.1161/01.cir.99.4.578
ISSN1524-4539
AutoresChristophe Depré, Jean‐Louis Vanoverschelde, Heinrich Taegtmeyer,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculationVol. 99, No. 4Glucose for the Heart Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBGlucose for the Heart Christophe Depre, Jean-Louis J. Vanoverschelde and Heinrich Taegtmeyer Christophe DepreChristophe Depre 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. , Jean-Louis J. VanoverscheldeJean-Louis J. Vanoverschelde 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. and Heinrich TaegtmeyerHeinrich Taegtmeyer 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. Originally published2 Feb 1999https://doi.org/10.1161/01.CIR.99.4.578Circulation. 1999;99:578–588The 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,1234 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.256 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).Regulation of Glucose Metabolism in Normoxic HeartThe 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)×arterial concentration of glucose×flow. 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.16Regulatory Steps of Glucose MetabolismGlucose TransportThe transporters regulating the uptake of glucose belong to the GLUT family171819 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,171819 resulting in an increased maximal velocity of transport.HexokinaseGlucose 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.25Glycogen MetabolismAlthough 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.2930A 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.3435 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.36376-Phosphofructo-1-KinaseThe 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,3839 whereas AMP and fructose 2,6-diphosphate are positive effectors.4041 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.424344GAPDH 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.45Pyruvate 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 PyruvatePyruvate 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.484950 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+.5152 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.52Integrative Mechanisms Regulating Glucose MetabolismLong-Chain Fatty Acid MetabolismThe 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 β-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).5455 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 β-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.The Krebs CycleThe 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 ShuttleThis 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 UptakeSubstrate SupplyQuantity 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.4459 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.5455 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.2944 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.7Hormonal MilieuThe 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-α. 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 transport6667 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.7071 Acetylcholine may downregulate glucose utilization by increasing the concentration of cGMP (see below).Cardiac WorkTight 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 parallel7273 through a recruitment of glucose transporters to the plasma membrane.6774 The positive inotropic action of epinephrine also results in increased heart work and a marked acceleration of glucose uptake and oxidation.3644 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.Glucose Metabolism in the Ischemic and Reperfused HeartGlucose 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.7576 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.808182 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.8283848586 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.8188The 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.89Glucose UptakeThe 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,91929394 and if oxygen deprivation is prolonged, the transcription of glucose transporters is also modified.959697 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.83Glycolytic FluxStimulation 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+-ATPase103104 and the sarcoendoplasmic Ca2+-ATPase.Glycogen MetabolismGlycogen 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.7381105106107108109 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.3112113114 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,117118 suggesting that hibernation may induce a reliance on glucose for energy provision similar to that observed in fetal heart.Glycogen and Ischemic PreconditioningAlthough the exact mechanism of preconditioning is most probably multifactorial, many studies have demonstrated an attenuation
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