(Circulation. 1997;95:313-315.)
© 1997 American Heart Association, Inc.
Articles |
Glucose Metabolism in the Ischemic Heart
the Cardiovascular Disease Research Group (G.D.L.), Faculty of Medicine, The University of Alberta, Edmonton, Alberta, Canada, and Department of Physiology and Biophysics (W.C.S.), School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Key Words: Editorials • glucose • fatty acids • myocardial infarction • GLUT 1 • GLUT 4
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Introduction |
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 Top Introduction References |
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A number of clinical trials are presently evaluating whether stimulating glucose metabolism is an effective therapeutic approach to lessening the severity of ischemic injury (see References 1, 2, and 3 for reviews). Several pharmacological agents with demonstrated anti-ischemic effects have also recently been shown to act by stimulating glucose metabolism (ie, ranolazine, trimetazidine, L-carnitine, and propionyl L-carnitine).3 4 Despite these encouraging results, the regulation of glucose metabolism during ischemia remains poorly understood. Although many experimental studies have addressed the changes in cellular metabolism that occur during and subsequent to ischemia,3 5 little is known about the effects of ischemia on the actual transport of glucose into the heart. It has long been known that myocardial ischemia results in an increase in the rate of glycolysis and a switch from lactate uptake by the heart to lactate production.5 The glucose for glycolysis originates from both the breakdown of myocardial glycogen stores and the uptake of glucose from the blood (Figure
). The rate of glucose uptake by the heart during ischemia is dependent on the severity of the reduction in blood flow.6 It is increased with less severe ischemia but decreases with severe ischemia when glucose delivery to the tissue is very low. In any case, ischemia consistently causes a large increase in the extraction of glucose from the blood, reflecting a greater capacity for glucose transport across the sarcolemmal membrane.6
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A family of glucose transporters has only recently been cloned and characterized, with GLUT-1 and GLUT-4 being responsible for glucose transport in the heart (see Reference 7 for review). Although ischemia results in a flow-dependent fall in glucose delivery and a decrease in interstitial glucose levels,8 glucose uptake rates can still be accelerated. In this issue of Circulation, Young et al9 demonstrate that if canine hearts are subjected to low-flow ischemia, there is a significant increase in the translocation of both GLUT-1 and GLUT-4 from the intracellular pool to the sarcolemmal membrane. This important finding demonstrates that the ischemia-induced decrease in the driving force for glucose transport across the sarcolemma is compensated for by an increase in the membrane conductance for glucose. This provides a clear mechanism for the greater extraction of glucose by the heart during ischemia.
Reductions in coronary artery blood flow result in a nonuniform distribution of blood flow across the left ventricular wall. With the moderate level of ischemia used in the study by Young et al,9 there was a significant reduction in subendocardial blood flow (
60%) without a significant reduction in subepicardial flow.10 This is also reflected in a greater rate of glycogen breakdown in the subendocardium than in the subepicardium during ischemia.7 Young and colleagues took care to perform their studies on the inner half of the ischemic zone. It is very likely that the reductions in coronary artery flow did not cause any translocation of GLUT-1 and GLUT-4 into the sarcolemma in the outer subepicardial layer and likewise did not result in a large increase in glucose extraction in the outer region.
Although ischemia clearly increases the number of glucose transporters in the sarcolemmal membrane,9 11 it is not yet known if ischemia also increases the activity of the transporters residing in the membrane. Studies in skeletal muscle12 show that exercise results in both a greater number of transporters in the plasma membrane and a twofold increase in the rate of glucose transport into sarcolemmal vesicles for a given number of glucose transporters. This is due to an increase in Vmax and not to an increase in glucose affinity for the transporters. Increased contractile work in isolated rat hearts results in a sevenfold increase in 3-O-methyl glucose transport into the heart but only a threefold increase in total glucose transporter number,13 suggesting a similar response to an increase in workload in the heart. It is possible that ischemia may also result in an increase in the transport activity of GLUT-1 and GLUT-4 in addition to their translocation into the membrane.
Insulin will also result in the translocation of GLUT-1 and GLUT-4 into the plasma membrane of the heart.14 It is not known if insulin and ischemia result in the translocation of GLUT-1 and GLUT-4 from the same intracellular pool, nor whether stimulation of translocation is synergistic or occurs by the same mechanism. It is possible that the effects are additive in vivo, as is the case for the effect of insulin and hypoxia on glucose transport in skeletal muscle.15 Insulin also activates hexokinase in isolated rat hearts and causes the transfer of hexokinase to the mitochondrial membrane, thus increasing the phosphorylation of free glucose in the cytoplasm.16 The effects of ischemia on hexokinase activity are not known. Studies in isolated quiescent cultured cardiomyocytes suggest that glucose phosphorylation by hexokinase, rather than transport across the sarcolemmal membrane, is the rate-limiting step in insulin-stimulated glucose utilization17 ; however, this has not been shown in a working heart.
The translocation of GLUT-1 and GLUT-4 has potentially important consequences for the ability of the myocardium to withstand an episode of ischemia. During a mild to moderate episode of ischemia, accelerated rates of glucose uptake and glycolysis may provide an important source of ATP to maintain optimal control of membrane ion flux (see Reference 18 for example). As a result, increasing the translocation of GLUT-1 and GLUT-4 to the sarcolemmal membrane may well increase the rate of glycolysis and afford some protection to the ischemic heart. It should be recognized, however, that during severe ischemia, high glycolytic rates may actually contribute to ischemic injury, secondary to the production of glycolytic products (lactate and protons).19 It is unlikely that the increased translocation of GLUT-1 and GLUT-4 to the sarcolemmal membrane contributes to this accumulation of glycolytic products because under these more severe ischemic conditions, coronary flow is limiting for glucose uptake.
The translocation of GLUT-1 and GLUT-4 into the sarcolemmal membrane during ischemia also has potential implications for rates of glucose metabolism during reperfusion. Presumably, GLUT-1 and GLUT-4 continue to reside in greater numbers in the sarcolemma during reperfusion and gradually return to preischemic levels. However, this remains to be demonstrated. Direct measurements of glycolytic rates subsequent to ischemia have shown that glycolytic rates return to or exceed preischemic rates,20 21 even though heart function can be markedly impaired. Whether increased levels of GLUT-1 and GLUT-4 in the membrane contribute to these high rates of glycolysis has yet to be determined.
It is important to note that the rate of glucose uptake during ischemia is not controlled at a discrete regulatory point but rather is regulated at multiple sites, namely glucose transport, hexokinase activity, the rates of glucose 6-phosphate flux to and from glycogen, various points along the glycolytic pathway, and the ability of the mitochondria to oxidize pyruvate and cytosolically derived NADH (see Figure). Given a constant supply of glucose 6-phosphate, the primary regulators of glycolytic rates are the activity of phosphofructokinase and, during more severe ischemia, flux through glyceraldehyde 3-phosphate dehydrogenase5 (Figure
). Although glucose metabolism is an important source of energy for the heart, it should be recognized that the oxidation of fatty acids is normally the primary source of acetyl CoA for the Krebs cycle (Figure). During mild to moderate episodes of ischemia, fatty acid oxidation rates decrease but remain an important source of energy. With the moderate level of ischemia used in the study by Young et al9 (40% to 50% decrease in mean coronary flow), pyruvate oxidation is impaired,22 and fatty acid oxidation remains the primary source of acetyl CoA. During reperfusion, fatty acid oxidation quickly recovers and dominates as the source of energy (see Reference 3 for review). This is due in part to the high levels of fatty acids that occur in most clinically relevant conditions of myocardial ischemia but also to a direct increase in fatty acid oxidation rates. The main consequence of this is that glucose oxidation rates are markedly inhibited. As a result, high glycolytic rates (possibly due to increased glucose transport) and low glucose oxidation rates can result in a substantial uncoupling of glycolysis from glucose oxidation. This uncoupling of glycolysis from glucose oxidation contributes to the production of protons from glucose metabolism during reperfusion and can contribute to ischemic injury.3 20 21 The production of protons appears to be an important contributor to the decreased efficiency seen during reperfusion.20 21 Stimulation of glucose oxidation, either directly or by inhibiting fatty acid oxidation, results in a significant increase in cardiac function and efficiency.3 20 21 Therefore, it appears that high rates of fatty acid oxidation contribute to a marked decrease in cardiac efficiency during reperfusion by primarily inhibiting glucose oxidation and flux through pyruvate dehydrogenase (PDH) (Figure).
A number of different approaches can be used to manipulate energy metabolism in the heart. One is to increase glucose uptake and decrease circulating fatty acid levels with the use of an infusion of glucose and insulin.2 Although early clinical studies using this approach met with limited success, this approach is being resurrected, and a number of well-controlled trials are now being undertaken or planned. Another approach to increase glucose metabolism is to stimulate myocardial glucose oxidation by directly increasing PDH (the rate-limiting enzyme for glucose oxidation). This can be accomplished by directly stimulating PDH or indirectly stimulating PDH by inhibiting fatty acid oxidation or lowering intramitochondrial acetyl CoA (see Reference 3 for review). Agents that increase glucose oxidation, such as dichloroacetate, ranolazine, trimetazidine, L-carnitine, and propionyl L-carnitine, have all been shown to dramatically improve recovery of mechanical function after ischemia (see Reference 3 for review). Clinical trials have confirmed the experimental studies and have shown the antianginal properties of these agents can occur independently of hemodynamic changes.
Traditional therapies for the treatment of angina and acute myocardial infarction act by improving oxygen delivery and/or decreasing the myocardial oxygen demand. Agents that alter energy metabolism in the heart offer an exciting new approach to treating ischemic heart disease and other cardiovascular disorders, such as intermittent claudication. Pharmacological optimization of cardiac energy metabolism, without causing any direct negative hemodynamic, inotropic, or chronotropic effects, may prove particularly useful for the treatment of ischemic heart disease, especially in symptomatic patients already receiving maximally tolerated traditional therapies. Experimental and clinical data now support the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism is an effective approach to treating acute myocardial infarction and exercise-induced angina.1 2 3 Whether agents that directly modify GLUT-1 or GLUT-4 translocation and activity would have therapeutic utility in treating heart disease remains to be determined. Additional studies are required to understand how glucose metabolism is regulated during and after ischemia, including studies that define the cellular mechanism responsible for GLUT-1 and GLUT-4 translocation to the sarcolemmal membrane.
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Footnotes |
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Reprint requests to Dr Gary D. Lopaschuk, 423 Heritage Medical Research Bldg, The University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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