© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Regulation of energy substrate metabolism in the diabetic heart
aDepartment of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA
bCardiovascular Disease Research Group and Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alta., Canada T6G 2S2
cDiabetes Discovery, Novo Nordisk, DK-2880 Bagsvaerd, Denmark
* Corresponding author. Tel.: +1 (216) 368-3952; fax: +1 (216) 368-3952; e-mail: WCS4@po.cwru.edu
Received 20 January 1997; accepted 23 January 1997
KEYWORDS Diabetes; Fatty acids; Glycolysis; Myocardial ischemia; Lactate; Myocardial metabolism; Pyruvate dehydrogenase
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1 Introduction |
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Following a myocardial infarction diabetic patients have almost twice the rate of mortality and 3 times the rate of progression to congestive heart failure when compared to nondiabetic patients [1]. These observations suggest that defects specific to the diabetic myocardium contribute to the greater mortality in diabetic patients [1, 2]. Abnormalities in myocardial energy metabolism in the diabetic population are probably an important contributing factor to this greater mortality. Normal cardiac function is dependent on a constant rate of resynthesis of ATP by mitochondrial oxidative phosphorylation and, to a much lesser extent, glycolysis. Oxidation of fatty acids is normally responsible for about 60–90% of the ATP resynthesized [3–7], with the balance coming from the oxidation of pyruvate derived from glycolysis and lactate uptake (Fig. 1). Even in the absence of diabetes myocardial ischemia results in profound derangements in myocardial substrate utilization, particularly impaired pyruvate oxidation
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2 Effects on glucose transport and glycolysis |
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3 Role of circulating substrate and insulin levels |
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4 Effects on pyruvate oxidation |
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5 Fatty acid oxidation and the tricarboxylic acid cycle |
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5.1 Fatty acid supply and myocardial uptake
5.2 Mitochondrial fatty acid uptake
5.3 Mitochondrial fatty acid β-oxidation
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6 Contribution of substrate metabolism to contractile dysfunction in the diabetic heart |
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7 Summary and conclusions |
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I. V. Turko, S. Marcondes, and F. Murad Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2289 - H2294. [Abstract] [Full Text] [PDF]
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S. Ghosh, N. B. Standen, and M. Galinanes Failure to precondition pathological human myocardium J. Am. Coll. Cardiol., March 1, 2001; 37(3): 711 - 718. [Abstract] [Full Text] [PDF]
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M. E. Young, G. W. Goodwin, J. Ying, P. Guthrie, C. R. Wilson, F. A. Laws, and H. Taegtmeyer Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids Am J Physiol Endocrinol Metab, March 1, 2001; 280(3): E471 - E479. [Abstract] [Full Text] [PDF]
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L. M. King, R. J. Sidell, J. R. Wilding, G. K. Radda, and K. Clarke Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1173 - H1181. [Abstract] [Full Text] [PDF]
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D. D. Belke, T. S. Larsen, E. M. Gibbs, and D. L. Severson Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E1104 - E1113. [Abstract] [Full Text] [PDF]
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J. D Militante, J. B Lombardini, and S. W Schaffer The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus Cardiovasc Res, June 1, 2000; 46(3): 393 - 402. [Abstract] [Full Text] [PDF]
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J. Sakamoto, R. L. Barr, K. M. Kavanagh, and G. D. Lopaschuk Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1196 - H1204. [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. J van der Vusse, M. van Bilsen, and J. F.C Glatz Cardiac fatty acid uptake and transport in health and disease Cardiovasc Res, January 14, 2000; 45(2): 279 - 293. [Abstract] [Full Text] [PDF]
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N. S Dhalla, X. Liu, V. Panagia, and N. Takeda Subcellular remodeling and heart dysfunction in chronic diabetes Cardiovasc Res, November 1, 1998; 40(2): 239 - 247. [Abstract] [Full Text] [PDF]
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M. E. Young, F. A. Laws, G. W. Goodwin, and H. Taegtmeyer Reactivation of Peroxisome Proliferator-activated Receptor alpha Is Associated with Contractile Dysfunction in Hypertrophied Rat Heart J. Biol. Chem., November 21, 2001; 276(48): 44390 - 44395. [Abstract] [Full Text] [PDF]
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J. C. Baker, X. Yan, T. Peng, S. Kasten, and T. E. Roche Marked Differences between Two Isoforms of Human Pyruvate Dehydrogenase Kinase J. Biol. Chem., May 19, 2000; 275(21): 15773 - 15781. [Abstract] [Full Text] [PDF]
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