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Metabolic dysfunction in diabetic cardiomyopathy

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Abstract

Diabetic cardiomyopathy (DCM) is defined as cardiac disease independent of vascular complications during diabetes. The number of new cases of DCM is rising at epidemic rates in proportion to newly diagnosed cases of diabetes mellitus (DM) throughout the world. DCM is a heart failure syndrome found in diabetic patients that is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction, occurring in the absence of hypertension and coronary artery disease. DCM and other diabetic complications are caused in part by elevations in blood glucose and lipids, characteristic of DM. Although there are pathological consequences to hyperglycemia and hyperlipidemia, the combination of the two metabolic abnormalities potentiates the severity of diabetic complications. A natural competition exists between glucose and fatty acid metabolism in the heart that is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes. Inhibition of these glycolytic enzymes not only controls flux of substrate through the glycolytic pathway, but also leads to the diversion of glycolytic intermediate substrate through pathological pathways, which mediate the onset of diabetic complications. The present review describes the limiting steps involved in the development of these pathological pathways and the factors involved in the regulation of these limiting steps. Additionally, therapeutic options with demonstrated or postulated effects on DCM are described.

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Abbreviations

ACEI:

Angiotensin-converting enzyme inhibitor

ADP:

Adenosine diphosphate

AGES:

Advanced glycation end products

AMP:

Adenosine monophosphate

ARB:

Angiotensin receptor blockers

ATP:

Adenosine triphosphate

BMI:

Body mass index

CASQ2:

Calsequestrin

CCB:

Calcium channel blockers

CHF:

Congestive heart failure

COX:

Cytochrome oxidase

CPT-1:

Carnitine palmitoyltransferase-1

CVD:

Cardiovascular disease

DCM:

Diabetic cardiomyopathy

DM:

Diabetes mellitus

FAT:

Fatty acid translocase

FKBP:

FK 506 binding protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GLP-1:

Glucagon-like peptide-1

GLUT:

Glucose transporter

GSH/GSSG:

Glutathione redox ratio

HMG-COA:

3-hydroxy-3-methylglutaryl coenzyme A

LV:

Left ventricle

LVDD:

Left ventricular diastolic dysfunction

LVH:

Left ventricular hypertrophy

NADPH:

Nicotinamide adenine dinucleotide phosphate

NCX:

Na+/Ca2+ exchanger

O-GlcNAC:

O-linked N-acetylglucosamine

PDH:

Pyruvate dehydrogenase complex

PFK:

Phosphofructokinase

PKC:

Protein kinase C

PPAR:

Peroxisome proliferation-activated receptor

RAAS:

Renin–angiotensin aldosterone system

ROS:

Reactive oxygen species

SERCA2A:

Sarco(endo)plasmic reticulum calcium ATPase

SR:

Sarcoplasmic reticulum

STZ:

Streptozotocin

TFAM:

Mitochondrial transcription factor A

TZD:

Thiazolidinediones

T1D:

Type 1 diabetes mellitus

T2D:

Type 2 diabetes mellitus

ZFR:

Zucker fatty rats

References

  1. Roger VL, Go AS, Lloyd-Jones DM et al (2012) Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125:e2–e220

    PubMed  Google Scholar 

  2. Anand SS, Yusuf S (2011) Stemming the global tsunami of cardiovascular disease. Lancet 377:529–532

    PubMed  Google Scholar 

  3. Yach D, Stuckler D, Brownell KD (2006) Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat Med 12:62–66

    CAS  PubMed  Google Scholar 

  4. Shao CH, Rozanski GJ, Patel KP et al (2007) Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats. J Mol Cell Cardiol 42:234–246

    CAS  PubMed  Google Scholar 

  5. Pereira L, Matthes J, Schuster I et al (2006) Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55:608–615

    CAS  PubMed  Google Scholar 

  6. Schafer SA, Machicao F, Fritsche A et al (2011) New type 2 diabetes risk genes provide new insights in insulin secretion mechanisms. Diabetes Res Clin Pract 93(Suppl 1):S9–S24

    PubMed  Google Scholar 

  7. An D, Rodrigues B (2006) Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291:H1489–H1506

    CAS  PubMed  Google Scholar 

  8. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223

    PubMed  Google Scholar 

  9. Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA (2011) RAGE biology, atherosclerosis and diabetes. Clin Sci (Lond) 121:43–55

    CAS  Google Scholar 

  10. Duncan JG (2011) Mitochondrial dysfunction in diabetic cardiomyopathy. Biochim Biophys Acta 1813:1351–1359

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Department of Health and Human Services CfDCaP (2011) Atlanta. GA. National Diabetes Fact Sheet, National Estimates and General Information on Diabetes and Prediabetes in the United States

    Google Scholar 

  12. Garcia MJ, McNamara PM, Gordon T et al (1974) Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 23:105–111

    CAS  PubMed  Google Scholar 

  13. Ren J, Ceylan-Isik AF (2004) Diabetic cardiomyopathy: do women differ from men? Endocrine 25:73–83

    CAS  PubMed  Google Scholar 

  14. Schilling JD, Mann DL (2012) Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin 8:619–631

    PubMed Central  PubMed  Google Scholar 

  15. Lacombe VA, Viatchenko-Karpinski S, Terentyev D et al (2007) Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol 293:R1787–R1797

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Howarth FC, Qureshi MA, Hassan Z et al (2011) Changing pattern of gene expression is associated with ventricular myocyte dysfunction and altered mechanisms of Ca2+ signalling in young type 2 Zucker diabetic fatty rat heart. Exp Physiol 96:325–337

    CAS  PubMed  Google Scholar 

  17. Wold LE, Dutta K, Mason MM et al (2005) Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats. J Mol Cell Cardiol 39:297–307

    CAS  PubMed  Google Scholar 

  18. Fang ZY, Prins JB, Marwick TH (2004) Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25:543–567

    CAS  PubMed  Google Scholar 

  19. McGavock JM, Lingvay I, Zib I et al (2007) Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116:1170–1175

    PubMed  Google Scholar 

  20. Ng AC, Delgado V, Bertini M et al (2010) Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus. Circulation 122:2538–2544

    PubMed  Google Scholar 

  21. Greer JJ, Ware DP, Lefer DJ (2006) Myocardial infarction and heart failure in the db/db diabetic mouse. Am J Physiol Heart Circ Physiol 290:H146–H153

    CAS  PubMed  Google Scholar 

  22. Hoshida S, Yamashita N, Otsu K et al (2000) Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 278:H256–H262

    CAS  PubMed  Google Scholar 

  23. Fauconnier J, Andersson DC, Zhang SJ et al (2007) Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species. Diabetes 56:1136–1142

    CAS  PubMed  Google Scholar 

  24. Graham ML, Janecek JL, Kittredge JA et al (2011) The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp Med 61:356–360

    CAS  PubMed  Google Scholar 

  25. Wold LE, Ren J (2004) Streptozotocin directly impairs cardiac contractile function in isolated ventricular myocytes via a p38 MAP kinase-dependent oxidative stress mechanism. Biochem Biophys Res Comm 318:1066–1071

    CAS  PubMed  Google Scholar 

  26. Corsetti JP, Sparks JD, Peterson RG et al (2000) Effect of dietary fat on the development of non-insulin dependent diabetes mellitus in obese Zucker diabetic fatty male and female rats. Atherosclerosis 148:231–241

    CAS  PubMed  Google Scholar 

  27. Tokuyama Y, Sturis J, DePaoli AM et al (1995) Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes 44:1447–1457

    CAS  PubMed  Google Scholar 

  28. Iida M, Murakami T, Ishida K et al (1996) Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun 222:19–26

    CAS  PubMed  Google Scholar 

  29. Martin SS, Qasim A, Reilly MP (2008) Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 52:1201–1210

    CAS  PubMed  Google Scholar 

  30. Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783

    CAS  PubMed  Google Scholar 

  31. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    CAS  PubMed  Google Scholar 

  32. Randle PJ, Garland PB, Hales CN et al (1966) Interactions of metabolism and the physiological role of insulin. Recent Prog Horm Res 22:1–48

    CAS  PubMed  Google Scholar 

  33. Neely JR, Morgan HE (1974) Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 36:413–459

    CAS  PubMed  Google Scholar 

  34. Sambandam N, Lopaschuk GD (2003) AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res 42:238–256

    CAS  PubMed  Google Scholar 

  35. Chappell JB, Robinson BH (1968) Penetration of the mitochondrial membrane by tricarboxylic acid anions. Biochem Soc Symp 27:123–133

    CAS  PubMed  Google Scholar 

  36. Finck BN, Lehman JJ, Leone TC et al (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Schaffer SW, Seyed-Mozaffari M, Cutcliff CR et al (1986) Postreceptor myocardial metabolic defect in a rat model of non-insulin-dependent diabetes mellitus. Diabetes 35:593–597

    CAS  PubMed  Google Scholar 

  38. Serpillon S, Floyd BC, Gupte RS et al (2009) Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol 297:H153–H162

    CAS  PubMed  Google Scholar 

  39. Li SY, Sigmon VK, Babcock SA et al (2007) Advanced glycation endproduct induces ROS accumulation, apoptosis, MAP kinase activation and nuclear O-GlcNAcylation in human cardiac myocytes. Life Sci 80:1051–1056

    CAS  PubMed  Google Scholar 

  40. Yan SF, Ramasamy R, Bucciarelli LG et al (2004) RAGE and its ligands: a lasting memory in diabetic complications? Diab Vasc Dis Res 1:10–20

    PubMed  Google Scholar 

  41. Fulop N, Mason MM, Dutta K et al (2007) Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol 292:C1370–C1378

    CAS  PubMed  Google Scholar 

  42. Hu Y, Belke D, Suarez J et al (2005) Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res 96:1006–1013

    CAS  PubMed  Google Scholar 

  43. Clark RJ, McDonough PM, Swanson E et al (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278:44230–44237

    CAS  PubMed  Google Scholar 

  44. Cotter MA, Cameron NE, Robertson S (1992) Polyol pathway-mediated changes in cardiac muscle contractile properties: studies in streptozotocin-diabetic and galactose-fed rats. Exp Physiol 77:829–838

    CAS  PubMed  Google Scholar 

  45. Trueblood N, Ramasamy R (1998) Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. Am J Physiol 275:H75–H83

    CAS  PubMed  Google Scholar 

  46. Ojaimi C, Kinugawa S, Recchia FA et al (2010) Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism. Cardiovasc Diabetol 9:43

    PubMed Central  PubMed  Google Scholar 

  47. Du XL, Edelstein D, Rossetti L et al (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97:12222–12226

    CAS  PubMed  Google Scholar 

  48. Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    CAS  PubMed  Google Scholar 

  49. Pacher P, Szabo C (2007) Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 25:235–260

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Du X, Matsumura T, Edelstein D et al (2003) Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 112:1049–1057

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Schaffer SW, Jong CJ, Mozaffari M (2012) Role of oxidative stress in diabetes-mediated vascular dysfunction: unifying hypothesis of diabetes revisited. Vascul Pharmacol 57:139–149

    CAS  PubMed  Google Scholar 

  52. Wieland O, Siess E, Schulze-Wethmar FH et al (1971) Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting, and refeeding on pyruvate dehydrogenase interconversion. Arch Biochem Biophys 143:593–601

    CAS  PubMed  Google Scholar 

  53. Hansford RG, Cohen L (1978) Relative importance of pyruvate dehydrogenase interconversion and feed-back inhibition in the effect of fatty acids on pyruvate oxidation by rat heart mitochondria. Arch Biochem Biophys 191:65–81

    CAS  PubMed  Google Scholar 

  54. McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425

    CAS  PubMed  Google Scholar 

  55. Hopkins TA, Sugden MC, Holness MJ et al (2003) Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-alpha transgenic mice. Am J Physiol Heart Circ Physiol 285:H270–H276

    CAS  PubMed  Google Scholar 

  56. Campbell FM, Kozak R, Wagner A et al (2002) A role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the control of cardiac malonyl-CoA levels: reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase. J Biol Chem 277:4098–4103

    CAS  PubMed  Google Scholar 

  57. Chatham JC, Forder JR (1997) Relationship between cardiac function and substrate oxidation in hearts of diabetic rats. Am J Physiol 273:H52–H58

    CAS  PubMed  Google Scholar 

  58. Connelly KA, Kelly DJ, Zhang Y et al (2009) Inhibition of protein kinase C-beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail 2:129–137

    CAS  PubMed  Google Scholar 

  59. Ricci C, Pastukh V, Leonard J et al (2008) Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis. Am J Physiol Cell Physiol 294:C413–C422

    CAS  PubMed  Google Scholar 

  60. Luiken JJ, Arumugam Y, Dyck DJ et al (2001) Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J Biol Chem 276:40567–40573

    CAS  PubMed  Google Scholar 

  61. Coort SL, Willems J, Coumans WA et al (2002) Sulfo-N-succinimidyl esters of long chain fatty acids specifically inhibit fatty acid translocase (FAT/CD36)-mediated cellular fatty acid uptake. Mol Cell Biochem 239:213–219

    CAS  PubMed  Google Scholar 

  62. Lopaschuk GD, Ussher JR, Folmes CD et al (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258

    CAS  PubMed  Google Scholar 

  63. Chabowski A, Coort SL, Calles-Escandon J et al (2004) Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab 287:E781–E789

    CAS  PubMed  Google Scholar 

  64. Luiken JJ, Coort SL, Koonen DP et al (2004) Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters. Pflugers Arch 448:1–15

    CAS  PubMed  Google Scholar 

  65. Carley AN, Severson DL (2005) Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta 1734:112–126

    CAS  PubMed  Google Scholar 

  66. Holland WL, Brozinick JT, Wang LP et al (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179

    CAS  PubMed  Google Scholar 

  67. Rodrigues B, Xiang H, McNeill JH (1988) Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats. Diabetes 37:1358–1364

    CAS  PubMed  Google Scholar 

  68. Sakamoto J, Barr RL, Kavanagh KM et al (2000) Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart. Am J Physiol Heart Circ Physiol 278:H1196–H1204

    CAS  PubMed  Google Scholar 

  69. Kudo N, Barr AJ, Barr RL et al (1995) High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270:17513–17520

    CAS  PubMed  Google Scholar 

  70. Gamble J, Lopaschuk GD (1997) Insulin inhibition of 5′ adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism 46:1270–1274

    CAS  PubMed  Google Scholar 

  71. Young ME, Goodwin GW, Ying J et al (2001) Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids. Am J Physiol Endocrinol Metab 280:E471–E479

    CAS  PubMed  Google Scholar 

  72. Finck BN, Han X, Courtois M et al (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 100:1226–1231

    CAS  PubMed  Google Scholar 

  73. Chen W, Xia Y, Zhao X et al (2012) The critical role of astragalus polysaccharides for the improvement of PPRAalpha-mediated lipotoxicity in diabetic cardiomyopathy. PLoS ONE 7:e45541

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Yu BC, Chang CK, Ou HY et al (2008) Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats. Cardiovasc Res 80:78–87

    CAS  PubMed  Google Scholar 

  75. Cheng L, Ding G, Qin Q et al (2004) Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10:1245–1250

    CAS  PubMed  Google Scholar 

  76. Burkart EM, Sambandam N, Han X et al (2007) Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest 117:3930–3939

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Bowman RH (1966) Effects of diabetes, fatty acids, and ketone bodies on tricarboxylic acid cycle metabolism in the perfused rat heart. J Biol Chem 241:3041–3048

    CAS  PubMed  Google Scholar 

  78. Taegtmeyer H, Passmore JM (1985) Defective energy metabolism of the heart in diabetes. Lancet 1:139–141

    CAS  PubMed  Google Scholar 

  79. Kuo TH, Moore KH, Giacomelli F et al (1983) Defective oxidative metabolism of heart mitochondria from genetically diabetic mice. Diabetes 32:781–787

    CAS  PubMed  Google Scholar 

  80. Pierce GN, Dhalla NS (1985) Heart mitochondrial function in chronic experimental diabetes in rats. Can J Cardiol 1:48–54

    CAS  PubMed  Google Scholar 

  81. Tomita M, Mukae S, Geshi E et al (1996) Mitochondrial respiratory impairment in streptozotocin-induced diabetic rat heart. Jpn Circ J 60:673–682

    CAS  PubMed  Google Scholar 

  82. Boudina S, Sena S, O’Neill BT et al (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695

    PubMed  Google Scholar 

  83. Suarez J, Hu Y, Makino A et al (2008) Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes. Am J Physiol Cell Physiol 295:C1561–C1568

    CAS  PubMed  Google Scholar 

  84. Zungu M, Young ME, Stanley WC et al (2009) Chronic treatment with the peroxisome proliferator-activated receptor alpha agonist Wy-14,643 attenuates myocardial respiratory capacity and contractile function. Mol Cell Biochem 330:55–62

    CAS  PubMed  Google Scholar 

  85. Boudina S, Sena S, Theobald H et al (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–2466

    CAS  PubMed  Google Scholar 

  86. von Bibra H, Hansen A, Dounis V et al (2004) Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart 90:1483–1484

    Google Scholar 

  87. von Bibra H, Siegmund T, Hansen A et al (2007) Augmentation of myocardial function by improved glycemic control in patients with type 2 diabetes mellitus. Dtsch Med Wochenschr 132:729–734

    Google Scholar 

  88. McGuire DK, Inzucchi SE (2008) New drugs for the treatment of diabetes mellitus: part I: thiazolidinediones and their evolving cardiovascular implications. Circulation 117:440–449

    PubMed  Google Scholar 

  89. Sharma AM, Staels B (2007) Review: peroxisome proliferator-activated receptor gamma and adipose tissue–understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab 92:386–395

    CAS  PubMed  Google Scholar 

  90. Masoudi FA, Inzucchi SE (2007) Diabetes mellitus and heart failure: epidemiology, mechanisms, and pharmacotherapy. Am J Cardiol 99:113B–132B

    CAS  PubMed  Google Scholar 

  91. Masoudi FA, Inzucchi SE, Wang Y et al (2005) Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111:583–590

    CAS  PubMed  Google Scholar 

  92. Nikolaidis LA, Elahi D, Hentosz T et al (2004) Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 110:955–961

    CAS  PubMed  Google Scholar 

  93. Sokos GG, Nikolaidis LA, Mankad S et al (2006) Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 12:694–699

    CAS  PubMed  Google Scholar 

  94. Chiasson JL, Josse RG, Gomis R et al (2002) Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072–2077

    CAS  PubMed  Google Scholar 

  95. Hanefeld M, Josse RG, Chiasson JL (2005) Alpha-glucosidase inhibitors for patients with type 2 diabetes: response to van de Laar et al. Diabet Care 28:1840 (author reply 1)

    Google Scholar 

  96. Konduracka E, Gackowski A, Rostoff P et al (2007) Diabetes-specific cardiomyopathy in type 1 diabetes mellitus: no evidence for its occurrence in the era of intensive insulin therapy. Eur Heart J 28:2465–2471

    PubMed  Google Scholar 

  97. Haas SJ, Vos T, Gilbert RE et al (2003) Are beta-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials. Am Heart J 146:848–853

    CAS  PubMed  Google Scholar 

  98. Fonseca V, Bakris GL, Bell DS et al (2007) Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI. Diabet Med 24:759–763

    CAS  PubMed  Google Scholar 

  99. Ramasubbu K, Estep J, White DL et al (2008) Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 51:415–426

    CAS  PubMed  Google Scholar 

  100. Stolen TO, Hoydal MA, Kemi OJ et al (2009) Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 105:527–536

    CAS  PubMed  Google Scholar 

  101. Howarth FC, Almugaddum FA, Qureshi MA et al (2010) The effects of heavy long-term exercise on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rat. J Diabet Complicat 24:278–285

    Google Scholar 

  102. Rubenstrunk A, Hanf R, Hum DW et al (2007) Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 1771:1065–1081

    CAS  PubMed  Google Scholar 

  103. Goa KL, Barradell LB, Plosker GL (1996) Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia. Drugs 52:725–753

    CAS  PubMed  Google Scholar 

  104. Gross B, Staels B (2007) PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. Best Pract Res Clin Endocrinol Metab 21:687–710

    CAS  PubMed  Google Scholar 

  105. Davidoff AJ, Mason MM, Davidson MB et al (2004) Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 286:E718–E724

    CAS  PubMed  Google Scholar 

  106. Dong F, Fang CX, Yang X et al (2006) Cardiac overexpression of catalase rescues cardiac contractile dysfunction induced by insulin resistance: role of oxidative stress, protein carbonyl formation and insulin sensitivity. Diabetologia 49:1421–1433

    CAS  PubMed  Google Scholar 

  107. Wold LE, Ceylan-Isik AF, Fang CX et al (2006) Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. Free Radic Biol Med 40:1419–1429

    CAS  PubMed  Google Scholar 

  108. Yaras N, Bilginoglu A, Vassort G et al (2007) Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade. Am J Physiol Heart Circ Physiol 292:H912–H920

    CAS  PubMed  Google Scholar 

  109. Shekelle PG, Rich MW, Morton SC et al (2003) Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 41:1529–1538

    CAS  PubMed  Google Scholar 

  110. Sowers JR, Epstein M, Frohlich ED (2001) Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 37:1053–1059

    CAS  PubMed  Google Scholar 

  111. Murarka S, Movahed MR (2010) Diabetic cardiomyopathy. J Card Fail 16:971–979

    PubMed  Google Scholar 

  112. Zaman AK, Fujii S, Goto D et al (2004) Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. J Mol Cell Cardiol 37:525–535

    CAS  PubMed  Google Scholar 

  113. Orea-Tejeda A, Colin-Ramirez E, Castillo-Martinez L et al (2007) Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Rev Invest Clin 59:103–107

    CAS  PubMed  Google Scholar 

  114. Shimada T (1993) Correlation between metabolic and histopathological changes in the myocardium of the KK mouse. Effect of diltiazem on the diabetic heart. Jpn Heart J 34:617–626

    CAS  PubMed  Google Scholar 

  115. Afzal N, Ganguly PK, Dhalla KS et al (1988) Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 37:936–942

    CAS  PubMed  Google Scholar 

  116. Afzal N, Pierce GN, Elimban V et al (1989) Influence of verapamil on some subcellular defects in diabetic cardiomyopathy. Am J Physiol 256:E453–E458

    CAS  PubMed  Google Scholar 

  117. Shah TS, Satia MC, Gandhi TP et al (1995) Effects of chronic nifedipine treatment on streptozotocin-induced diabetic rats. J Cardiovasc Pharmacol 26:6–12

    CAS  PubMed  Google Scholar 

  118. Higa S, Shimabukuro M, Shinzato T et al (1995) Long-term nifedipine treatment reduces calcium overload in isolated reperfused hearts of diabetic rats. Gen Pharmacol 26:1679–1686

    CAS  PubMed  Google Scholar 

  119. Aneja A, Tang WH, Bansilal S et al (2008) Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 121:748–757

    PubMed  Google Scholar 

  120. Suarez J, Scott B, Dillmann WH (2008) Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol 295:R1439–R1445

    CAS  PubMed  Google Scholar 

  121. Wang M, Zhang WB, Zhu JH et al (2010) Breviscapine ameliorates cardiac dysfunction and regulates the myocardial Ca(2+)-cycling proteins in streptozotocin-induced diabetic rats. Acta Diabetol 47:209–218

    CAS  PubMed  Google Scholar 

  122. Giles TD, Ouyang J, Kerut EK et al (1998) Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat. Am J Physiol 274:H295–H307

    CAS  PubMed  Google Scholar 

  123. Liu X, Wang J, Takeda N et al (1999) Changes in cardiac protein kinase C activities and isozymes in streptozotocin-induced diabetes. Am J Physiol 277:E798–E804

    CAS  PubMed  Google Scholar 

  124. Malhotra A, Kang BP, Cheung S et al (2001) Angiotensin II promotes glucose-induced activation of cardiac protein kinase C isozymes and phosphorylation of troponin I. Diabetes 50:1918–1926

    CAS  PubMed  Google Scholar 

  125. Shizukuda Y, Buttrick PM (2001) Protein kinase C(epsilon) modulates apoptosis induced by beta -adrenergic stimulation in adult rat ventricular myocytes via extracellular signal-regulated kinase (ERK) activity. J Mol Cell Cardiol 33:1791–1803

    CAS  PubMed  Google Scholar 

  126. Pastukh V, Wu S, Ricci C et al (2005) Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport. Am J Physiol Heart Circ Physiol 288:H1965–H1975

    CAS  PubMed  Google Scholar 

  127. Wakasaki H, Koya D, Schoen FJ et al (1997) Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci USA 94:9320–9325

    CAS  PubMed  Google Scholar 

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Mr. Isfort and Drs. Stevens, Schaffer, Jong, and Wold declare that they have no conflicts of interest or financial ties to disclose.

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Correspondence to Loren E. Wold.

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Michael Isfort, Sarah C. W. Stevens equally contributed to this manuscript.

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Isfort, M., Stevens, S.C.W., Schaffer, S. et al. Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail Rev 19, 35–48 (2014). https://doi.org/10.1007/s10741-013-9377-8

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