Molecular and Cellular Biochemistry

, Volume 299, Issue 1–2, pp 5–18 | Cite as

Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: Role of sarcolemmal substrate transporters

  • Susan L. M. Coort
  • Arend Bonen
  • Ger J. van der Vusse
  • Jan F. C. Glatz
  • Joost J. F. P. LuikenEmail author


Cardiovascular disease is the primary cause of death in obesity and type-2 diabetes mellitus (T2DM). Alterations in substrate metabolism are believed to be involved in the development of both cardiac dysfunction and insulin resistance in these conditions. Under physiological circumstances the heart utilizes predominantly long-chain fatty acids (LCFAs) (60–70%), with the remainder covered by carbohydrates, i.e., glucose (20%) and lactate (10%). The cellular uptake of both LCFA and glucose is regulated by the sarcolemmal amount of specific transport proteins, i.e., fatty acid translocase (FAT)/CD36 and GLUT4, respectively. These transport proteins are not only present at the sarcolemma, but also in intracellular storage compartments. Both an increased workload and the hormone insulin induce translocation of FAT/CD36 and GLUT4 to the sarcolemma. In this review, recent findings on the insulin and contraction signalling pathways involved in substrate uptake and utilization by cardiac myocytes under physiological conditions are discussed. New insights in alterations in substrate uptake and utilization during insulin resistance and its progression towards T2DM suggest a pivotal role for substrate transporters. During the development of obesity towards T2DM alterations in cardiac lipid homeostasis were found to precede alterations in glucose homeostasis. In the early stages of T2DM, relocation of FAT/CD36 to the sarcolemma is associated with the myocardial accumulation of triacylglycerols (TAGs) eventually leading to an impaired insulin-stimulated GLUT4-translocation. These novel insights may result in new strategies for the prevention of development of cardiac dysfunction and insulin resistance in obesity and T2DM.


CD36 fatty acid uptake GLUT4 type-2 diabetes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Seidell JC: Prevalence and time trends of obesity in Europe. J Endocrinol Invest 25: 816–822, 2002PubMedGoogle Scholar
  2. 2.
    Passa P: Diabetes trends in Europe. Diabetes Metab Res Rev 18(Suppl 3): S3–S8, 2002PubMedGoogle Scholar
  3. 3.
    Riste L, Khan F, Cruickshank K: High prevalence of type 2 diabetes in all ethnic groups, including Europeans, in a British inner city: relative poverty, history, inactivity, or 21st century Europe? Diabetes Care 24: 1377–1383, 2001PubMedGoogle Scholar
  4. 4.
    Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney EF, Rios-Burrows N, Mokdad AH, Ford ES, Imperatore G, Narayan KM: The evolving diabetes burden in the United States. Ann Intern Med 140: 945–950, 2004PubMedGoogle Scholar
  5. 5.
    Strumpf E: The obesity epidemic in the United States: causes and extent, risks and solutions. Issue Brief (Commonw Fund) 1–6, 2004Google Scholar
  6. 6.
    Perry IJ: Healthy diet and lifestyle clustering and glucose intolerance. Proc Nutr Soc 61: 543–551, 2002PubMedGoogle Scholar
  7. 7.
    Perusse L, Chagnon YC, Bouchard C: Etiology of massive obesity: role of genetic factors. World J Surg 22: 907–912, 1998PubMedGoogle Scholar
  8. 8.
    Remacle C, Bieswal F, Reusens B: Programming of obesity and cardiovascular disease. Int J Obes Relat Metab Disord 28(Suppl 3): S46–S53, 2004PubMedGoogle Scholar
  9. 9.
    Aneja A, El-Atat F, McFarlane SI, Sowers JR: Hypertension and obesity. Recent Prog Horm Res 59: 169–205, 2004PubMedGoogle Scholar
  10. 10.
    Mensah GA, Mokdad AH, Ford E, Narayan KM, Giles WH, Vinicor F, Deedwania PC: Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications. Cardiol Clin 22: 485–504, 2004PubMedGoogle Scholar
  11. 11.
    Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB, Sr., Wilson PW, Savage PJ: Trends in cardiovascular complications of diabetes. Jama 292: 2495–2499, 2004PubMedGoogle Scholar
  12. 12.
    Grundy SM:. What is the contribution of obesity to the metabolic syndrome? Endocrinol Metab Clin North Am 33: 267–282, table of contents, 2004PubMedGoogle Scholar
  13. 13.
    Tang WH, Young JB: Cardiomyopathy and heart failure in diabetes. Endocrinol Metab Clin North Am 30: 1031–1046, 2001PubMedGoogle Scholar
  14. 14.
    Bertoni AG, Tsai A, Kasper EK, Brancati FL: Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care 26: 2791–2795, 2003PubMedGoogle Scholar
  15. 15.
    Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK: Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 42: 328–335, 2003PubMedGoogle Scholar
  16. 16.
    Vanninen E, Mustonen J, Vainio P, Lansimies E, Uusitupa M: Left ventricular function and dimensions in newly diagnosed non-insulin-dependent diabetes mellitus. Am J Cardiol 70: 371–378, 1992PubMedGoogle Scholar
  17. 17.
    Di Bonito P, Cuomo S, Moio N, Sibilio G, Sabatini D, Quattrin S, Capaldo B: Diastolic dysfunction in patients with non-insulin-dependent diabetes mellitus of short duration. Diabet Med 13: 321–324, 1996PubMedGoogle Scholar
  18. 18.
    Bell DS: Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 18: 708–714, 1995PubMedGoogle Scholar
  19. 19.
    Taegtmeyer H, King LM, Jones BE: Energy substrate metabolism, myocardial ischemia, and targets for pharmacotherapy. Am J Cardiol 82: 54K–60K, 1998PubMedGoogle Scholar
  20. 20.
    Van der Vusse GJ, de Groot MJ: Interrelationship between lactate and cardiac fatty acid metabolism. Mol Cell Biochem 116: 11–17, 1992PubMedGoogle Scholar
  21. 21.
    Glatz JF, Borchers T, Spener F, van der Vusse GJ: Fatty acids in cell signalling: modulation by lipid binding proteins. Prostaglandins Leukot Essent Fatty Acids 52: 121–127, 1995PubMedGoogle Scholar
  22. 22.
    Van der Vusse GJ, Glatz JF, Stam HC, Reneman RS: Fatty acid homeostasis in the normoxic and ischemic heart. Physiol Rev 72: 881–940, 1992PubMedGoogle Scholar
  23. 23.
    Mueckler M: Facilitative glucose transporters. Eur J Biochem 219: 713–725, 1994PubMedGoogle Scholar
  24. 24.
    Fischer Y, Thomas J, Sevilla L, Munoz P, Becker C, Holman G, Kozka IJ, Palacin M, Testar X, Kammermeier H, Zorzano A: Insulin-induced recruitment of glucose transporter 4 (GLUT4) and GLUT1 in isolated rat cardiac myocytes. Evidence of the existence of different intracellular GLUT4 vesicle populations. J Biol Chem 272: 7085–7092, 1997PubMedGoogle Scholar
  25. 25.
    Zorzano A, Sevilla L, Camps M, Becker C, Meyer J, Kammermeier H, Munoz P, Guma A, Testar X, Palacin M, Blasi J, Fischer Y: Regulation of glucose transport, and glucose transporters expression and trafficking in the heart: studies in cardiac myocytes. Am J Cardiol 80: 65A–76A, 1997PubMedGoogle Scholar
  26. 26.
    Spector AA: Plasma lipid transport. Clin Physiol Biochem 2: 123–134, 1984PubMedGoogle Scholar
  27. 27.
    Van der Vusse GJ, van Bilsen M, Glatz JF: Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res 45: 279–293, 2000PubMedGoogle Scholar
  28. 28.
    Hamilton JA, Kamp F: How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes 48: 2255–2269, 1999PubMedGoogle Scholar
  29. 29.
    Pownall HJ, Hamilton JA: Energy translocation across cell membranes and membrane models. Acta Physiol Scand 178: 357–365, 2003PubMedGoogle Scholar
  30. 30.
    Luiken JJ, van Nieuwenhoven FA, America G, van der Vusse GJ, Glatz JF: Uptake and metabolism of palmitate by isolated cardiac myocytes from adult rats: involvement of sarcolemmal proteins. J Lipid Res 38: 745–758, 1997PubMedGoogle Scholar
  31. 31.
    Luiken JJ, Schaap FG, van Nieuwenhoven FA, van der Vusse GJ, Bonen A, Glatz JF: Cellular fatty acid transport in heart and skeletal muscle as facilitated by proteins. Lipids 34(Suppl): S169–S175, 1999PubMedGoogle Scholar
  32. 32.
    Bonen A, Luiken JJ, Glatz JF: Regulation of fatty acid transport and membrane transporters in health and disease. Mol Cell Biochem 239: 181–192, 2002PubMedGoogle Scholar
  33. 33.
    Brinkmann JF, Abumrad NA, Ibrahimi A, van der Vusse GJ, Glatz JF: New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36. Biochem J 367: 561–570, 2002PubMedGoogle Scholar
  34. 34.
    Glatz JF, Luiken JJ, Bonen A: Involvement of membrane-associated proteins in the acute regulation of cellular fatty acid uptake. J Mol Neurosci 16: 123–132; discussion 51–57, 2001PubMedGoogle Scholar
  35. 35.
    Luiken JJ, Bonen A, Glatz JF: Cellular fatty acid uptake is acutely regulated by membrane-associated fatty acid-binding proteins. Prostaglandins Leukot Essent Fatty Acids 67: 73–78, 2002PubMedGoogle Scholar
  36. 36.
    Coort SL, Willems J, Coumans WA, van der Vusse GJ, Bonen A, Glatz JF, Luiken JJ: 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, 2002PubMedGoogle Scholar
  37. 37.
    Stremmel W, Strohmeyer G, Borchard F, Kochwa S, Berk PD: Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes. Proc Natl Acad Sci USA 82: 4–8, 1985PubMedGoogle Scholar
  38. 38.
    Stahl A: A current review of fatty acid transport proteins (SLC27). Pflugers Arch 447: 722–727, 2004PubMedGoogle Scholar
  39. 39.
    Schaap FG, Hamers L, Van der Vusse GJ, Glatz JF: Molecular cloning of fatty acid-transport protein cDNA from rat. Biochim Biophys Acta 1354: 29–34, 1997PubMedGoogle Scholar
  40. 40.
    Gimeno RE, Ortegon AM, Patel S, Punreddy S, Ge P, Sun Y, Lodish HF, Stahl A: Characterization of a heart-specific fatty acid transport protein. J Biol Chem 278: 16039–16044, 2003PubMedGoogle Scholar
  41. 41.
    Schaap FG, Binas B, Danneberg H, van der Vusse GJ, Glatz JF: Impaired long-chain fatty acid utilization by cardiac myocytes isolated from mice lacking the heart-type fatty acid binding protein gene. Circ Res 85: 329–337, 1999PubMedGoogle Scholar
  42. 42.
    Glatz JF, Storch J: Unravelling the significance of cellular fatty acid-binding proteins. Curr Opin Lipidol 12: 267–274, 2001PubMedGoogle Scholar
  43. 43.
    Gargiulo CE, Stuhlsatz-Krouper SM, Schaffer JE: Localization of adipocyte long-chain fatty acyl-CoA synthetase at the plasma membrane. J Lipid Res 40: 881–892, 1999PubMedGoogle Scholar
  44. 44.
    Knudsen J, Neergaard TB, Gaigg B, Jensen MV, Hansen JK: Role of acyl-CoA binding protein in acyl-CoA metabolism and acyl-CoA-mediated cell signaling. J Nutr 130: 294S–298S, 2000PubMedGoogle Scholar
  45. 45.
    Faergeman NJ, Knudsen J: Acyl-CoA binding protein is an essential protein in mammalian cell lines. Biochem J 368: 679–682, 2002PubMedGoogle Scholar
  46. 46.
    Eaton S: Control of mitochondrial beta-oxidation flux. Prog Lipid Res 41: 197–239, 2002PubMedGoogle Scholar
  47. 47.
    Schulz H: Regulation of fatty acid oxidation in heart. J Nutr 124: 165–171, 1994PubMedGoogle Scholar
  48. 48.
    Ghisla S: Beta-oxidation of fatty acids. A century of discovery. Eur J Biochem 271: 459–461, 2004Google Scholar
  49. 49.
    Taegtmeyer H: Genetics of energetics: transcriptional responses in cardiac metabolism. Ann Biomed Eng 28: 871–876, 2000PubMedGoogle Scholar
  50. 50.
    Van Bilsen M, Van der Vusse GJ, Gilde AJ, Lindhout M, van der Lee KA: Peroxisome proliferator-activated receptors: lipid binding proteins controling gene expression. Mol Cell Biochem 239:131–138, 2002PubMedGoogle Scholar
  51. 51.
    Gilde AJ, Van Bilsen M: Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 178: 425–434, 2003PubMedGoogle Scholar
  52. 52.
    Bers DM: Cardiac excitation-contraction coupling. Nature 415: 198–205, 2002PubMedGoogle Scholar
  53. 53.
    Till M, Kolter T, Eckel J: Molecular mechanisms of contraction-induced translocation of GLUT4 in isolated cardiomyocytes. Am J Cardiol 80: 85A–89A, 1997PubMedGoogle Scholar
  54. 54.
    Russell RR, 3rd, Bergeron R, Shulman GI, Young LH: Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 277: H643–H649, 1999PubMedGoogle Scholar
  55. 55.
    Luiken JJ, Willems J, Van der Vusse GJ, Glatz JF: Electrostimulation enhances FAT/CD36-mediated long-chain fatty acid uptake by isolated rat cardiac myocytes. Am J Physiol Endocrinol Metab 281: E704–E712, 2001PubMedGoogle Scholar
  56. 56.
    Doskeland SO, Maronde E, Gjertsen BT: The genetic subtypes of cAMP-dependent protein kinase–functionally different or redundant? Biochim Biophys Acta 1178: 249–258, 1993PubMedGoogle Scholar
  57. 57.
    Beebe SJ: The cAMP-dependent protein kinases and cAMP signal transduction. Semin Cancer Biol 5: 285–294, 1994PubMedGoogle Scholar
  58. 58.
    Gerhardstein BL, Puri TS, Chien AJ, Hosey MM: Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels. Biochemistry 38: 10361–10370, 1999PubMedGoogle Scholar
  59. 59.
    Tong CW, Gaffin RD, Zawieja DC, Muthuchamy M: Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics. J Physiol 558: 927–941, 2004PubMedGoogle Scholar
  60. 60.
    Boone AN, Rodrigues B, Brownsey RW: Multiple-site phosphorylation of the 280 kDa isoform of acetyl-CoA carboxylase in rat cardiac myocytes: evidence that cAMP-dependent protein kinase mediates effects of beta-adrenergic stimulation. Biochem J 341(Pt 2): 347–354, 1999PubMedGoogle Scholar
  61. 61.
    Dyck JR, Kudo N, Barr AJ, Davies SP, Hardie DG, Lopaschuk GD: Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5′-AMP activated protein kinase. Eur J Biochem 262: 184–190, 1999PubMedGoogle Scholar
  62. 62.
    Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, Witters LA: Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem 265: 1502–1509, 1990PubMedGoogle Scholar
  63. 63.
    Ha J, Daniel S, Broyles SS, Kim KH: Critical phosphorylation sites for acetyl-CoA carboxylase activity. J Biol Chem 269: 22162–22168, 1994PubMedGoogle Scholar
  64. 64.
    Luiken JJ, Willems J, Coort SL, Coumans WA, Bonen A, Van Der Vusse GJ, Glatz JF: Effects of cAMP modulators on long-chain fatty-acid uptake and utilization by electrically stimulated rat cardiac myocytes. Biochem J 367: 881–887, 2002PubMedGoogle Scholar
  65. 65.
    Abdel-Aleem S, Badr M, Frangakis C: Stimulation of fatty acid oxidation in myocytes by phosphodiesterase inhibitors and adenosine analogues. Life Sci 48: PL97–PL102, 1991PubMedGoogle Scholar
  66. 66.
    Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D: LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13: 2004–2008, 2003PubMedGoogle Scholar
  67. 67.
    Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG: CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113: 274–284, 2004PubMedGoogle Scholar
  68. 68.
    Hardie DG: AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord 5: 119–125, 2004PubMedGoogle Scholar
  69. 69.
    Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH: Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 285: E629–E636, 2003PubMedGoogle Scholar
  70. 70.
    Merrill GF, Kurth EJ, Hardie DG, Winder WW: AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 273: E1107–E1112, 1997PubMedGoogle Scholar
  71. 71.
    Bergeron R, Russell RR, 3rd, Young LH, Ren JM, Marcucci M, Lee A, Shulman GI: Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol 276: E938–E944, 1999PubMedGoogle Scholar
  72. 72.
    Luiken JJ, Coort SL, Willems J, Coumans WA, Bonen A, van der Vusse GJ, Glatz JF: Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes 52: 1627–1634, 2003PubMedGoogle Scholar
  73. 73.
    Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD: 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, 1995PubMedGoogle Scholar
  74. 74.
    Kaushik VK, Young ME, Dean DJ, Kurowski TG, Saha AK, Ruderman NB: Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am J Physiol Endocrinol Metab 281: E335–E340, 2001PubMedGoogle Scholar
  75. 75.
    Newton AC: Protein kinase C: structure, function, and regulation. J Biol Chem 270: 28495–28498, 1995PubMedGoogle Scholar
  76. 76.
    Mochly-Rosen D, Gordon AS: Anchoring proteins for protein kinase C: a means for isozyme selectivity. Faseb J 12: 35–42, 1998PubMedGoogle Scholar
  77. 77.
    Toker A:. Signaling through protein kinase C. Front Biosci 3: D1134–D1147, 1998PubMedGoogle Scholar
  78. 78.
    Puceat M, Hilal-Dandan R, Strulovici B, Brunton LL, Brown JH: Differential regulation of protein kinase C isoforms in isolated neonatal and adult rat cardiomyocytes. J Biol Chem 269: 16938–16944, 1994PubMedGoogle Scholar
  79. 79.
    Steinberg SF, Goldberg M, Rybin VO: Protein kinase C isoform diversity in the heart. J Mol Cell Cardiol 27: 141–153, 1995PubMedCrossRefGoogle Scholar
  80. 80.
    Malhotra A, Kang BP, Opawumi D, Belizaire W, Meggs LG: Molecular biology of protein kinase C signaling in cardiac myocytes. Mol Cell Biochem 225: 97–107, 2001PubMedGoogle Scholar
  81. 81.
    Schaub MC, Kunz B: Regulation of contraction in cardiac and smooth muscles. J Cardiovasc Pharmacol 8(Suppl 8): S117–S123, 1986PubMedCrossRefGoogle Scholar
  82. 82.
    Korzick DH: Regulation of cardiac excitation-contraction coupling: a cellular update. Adv Physiol Educ 27:192–200, 2003PubMedCrossRefGoogle Scholar
  83. 83.
    Luiken JJ, Coort SL, Koonen DP, Bonen A, Glatz JF: Signalling components involved in contraction-inducible substrate uptake into cardiac myocytes. Proc Nutr Soc 63: 251–258Google Scholar
  84. 84.
    Rose AJ, Michell BJ, Kemp BE, Hargreaves M: Effect of exercise on protein kinase C activity and localization in human skeletal muscle. J Physiol 561: 861–870, 2004PubMedGoogle Scholar
  85. 85.
    Richter EA, Vistisen B, Maarbjerg SJ, Sajan M, Farese RV, Kiens B: Differential effect of bicycling exercise intensity on activity and phosphorylation of atypical protein kinase C and extracellular signal-regulated protein kinase in skeletal muscle. J Physiol 560: 909–918, 2004PubMedGoogle Scholar
  86. 86.
    Perrini S, Henriksson J, Zierath JR, Widegren U: Exercise-induced protein kinase C isoform-specific activation in human skeletal muscle. Diabetes 53: 21–24, 2004PubMedGoogle Scholar
  87. 87.
    Coort SL, Hasselbaink DM, Koonen DP, Willems J, Coumans WA, Chabowski A, van der Vusse GJ, Bonen A, Glatz JF, Luiken JJ: Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes 53: 1655–1663, 2004PubMedGoogle Scholar
  88. 88.
    Brownsey RW, Boone AN, Allard MF: Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc Res 34: 3–24, 1997PubMedGoogle Scholar
  89. 89.
    Hiraoka M: A novel action of insulin on cardiac membrane. Circ Res 92: 707–709, 2003PubMedGoogle Scholar
  90. 90.
    Pirola L, Johnston AM, Van Obberghen E: Modulation of insulin action. Diabetologia 47: 170–184, 2004PubMedGoogle Scholar
  91. 91.
    Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799–806, 2001PubMedGoogle Scholar
  92. 92.
    Taha C, Klip A: The insulin signaling pathway. J Membr Biol 169: 1–12, 1999PubMedGoogle Scholar
  93. 93.
    Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert ML, Quon MJ, Lea-Currie R, Sen A, Farese RV: PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes. J Clin Endocrinol Metab 87: 716–723, 2002PubMedGoogle Scholar
  94. 94.
    Slot JW, Geuze HJ, Gigengack S, James DE, Lienhard GE: Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. Proc Natl Acad Sci USA 88: 7815–7819, 1991PubMedGoogle Scholar
  95. 95.
    Luiken JJ, Koonen DP, Willems J, Zorzano A, Becker C, Fischer Y, Tandon NN, Van Der Vusse GJ, Bonen A, Glatz JF: Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes 51: 3113–3119, 2002PubMedGoogle Scholar
  96. 96.
    Dyck DJ, Steinberg G, Bonen A: Insulin increases FA uptake and esterification but reduces lipid utilization in isolated contracting muscle. Am J Physiol Endocrinol Metab 281: E600–E607, 2001PubMedGoogle Scholar
  97. 97.
    Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA: Obesity and insulin resistance in humans: a dose-response study. Metabolism 39: 452–459, 1990PubMedGoogle Scholar
  98. 98.
    Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K: Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes 51: 1110–1117, 2002PubMedGoogle Scholar
  99. 99.
    Coort SL, Luiken JJ, van der Vusse GJ, Bonen A, Glatz JF: Increased FAT (fatty acid translocase)/CD36-mediated long-chain fatty acid uptake in cardiac myocytes from obese Zucker rats. Biochem Soc Trans 32: 83–85, 2004PubMedGoogle Scholar
  100. 100.
    Belke DD, Larsen TS, Gibbs EM, Severson DL. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab 279: E1104–E1113, 2000PubMedGoogle Scholar
  101. 101.
    Desrois M, Sidell RJ, Gauguier D, King LM, Radda GK, Clarke K: Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res 61: 288–296, 2004PubMedGoogle Scholar
  102. 102.
    Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, Diamant M: High-fat diet induced cardiac dysfunction is associated with altered myocardial insulin signalling in rats. Diabetologia 48: 1229–1237, 2005PubMedGoogle Scholar
  103. 103.
    Kolter T, Uphues I, Eckel J: Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats. Am J Physiol 273: E59–E67, 1997PubMedGoogle Scholar
  104. 104.
    Uphues I, Chern Y, Eckel J: Insulin-dependent translocation of the small GTP-binding protein rab3C in cardiac muscle: studies on insulin-resistant Zucker rats. FEBS Lett 377: 109–112, 1995PubMedGoogle Scholar
  105. 105.
    Luiken JJ, Arumugam Y, Dyck DJ, Bell RC, Pelsers MM, Turcotte LP, Tandon NN, Glatz JF, Bonen A: Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J Biol Chem 276: 40567–40573, 2001PubMedGoogle Scholar
  106. 106.
    Glatz JF, van Breda E, Keizer HA, de Jong YF, Lakey JR, Rajotte RV, Thompson A, van der Vusse GJ, Lopaschuk GD: Rat heart fatty acid-binding protein content is increased in experimental diabetes. Biochem Biophys Res Commun 199: 639–646, 1994PubMedGoogle Scholar
  107. 107.
    Knuuti J, Takala TO, Nagren K, Sipila H, Turpeinen AK, Uusitupa MI, Nuutila P: Myocardial fatty acid oxidation in patients with impaired glucose tolerance. Diabetologia 44: 184–187, 2001PubMedGoogle Scholar
  108. 108.
    Turpeinen AK, Kuikka JT, Vanninen E, Uusitupa MI: Abnormal myocardial kinetics of 123I-heptadecanoic acid in subjects with impaired glucose tolerance. Diabetologia 40: 541–549, 1997PubMedGoogle Scholar
  109. 109.
    Schon HR: I-123 heptadecanoic acid–value and limitations in comparison with C-11 palmitate. Eur J Nucl Med 12(Suppl): S16–S19, 1986PubMedCrossRefGoogle Scholar
  110. 110.
    Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97: 1784–1789, 2000PubMedGoogle Scholar
  111. 111.
    Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen CB, Nielsen LB: Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology 144: 3483–3490, 2003PubMedGoogle Scholar
  112. 112.
    Atkinson LL, Kozak R, Kelly SE, Onay Besikci A, Russell JC, Lopaschuk GD: Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats. Am J Physiol Endocrinol Metab 284: E923–E930, 2003PubMedGoogle Scholar
  113. 113.
    Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, Youker KA, Taegtmeyer H: Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 51: 2587–2595, 2002PubMedGoogle Scholar
  114. 114.
    Igal RA, Wang S, Gonzalez-Baro M, Coleman RA: Mitochondrial glycerol phosphate acyltransferase directs the incorporation of exogenous fatty acids into triacylglycerol. J Biol Chem 276: 42205–42212, 2001PubMedGoogle Scholar
  115. 115.
    Bonen A, Parolin ML, Steinberg GR, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ, Heigenhauser GJ, Dyck DJ: Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. Faseb J 18: 1144–1146, 2004PubMedGoogle Scholar
  116. 116.
    Unger RH: Lipotoxic diseases. Annu Rev Med 53: 319–336, 2002PubMedGoogle Scholar
  117. 117.
    Randle PJ, Kerbey AL, Espinal J: Mechanisms decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab Rev 4: 623–638, 1988PubMedCrossRefGoogle Scholar
  118. 118.
    Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785–789, 1963PubMedGoogle Scholar
  119. 119.
    Nuutila P, Knuuti MJ, Raitakari M, Ruotsalainen U, Teras M, Voipio-Pulkki LM, Haaparanta M, Solin O, Wegelius U, Yki-Jarvinen H: Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol 267: E941–E946, 1994PubMedGoogle Scholar
  120. 120.
    Frayn KN: The glucose-fatty acid cycle: a physiological perspective. Biochem Soc Trans 31: 1115–1119, 2003PubMedGoogle Scholar
  121. 121.
    Unger RH, Orci L: Diseases of liporegulation: new perspective on obesity and related disorders. Faseb J 15: 312–321, 2001PubMedGoogle Scholar
  122. 122.
    Ohanian J, Ohanian V: Sphingolipids in mammalian cell signalling. Cell Mol Life Sci 58: 2053–2068, 2001PubMedGoogle Scholar
  123. 123.
    Adams JM, 2nd, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ: Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53: 25–31, 2004PubMedGoogle Scholar
  124. 124.
    Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M, Zendzian-Piotrowska M, Brzezinska Z, Gorski J: Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 53: 1215–1221, 2004PubMedGoogle Scholar
  125. 125.
    Itani SI, Ruderman NB, Schmieder F, Boden G: Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51: 2005–2011, 2002PubMedGoogle Scholar
  126. 126.
    Turinsky J, O'Sullivan DM, Bayly BP: 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem 265: 16880–16885, 1990Google Scholar
  127. 127.
    Powell DJ, Turban S, Gray A, Hajduch E, Hundal HS: Intracellular ceramide synthesis and protein kinase Czeta activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells. Biochem J 382: 619–629, 2004PubMedGoogle Scholar
  128. 128.
    Chavez JA, Summers SA: Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys 419: 101–109, 2003PubMedGoogle Scholar
  129. 129.
    Schmitz-Peiffer C, Craig DL, Biden TJ: Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 274: 24202–24210, 1999PubMedGoogle Scholar
  130. 130.
    Hajduch E, Balendran A, Batty IH, Litherland GJ, Blair AS, Downes CP, Hundal HS: Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia 44: 173–183, 2001PubMedGoogle Scholar
  131. 131.
    Summers SA, Garza LA, Zhou H, Birnbaum MJ: Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol Cell Biol 18: 5457–5464, 1998PubMedGoogle Scholar
  132. 132.
    Heydrick SJ, Ruderman NB, Kurowski TG, Adams HB, Chen KS: Enhanced stimulation of diacylglycerol and lipid synthesis by insulin in denervated muscle. Altered protein kinase C activity and possible link to insulin resistance. Diabetes 40: 1707–1711, 1991PubMedGoogle Scholar
  133. 133.
    Avignon A, Yamada K, Zhou X, Spencer B, Cardona O, Saba-Siddique S, Galloway L, Standaert ML, Farese RV: Chronic activation of protein kinase C in soleus muscles and other tissues of insulin-resistant type II diabetic Goto-Kakizaki (GK), obese/aged, and obese/Zucker rats. A mechanism for inhibiting glycogen synthesis. Diabetes 45: 1396–1404, 1996PubMedGoogle Scholar
  134. 134.
    Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ: Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46: 169–178, 1997PubMedGoogle Scholar
  135. 135.
    Qu X, Seale JP, Donnelly R: Tissue and isoform-selective activation of protein kinase C in insulin-resistant obese Zucker rats - effects of feeding. J Endocrinol 162: 207–214, 1999PubMedGoogle Scholar
  136. 136.
    Cooper DR, Watson JE, Dao ML: Decreased expression of protein kinase-C alpha, beta, and epsilon in soleus muscle of Zucker obese (fa/fa) rats. Endocrinology 133: 2241–2247, 1993PubMedGoogle Scholar
  137. 137.
    Chin JE, Liu F, Roth RA:. Activation of protein kinase C alpha inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. Mol Endocrinol 8: 51–58, 1994PubMedGoogle Scholar
  138. 138.
    Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL: Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes 49: 1353–1358, 2000PubMedGoogle Scholar
  139. 139.
    Itani SI, Pories WJ, Macdonald KG, Dohm GL: Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism 50: 553–557, 2001PubMedGoogle Scholar
  140. 140.
    Lilly K, Chung C, Kerner J, VanRenterghem R, Bieber LL: Effect of etomoxiryl-CoA on different carnitine acyltransferases. Biochem Pharmacol 43: 353–361, 1992PubMedGoogle Scholar
  141. 141.
    Hubinger A, Weikert G, Wolf HP, Gries FA: The effect of etomoxir on insulin sensitivity in type 2 diabetic patients. Horm Metab Res 24: 115–118, 1992PubMedCrossRefGoogle Scholar
  142. 142.
    Hubinger A, Knode O, Susanto F, Reinauer H, Gries FA: Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM. Horm Metab Res 29: 436–439, 1997PubMedGoogle Scholar
  143. 143.
    Schmitz FJ, Rosen P, Reinauer H: Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor Etomoxir. Horm Metab Res 27: 515–522, 1995PubMedGoogle Scholar
  144. 144.
    Rupp H, Jacob R: Metabolically-modulated growth and phenotype of the rat heart. Eur Heart J 13(Suppl D): 56–61, 1992PubMedGoogle Scholar
  145. 145.
    Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, Thorell A, Goodyear LJ: AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 50: 921–927, 2001PubMedGoogle Scholar
  146. 146.
    Kimura T: Positive inotropic and chronotropic effects of 8-substituted derivatives of cyclic AMP and activation of protein kinase A. Jpn J Pharmacol 57: 1–11, 1991PubMedGoogle Scholar
  147. 147.
    Kramer D, Shapiro R, Adler A, Bush E, Rondinone CM: Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism 50: 1294–1300, 2001PubMedGoogle Scholar
  148. 148.
    Oakes ND, Thalen PG, Jacinto SM, Ljung B: Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability. Diabetes 50: 1158–1165, 2001PubMedGoogle Scholar
  149. 149.
    Oakes ND, Kennedy CJ, Jenkins AB, Laybutt DR, Chisholm DJ, Kraegen EW: A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat. Diabetes 43: 1203–1210, 1994PubMedGoogle Scholar
  150. 150.
    Yue Tl TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH: In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104: 2588–2594, 2001PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Susan L. M. Coort
    • 1
  • Arend Bonen
    • 2
  • Ger J. van der Vusse
    • 3
  • Jan F. C. Glatz
    • 1
  • Joost J. F. P. Luiken
    • 1
    • 4
    • 5
    Email author
  1. 1.Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
  2. 2.Department of Human Biology and Nutritional SciencesGuelph UniversityGuelphCanada
  3. 3.Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
  4. 4.Department of Biochemical Physiology and Institute of BiomembranesUtrecht UniversityUtrechtThe Netherlands
  5. 5.Department of Molecular Genetics, CARIMMaastricht UniversityMaastrichtThe Netherlands

Personalised recommendations