Wiener Medizinische Wochenschrift

, Volume 164, Issue 15–16, pp 320–329 | Cite as

Intracellular lipid accumulation and shift during diabetes progression

  • Peter Wolf
  • Yvonne Winhofer
  • Christian-Heinz Anderwald
  • Martin Krššák
  • Michael Krebs
review

Summary

In past decades, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease developed into a global public health disease with an endemic scale. Although up to now the pathogenesis of T2DM is still poorly understood, ectopic lipid accumulation is one of the strongest predictors for T2DM and is closely associated with insulin resistance.

This review aims (i) to overview recent literature on the impact of intracellular lipid deposition, (ii) to point out changes in ectopic fat accumulation during diabetes progression or shortly after initializing individual therapy, and finally (iii) to expose unsolved questions and future perspectives in the role of ectopic lipids for the development of insulin resistance and T2DM.

Keywords

Insulin resistance Ectopic lipid deposition Glucose tolerance Type 2 diabetes mellitus Intramyocellular lipid content NAFLD Diabetic cardiomyopathy 

Ektope Fettspeicherung bei Insulinresistenz und Diabetes Mellitus Typ 2

Zusammenfassung

Studien legen Nahe, dass die ektope Ablagerung von Lipiden in insulinsensitiven Organen wie dem Skelettmuskel oder der Leber eine entscheidende Rolle in der Entstehung von Insulinresistenz und Typ 2 Diabetes Mellitus (T2DM) spielt.

Ziel dieser Übersichtsarbeit ist es daher, einerseits i) einen Überblick über die rezente Datenlage zu metabolischen Auswirkungen ektoper Fettspeicherung zu geben, ii) die Möglichkeiten einer Beeinflussung der ektopen Fettspeicherung durch Lebensstilmodifikation oder medikamentöse Therapie darzustellen, sowie iii) auf zukünftige Problemstellungen wie die Bedeutung der Zusammensetzung der ektop gespeicherten Fettsäuren näher einzugehen.

Schlüsselwörter

Intrahepatischer Fettgehalt Fettsäuren Glukosetoleranz Herzfettgehalt 

References

  1. 1.
    Rieder A, Rathmanner T, Kiefer I, Dorner T, Kunze M. Österreichischer Diabetesbericht 2004 – Daten, Fakten, Strategien. 2004. http://www.oedg.org/pdf/Diabetesbericht_I.pdf.
  2. 2.
    Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8(1):29.Google Scholar
  3. 3.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171–6.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473–81.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Perseghin G. Viewpoints on the way to a consensus session: where does insulin resistance start? The liver. Diabetes Care. 2009;32(Suppl. 2):S164–7.Google Scholar
  7. 7.
    Birkenfeld AL, Shulman GI. Non alcoholic fatty liver disease, hepatic insulin resistance and type 2 diabetes. Hepatology. 2014;59(2):713–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375(9733):2267–77.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Mcgavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation. 2007;116:1170–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Krššák M, Winhofer Y, Göbl C, Bischof M, Reiter G, Kautzky-Willer A, et al. Insulin resistance is not associated with myocardial steatosis in women. Diabetologia. 2011;54(7):1871–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Rijzewijk L, van der Meer R, Smit J, Diamant M, Bax JJ, Hammer S, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52(22):1793–9.PubMedCrossRefGoogle Scholar
  12. 12.
    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. 1963;1(7285):785–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Randle PJ, Garland PB, Newsholmei EA, Hales CN. The glucose fatty acid cycle in obesity and maturity onset diabetes mellitus. Ann N Y Acad Sci. 1965;131(1):324–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes. 1988;37(8):1020–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes. 1997;46(6):1001–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, et al. Mechanism of free fatty acid—induced insulin resistance in humans. J Clin Invest. 1996;97(12):2859–65.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Pan D, Lillioja S, Kriketos D, Milner M, Baur L, Bogardus C, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997;46(6):983–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Forouhi NG, Jenkinson G, Thomas EL, Mullick S, Mierisova S, Bhonsle U, et al. Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men. Diabetologia. 1999;42:932–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Krssak M, Petersen KF, Dresner A, Dipietro L, Vogel SM, Rothman DL, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1 H NMR spectroscopy study. Diabetologia. 1999;42:113–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350(7):664–71.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Petersen KF, Dufour S, Shulman GI. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2005;2(9):e233.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(31):12587–94.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Szendroedi J, Kaul K, Kloock L, Straßburger K, Schmid A, Chmelik M, et al. Lower fasting muscle mitochondrial activity relates to hepatic steatosis in humans. Diabetes Care. 2014;37(2):468–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Hwang J-H, Stein DT, Barzilai N, Cui M-H, Tonelli J, Kishore P, et al. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol Endocrinol Metab. 2007;293(6):E1663–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Anderwald C, Bernroider E, Krssak M, Stingl H, Brehm A, Bischof MG, et al. Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle. Diabetes. 2002;51(10):3025–32.PubMedCrossRefGoogle Scholar
  26. 26.
    Krssak M, Brehm A, Bernroider E, Anderwald C, Nowotny P, Man CD, et al. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes. 2004;53:3048–56.Google Scholar
  27. 27.
    Williams KH, Shackel NA, Gorrell MD, Mclennan SV, Twigg SM, et al. Diabetes and nonalcoholic fatty liver disease: a pathogenic duo. Endocr Rev. 2013;34(1):84–129.PubMedCrossRefGoogle Scholar
  28. 28.
    Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, et al. General and abdominal adiposity and risk of death in europe. N Engl J Med. 2008;359:2105–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang Y, Rimm EB, Stampfer MJ, Willett WC, Hu FB. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr. 2005;81:555–63.PubMedGoogle Scholar
  30. 30.
    Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009;106(36):15430–5.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1285–6.CrossRefGoogle Scholar
  32. 32.
    Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008;168(15):1609–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Lingvay I, Esser V, Legendre JL, Price AL, Wertz KM, Adams-Huet B, et al. Noninvasive quantification of pancreatic fat in humans. J Clin Endocrinol Metab. 2009;94(10):4070–6.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Heni M, Staiger H, Schwenzer NF, Peter A, Schick F, Claussen CD, et al. Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: a nuclear magnetic resonance study. Diabetes Metab Res Rev. 2010;26(3):200–5.Google Scholar
  35. 35.
    Tushuizen M, Bunck M, Pouwels P, Bontemps S, Van Waesberghe J, Schindhelm R, et al. Pancreatic fat content and b-cell function in men with and without type 2 diabetes. Diabetes Care. 2007;30(11):2916–21.Google Scholar
  36. 36.
    Bertoni A, Tsai A, Kasper E, Brancati F. Diabetes and idiopathic cardiomyopathy. Diabets Care. 2003;26(10):2791–5.CrossRefGoogle Scholar
  37. 37.
    Bell DSH. Diabetic cardiomyopathy. Diabetes Care. 2003;26(10):2949–51.PubMedCrossRefGoogle Scholar
  38. 38.
    Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D’Ambrosia G, Arbique D, Vongpatanasin W, et al. Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn Reson Med. 2003;49(3):417–23.PubMedCrossRefGoogle Scholar
  39. 39.
    Iozzo P, Lautamaki R, Borra R, Lehto H-R, Bucci M, Viljanen A, et al. Contribution of glucose tolerance and gender to cardiac adiposity. J Clin Endocrinol Metab. 2009;94(11):4472–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Hammer S, van der Meer RW, Lamb HJ, Schär M, de Roos A, Smit JWA, et al. Progressive caloric restriction induces dose-dependent changes in myocardial triglyceride content and diastolic function in healthy men. J Clin Endocrinol Metab. 2008;93(2):497–503.Google Scholar
  41. 41.
    Hammer S, Van Der Meer RW, Lamb HJ, De Boer HH, Bax JJ, De Roos A, et al. Short-term flexibility of myocardial triglycerides and diastolic function in patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2008;295:714–8.Google Scholar
  42. 42.
    Winhofer Y, Krssák M, Jankovic D, Anderwald C-H, Reiter G, Hofer A, et al. Short-term hyperinsulinemia and hyperglycemia increase myocardial lipid content in normal subjects. Diabetes. 2012;61(5):1210–6.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Bonapace S, Perseghin G, Molon G, Canali G, Bertolini L, Zoppini G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care. 2012;35(2):389–95.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Perseghin G, Lattuada G, De Cobelli F, Esposito A, Belloni E, Ntali G, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology. 2008;47(1):51–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology. 2014;59(2):461–70.PubMedCrossRefGoogle Scholar
  46. 46.
    Rijzewijk LJ, Jonker JT, van der Meer RW, Lubberink M, de Jong HW, Romijn JA, et al. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol. 2010;56(3):225–33.Google Scholar
  47. 47.
    Lautamäki R, Borra R, Iozzo P, Komu M, Lehtima T, Salmi M, et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2006;291:282–90.CrossRefGoogle Scholar
  48. 48.
    Thomsen C, Becker U, Winkler K, Christoffersen P, Jensen M, Henriksen O. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Med. 1994;12(3):487–95.Google Scholar
  49. 49.
    Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol. 1999;276(5):E977–89.PubMedGoogle Scholar
  50. 50.
    Reingold J, McGavock J, Kaka S, Tillery T, Victor R, Szczepaniak L. Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensitivity of the method. Am J Physiol Endocrinol Metab. 2005;289:E935–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Krssak M, Hofer H, Wrba F, Meyerspeer M, Brehm A, Steindl P, et al. Liver fat content and insulin resistance in chronic hepatitis C patients. Eur J Radiol. 2010;74(3):e60–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Longo R, Ricci C, Masutti F, Vidimari R, Croce L, Vercich L, et al. Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol. 1993;28(4):297–302.PubMedCrossRefGoogle Scholar
  53. 53.
    Dixon W. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189-94.PubMedCrossRefGoogle Scholar
  54. 54.
    Boesch C, Slotboom J, Hoppeler H, Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR-spectroscopy. Magn Reson Med. 1997;37(4):484–93.PubMedCrossRefGoogle Scholar
  55. 55.
    Dimitrov I, Ren J, Douglas D, Sherry A, Malloy C. In vivo detection of trans-fatty acids by 13C MRS at 7T. Proc Intl Soc Mag Reson Med. 2010;374.Google Scholar
  56. 56.
    Gajdosik M, Chmelik M, Just-Kukurova I, Bogner W, Valkovic L, Trattnig S, et al. In vivo relaxation behavior of liver compounds at 7 tesla, measured by single-voxel proton MR spectroscopy. J Magn Reson Imaging. In press 2013.Google Scholar
  57. 57.
    Hwang J, Bluml S, Leaf A, Ross B. In vivo characterization of fatty acids in human adipose tissue using natural abundance 1H decoupled 13C MRS at 1.5 T: clinical applications to dietary therapy. NMR Biomed. 2003;16:160–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson N, Walton D, Sachinwalla T, Thompson C, Smith K, Ruell P, et al. Noninvasive assessment of hepatic lipid composition: advancing understanding and management of fatty liver disorders. Hepatology. 2008;47:1513–23.PubMedCrossRefGoogle Scholar
  59. 59.
    Ren J, Dimitrov I, Sherry A, Malloy C. Composition of adipose tissue and marrow fat in humans by 1H NMR at 7 Tesla. J Lipid Res. 2008;49:2055–62.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Valkovic L, Gajdosik M, Traussnigg S, Wolf P, Chmelik M, Bogner W, et al. Assessment of hepatic metabolism by fast and localiced 31P MRS saturation transfer at 7T: reproducibiltiy and first clinical application in patients with non alcoholic fatty liver disease. Eur Radiol. 2014;24(7):1602–9.Google Scholar
  61. 61.
    Petersen K, Shulman G. Etiology of insulin resistance. Am J Med. 2006;119(5):10–6.CrossRefGoogle Scholar
  62. 62.
    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 ikB-alpha. Diabetes. 2002;51:2005–11.PubMedCrossRefGoogle Scholar
  63. 63.
    Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277(52):50230–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Schmitz-Peiffer C. Protein kinase C and lipid-induced insulin. Ann N Y Acad Sci. 2002;967:146–57.PubMedCrossRefGoogle Scholar
  65. 65.
    Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–71.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Cortright RN, Azevedo JL, Zhou Q, Sinha M, Pories WJ, Itani SI, et al. Protein kinase C modulates insulin action in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278(3):E553–62.PubMedGoogle Scholar
  67. 67.
    Bollag GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland DE. Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci U S A. 1986;83(16):5822–4.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Nowotny B, Zahiragic L, Krog D, Nowotny PJ, Herder C, Carstensen M, et al. Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. Diabetes. 2013;62:2240–8.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology. 2012;142(7):1444.e2–6.e2.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2011;108(39):16381–5.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279(31):32345–53.PubMedCrossRefGoogle Scholar
  72. 72.
    Jornayvaz FR, Birkenfeld AL, Jurczak MJ, Kanda S, Guigni BA, Jiang DC. Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc Natl Acad Sci U S A. 2011;108(14):5748–52.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Zhang L, Ussher JR, Oka T, Cadete VJJ, Wagg C, Lopaschuk GD. Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation. Cardiovasc Res. 2011;89(1):148–56.PubMedCrossRefGoogle Scholar
  74. 74.
    Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H, et al. DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem. 2009;284(52):36312–23.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Amati F. Revisiting the diacylglycerol-induced insulin resistance hypothesis. Obes Rev. 2012;13(21):40–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Brown JM, Betters JL, Lord C, Ma Y, Han X, Yang K, et al. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J Lipid Res. 2010;51(11):3306–15.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Timmers S, Nabben M, Bosma M, van Bree B, Lenaers E, van Beurden D, et al. Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity. Proc Natl Acad Sci U S A. 2012;109(29):11711–6.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Cantley JL, Yoshimura T, Camporez JPG, Zhang D, Jornayvaz FR, Kumashiro N, et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci U S A. 2013;110(5):1869–74.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Rando R, Young N. The stereospecific activation of protein kinase C. Biochem Biophys Res. 1984;122(2):818–23.Google Scholar
  80. 80.
    Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006;312(5774):734–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Huijsman E, Van De Par C, Economou C, Van Der Poel C, Lynch GS, Schoiswohl G, et al. Adipose triacylglycerol lipase deletion alters whole body energy metabolism and impairs exercise performance in mice. Am J Clin Nutr. 2009;297:505–13.Google Scholar
  82. 82.
    Sitnick MT, Basantani MK, Cai L, Schoiswohl G, Yazbeck CF, Distefano G, et al. Skeletal muscle triacylglycerol hydrolysis does not influence metabolic complications of obesity. Diabetes. 2013;62(10):3350–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Tuunanen H, Engblom E, Naum A, Någren K, Hesse B, Airaksinen KEJ, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114(20):2130–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, et al. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2005;90(6):3191–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54(3):603–8.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc Natl Acad Sci U S A. 2012;109(21):8236–40.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A. 2011;108(33):13705–9.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Van der Meer RW, Hammer S, Lamb HJ, Frölich M, Diamant M, Rijzewijk LJ, et al. Effects of short-term high-fat, high-energy diet on hepatic and myocardial triglyceride content in healthy men. J Clin Endocrinol Metab. 2008;93(7):2702–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, et al. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab. 2005;72205:930–4.Google Scholar
  90. 90.
    Petersen KF, Krssak M, Inzucchi S, Cline GW, Dufour S, Shulman GI. Mechanism of troglitazone action in type 2 diabetes. Diabetes. 2000;49:827–31.PubMedCrossRefGoogle Scholar
  91. 91.
    Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, et al. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes. 2003;52(6):1364–70.PubMedCrossRefGoogle Scholar
  92. 92.
    Ravikumar B, Gerrard J, Man CD, Firbank MJ, Lane A, English PT, et al. Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content. Diabetes. 2008;57:2288–95.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation. 2009;119(15):2069–77.PubMedCrossRefGoogle Scholar
  94. 94.
    Jankovic D, Winhofer Y, Promintzer-Schifferl M, Wohlschläger E, Anderwald CH, Wolf P, et al. Effects of insulin therapy on myocardial lipid content and cardiac geometry in patients with type-2 diabetes mellitus. PLoS One. 2012;7(12):1–7.CrossRefGoogle Scholar
  95. 95.
    Lingvay I, Raskin P, Szczepaniak LS. Effect of insulin and metformin combination on hepatic steatosis in type 2 diabetes: treatment of hepatic steatosis in diabetes. J Diabetes Complications. 2008;21(3):137–42.CrossRefGoogle Scholar
  96. 96.
    Thamer C, Machann J, Bachmann O, Haap M, Dahl D, Wietek B, et al. Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. J Clin Endocrinol Metab. 2003;88(4):1785–91.PubMedCrossRefGoogle Scholar
  97. 97.
    Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001;86(12):5755–61.PubMedCrossRefGoogle Scholar
  98. 98.
    Bergman BC, Hunerdosse DM, Kerege A, Playdon MC, Perreault L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia. 2012;55(4):1140–50.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Szendroedi J, Schmid AI, Chmelik M, Toth C, Brehm A, Krssak M, et al. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med. 2007;4(5):e154.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Schmid AI, Szendroedi J, Chmelik M, Krssák M, Moser E, Roden M. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care. 2011;34(2):448–53.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Szendroedi J, Chmelik M, Schmid AI, Nowotny P, Brehm A, Krssak M, et al. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology. 2009;50(4):1079–86.PubMedCrossRefGoogle Scholar
  102. 102.
    Franko A, von Kleist-Retzow J-C, Neschen S, Wu M, Schommers P, Böse M, et al. Liver adapts mitochondrial function to insulin resistant and diabetic states in mice. J Hepatol. 2014;60(4):816–23.PubMedCrossRefGoogle Scholar
  103. 103.
    Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14(6):804–10.Google Scholar
  104. 104.
    Johnson NA, Walton DW, Sachinwalla T, Thompson CH, Smith K, Ruell PA, et al. Noninvasive assessment of hepatic lipid composition: advancing understanding and management of fatty liver disorders. Hepatology. 2008;47(5):1513–23.PubMedCrossRefGoogle Scholar
  105. 105.
    De Wit NJW, Afman LA, Mensink M, Müller M. Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol. 2012;57:1370–3.PubMedCrossRefGoogle Scholar
  106. 106.
    Allard JP, Aghdassi E, Mohammed S, Raman M, Avand G, Arendt BM, et al. Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. J Hepatol. 2008;48(2):300–7.PubMedCrossRefGoogle Scholar
  107. 107.
    De Wit N, Derrien M, Bosch-Vermeulen H, Oosterink E, Keshtkar S, Duval C, et al. Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol. 2012;303(5):G589–99.Google Scholar
  108. 108.
    Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr. 2012;95:1003–12.PubMedCrossRefGoogle Scholar
  109. 109.
    Rosqvist F, Iggman D, Kullberg J, Jonathan Cedernaes J, Johansson H-E, Larsson A, et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes. 2014;63(7):2356–68.Google Scholar
  110. 110.
    Jans A, Konings E, Goossens GH, Bouwman FG, Moors CC, Boekschoten MV, et al. PUFAs acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increase postprandial insulin sensitivity. Am J Clin Nutr. 2012;95:825–36.PubMedCrossRefGoogle Scholar
  111. 111.
    Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR, et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest. 2012;122(11):3919–30.Google Scholar
  112. 112.
    Duda MK, O’Shea KM, Stanley WC. Omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res. 2009;84(1):33–41.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Estruch R, Ros E, Salas-Salvadó J, Covas M-I, Corella D, et al. Primary prevention of cardiovascular disease with a mediterranean diet. N Engl J Med. 2013;368(14):1279–90.Google Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Peter Wolf
    • 1
  • Yvonne Winhofer
    • 1
  • Christian-Heinz Anderwald
    • 1
    • 3
    • 4
    • 5
  • Martin Krššák
    • 1
    • 2
  • Michael Krebs
    • 1
  1. 1.Division of Endocrinology and Metabolism, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
  2. 2.High Field MR-Centre, Department of Biomedical Imaging and Image-Guided TherapyMedical University of ViennaViennaAustria
  3. 3.Metabolic UnitInstitute of Biomedical Engineering, National Research CouncilPadovaItaly
  4. 4.Mariahilf Community PharmacyArnoldsteinAustria
  5. 5.Medical DirectionSpecialized Hospital Complex AgathenhofMicheldorfAustria

Personalised recommendations