Mitochondrial function refers to a broad spectrum of features such as resting mitochondrial activity, (sub)maximal oxidative phosphorylation capacity (OXPHOS), and mitochondrial dynamics, turnover, and plasticity. The interaction between mitochondria and insulin sensitivity is bidirectional and varies depending on tissue, experimental model, methodological approach, and features of mitochondrial function tested. In human skeletal muscle, mitochondrial abnormalities may be inherited (e.g., lower mitochondrial content) or acquired (e.g., impaired OXPHOS capacity and plasticity). Abnormalities ultimately lead to lower mitochondrial functionality due to or resulting in insulin resistance and type 2 diabetes mellitus. Similar mechanisms can also operate in adipose tissue and heart muscle. In contrast, mitochondrial oxidative capacity is transiently upregulated in the liver of obese insulin-resistant humans with or without fatty liver, giving rise to oxidative stress and declines in advanced fatty liver disease. These data suggest a highly tissue-specific interaction between insulin sensitivity and oxidative metabolism during the course of metabolic diseases in humans.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW. 1.  et al. 2012. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology 56:952–60 [Google Scholar]
  2. Adjeitey CN, Mailloux RJ, deKemp RA, Harper ME. 2.  2013. Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production. Am. J. Physiol. Endocrinol. Metab. 305:E405–15 [Google Scholar]
  3. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. 3.  2009. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J. Am. Coll. Cardiol. 54:1891–98 [Google Scholar]
  4. Anderson EJ, Rodriguez E, Anderson CA, Thayne K, Chitwood WR, Kypson AP. 4.  2011. Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am. J. Physiol. Heart Circ. Physiol. 300:H118–24 [Google Scholar]
  5. Antoun G, McMurray F, Thrush AB, Patten DA, Peixoto AC. 5.  et al. 2015. Impaired mitochondrial oxidative phosphorylation and supercomplex assembly in rectus abdominis muscle of diabetic obese individuals. Diabetologia 58:2861–66 [Google Scholar]
  6. Bach D, Naon D, Pich S, Soriano FX, Vega N. 6.  et al. 2005. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α and interleukin-6. Diabetes 54:2685–93 [Google Scholar]
  7. Befroy DE, Kibbey RG, Perry RJ, Petersen KF, Rothman DL. 7.  et al. 2015. Response to Burgess. Nat. Med. 21:109–10 [Google Scholar]
  8. Befroy DE, Perry RJ, Jain N, Dufour S, Cline GW. 8.  et al. 2014. Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nat. Med. 20:98–102 [Google Scholar]
  9. Begriche K, Igoudjil A, Pessayre D, Fromenty B. 9.  2006. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6:1–28 [Google Scholar]
  10. Benard G, Faustin B, Passerieux E, Galinier A, Rocher C. 10.  et al. 2006. Physiological diversity of mitochondrial oxidative phosphorylation. Am. J. Physiol. Cell Physiol. 291:C1172–82 [Google Scholar]
  11. Bhat G, Baba CS, Pandey A, Kumari N, Choudhuri G. 11.  2012. Life style modification improves insulin resistance and liver histology in patients with non-alcoholic fatty liver disease. World J. Hepatol. 4:209–17 [Google Scholar]
  12. Bogacka I, Xie H, Bray GA, Smith SR. 12.  2005. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54:1392–99 [Google Scholar]
  13. Bouderba S, Sanz MN, Sánchez-Martín C, El-Mir MY, Villanueva GR. 13.  et al. 2012. Hepatic mitochondrial alterations and increased oxidative stress in nutritional diabetes-prone Psammomys obesus model. Exp. Diabetes Res. 2012:430176 [Google Scholar]
  14. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ. 14.  et al. 2007. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–66 [Google Scholar]
  15. Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsøe R, Dela F. 15.  2007. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50:790–96 [Google Scholar]
  16. Brady LJ, Brady PS, Romsos DR, Hoppel CL. 16.  1985. Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob/ob) mice. Biochem. J. 231:439–44 [Google Scholar]
  17. Brand MD, Nicholls DG. 17.  2011. Assessing mitochondrial dysfunction in cells. Biochem. J. 435:297–312 [Google Scholar]
  18. Brehm A, Krssák M, Schmid AI, Nowotny P, Waldhäusl W, Roden M. 18.  2006. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 55:136–40 [Google Scholar]
  19. Brehm A, Krssák M, Schmid AI, Nowotny P, Waldhäusl W, Roden M. 19.  2010. Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 299:E33–38 [Google Scholar]
  20. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW. 20.  et al. 2005. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146:5341–49 [Google Scholar]
  21. Burgess SC, Merritt ME, Jones JG, Browning JD, Sherry AD. 21.  et al. 2015. Limitations of detection of anaplerosis and pyruvate cycling from metabolism of [1-13C] acetate. Nat. Med. 21:108–9 [Google Scholar]
  22. Cheng Z, Guo S, Copps K, Dong X, Kollipara R. 22.  et al. 2009. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat. Med. 15:1307–11 [Google Scholar]
  23. Chiappini F, Barrier A, Saffroy R, Domart MC, Dagues N. 23.  et al. 2006. Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray. Lab. Investig. 86:154–65 [Google Scholar]
  24. Chmelík M, Schmid AI, Gruber S, Szendroedi J, Krssák M. 24.  et al. 2008. Three-dimensional high-resolution magnetic resonance spectroscopic imaging for absolute quantification of 31P metabolites in human liver. Magn. Reson. Med. 60:796–802 [Google Scholar]
  25. Chomentowski P, Coen PM, Radiková Z, Goodpaster BH, Toledo FG. 25.  2011. Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J. Clin. Endocrinol. Metab. 96:494–503 [Google Scholar]
  26. Choudhury J, Sanyal AJ. 26.  2004. Clinical aspects of fatty liver disease. Semin. Liver Dis. 24:349–62 [Google Scholar]
  27. Cipolat S, de Brito OM, Dal Zilio B, Scorrano L. 27.  2004. OPA1 requires mitofusin 1 to promote mitochondrial fusion. PNAS 101:15927–32 [Google Scholar]
  28. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. 28.  1999. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282:1659–64 [Google Scholar]
  29. Cree-Green M, Newcomer BR, Brown MS, Baumgartner AD, Bergman B. 29.  et al. 2015. Delayed skeletal muscle mitochondrial ADP recovery in youth with type 1 diabetes relates to muscle insulin resistance. Diabetes 64:383–92 [Google Scholar]
  30. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW. 30.  et al. 2003. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J. Am. Coll. Cardiol. 42:328–35 [Google Scholar]
  31. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S. 31.  et al. 1999. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–48 [Google Scholar]
  32. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. 32.  2002. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr. Rev. 23:599–622 [Google Scholar]
  33. Fisher-Wellman KH, Weber TM, Cathey BL, Brophy PM, Gilliam LA. 33.  et al. 2014. Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans. Diabetes 63:132–41 [Google Scholar]
  34. Flannery C, Dufour S, Rabol R, Shulman GI, Petersen KF. 34.  2012. Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes 61:2711–17 [Google Scholar]
  35. Frayn KN, Langin D, Karpe F. 35.  2008. Fatty acid–induced mitochondrial uncoupling in adipocytes is not a promising target for treatment of insulin resistance unless adipocyte oxidative capacity is increased. Diabetologia 51:394–97 [Google Scholar]
  36. Fritsch M, Koliaki C, Livingstone R, Phielix E, Bierwagen A. 36.  et al. 2015. Time course of postprandial hepatic phosphorus metabolites in lean, obese and type 2 diabetes patients. Am. J. Clin. Nutr. 102:1051–58 [Google Scholar]
  37. Galgani JE, Vasquez K, Watkins G, Dupuy A, Bertrand-Michel J. 37.  et al. 2013. Enhanced skeletal muscle lipid oxidative efficiency in insulin-resistant versus insulin-sensitive nondiabetic, nonobese humans. J. Clin. Endocrinol. Metab. 98:E646–53 [Google Scholar]
  38. Galloway CA, Yoon Y. 38.  2013. Mitochondrial morphology in metabolic diseases. Antioxid. Redox Signal. 19:415–30 [Google Scholar]
  39. Gancheva S, Koliaki C, Bierwagen A, Nowotny P, Heni M. 39.  et al. 2015. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 64:1966–75 [Google Scholar]
  40. Gao AW, Cantó C, Houtkooper RH. 40.  2014. Mitochondrial response to nutrient availability and its role in metabolic disease. EMBO Mol. Med. 6:580–89 [Google Scholar]
  41. Gnaiger E. 41.  2009. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41:1837–45 [Google Scholar]
  42. Goldstein BJ, Mahadev K, Wu X. 42.  2005. Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes 54:311–21 [Google Scholar]
  43. Gomes LC, Di Benedetto G, Scorrano L. 43.  2011. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13:589–98 [Google Scholar]
  44. Hales KG. 44.  2004. The machinery of mitochondrial fusion, division, and distribution, and emerging connections to apoptosis. Mitochondrion 4:285–308 [Google Scholar]
  45. Hales KG, Fuller MT. 45.  1997. Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90:121–29 [Google Scholar]
  46. Hansen M, Lund MT, Gregers E, Kraunsøe R, Van Hall G. 46.  et al. 2015. Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB. Obesity (Silver Spring) 23:2022–29 [Google Scholar]
  47. Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ. 47.  et al. 2009. Insulin resistance is a cellular antioxidant defense mechanism. PNAS 106:17787–92 [Google Scholar]
  48. Holloszy JO. 48.  2013. “Deficiency” of mitochondria in muscle does not cause insulin resistance. Diabetes 62:1036–40 [Google Scholar]
  49. How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS. 49.  2006. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 55:466–73 [Google Scholar]
  50. Iozzo P, Bucci M, Roivainen A, Någren K, Järvisalo MJ. 50.  et al. 2010. Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals. Gastroenterology 139:846–56.e6 [Google Scholar]
  51. Jahansouz C, Serrot FJ, Frohnert BI, Foncea RE, Dorman RB. 51.  et al. 2015. Roux-en-Y gastric bypass acutely decreases protein carbonylation and increases expression of mitochondrial biogenesis genes in subcutaneous adipose tissue. Obes. Surg. 25:2376–85 [Google Scholar]
  52. Jelenik T, Roden M. 52.  2013. Mitochondrial plasticity in obesity and diabetes mellitus. Antioxid. Redox Signal. 19:258–68 [Google Scholar]
  53. Jelenik T, Séquaris G, Kaul K, Ouwens DM, Phielix E. 53.  et al. 2014. Tissue-specific differences in the development of insulin resistance in a mouse model for type 1 diabetes. Diabetes 63:3856–67 [Google Scholar]
  54. Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ. 54.  et al. 2012. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic. Biol. Med. 52:1–6 [Google Scholar]
  55. Kelley DE, He J, Menshikova EV, Ritov VB. 55.  2002. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944–50 [Google Scholar]
  56. Kelley DE, Mandarino LJ. 56.  2000. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49:677–83 [Google Scholar]
  57. Kemp GJ, Brindle KM. 57.  2012. What do magnetic resonance-based measurements of Pi→ATP flux tell us about skeletal muscle metabolism?. Diabetes 61:1927–34 [Google Scholar]
  58. Koliaki C, Roden M. 58.  2013. Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease. Mol. Cell. Endocrinol. 379:35–42 [Google Scholar]
  59. Koliaki C, Roden M. 59.  2014. Do mitochondria care about insulin resistance?. Mol. Metab. 3:351–53 [Google Scholar]
  60. Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P. 60.  et al. 2015. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21:739–46 [Google Scholar]
  61. Kraunsøe R, Boushel R, Hansen CN, Schjerling P, Qvortrup K. 61.  et al. 2010. Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. J. Physiol. 588:Part 122023–32 [Google Scholar]
  62. Kotiadis VN, Duchen MR, Osellame LD. 62.  2014. Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim. Biophys. Acta 1840:1254–65 [Google Scholar]
  63. Kotronen A, Seppälä-Lindroos A, Vehkavaara S, Bergholm R, Frayn KN. 63.  et al. 2009. Liver fat and lipid oxidation in humans. Liver Int. 29:1439–46 [Google Scholar]
  64. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M. 64.  et al. 2008. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7:45–56 [Google Scholar]
  65. Larsen S, Nielsen J, Hansen CN, Nielsen LB, Wibrand F. 65.  et al. 2012. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J. Physiol. 590:3349–60 [Google Scholar]
  66. Lee HJ, Chung K, Lee H, Lee K, Lim JH, Song J. 66.  2011. Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells. Diabetologia 54:1437–46 [Google Scholar]
  67. Lefort N, Glancy B, Bowen B, Willis WT, Bailowitz Z. 67.  et al. 2010. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 59:2444–52 [Google Scholar]
  68. Liesa M, Shirihai OS. 68.  2013. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17:491–506 [Google Scholar]
  69. Long YC, Cheng Z, Copps KD, White MF. 69.  2011. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol. Cell. Biol. 31:430–41 [Google Scholar]
  70. Maassen JA, Romijn JA, Heine RJ. 70.  2007. Fatty acid–induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus. Diabetologia 50:2036–41 [Google Scholar]
  71. Machado MV, Ferreira DM, Castro RE, Silvestre AR, Evangelista T. 71.  et al. 2012. Liver and muscle in morbid obesity: the interplay of fatty liver and insulin resistance. PLOS ONE 7:e31738 [Google Scholar]
  72. Martin SD, Morrison S, Konstantopoulos N, McGee SL. 72.  2014. Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action. Mol. Metab. 3:408–18 [Google Scholar]
  73. Metzler B, Schocke MF, Steinboeck P, Wolf C, Judmaier W. 73.  et al. 2002. Decreased high-energy phosphate ratios in the myocardium of men with diabetes mellitus type I. J. Cardiovasc. Magn. Reson. 4:493–502 [Google Scholar]
  74. Miele L, Grieco A, Armuzzi A, Candelli M, Forgione A. 74.  et al. 2003. Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test. Am. J. Gastroenterol. 98:2335–36 [Google Scholar]
  75. Mingrone G, Manco M, Calvani M, Castagneto M, Naon D, Zorzano A. 75.  2005. Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?. Diabetologia 48:2108–14 [Google Scholar]
  76. Misu H, Takamura T, Matsuzawa N, Shimizu A, Ota T. 76.  et al. 2007. Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. Diabetologia 50:268–77 [Google Scholar]
  77. Mitchell T, Chacko B, Ballinger SW, Bailey SM, Zhang J, Darley-Usmar V. 77.  2013. Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics. Biochem. Soc. Trans. 41:127–33 [Google Scholar]
  78. Mogensen M, Sahlin K, Fernström M, Glintborg D, Vind BF. 78.  et al. 2007. Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56:1592–99 [Google Scholar]
  79. Mohanty JG, Jaffe JS, Schulman ES, Raible DG. 79.  1997. A highly sensitive fluorescent micro-assay of H2O2 release from activated human leukocytes using a dihydroxyphenoxazine derivative. J. Immunol. Methods 202:133–41 [Google Scholar]
  80. Mollica MP, Lionetti L, Moreno M, Lombardi A, De Lange P. 80.  et al. 2009. 3,5-diiodo-L-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet. J. Hepatol. 51:363–70 [Google Scholar]
  81. Montaigne D, Marechal X, Coisne A, Debry N, Modine T. 81.  et al. 2014. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130:554–64 [Google Scholar]
  82. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S. 82.  et al. 2003. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34:267–73 [Google Scholar]
  83. Moreno-Navarrete JM, Ortega F, Moreno M, Ricart W, Fernández-Real JM. 83.  2014. Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis. Diabetologia 57:1957–67 [Google Scholar]
  84. Morino K, Petersen KF, Dufour S, Befroy D, Frattini J. 84.  et al. 2005. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115:3587–93 [Google Scholar]
  85. Morris EM, Rector RS, Thyfault JP, Ibdah JA. 85.  2011. Mitochondria and redox signaling in steatohepatitis. Antioxid. Redox Signal. 15:485–504 [Google Scholar]
  86. Murphy MP. 86.  2009. How mitochondria produce reactive oxygen species. Biochem. J. 417:1–13 [Google Scholar]
  87. Mustelin L, Pietilainen KH, Rissanen A, Sovijarvi AR, Piirila P. 87.  et al. 2008. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am. J. Physiol. Endocrinol. Metab. 295:E148–54 [Google Scholar]
  88. Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM. 88.  et al. 2008. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57:1166–75 [Google Scholar]
  89. Nair S, P Chacko V, Arnold C, Diehl AM. 89.  2003. Hepatic ATP reserve and efficiency of replenishing: comparison between obese and nonobese normal individuals. Am. J. Gastroenterol. 98:466–70 [Google Scholar]
  90. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL. 90.  et al. 2008. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol. 48:993–99 [Google Scholar]
  91. Paganini AT, Foley JM, Meyer RA. 91.  1997. Linear dependence of muscle phosphocreatine kinetics on oxidative capacity. Am. J. Physiol. 272:C501–10 [Google Scholar]
  92. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R. 92.  et al. 2003. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. PNAS 100:8466–71 [Google Scholar]
  93. Pérez-Carreras M, Del Hoyo P, Martín MA, Rubio JC, Martín A. 93.  et al. 2003. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38:999–1007 [Google Scholar]
  94. Perry CG, Kane DA, Lanza IR, Neufer PD. 94.  2013. Methods for assessing mitochondrial function in diabetes. Diabetes 62:1041–53 [Google Scholar]
  95. Perry RJ, Kim T, Zhang X-M, Lee H-Y, Pesta D. 95.  et al. 2013. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18:740–48 [Google Scholar]
  96. Perseghin G, Lattuada G, De Cobelli F, Esposito A, Belloni E. 96.  et al. 2008. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47:51–58 [Google Scholar]
  97. Perseghin G, Ntali G, De Cobelli F, Lattuada G, Esposito A. 97.  et al. 2007. Abnormal left ventricular energy metabolism in obese men with preserved systolic and diastolic functions is associated with insulin resistance. Diabetes Care 30:1520–26 [Google Scholar]
  98. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. 98.  2004. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350:664–71 [Google Scholar]
  99. Petersen KF, Dufour S, Shulman GI. 99.  2005. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLOS Med. 2:e233 [Google Scholar]
  100. Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. 100.  2014. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia 57:572–81 [Google Scholar]
  101. Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R. 101.  et al. 2008. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57:2943–49 [Google Scholar]
  102. Ping P, Gustafsson ÅB, Bers DM, Blatter LA, Cai H. 102.  et al. 2015. Harnessing the power of integrated mitochondrial biology and physiology: a special report on the NHLBI Mitochondria in Heart Diseases Initiative. Circ. Res. 117:234–38 [Google Scholar]
  103. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M. 103.  et al. 2007. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476–91 [Google Scholar]
  104. Raffaella C, Francesca B, Italia F, Marina P, Giovanna L, Susanna I. 104.  2008. Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. Obesity 16:958–64 [Google Scholar]
  105. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA. 105.  et al. 1977. Evidence for cardiomyopathy in familial diabetes mellitus. J. Clin. Investig. 60:884–99 [Google Scholar]
  106. Rimessi A, Giorgi C, Pinton P, Rizzuto R. 106.  2008. The versatility of mitochondrial calcium signals: from stimulation of cell metabolism to induction of cell death. Biochim. Biophys. Acta 1777:808–16 [Google Scholar]
  107. Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG. 107.  et al. 2010. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am. J. Physiol. Endocrinol. Metab. 298:E49–58 [Google Scholar]
  108. Roden M. 108.  2006. Mechanisms of disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance. Nat. Clin. Pract. Endocrinol. Metab. 2:335–48 [Google Scholar]
  109. Rogers GW, Brand MD, Petrosyan S, Ashok D, Elorza AA. 109.  et al. 2011. High throughput microplate respiratory measurements using minimal quantities of isolated mitochondria. PLOS ONE 6:e21746 [Google Scholar]
  110. Romestaing C, Piquet MA, Letexier D, Rey B, Mourier A. 110.  et al. 2008. Mitochondrial adaptations to steatohepatitis induced by a methionine- and choline-deficient diet. Am. J. Physiol. Endocrinol. Metab. 294:110–19 [Google Scholar]
  111. Samuel VT, Petersen KF, Shulman GI. 111.  2010. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–77 [Google Scholar]
  112. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ. 112.  et al. 2001. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–92 [Google Scholar]
  113. Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L. 113.  et al. 2015. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J. Clin. Invest. 125:4447–62 [Google Scholar]
  114. Satapati S, Sunny NE, Kucejova B, Fu X, He TT. 114.  et al. 2012. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J. Lipid Res. 53:1080–92 [Google Scholar]
  115. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE. 115.  et al. 2003. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107:3040–46 [Google Scholar]
  116. Schmid AI, Chmelík M, Szendroedi J, Krssák M, Brehm A. 116.  et al. 2008. Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment. NMR Biomed. 21:437–43 [Google Scholar]
  117. Schmid AI, Szendroedi J, Chmelik M, Krssák M, Moser E, Roden M. 117.  2011. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care 34:448–53 [Google Scholar]
  118. Serviddio G, Bellanti F, Tamborra R, Rollo T, Capitanio N. 118.  et al. 2008. Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 57:957–65 [Google Scholar]
  119. Serviddio G, Bellanti F, Vendemiale G, Altomare E. 119.  2011. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 5:233–44 [Google Scholar]
  120. Shulman GI. 120.  2014. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371:2237–38 [Google Scholar]
  121. Starkov AA. 121.  2010. Measurement of mitochondrial ROS production. Methods Mol. Biol. 648:245–55 [Google Scholar]
  122. Sunny NE, Parks EJ, Browning JD, Burgess SC. 122.  2011. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14:804–10 [Google Scholar]
  123. Szendroedi J, Chmelik M, Schmid AI, Nowotny P, Brehm A. 123.  et al. 2009. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50:1079–86 [Google Scholar]
  124. Szendroedi J, Kaul K, Kloock L, Straßburger K, Schmid AI. 124.  et al. 2014. Lower fasting muscle mitochondrial activity relates to hepatic steatosis in humans. Diabetes Care 37:468–74 [Google Scholar]
  125. Szendroedi J, Phielix E, Roden M. 125.  2011. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8:92–103 [Google Scholar]
  126. Szendroedi J, Roden M. 126.  2008. Mitochondrial fitness and insulin sensitivity in humans. Diabetologia 51:2155–67 [Google Scholar]
  127. Szendroedi J, Schmid AI, Chmelik M, Krssak M, Nowotny P. 127.  et al. 2011. Skeletal muscle phosphodiester content relates to body mass and glycemic control. PLOS ONE 6:e21846 [Google Scholar]
  128. Szendroedi J, Schmid AI, Chmelik M, Toth C, Brehm A. 128.  et al. 2007. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLOS Med. 4:e154 [Google Scholar]
  129. Takamura T, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T. 129.  et al. 2008. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (Silver Spring) 16:2601–9 [Google Scholar]
  130. Tao H, Zhang Y, Zeng X, Shulman GI, Jin S. 130.  2014. Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat. Med. 20:1263–69 [Google Scholar]
  131. Trevellin E, Scorzeto M, Olivieri M, Granzotto M, Valerio A. 131.  et al. 2014. Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms. Diabetes 63:2800–11 [Google Scholar]
  132. Twig G, Hyde B, Shirihai OS. 132.  2008. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim. Biophys. Acta 1777:1092–97 [Google Scholar]
  133. Vernochet C, Damilano F, Mourier A, Bezy O, Mori MA. 133.  et al. 2014. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J. 28:4408–19 [Google Scholar]
  134. Vernochet C, Mourier A, Bezy O, Macotela Y, Boucher J. 134.  et al. 2012. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 16:765–76 [Google Scholar]
  135. Westermeier F, Navarro-Marquez M, López-Crisosto C, Bravo-Sagua R, Quiroga C. 135.  et al. 2015. Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy. Biochim. Biophys. Acta 1853:1113–18 [Google Scholar]
  136. Zorzano A, Liesa M, Palacín M. 136.  2009. Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes. Int. J. Biochem. Cell Biol. 41:1846–54 [Google Scholar]
  137. Zungu M, Schisler J, Willis MS. 137.  2011. All the little pieces—regulation of mitochondrial fusion and fission by ubiquitin and small ubiquitin-like modifier and their potential relevance in the heart. Circ. J. 75:2513–21 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error