Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of mitochondria in insulin resistance and type 2 diabetes mellitus

Nature Reviews Endocrinology volume 8, pages 92–103 (2012)Cite this article

Subjects

Abstract

Type 2 diabetes mellitus (T2DM) has been related to alterations of oxidative metabolism in insulin-responsive tissues. Overt T2DM can present with acquired or inherited reductions of mitochondrial oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and plasticity of mitochondria and/or lower mitochondrial content in skeletal muscle cells and potentially also in hepatocytes. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as the result of blunted mitochondrial plasticity. Hereditary insulin resistance is frequently associated with reduced mitochondrial activity at rest, probably due to diminished mitochondrial content. Lifestyle and pharmacological interventions can enhance the capacity for oxidative phosphorylation and mitochondrial content and improve insulin resistance in some (pre)diabetic cases. Various mitochondrial features can be abnormal but are not necessarily responsible for all forms of insulin resistance. Nevertheless, mitochondrial abnormalities might accelerate progression of insulin resistance and subsequent organ dysfunction via increased production of reactive oxygen species. This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity.

Key Points

  • Overt type 2 diabetes mellitus is associated with reduced oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and mitochondrial plasticity in insulin-responsive tissues

  • Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial plasticity that results in the inability of the organism to switch from fatty acid to glucose oxidation in skeletal muscle

  • Hereditary insulin resistance can be linked to reduced resting mitochondrial activity at least partly due to a decreased mitochondrial content

  • Lifestyle and pharmacological interventions can enhance oxidative phosphorylation capacity and mitochondrial content, and in most cases improve insulin resistance in (pre)diabetic states

  • Reduced oxidative phosphorylation capacity is unlikely to be the general cause of all forms of insulin resistance but might accelerate its progression and subsequent organ dysfunction via increased production of reactive oxygen species

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Parameters of mitochondrial function.
Figure 2: Role of mitochondria in metabolic inflexibility.
Figure 3: Basal and insulin-stimulated flux through the ATP synthase in humans.

Similar content being viewed by others

References

  1. Roden, M. Non-invasive studies of glycogen metabolism in human skeletal muscle using nuclear magnetic resonance spectroscopy. Curr. Opin. Clin. Nutr. Metab. Care 4, 261–266 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Simoneau, J. A. & Kelley, D. E. Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J. Appl. Physiol. 83, 166–171 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Ukropcova, B. et al. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes 56, 720–727 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Szendroedi, J. & Roden, M. Mitochondrial fitness and insulin sensitivity in humans. Diabetologia 51, 2155–2167 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Sivitz, W. I. & Yorek, M. A. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid. Redox. Signal 12, 537–577 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lowell, B. B. & Shulman, G. I. Mitochondrial dysfunction and type 2 diabetes. Science 307, 384–387 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Sreekumar, R. & Nair, K. S. Skeletal muscle mitochondrial dysfunction & diabetes. Indian J. Med. Res. 125, 399–410 (2007).

    CAS  PubMed  Google Scholar 

  8. Lanza, I. R. & Nair, K. S. Mitochondrial metabolic function assessed in vivo and in vitro. Curr. Opin. Clin. Nutr. Metab. Care 13, 511–517 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kemp, G. J. The interpretation of abnormal 31P magnetic resonance saturation transfer measurements of Pi/ATP exchange in insulin-resistant skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 294, E640–E642 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kraegen, E. W., Cooney, G. J. & Turner, N. Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 105, 7627–7628 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Holloszy, J. O. Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance. Am. J. Clin. Nutr. 89, 463S–466S (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Schiff, M. et al. Mitochondria and diabetes mellitus: untangling a conflictive relationship? J. Inherit. Metab. Dis. 32, 684–698 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Erion, D. M. & Shulman, G. I. Diacylglycerol-mediated insulin resistance. Nat. Med. 16, 400–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pagel-Langenickel, I., Bao, J., Pang, L. & Sack, M. N. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr. Rev. 31, 25–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Chance, B. et al. Control of oxidative metabolism and oxygen delivery in human skeletal muscle: a steady-state analysis of the work/energy cost transfer function. Proc. Natl Acad. Sci. USA 82, 8384–8388 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kacerovsky-Bielesz, G. et al. Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes. Diabetes 58, 1333–1341 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Szendroedi, J. et al. Impaired mitochondrial function and insulin resistance of skeletal muscle in mitochondrial diabetes. Diabetes Care 32, 677–679 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kemp, G. J. et al. Quantitative analysis by 31P magnetic resonance spectroscopy of abnormal mitochondrial oxidation in skeletal muscle during recovery from exercise. NMR Biomed. 6, 302–310 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Chance, B., Im, J., Nioka, S. & Kushmerick, M. Skeletal muscle energetics with PNMR: personal views and historic perspectives. NMR Biomed. 19, 904–926 (2006).

    Article  PubMed  Google Scholar 

  20. Prompers, J. J. et al. Dynamic MRS and MRI of skeletal muscle function and biomechanics. NMR Biomed. 19, 927–953 (2006).

    Article  PubMed  Google Scholar 

  21. Gnaiger, E. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41, 1837–1845 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kemp, G. J., Meyerspeer, M. & Moser, E. Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: a quantitative review. NMR Biomed. 20, 555–565 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Paganini, A. T., Foley, J. M. & Meyer, R. A. Linear dependence of muscle phosphocreatine kinetics on oxidative capacity. Am. J. Physiol. 272, C501–C510 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. di Prampero, P. E. Factors limiting maximal performance in humans. Eur. J. Appl. Physiol. 90, 420–429 (2003).

    Article  PubMed  Google Scholar 

  25. Rossignol, R., Letellier, T., Malgat, M., Rocher, C. & Mazat, J. P. Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases. Biochem. J. 347 (Pt 1), 45–53 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Endo, M. & Iino, M. Measurement of Ca2+ release in skinned fibers from skeletal muscle. Methods Enzymol. 157, 12–26 (1988).

    Article  CAS  PubMed  Google Scholar 

  27. Chance, B. & Conrad, H. Acid-linked functions of intermediates in oxidative phosphorylation. II. Experimental studies of the effect of pH upon respiratory, phosphorylative and transfer activities of liver and heart mitochondria. J. Biol. Chem. 234, 1568–1570 (1959).

    CAS  PubMed  Google Scholar 

  28. Brand, M. D. The efficiency and plasticity of mitochondrial energy transduction. Biochem. Soc. Trans. 33, 897–904 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Phielix, E. et al. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57, 2943–2949 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Messer, J. I., Jackman, M. R. & Willis, W. T. Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. Am. J. Physiol. Cell Physiol. 286, C565–C572 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Pagel-Langenickel, I. et al. A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in type 2 diabetes mellitus. Am. J. Physiol. Heart Circ. Physiol. 293, H2659–H2666 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Hoppeler, H. & Fluck, M. Plasticity of skeletal muscle mitochondria: structure and function. Med. Sci. Sports Exerc. 35, 95–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Morino, K. et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115, 3587–3593 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl Acad. Sci. USA 100, 8466–8471 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yadava, N. & Nicholls, D. G. Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. J. Neurosci. 27, 7310–7317 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Koves, T. R. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45–56 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Jucker, B. M. et al. Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR. Proc. Natl Acad. Sci. USA 97, 6880–6884 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chomentowski, P., Coen, P. M., Radiková, Z., Goodpaster, B. H. & Toledo, F. G. Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J. Clin. Endocrinol. Metab. 96, 494–503 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Schrauwen-Hinderling, V. B. et al. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 50, 113–120 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Boushel, R. et al. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50, 790–796 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ritov, V. B. et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54, 8–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Mogensen, M. et al. Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56, 1592–1599 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Stump, C. S., Short, K. R., Bigelow, M. L., Schimke, J. M. & Nair, K. S. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc. Natl Acad. Sci. USA 100, 7996–8001 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Szendroedi, J. et al. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med. 4, e154 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ritov, V. B. et al. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am. J. Physiol. Endocrinol. Metab. 298, E49–E58 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Hwang, H. et al. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes 59, 33–42 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Heilbronn, L. K., Gan, S. K., Turner, N., Campbell, L. V. & Chisholm, D. J. Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J. Clin. Endocrinol. Metab. 92, 1467–1473 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Toledo, F. G. et al. Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57, 987–994 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Mootha, V. K. et al. PGC 1α responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Karlsson, H. K., Ahlsen, M., Zierath, J. R., Wallberg-Henriksson, H. & Koistinen, H. A. Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients. Diabetes 55, 1283–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G. I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Szendroedi, J. et al. Reduced basal ATP synthetic flux of skeletal muscle in patients with previous acromegaly. PLoS ONE 3, e3958 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmid, A. I. et al. Comparison of measuring energy metabolism by different 31P MRS techniques in resting, ischemic and exercising muscle. Magn. Reson. Med. (in press).

  58. Petersen, K. F., Dufour, S. & Shulman, G. I. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2, e233 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Karakelides, H., Irving, B. A., Short, K. R., O'Brien, P. & Nair, K. S. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes 59, 89–97 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lefort, N. et al. 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, 2444–2452 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pospisilik, J. A. et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131, 476–491 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Nair, K. S. et al. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57, 1166–1175 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Reaven, G. M., Hollenbeck, C., Jeng, C. Y., Wu, M. S. & Chen, Y. D. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 37, 1020–1024 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Krssák, M. & Roden, M. The role of lipid accumulation in liver and muscle for insulin resistance and type 2 diabetes mellitus in humans. Rev. Endocr. Metab. Disord. 5, 127–134 (2004).

    Article  PubMed  Google Scholar 

  65. Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859–2865 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dresner, A. et al. Effects of free fatty acids on glucose transport and IRS 1 associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103, 253–259 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Holland, W. L. et al. Lipid mediators of insulin resistance. Nutr. Rev. 65, S39–46 (2007).

    Article  PubMed  Google Scholar 

  68. Samuel, V. T. et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279, 32345–32353 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Høeg, L. D. et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes 60, 64–73 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Brehm, A. et al. Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 299, E33–E38 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Chavez, A. O. et al. Effect of short-term free fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J. Clin. Endocrinol. Metab. 95, 422–429 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Richardson, D. K. et al. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J. Biol. Chem. 280, 10290–10297 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Soeters, M. R. et al. Muscle acylcarnitines during short-term fasting in lean healthy men. Clin. Sci. (Lond.) 116, 585–592 (2009).

    Article  CAS  Google Scholar 

  74. Turner, N. et al. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56, 2085–2092 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Holloway, G. P., Gurd, B. J., Snook, L. A., Lally, J. & Bonen, A. Compensatory increases in nuclear PGC1α protein are primarily associated with subsarcolemmal mitochondrial adaptations in ZDF rats. Diabetes 59, 819–828 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hancock, C. R. et al. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc. Natl Acad. Sci. USA 105, 7815–7820 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Iossa, S. et al. Effect of high-fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats. Br. J. Nutr. 90, 953–960 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Holloway, G. P. et al. Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. Am. J. Physiol. Endocrinol. Metab. 292, E1782–E1789 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J. & Olefsky, J. M. Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55, 2277–2285 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Holloway, G. P., Bonen, A. & Spriet, L. L. Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. Am. J. Clin. Nutr. 89, 455S–462S (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Noland, R. C. et al. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J. Biol. Chem. 284, 22840–22852 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mihalik, S. J. et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring) 18, 1695–1700 (2010).

    Article  CAS  Google Scholar 

  83. Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Adams, S. H. et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J. Nutr. 139, 1073–1081 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Brehm, A. et al. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 55, 136–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Lim, E. L., Hollingsworth, K. G., Thelwall, P. E. & Taylor, R. Measuring the acute effect of insulin infusion on ATP turnover rate in human skeletal muscle using phosphorus-31 magnetic resonance saturation transfer spectroscopy. NMR Biomed. 23, 952–957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kacerovsky, M. et al. Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes. J. Intern. Med. 269, 189–199 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Cline, G. W. et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Med. 341, 240–246 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Ortenblad, N. et al. Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect. Biochim. Biophys. Acta 1741, 206–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Krssák, M. et al. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 53, 3048–3056 (2004).

    Article  PubMed  Google Scholar 

  91. Kotronen, A., Westerbacka, J., Bergholm, R., Pietiläinen, K. H. & Yki-Järvinen, H. Liver fat in the metabolic syndrome. J. Clin. Endocrinol. Metab. 92, 3490–3497 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated fat, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Mantena, S. K. et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem. J. 417, 183–193 (2008).

    Article  Google Scholar 

  94. Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Caldwell, S. H. et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J. Hepatol. 31, 430–434 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Kawahara, H., Fukura, M., Tsuchishima, M. & Takase, S. Mutation of mitochondrial DNA in livers from patients with alcoholic hepatitis and nonalcoholic steatohepatitis. Alcohol Clin. Exp. Res. 31, S54–S60 (2007).

    Article  PubMed  Google Scholar 

  97. Sevastianova, K. et al. Nonalcoholic fatty liver disease: detection of elevated nicotinamide adenine dinucleotide phosphate with in vivo 3.0-T 31P MR spectroscopy with proton decoupling. Radiology 256, 466–473 (2010).

    Article  PubMed  Google Scholar 

  98. Miele, L. et al. Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test. Am. J. Gastroenterol. 98, 2335–2336 (2003).

    Article  PubMed  Google Scholar 

  99. Cortez-Pinto, H. et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282, 1659–1664 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Prikoszovich, T. et al. Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus. Diabetes Care 34, 430–436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Szendroedi, J. et al. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50, 1079–1086 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Schmid, A. I. et al. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes mellitus. Diabetes Care 34, 448–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Eckel, J., Wirdeier, A., Herberg, L. & Reinauer, H. Insulin resistance in the heart: studies on isolated cardiocytes of genetically obese Zucker rats. Endocrinology 116, 1529–1534 (1985).

    Article  CAS  PubMed  Google Scholar 

  104. Razeghi, P., Young, M. E., Cockrill, T. C., Frazier, O. H. & Taegtmeyer, H. Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106, 407–411 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Sharma, S. et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18, 1692–1700 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. McGavock, J. M. et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 (2007).

    Article  PubMed  Google Scholar 

  107. Rijzewijk, L. J. et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 (2008).

    Article  PubMed  Google Scholar 

  108. Rijzewijk, L. J. et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J. Am. Coll. Cardiol. 54, 1524–1532 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Diamant, M. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Metzler, B. et al. Decreased high-energy phosphate ratios in the myocardium of men with diabetes mellitus type I. J. Cardiovasc. Magn. Reson. 4, 493–502 (2002).

    Article  PubMed  Google Scholar 

  111. Scheuermann-Freestone, M. et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107, 3040–3046 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Perseghin, G. et al. Abnormal left ventricular energy metabolism in obese men with preserved systolic and diastolic functions is associated with insulin resistance. Diabetes Care 30, 1520–1526 (2007).

    Article  PubMed  Google Scholar 

  113. Perseghin, G. et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47, 51–58 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Anderson, E. J. et al. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J. Am. Coll. Cardiol. 54, 1891–1898 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parra, V. et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc. Res. 77, 387–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Schwartz, M. W., Figlewicz, D. P., Baskin, D. G., Woods, S. C. & Porte, D. Jr. Insulin in the brain: a hormonal regulator of energy balance. Endocr. Rev. 13, 387–414 (1992).

    CAS  PubMed  Google Scholar 

  117. Koch, L. et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Invest. 118, 2132–2147 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Schmoller, A. et al. Evidence for a relationship between body mass and energy metabolism in the human brain. J. Cereb. Blood Flow Metab. 30, 1403–1410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bischof, M. G. et al. Brain energy metabolism during hypoglycaemia in healthy and type 1 diabetic subjects. Diabetologia 47, 648–651 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Bischof, M. G. et al. Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans. Eur. J. Clin. Invest. 36, 164–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Rosen, E. D. & Spiegelman, B. M. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444, 847–853 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bogacka, I., Xie, H., Bray, G. A. & Smith, S. R. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54, 1392–1399 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Mattson, M. P. Perspective: Does brown fat protect against diseases of aging? Ageing Res. Rev. 9, 69–76 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Lidell, M. E. & Enerbäck, S. Brown adipose tissue—a new role in humans? Nat. Rev. Endocrinol. 6, 319–325 (2010).

    Article  PubMed  Google Scholar 

  125. Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F FDG detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192–199 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Holloszy, J. O. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem. 242, 2278–2282 (1967).

    CAS  PubMed  Google Scholar 

  128. Rabøl, R. et al. Reduced skeletal muscle mitochondrial respiration and improved glucose metabolism in nondiabetic obese women during a very low calorie dietary intervention leading to rapid weight loss. Metabolism 58, 1145–1152 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Simoneau, J. A., Veerkamp, J. H., Turcotte, L. P. & Kelley, D. E. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J. 13, 2051–2060 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Toledo, F. G. et al. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 56, 2142–2147 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Meex, R. C. et al. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59, 572–579 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Bruce, C. R., Kriketos, A. D., Cooney, G. J. & Hawley, J. A. Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with type 2 diabetes. Diabetologia 47, 23–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Hansen, D. et al. Continuous low- to moderate-intensity exercise training is as effective as moderate- to high-intensity exercise training at lowering blood HbA1c in obese type 2 diabetes patients. Diabetologia 52, 1789–1797 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M. K. & Schrauwen, P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53, 1714–1721 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Tainter, M. L., Cutting, W. C. & Stockton, A. B. Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. Am. J. Public Health Nations Health 24, 1045–1053 (1934).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cha, B. S. et al. Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARγ agonists. Am. J. Physiol. Endocrinol. Metab. 289, E151–E159 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Coletta, D. K. et al. Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia 52, 723–732 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zou, M. H. et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J. Biol. Chem. 279, 43940–43951 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Kukidome, D. et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55, 120–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Mathieu-Costello, O. et al. Regulation of skeletal muscle morphology in type 2 diabetic subjects by troglitazone and metformin: relationship to glucose disposal. Metabolism 52, 540–546 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Bujanda, L. et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol. 8, 40 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Nielsen, J. et al. Increased subsarcolemmal lipids in type 2 diabetes: effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 298, E706–E713 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Sreekumar, R., Halvatsiotis, P., Schimke, J. C. & Nair, K. S. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 51, 1913–1920 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 8, 870–879 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Conley, K. E., Jubrias, S. A. & Esselman, P. C. Oxidative capacity and ageing in human muscle. J. Physiol. 526 (Pt 1), 203–210 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Nair, S., V, P. C., Arnold, C. & Diehl, A. M. Hepatic ATP reserve and efficiency of replenishing: comparison between obese and nonobese normal individuals. Am. J. Gastroenterol. 98, 466–470 (2003).

    CAS  PubMed  Google Scholar 

  151. Chance, B., Eleff, S., Leigh, J. S. Jr, Sokolow, D. & Sapega, A. Mitochondrial regulation of phosphocreatine/inorganic phosphate ratios in exercising human muscle: a gated 31P NMR study. Proc. Natl Acad. Sci. USA 78, 6714–6718 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Binzoni, T., Ferretti, G., Schenker, K. & Cerretelli, P. Phosphocreatine hydrolysis by 31P-NMR at the onset of constant-load exercise in humans. J. Appl. Physiol. 73, 1644–1649 (1992).

    Article  CAS  PubMed  Google Scholar 

  153. Vorgerd, M. et al. Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul. Disord. 10, 430–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  154. Lodi, R. et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia. Ann. Neurol. 49, 590–596 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Brown, T. R., Ugurbil, K. & Shulman, R. G. 31P nuclear magnetic resonance measurements of ATPase kinetics in aerobic Escherichia coli cells. Proc. Natl Acad. Sci. USA 74, 5551–5553 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Schmid, A. I. et al. Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment. NMR Biomed. 21, 437–443 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Diepart, C. et al. Comparison of methods for measuring oxygen consumption in tumor cells in vitro. Anal. Biochem. 396, 250–256 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Beeson, C. C., Beeson, G. C. & Schnellmann, R. G. A high-throughput respirometric assay for mitochondrial biogenesis and toxicity. Anal. Biochem. 404, 75–81 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, D-40225, Germany

    Julia Szendroedi, Esther Phielix & Michael Roden

  2. Department of Metabolic Diseases, University Clinics Düsseldorf, Heinrich-Heine University, Düsseldorf, D-40225, Germany

    Julia Szendroedi & Michael Roden

Authors
  1. Julia Szendroedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esther Phielix
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Roden
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data and contributed equally to writing the article. J. Szendroedi and M. Roden provided substantial contributions to discussions of the content, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Michael Roden.

Ethics declarations

Competing interests

M. Roden declares an association with the following company: Takeda (consultant). The other authors declare no competing interests.

Supplementary information

Supplementary Figure 1

Cellular processes in insulin-responsive tissues. a. In the fasting state, glucose uptake into insulin-responsive tissues decreases and fuel selection switches from glucose to lipid oxidation (metabolic flexibility). Substrate availability and energy demand are low. b. The insulin-resistant state is characterized by the inability to adapt ATP synthetic flux rates (fATP) to substrate availability; lipid oxidation rates are, therefore, not increased adequately. Lipid metabolites (Acyl-CoA, DAG, ceramides) increase and TG accumulate. Mitochondrial plasticity, for example metabolic flexibility, is the limiting factor for in vivo ATP synthetic rates in insulin-resistant humans. c. During hyperinsulinemia, glucose uptake increases in insulin-responsive tissues, fuel selection switches from lipid to glucose oxidation (metabolic flexibility). In the insulin-stimulated state, energy demand is high and ATP synthetic flux rate is increased. d. In the insulin-resistant state, glucose transport and phosphorylation is reduced and lipid oxidation rates are not decreased adequately. DAG and ceramides induce insulin resistance. Abbreviations: DAG, diacylglycerol; FFA, free fatty acids; GLUT, glucose transporter; IR, insulin receptor; IRS, insulin receptor substrate; TCA, tricarboxylic acid; TG, triglycerides. (PPT 139 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szendroedi, J., Phielix, E. & Roden, M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 8, 92–103 (2012). https://doi.org/10.1038/nrendo.2011.138

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.138

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing