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Mitochondrial dysfunction and type 2 diabetes

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Abstract

Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant patients with type 2 diabetes. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular and intrahepatic fatty acid metabolites; these include increased fat delivery to muscle and liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism, and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular and biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for the treatment of the metabolic syndrome and type 2 diabetes.

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References and Recommended Reading

  1. Zimmet P, Alberti KG, Shaw J: Global and societal implications of the diabetes epidemic. Nature 2001, 414:782–787.

    Article  PubMed  CAS  Google Scholar 

  2. Lillioja S, Mott DM, Howard BV, et al.: Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988, 318:1217–1225.

    Article  PubMed  CAS  Google Scholar 

  3. Lillioja S, Mott DM, Spraul M, et al.: Insulin resistance and insulin secretory dysfunction as precursors of non-insulindependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993, 329:1988–1992.

    Article  PubMed  CAS  Google Scholar 

  4. DeFronzoRA: Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 1992, 35:389–397.

    Article  Google Scholar 

  5. Warram JH, Martin BC, Krolewski AS, et al.: Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990, 113:909–915.

    PubMed  CAS  Google Scholar 

  6. Azen SP, Peters RK, Berkowitz K, et al.: TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebocontrolled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials 1998, 19:217–231.

    Article  PubMed  CAS  Google Scholar 

  7. Shulman GI, Rothman DL, Jue T, et al.: Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990, 322:223–228.

    Article  PubMed  CAS  Google Scholar 

  8. Rothman DL, Shulman RG, Shulman GI: 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest 1992, 89:1069–1075.

    PubMed  CAS  Google Scholar 

  9. Rothman DL, Magnusson I, Cline G, et al.: Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 1995, 92:983–987.

    Article  PubMed  CAS  Google Scholar 

  10. Cline GW, Petersen KF, Krssak M, et al.: Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 1999, 341:240–246.

    Article  PubMed  CAS  Google Scholar 

  11. Boden G, Shulman GI: Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 2002, 32(suppl 3):14–23.

    Article  PubMed  CAS  Google Scholar 

  12. Krssak M, Petersen KF, Dresner A, et al.: Intramyocellular lipid concentrations are correlated with insulin sensitivity in man: a 1H NMR spectroscopy study. Diabetologia 1999, 41:113–116.

    Article  Google Scholar 

  13. Roden M, Price TB, Perseghin G, et al.: Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996, 97:2859–2865.

    PubMed  CAS  Google Scholar 

  14. Petersen KF, Hendler R, Price T, et al.: 13C/31P NMR studies on the mechanism of insulin resistance in obesity. Diabetes 1998, 47:381–386.

    Article  PubMed  CAS  Google Scholar 

  15. Dresner A, Laurent D, Marcucci M, et al.: Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999, 103:253–259.

    PubMed  CAS  Google Scholar 

  16. Griffin ME, Marcucci MJ, Cline GW, et al.: Free fatty acidinduced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999, 48:1270–1274.

    Article  PubMed  CAS  Google Scholar 

  17. Yin MJ, Yamamoto Y, Gaynor RB: The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998, 396:77–80.

    Article  PubMed  CAS  Google Scholar 

  18. Yuan M, Konstantopoulos N, Lee J, et al.: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001, 293:1673–1677.

    Article  PubMed  CAS  Google Scholar 

  19. Kim JK, Kim YJ, Fillmore JJ, et al.: Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001, 108:437–446.

    Article  PubMed  CAS  Google Scholar 

  20. Hundal RS, Petersen KF, Mayerson AB, et al.: Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 2002, 109:1321–1326.

    Article  PubMed  CAS  Google Scholar 

  21. Yu C, Chen Y, Cline GW, 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, 277:50230–50236.

    Article  PubMed  CAS  Google Scholar 

  22. 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 IkappaBalpha. Diabetes 2002, 51:2005–2011.

    Article  PubMed  CAS  Google Scholar 

  23. Hotamisligil GS, Peraldi P, Budavari A, et al.: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996, 271:665–668.

    Article  PubMed  CAS  Google Scholar 

  24. Bjorntorp P: Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol 1992, 20(suppl 8):S26-S28.

    PubMed  Google Scholar 

  25. Foley JE, Thuillez P, Lillioja S, et al.: Insulin sensitivity in adipocytes from subjects with varying degrees of glucose tolerance. Am J Physiol 1986, 251:E306-E310.

    PubMed  CAS  Google Scholar 

  26. Saghizadeh M, Ong JM, Garvey WT, et al.: The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 1996, 97:1111–1116.

    PubMed  CAS  Google Scholar 

  27. Beisel WR: Herman Award Lecture, 1995: infection-induced malnutrition-from cholera to cytokines. Am J Clin Nutr 1995, 62:813–819.

    PubMed  CAS  Google Scholar 

  28. Steppan CM, Lazar MA: Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 2002, 13:18–23.

    Article  PubMed  CAS  Google Scholar 

  29. Fukuhara A, Matsuda M, Nishizawa M, et al.: Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 2005, 307:426–430.

    Article  PubMed  CAS  Google Scholar 

  30. Hug C, Lodish HF: Medicine. Visfatin: a new adipokine. Science 2005, 307:366–367.

    Article  PubMed  CAS  Google Scholar 

  31. Moitra J, Mason MM, Olive M, et al.: Life without white fat: a transgenic mouse. Genes Dev 1998, 12:3168–3181.

    PubMed  CAS  Google Scholar 

  32. Gavrilova O, Marcus-Samuels B, Graham D, et al.: Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000, 105:271–278.

    PubMed  CAS  Google Scholar 

  33. Kim JK, Gavrilova O, Chen Y, et al.: Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000, 275:8456–8460.

    Article  PubMed  CAS  Google Scholar 

  34. Petersen KF, Oral EA, Dufour S, et al.: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002, 109:1345–1350. Showed that patients with generalized lipodystrophy had severe type 2 diabetes, hepatic steatosis, and hepatic insulin resistance in the absence of intra-abdominal fat. During leptin replacement treatment, the hepatic lipid stores were mobilized and this was associated with normalization of hepatic glucose production and suppression by insulin. The study strongly supports the hypothesis that hepatic lipid accumulation causes hepatic insulin resistance.

    Article  PubMed  CAS  Google Scholar 

  35. Conley KE, Jubrias SA, Esselman PC: Oxidative capacity and ageing in human muscle. J Physiol 2000, 526(Pt 1):203–210.

    Article  PubMed  CAS  Google Scholar 

  36. Petersen KF, Befroy D, Dufour S, et al.: Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003, 300:1140–1142. The insulin clamp and 13C and 31P MRS techniques were used to assess muscle insulin sensitivity and mitochondrial oxidative function in lean, sedentary elderly subjects. The findings support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly by an age-associated accumulation of IMCL.

    Article  PubMed  CAS  Google Scholar 

  37. Michikawa Y, Mazzucchelli F, Bresolin N, et al.: Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 1999, 286:774–779.

    Article  PubMed  CAS  Google Scholar 

  38. Petersen KF, Dufour S, Befroy D, et al.: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004, 350:664–671. Illustrated that insulin resistance in lean offspring of parents with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly due to an inherited defect in mitochondrial oxidative function.

    Article  PubMed  CAS  Google Scholar 

  39. Wu Z, Puigserver P, Andersson U, et al.: Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98:115–124.

    Article  PubMed  CAS  Google Scholar 

  40. Lin J, Wu H, Tarr PT, et al.: Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002, 418:797–801.

    Article  PubMed  CAS  Google Scholar 

  41. Zong H, Ren JM, Young LH, et al.: AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 2002, 99:15983–15987.

    Article  PubMed  CAS  Google Scholar 

  42. Wu H, Kanatous SB, Thurmond FA, et al.: Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 2002, 296:349–352.

    Article  PubMed  CAS  Google Scholar 

  43. Patti ME, Butte AJ, Crunkhorn S, 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 U S A 2003, 100:8466–8471.

    Article  PubMed  CAS  Google Scholar 

  44. Mikines KJ, Sonne B, Farrell PA, et al.: Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol 1988, 254:E248-E259.

    PubMed  CAS  Google Scholar 

  45. Perseghin G, Price TB, Petersen KF, et al.: Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 1996, 335:1357–1362.

    Article  PubMed  CAS  Google Scholar 

  46. Knowler WC, Barrett-Connor E, Fowler SE, et al.: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393–403.

    Article  PubMed  CAS  Google Scholar 

  47. Henry RR, Scheaffer L, Olefsky JM: Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1985, 61:917–925.

    Article  PubMed  CAS  Google Scholar 

  48. Petersen KF, Dufour S, Befroy D, et al.: Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance and hyperglycemia by moderate weight reduction in patients with type 2 diabetes mellitus. Diabetes 2005, 54:603–608.

    Article  PubMed  CAS  Google Scholar 

  49. Jeng CY, Sheu WH, Fuh MM, et al.: Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 1994, 43:1440–1444.

    Article  PubMed  CAS  Google Scholar 

  50. Maggs DG, Buchanan TA, Burant CF, et al.: Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998, 128:176–185.

    PubMed  CAS  Google Scholar 

  51. Magnusson I, Rothman DL, Katz LD, et al.: Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest 1992, 90:1323–1327.

    PubMed  CAS  Google Scholar 

  52. Hundal RS, Krssak M, Dufour S, et al.: Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000, 49:2063–2069.

    Article  PubMed  CAS  Google Scholar 

  53. Landau BR, Wahren J, Chandramouli V, et al.: Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest 1996, 98:378–385.

    Article  PubMed  CAS  Google Scholar 

  54. Petersen KF, Krssak M, Navarro V, et al.: Contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in cirrhosis. Am J Physiol 1999, 276:E529-E535.

    PubMed  CAS  Google Scholar 

  55. Mayerson AB, Hundal RS, Dufour S, et al.: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002, 51:797–802. Demonstrated that thiazolidinedione therapy enhances insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes. The results support the hypothesis that a redistribution of fat from insulin-responsive organs into peripheral adipocytes will improve insulin sensitivity.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, PO Box 208020, 06520-8020, New Haven, CT, USA

    Kitt Falk Petersen MD

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  1. Rebecca Parish MD
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Parish, R., Petersen, K.F. Mitochondrial dysfunction and type 2 diabetes. Curr Diab Rep 5, 177–183 (2005). https://doi.org/10.1007/s11892-005-0006-3

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