Skip to main content
SpringerLink
Log in

Mitochondria and Oxidative Stress in Diabetes

  • Chapter
  • First Online:
Studies in Diabetes

  • 1742 Accesses

Abstract

As they are essential for aerobic metabolism, mitochondria are of obvious interest in regard to the pathophysiology of diabetes. In this regard, it is important to consider that in addition to their metabolic action, mitochondria also contribute substantially to the production of reactive oxygen species (ROS). Ultimately this leads to oxidative damage and organ dysfunction. Hence, it is not surprising that diabetes-related perturbations in mitochondrial ROS production have been identified which likely impact the pathophysiology underlying the disorder as well as its complications.

In this chapter, we will first discuss the origin and assessment of ROS and oxidative damage. We then address the generation of ROS in different cell and tissue types as related to defective pancreatic insulin secretion and peripheral insulin action. Next, we address the role of ROS in the complications of diabetes. Finally, we discuss possible therapeutic approaches designed to mitigate ROS.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. UKPDS Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853

    Google Scholar 

  2. Gautier JF, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, Polonsky KS, Bogardus C, Pratley RE (2001) Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 50:1828–1833

    CAS  PubMed  Google Scholar 

  3. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA (1992) The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41:1575–1586

    CAS  PubMed  Google Scholar 

  4. Perseghin G, Ghosh S, Gerow K, Shulman GI (1997) Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 46:1001–1009

    CAS  PubMed  Google Scholar 

  5. Hoeldtke RD, Bryner KD, McNeill DR, Warehime SS, Van Dyke K, Hobbs G (2003) Oxidative stress and insulin requirements in patients with recent-onset type 1 diabetes. J Clin Endocrinol Metab 88:1624–1628

    CAS  PubMed  Google Scholar 

  6. Marra G, Cotroneo P, Pitocco D, Manto A, Di Leo MA, Ruotolo V, Caputo S, Giardina B, Ghirlanda G, Santini SA (2002) Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender difference. Diabetes Care 25:370–375

    PubMed  Google Scholar 

  7. Collins AR, Raslova K, Somorovska M, Petrovska H, Ondrusova A, Vohnout B, Fabry R, Dusinska M (1998) DNA damage in diabetes: correlation with a clinical marker. Free Radic Biol Med 25:373–377

    CAS  PubMed  Google Scholar 

  8. Nourooz-Zadeh J, Tajaddini-Sarmadi J, McCarthy S, Betteridge DJ, Wolff SP (1995) Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 44:1054–1058

    CAS  PubMed  Google Scholar 

  9. Gopaul NK, Anggard EE, Mallet AI, Betteridge DJ, Wolff SP, Nourooz-Zadeh J (1995) Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett 368:225–229

    CAS  PubMed  Google Scholar 

  10. Kanauchi M, Nishioka H, Hashimoto T (2002) Oxidative DNA damage and tubulointerstitial injury in diabetic nephropathy. Nephron 91:327–329

    CAS  PubMed  Google Scholar 

  11. Rehman A, Nourooz-Zadeh J, Moller W, Tritschler H, Pereira P, Halliwell B (1999) Increased oxidative damage to all DNA bases in patients with type II diabetes mellitus. FEBS Lett 448:120–122

    CAS  PubMed  Google Scholar 

  12. Shin CS, Moon BS, Park KS, Kim SY, Park SJ, Chung MH, Lee HK (2001) Serum 8-hydroxy-guanine levels are increased in diabetic patients. Diabetes Care 24:733–737

    CAS  PubMed  Google Scholar 

  13. Du Y, Miller CM, Kern TS (2003) Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med 35:1491–1499

    CAS  PubMed  Google Scholar 

  14. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    CAS  PubMed  Google Scholar 

  15. Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M (2001) Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 276:25096–25100

    CAS  PubMed  Google Scholar 

  16. Boss O, Hagen T, Lowell BB (2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49:143–156

    CAS  PubMed  Google Scholar 

  17. Green K, Brand MD, Murphy MP (2004) Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 53:S110–S118

    CAS  PubMed  Google Scholar 

  18. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    CAS  PubMed  Google Scholar 

  19. Pessin JE, Richardson JM, Sivitz WI (1991) Regulation of the glucose transporter in animal models of diabetes. Adv Exp Med Biol 293:249–262

    CAS  PubMed  Google Scholar 

  20. Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 29:169–202

    CAS  PubMed  Google Scholar 

  21. Fridovich I (1997) Superoxide anion radical (O2 –·), superoxide dismutases, and related matters. J Biol Chem 272:18515–18517

    CAS  PubMed  Google Scholar 

  22. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605

    CAS  PubMed  Google Scholar 

  23. Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25:222–230

    Google Scholar 

  24. Grivennikova VG, Vinogradov AD (2006) Generation of superoxide by the mitochondrial complex I. Biochim Biophys Acta 1757:553–561

    CAS  PubMed  Google Scholar 

  25. Han DW, Cadenas E (2001) Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J 353:411–416

    CAS  PubMed  Google Scholar 

  26. St-Pierre JB, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 4277:44784–44790

    Google Scholar 

  27. Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lambert AJ, Brand MD (2004) Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH: ubiquinone oxidoreductase (complex I). J Biol Chem 279:39414–39420

    CAS  PubMed  Google Scholar 

  29. Skulachev VP (1998) Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1363:100–124

    CAS  PubMed  Google Scholar 

  30. Gardner PR (1997) Superoxide-driven aconitase FE-S center cycling. Biosci Rep 17:33–42

    CAS  PubMed  Google Scholar 

  31. Vasquez-Vivar J, Kalyanaraman B, Kennedy MC (2000) Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. J Biol Chem 275:14064–14069

    CAS  PubMed  Google Scholar 

  32. Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581

    CAS  PubMed  Google Scholar 

  33. Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26:1589–1596

    CAS  PubMed  Google Scholar 

  34. Cross AR, Jones OT (1991) Enzymic mechanisms of superoxide production. Biochim Biophys Acta 1057:281–298

    CAS  PubMed  Google Scholar 

  35. Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795

    CAS  PubMed  Google Scholar 

  36. O’Malley Y, Fink BD, Ross NC, Prisinzano TE, Sivitz WI (2006) Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem 281:39766–39775

    PubMed  Google Scholar 

  37. Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073

    CAS  PubMed  Google Scholar 

  38. Murphy MP (1997) Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol 15:326–330

    CAS  PubMed  Google Scholar 

  39. Jekabsons MB, Nicholls DG (2004) In situ respiration and bioenergetic status of mitochondria in primary cerebellar granule neuronal cultures exposed continuously to glutamate. J Biol Chem 279:32989–33000

    CAS  PubMed  Google Scholar 

  40. Laurindo FR, Fernandes DC, Santos CX (2008) Assessment of superoxide production and NADPH oxidase activity by HPLC analysis of dihydroethidium oxidation products. Methods Enzymol 441:237–260

    CAS  PubMed  Google Scholar 

  41. Kundu K, Knight SF, Willett N, Lee S, Taylor WR, Murthy N (2009) Hydrocyanines: a class of fluorescent sensors that can image reactive oxygen species in cell culture, tissue, and in vivo. Angew Chem Int Ed Engl 48:299–303

    CAS  PubMed  Google Scholar 

  42. Miller FJ Jr, Gutterman DD, Rios CD, Heistad DD, Davidson BL (1998) Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 82:1298–1305

    CAS  PubMed  Google Scholar 

  43. Dikalov SI, Li W, Doughan AK, Blanco RR, Zafari AM (2012) Mitochondrial reactive oxygen species and calcium uptake regulate activation of phagocytic NADPH oxidase. Am J Physiol Regul Integr Comp Physiol 302:R1134–R1142

    CAS  PubMed  Google Scholar 

  44. Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, Sivitz W, Monnier VM (2005) Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes 54:3103–3111

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Robinson KM, Janes MS, Beckman JS (2008) The selective detection of mitochondrial superoxide by live cell imaging. Nat Protoc 3:941–947

    CAS  PubMed  Google Scholar 

  46. Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463–466

    CAS  PubMed  Google Scholar 

  47. Sakurai K, Katoh M, Someno K, Fujimoto Y (2001) Apoptosis and mitochondrial damage in INS-1 cells treated with alloxan. Biol Pharm Bull 24:876–882

    CAS  PubMed  Google Scholar 

  48. Turk J, Corbett JA, Ramanadham S, Bohrer A, McDaniel ML (1993) Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. Biochem Biophys Res Commun 197:1458–1464

    CAS  PubMed  Google Scholar 

  49. Kubisch HM, Wang J, Bray TM, Phillips JP (1997) Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress. Diabetes 46:1563–1566

    CAS  PubMed  Google Scholar 

  50. Mysore TB, Shinkel TA, Collins J, Salvaris EJ, Fisicaro N, Murray-Segal LJ, Johnson LE, Lepore DA, Walters SN, Stokes R, Chandra AP, O’Connell PJ, d’Apice AJ, Cowan PJ (2005) Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function. Diabetes 54:2109–2116

    CAS  PubMed  Google Scholar 

  51. Sklavos MM, Bertera S, Tse HM, Bottino R, He J, Beilke JN, Coulombe MG, Gill R, Crapo JD, Trucco M, Piganelli JD (2010) Redox modulation protects islets from transplant-related injury. Diabetes 59:1731–1738

    CAS  PubMed  Google Scholar 

  52. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H (2003) Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581–587

    CAS  PubMed  Google Scholar 

  53. Li M, Peterson S, Husney D, Inaba M, Guo K, Terada E, Morita T, Patil K, Kappas A, Ikehara S, Abraham NG (2007) Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin. Antioxid Redox Signal 9:855–863

    PubMed  Google Scholar 

  54. Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127

    CAS  PubMed  Google Scholar 

  55. Di Noia MA, Van Driesche S, Palmieri F, Yang LM, Quan S, Goodman AI, Abraham NG (2006) Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. J Biol Chem 281:15687–15693

    PubMed  Google Scholar 

  56. Hayden MR, Sowers JR (2007) Isletopathy in Type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal 9:891–910

    CAS  PubMed  Google Scholar 

  57. Oprescu AI, Bikopoulos G, Naassan A, Allister EM, Tang C, Park E, Uchino H, Lewis GF, Fantus IG, Rozakis-Adcock M, Wheeler MB, Giacca A (2007) Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. Diabetes 56:2927–2937

    CAS  PubMed  Google Scholar 

  58. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99

    CAS  PubMed  Google Scholar 

  59. Emre Y, Hurtaud C, Karaca M, Nubel T, Zavala F, Ricquier D (2007) Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proc Natl Acad Sci USA 104:19085–19090

    CAS  PubMed  Google Scholar 

  60. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755

    CAS  PubMed  Google Scholar 

  61. Schrauwen P, Hesselink MKC (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53:1412–1417

    CAS  PubMed  Google Scholar 

  62. Schrauwen P (2007) High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc 66:33–41

    CAS  PubMed  Google Scholar 

  63. Russell AP, Gastaldi G, Bobbioni-Harsch E, Arboit P, Gobelet C, Deriaz O, Golay A, Witztum JL, Giacobino JP (2003) Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids? FEBS Lett 551:104–106

    CAS  PubMed  Google Scholar 

  64. Hesselink MKC, Mensink M, Schrauwen P (2003) Human uncoupling protein-3 and obesity: an update. Obes Res 11:1429–1443

    CAS  PubMed  Google Scholar 

  65. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, Aziz S, Johnson JI, Bugger H, Zaha VG, Abel ED (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–2466

    CAS  PubMed  Google Scholar 

  66. Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA, Yun UJ, McQueen AP, Wayment B, Litwin SE, Abel ED (2008) Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 57:2924–2932

    CAS  PubMed  Google Scholar 

  67. Herlein JA, Fink BD, O’Malley Y, Sivitz WI (2009) Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology 150:46–55

    CAS  PubMed  Google Scholar 

  68. Yu LF, Herlein JA, Sivitz WI (2013) Mitochondrial function in diabetes: novel methodology and new insight. Diabetes 62(6):1833–1842

    CAS  PubMed  Google Scholar 

  69. Herlein JA, Fink BD, Sivitz WI (2010) Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. Metabolism 59:247–257

    CAS  PubMed  PubMed Central  Google Scholar 

  70. American Diabetes Association (2009) Diagnosis and classification of diabetes mellitus. Diabetes Care 32(Suppl 1):S62–S67

    Google Scholar 

  71. Yuzefovych LV, Solodushko VA, Wilson GL, Rachek LI (2012) Protection from palmitate-induced mitochondrial DNA damage prevents from mitochondrial oxidative stress, mitochondrial dysfunction, apoptosis, and impaired insulin signaling in rat L6 skeletal muscle cells. Endocrinology 153:92–100

    CAS  PubMed  Google Scholar 

  72. Bravard A, Lefai E, Meugnier E, Pesenti S, Disse E, Vouillarmet J, Peretti N, Rabasa-Lhoret R, Laville M, Vidal H, Rieusset J (2011) FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. Diabetes 60:258–268

    CAS  PubMed  Google Scholar 

  73. Bastar I, Seckin S, Uysal M, Aykac-Toker G (1998) Effect of streptozotocin on glutathione and lipid peroxide levels in various tissues of rats. Res Commun Mol Pathol Pharmacol 102:265–272

    CAS  PubMed  Google Scholar 

  74. Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, Diehl AM (2000) Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys 378:259–268

    CAS  PubMed  Google Scholar 

  75. Valle A, Catalan V, Rodriguez A, Rotellar F, Valenti V, Silva C, Salvador J, Fruhbeck G, Gomez-Ambrosi J, Roca P, Oliver J (2012) Identification of liver proteins altered by type 2 diabetes mellitus in obese subjects. Liver Int 32:951–961

    CAS  PubMed  Google Scholar 

  76. Hao J, Shen W, Sun L, Long J, Sharman E, Shi X, Liu J (2011) Mitochondrial dysfunction in the liver of type 2 diabetic Goto-Kakizaki rats: improvement by a combination of nutrients. Br J Nutr 106:648–655

    CAS  PubMed  Google Scholar 

  77. Traverso N, Menini S, Odetti P, Pronzato MA, Cottalasso D, Marinari UM (2002) Diabetes impairs the enzymatic disposal of 4-hydroxynonenal in rat liver. Free Radic Biol Med 32:350–359

    CAS  PubMed  Google Scholar 

  78. Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG (1993) Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42:801–813

    CAS  PubMed  Google Scholar 

  79. Knockaert L, Fromenty B, Robin MA (2011) Mechanisms of mitochondrial targeting of cytochrome P450 2E1: physiopathological role in liver injury and obesity. FEBS J 278:4252–4260

    CAS  PubMed  Google Scholar 

  80. Wang CH, Wang CC, Huang HC, Wei YH (2012) Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes. FEBS J 280:1039–1050

    Google Scholar 

  81. Chevillotte E, Giralt M, Miroux B, Ricquier D, Villarroya F (2007) Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 56:1042–1050

    CAS  PubMed  Google Scholar 

  82. Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K (2012) Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2:799

    PubMed  PubMed Central  Google Scholar 

  83. Yan J, Zhao Y, Suo S, Liu Y, Zhao B (2012) Green tea catechins ameliorate adipose insulin resistance by improving oxidative stress. Free Radic Biol Med 52:1648–1657

    CAS  PubMed  Google Scholar 

  84. Findeisen HM, Gizard F, Zhao Y, Qing H, Jones KL, Cohn D, Heywood EB, Bruemmer D (2011) Glutathione depletion prevents diet-induced obesity and enhances insulin sensitivity. Obesity 19:2429–2432

    CAS  PubMed  Google Scholar 

  85. Nishikawa T, Edelstein D, Brownlee M (2000) The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 77:S26–S30

    CAS  PubMed  Google Scholar 

  86. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97:12222–12226

    CAS  PubMed  Google Scholar 

  87. Kiritoshi S, Nishikawa T, Sonoda K, Kukidome D, Senokuchi T, Matsuo T, Matsumura T, Tokunaga H, Brownlee M, Araki E (2003) Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52:2570–2577

    CAS  PubMed  Google Scholar 

  88. Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC, Epstein PN (2004) Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 53:1336–1343

    CAS  PubMed  Google Scholar 

  89. Coppey LJ, Gellett JS, Davidson EP, Yorek MA (2003) Preventing superoxide formation in epineurial arterioles of the sciatic nerve from diabetic rats restores endothelium-dependent vasodilation. Free Radic Res 37:33–40

    CAS  PubMed  Google Scholar 

  90. Busik JV, Mohr S, Grant MB (2008) Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes 57:1952–1965

    CAS  PubMed  Google Scholar 

  91. Zhang L, Yu C, Vasquez FE, Galeva N, Onyango I, Swerdlow RH, Dobrowsky RT (2010) Hyperglycemia alters the Schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production. J Proteome Res 9:458–471

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu Y, Song XD, Liu W, Zhang TY, Zuo J (2003) Glucose deprivation induces mitochondrial dysfunction and oxidative stress in PC12 cell line. J Cell Mol Med 7:49–56

    CAS  PubMed  Google Scholar 

  93. Paramo B, Hernandez-Fonseca K, Estrada-Sanchez AM, Jimenez N, Hernandez-Cruz A, Massieu L (2010) Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons. Neuroscience 167:1057–1069

    CAS  PubMed  Google Scholar 

  94. Fink BD, Herlein JA, O’Malley Y, Sivitz WI (2012) Endothelial cell and platelet bioenergetics: effect of glucose and nutrient composition. PLoS ONE 7:e39430

    CAS  PubMed  PubMed Central  Google Scholar 

  95. James AM, Murphy MP (2002) How mitochondrial damage affects cell function. J Biomed Sci 9:475–487

    CAS  PubMed  Google Scholar 

  96. Craven PA, Studer RK, Negrete H, DeRubertis FR (1995) Protein kinase C in diabetic nephropathy. J Diabetes Complications 9:241–245

    CAS  PubMed  Google Scholar 

  97. Yokota T, Ma RC, Park JY, Isshiki K, Sotiropoulos KB, Rauniyar RK, Bornfeldt KE, King GL (2003) Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes 52:838–845

    CAS  PubMed  Google Scholar 

  98. Kanwar M, Chan PS, Kern TS, Kowluru RA (2007) Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase. Invest Ophthalmol Vis Sci 48:3805–3811

    PubMed  Google Scholar 

  99. Cui Y, Xu X, Bi H, Zhu Q, Wu J, Xia X, Qiushi R, Ho PC (2006) Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive oxygen species in diabetic retinopathy. Exp Eye Res 83:807–816

    CAS  PubMed  Google Scholar 

  100. Brondani LA, de Souza BM, Duarte GC, Kliemann LM, Esteves JF, Marcon AS, Gross JL, Canani LH, Crispim D (2012) The UCP1-3826A/G polymorphism is associated with diabetic retinopathy and increased UCP1 and MnSOD2 gene expression in human retina. Invest Ophthalmol Vis Sci 53:7449–7457

    CAS  PubMed  Google Scholar 

  101. Kowluru RA, Abbas SN (2003) Diabetes-induced mitochondrial dysfunction in the retina. Invest Ophthalmol Vis Sci 44:5327–5334

    PubMed  Google Scholar 

  102. Kowluru RA, Kowluru V, Xiong Y, Ho YS (2006) Overexpression of mitochondrial superoxide dismutase in mice protects the retina from diabetes-induced oxidative stress. Free Radic Biol Med 41:1191–1196

    CAS  PubMed  Google Scholar 

  103. Friederich M, Fasching A, Hansell P, Nordquist L, Palm F (2008) Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta 1777:935–940

    CAS  PubMed  Google Scholar 

  104. de Cavanagh EM, Ferder L, Toblli JE, Piotrkowski B, Stella I, Fraga CG, Inserra F (2008) Renal mitochondrial impairment is attenuated by AT1 blockade in experimental type I diabetes. Am J Physiol Heart Circ Physiol 294:H456–H465

    PubMed  Google Scholar 

  105. Manabe E, Handa O, Naito Y, Mizushima K, Akagiri S, Adachi S, Takagi T, Kokura S, Maoka T, Yoshikawa T (2008) Astaxanthin protects mesangial cells from hyperglycemia-induced oxidative signaling. J Cell Biochem 103:1925–1937

    CAS  PubMed  Google Scholar 

  106. Coughlan MT, Thallas-Bonke V, Pete J, Long DM, Gasser A, Tong DC, Arnstein M, Thorpe SR, Cooper ME, Forbes JM (2007) Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy? Endocrinology 148:886–895

    CAS  PubMed  Google Scholar 

  107. Rosca MG, Mustata TG, Kinter MT, Ozdemir AM, Kern TS, Szweda LI, Brownlee M, Monnier VM, Weiss MF (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 289:F420–F430

    CAS  PubMed  Google Scholar 

  108. Rosen P, Wiernsperger NF (2006) Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress. Diabetes Metab Res Rev 22:323–330

    PubMed  Google Scholar 

  109. Moreira PI, Rolo AP, Sena C, Seica R, Oliveira CR, Santos MS (2006) Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem 2:299–308

    CAS  PubMed  Google Scholar 

  110. Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383

    CAS  PubMed  Google Scholar 

  111. Vincent AM, Olzmann JA, Brownlee M, Sivitz WI, Russell JW (2004) Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes 53:726–734

    CAS  PubMed  Google Scholar 

  112. Baron AD (2002) Insulin resistance and vascular function. J Diabetes Complications 16:92–102

    PubMed  Google Scholar 

  113. Sivitz WI, Wayson SM, Bayless ML, Sinkey CA, Haynes WG (2007) Obesity impairs vascular relaxation in human subjects: hyperglycemia exaggerates adrenergic vasoconstriction arterial dysfunction in obesity and diabetes. J Diabetes Complications 21:149–157

    PubMed  Google Scholar 

  114. Manna P, Das J, Ghosh J, Sil PC (2010) Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. Free Radic Biol Med 48:1465–1484

    CAS  PubMed  Google Scholar 

  115. De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM (2000) Endothelial dysfunction in diabetes. Br J Pharmacol 130:963–974

    PubMed  Google Scholar 

  116. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Salvemini D, Yorek MA (2001) Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Br J Pharmacol 134:21–29

    CAS  PubMed  Google Scholar 

  117. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA (2001) Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50:1927–1937

    CAS  PubMed  Google Scholar 

  118. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Yorek MA (2002) Effect of treating streptozotocin-induced diabetic rats with sorbinil, myo-inositol or aminoguanidine on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Int J Exp Diabetes Res 3:21–36

    PubMed  PubMed Central  Google Scholar 

  119. Yorek MA, Coppey LJ, Gellett JS, Davidson EP, Bing X, Lund DD, Dillon JS (2002) Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function. Am J Physiol Endocrinol Metab 283:E1067–E1075

    CAS  PubMed  Google Scholar 

  120. Nassar T, Kadery B, Lotan C, Da’as N, Kleinman Y, Haj-Yehia A (2002) Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol 436:111–118

    CAS  PubMed  Google Scholar 

  121. Keegan A, Cotter MA, Cameron NE (1999) Effects of diabetes and treatment with the antioxidant alpha-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats. Diabetologia 42:343–350

    CAS  PubMed  Google Scholar 

  122. Cameron NE, Cotter MA (1995) Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents. J Clin Invest 96:1159–1163

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Cameron NE, Cotter MA (2001) Effects of an extracellular metal chelator on neurovascular function in diabetic rats. Diabetologia 44:621–628

    CAS  PubMed  Google Scholar 

  124. Cameron NE, Cotter MA, Maxfield EK (1993) Anti-oxidant treatment prevents the development of peripheral nerve dysfunction in streptozotocin-diabetic rats. Diabetologia 36:299–304

    CAS  PubMed  Google Scholar 

  125. Cameron NE, Jack AM, Cotter MA (2001) Effect of alpha-lipoic acid on vascular responses and nociception in diabetic rats. Free Radic Biol Med 31:125–135

    CAS  PubMed  Google Scholar 

  126. Inkster ME, Cotter MA, Cameron NE (2002) Effects of trientine, a metal chelator, on defective endothelium-dependent relaxation in the mesenteric vasculature of diabetic rats. Free Radic Res 36:1091–1099

    CAS  PubMed  Google Scholar 

  127. Turkseven S, Kruger A, Mingone CJ, Kaminski P, Inaba M, Rodella LF, Ikehara S, Wolin MS, Abraham NG (2005) Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Physiol Heart Circ Physiol 289:H701–H707

    CAS  PubMed  Google Scholar 

  128. Dulak J, Deshane J, Jozkowicz A, Agarwal A (2008) Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation 117:231–241

    CAS  PubMed  Google Scholar 

  129. Li M, Kim DH, Tsenovoy PL, Peterson SJ, Rezzani R, Rodella LF, Aronow WS, Ikehara S, Abraham NG (2008) Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes 57:1526–1535

    CAS  PubMed  Google Scholar 

  130. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403

    CAS  PubMed  Google Scholar 

  131. Henriksen EJ (2002) Invited review: effects of acute exercise and exercise training on insulin resistance. J Appl Physiol 93:788–796

    CAS  PubMed  Google Scholar 

  132. Reznick RM, Shulman GI (2006) The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 574:33–39

    CAS  PubMed  Google Scholar 

  133. Rockl KS, Witczak CA, Goodyear LJ (2008) Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life 60:145–153

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Redman LM, Ravussin E (2008) Endocrine alterations in response to calorie restriction in humans. Mol Cell Endocrinol 299:129–136

    PubMed  Google Scholar 

  135. Guarente L (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103:1768–1773

    CAS  PubMed  Google Scholar 

  137. Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Matsumura T, Araki E (2006) 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

    CAS  PubMed  Google Scholar 

  138. Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH (2004) 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

    CAS  PubMed  Google Scholar 

  139. Kim JA, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102:401–414

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    CAS  PubMed  Google Scholar 

  141. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    CAS  PubMed  Google Scholar 

  142. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689

    CAS  PubMed  Google Scholar 

  143. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712–716

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Hung LM, Chen JK, Huang SS, Lee RS, Su MJ (2000) Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 47:549–555

    CAS  PubMed  Google Scholar 

  146. Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I (2008) Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 294:L478–L488

    CAS  PubMed  Google Scholar 

  147. Bouzakri K, Austin R, Rune A, Lassman ME, Garcia-Roves PM, Berger JP, Krook A, Chibalin AV, Zhang BB, Zierath JR (2008) Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes 57:1508–1516

    CAS  PubMed  Google Scholar 

  148. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56

    CAS  PubMed  Google Scholar 

  149. Fujii N, Jessen N, Goodyear LJ (2006) AMP-activated protein kinase and the regulation of glucose transport. Am J Physiol Endocrinol Metab 291:E867–E877

    CAS  PubMed  Google Scholar 

  150. Ruderman NB, Saha AK, Kraegen EW (2003) Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144:5166–5171

    CAS  PubMed  Google Scholar 

  151. Mayers RM, Leighton B, Kilgour E (2005) PDH kinase inhibitors: a novel therapy for type II diabetes? Biochem Soc Trans 33:367–370

    CAS  PubMed  Google Scholar 

  152. Gnaiger E (2008) Mitochondrial pathways and respiratory control, 2nd edn. OROBOROS MiPNet Publications, Innsbruck

    Google Scholar 

  153. Yorek MA (2003) The role of oxidative stress in diabetic vascular and neural disease. Free Radic Res 37:471–480

    CAS  PubMed  Google Scholar 

  154. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:154–160

    CAS  PubMed  Google Scholar 

  155. Ernster L, Forsmark P, Nordenbrand K (1992) The mode of action of lipid-soluble antioxidants in biological membranes: relationship between the effects of ubiquinol and vitamin E as inhibitors of lipid peroxidation in submitochondrial particles. Biofactors 3:241–248

    CAS  PubMed  Google Scholar 

  156. Maguire JJ, Wilson DS, Packer L (1989) Mitochondrial electron transport-linked tocopheroxyl radical reduction. J Biol Chem 264:21462–21465

    CAS  PubMed  Google Scholar 

  157. Fink BD, O’Malley Y, Dake BL, Ross NC, Prisinzano TE, Sivitz WI (2009) Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. PLoS One 4:e4250

    PubMed  PubMed Central  Google Scholar 

  158. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293:1338–1347

    PubMed  Google Scholar 

  159. Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K (2001) Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 103:919–925

    CAS  PubMed  Google Scholar 

  160. Smith AR, Visioli F, Hagen TM (2002) Vitamin C matters: increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid. FASEB J 16:125–144

    Google Scholar 

  161. May JM, Qu ZC, Li X (2003) Ascorbic acid blunts oxidant stress due to menadione in endothelial cells. Arch Biochem Biophys 411:136–144

    CAS  PubMed  Google Scholar 

  162. American Diabetes Association (2009) Standards of medical care in diabetes—2009. Diabetes Care 32:S13–S61

    Google Scholar 

  163. Yorek MA, Coppey LJ, Gellett JS, Davidson EP, Lund DD (2004) Effect of fidarestat and alpha-lipoic acid on diabetes-induced epineurial arteriole vascular dysfunction. Exp Diabesity Res 5:123–135

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Obrosova IG, Stevens MJ, Lang HJ (2001) Diabetes-induced changes in retinal NAD-redox status: pharmacological modulation and implications for pathogenesis of diabetic retinopathy. Pharmacology 62:172–180

    CAS  PubMed  Google Scholar 

  165. Dincer Y, Telci A, Kayali R, Yilmaz IA, Cakatay U, Akcay T (2002) Effect of alpha-lipoic acid on lipid peroxidation and anti-oxidant enzyme activities in diabetic rats. Clin Exp Pharmacol Physiol 29:281–284

    CAS  PubMed  Google Scholar 

  166. Yi X, Maeda N (2006) alpha-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet. Diabetes 55:2238–2244

    CAS  PubMed  Google Scholar 

  167. Kowluru RA, Odenbach S (2004) Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats. Diabetes 53:3233–3238

    CAS  PubMed  Google Scholar 

  168. Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA (1995) Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 38:1425–1433

    CAS  PubMed  Google Scholar 

  169. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R (2006) Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29:2365–2370

    CAS  PubMed  Google Scholar 

  170. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596

    CAS  PubMed  Google Scholar 

  171. James AM, Smith RA, Murphy MP (2004) Antioxidant and prooxidant properties of mitochondrial Coenzyme Q. Arch Biochem Biophys 423:47–56

    CAS  PubMed  Google Scholar 

  172. Fink BD, Herlein JA, Yorek MA, Fenner AM, Kerns RJ, Sivitz WI (2012) Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells. J Pharmacol Exp Ther 342:709–719

    CAS  PubMed  Google Scholar 

  173. Szeto HH (2008) Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann N Y Acad Sci 1147:112–121

    CAS  PubMed  Google Scholar 

  174. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH (2004) Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 279:34682–34690

    CAS  PubMed  Google Scholar 

  175. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW 3rd, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119:573–581

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Zhao GM, Qian X, Schiller PW, Szeto HH (2003) Comparison of [Dmt1]DALDA and DAMGO in binding and G protein activation at μ, δ, and κ opioid receptors. J Pharmacol Exp Ther 307:947–954

    CAS  PubMed  Google Scholar 

  177. Zhao K, Luo G, Zhao GM, Schiller PW, Szeto HH (2003) Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther 304:425–432

    CAS  PubMed  Google Scholar 

  178. Schiller PW, Nguyen TM, Berezowska I, Dupuis S, Weltrowska G, Chung NN, Lemieux C (2000) Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem 35:895–901

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Iowa, East 422 GH, Iowa City, IA, 52242, USA

    William I. Sivitz

Authors
  1. William I. Sivitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William I. Sivitz .

Editor information

Editors and Affiliations

  1. Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA

    Irina Obrosova

  2. Centre for Endocrinology and Metabolism, University of Brimingham, School of Clinical and Experimental Medicine, Birmingham, United Kingdom

    Martin J. Stevens

  3. Veterans Affairs Medical Center, University of Iowa, Iowa City, Iowa, USA

    Mark A. Yorek

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Sivitz, W.I. (2014). Mitochondria and Oxidative Stress in Diabetes. In: Obrosova, I., Stevens, M., Yorek, M. (eds) Studies in Diabetes. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4899-8035-9_5

Download citation

Publish with us

Policies and ethics

Search

Navigation