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.
Keywords
- Reactive Oxygen Species
- Electron Paramagnetic Resonance
- Reactive Oxygen Species Production
- Superoxide Production
- Mitochondrial Reactive Oxygen Species
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
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
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
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
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
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
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
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
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
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
Kanauchi M, Nishioka H, Hashimoto T (2002) Oxidative DNA damage and tubulointerstitial injury in diabetic nephropathy. Nephron 91:327–329
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
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
Du Y, Miller CM, Kern TS (2003) Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med 35:1491–1499
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
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
Boss O, Hagen T, Lowell BB (2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49:143–156
Green K, Brand MD, Murphy MP (2004) Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 53:S110–S118
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820
Pessin JE, Richardson JM, Sivitz WI (1991) Regulation of the glucose transporter in animal models of diabetes. Adv Exp Med Biol 293:249–262
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
Fridovich I (1997) Superoxide anion radical (O2 –·), superoxide dismutases, and related matters. J Biol Chem 272:18515–18517
Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605
Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25:222–230
Grivennikova VG, Vinogradov AD (2006) Generation of superoxide by the mitochondrial complex I. Biochim Biophys Acta 1757:553–561
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
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
Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472
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
Skulachev VP (1998) Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1363:100–124
Gardner PR (1997) Superoxide-driven aconitase FE-S center cycling. Biosci Rep 17:33–42
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
Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581
Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26:1589–1596
Cross AR, Jones OT (1991) Enzymic mechanisms of superoxide production. Biochim Biophys Acta 1057:281–298
Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795
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
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
Murphy MP (1997) Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol 15:326–330
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
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
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
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
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
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
Robinson KM, Janes MS, Beckman JS (2008) The selective detection of mitochondrial superoxide by live cell imaging. Nat Protoc 3:941–947
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
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
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
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
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
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
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
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
Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127
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
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
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
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
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
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
Schrauwen P, Hesselink MKC (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53:1412–1417
Schrauwen P (2007) High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc 66:33–41
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
Hesselink MKC, Mensink M, Schrauwen P (2003) Human uncoupling protein-3 and obesity: an update. Obes Res 11:1429–1443
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
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
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
Yu LF, Herlein JA, Sivitz WI (2013) Mitochondrial function in diabetes: novel methodology and new insight. Diabetes 62(6):1833–1842
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
American Diabetes Association (2009) Diagnosis and classification of diabetes mellitus. Diabetes Care 32(Suppl 1):S62–S67
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Nishikawa T, Edelstein D, Brownlee M (2000) The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 77:S26–S30
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
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
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
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
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
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
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
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
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
James AM, Murphy MP (2002) How mitochondrial damage affects cell function. J Biomed Sci 9:475–487
Craven PA, Studer RK, Negrete H, DeRubertis FR (1995) Protein kinase C in diabetic nephropathy. J Diabetes Complications 9:241–245
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
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
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
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
Kowluru RA, Abbas SN (2003) Diabetes-induced mitochondrial dysfunction in the retina. Invest Ophthalmol Vis Sci 44:5327–5334
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
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
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
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
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
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
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
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
Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383
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
Baron AD (2002) Insulin resistance and vascular function. J Diabetes Complications 16:92–102
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
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
De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM (2000) Endothelial dysfunction in diabetes. Br J Pharmacol 130:963–974
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
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
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
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
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
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
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
Cameron NE, Cotter MA (2001) Effects of an extracellular metal chelator on neurovascular function in diabetic rats. Diabetologia 44:621–628
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
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
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
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
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
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
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
Henriksen EJ (2002) Invited review: effects of acute exercise and exercise training on insulin resistance. J Appl Physiol 93:788–796
Reznick RM, Shulman GI (2006) The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 574:33–39
Rockl KS, Witczak CA, Goodyear LJ (2008) Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life 60:145–153
Redman LM, Ravussin E (2008) Endocrine alterations in response to calorie restriction in humans. Mol Cell Endocrinol 299:129–136
Guarente L (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176
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
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
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
Kim JA, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102:401–414
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
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
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
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
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
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
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
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
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
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
Ruderman NB, Saha AK, Kraegen EW (2003) Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144:5166–5171
Mayers RM, Leighton B, Kilgour E (2005) PDH kinase inhibitors: a novel therapy for type II diabetes? Biochem Soc Trans 33:367–370
Gnaiger E (2008) Mitochondrial pathways and respiratory control, 2nd edn. OROBOROS MiPNet Publications, Innsbruck
Yorek MA (2003) The role of oxidative stress in diabetic vascular and neural disease. Free Radic Res 37:471–480
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
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
Maguire JJ, Wilson DS, Packer L (1989) Mitochondrial electron transport-linked tocopheroxyl radical reduction. J Biol Chem 264:21462–21465
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
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
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
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
May JM, Qu ZC, Li X (2003) Ascorbic acid blunts oxidant stress due to menadione in endothelial cells. Arch Biochem Biophys 411:136–144
American Diabetes Association (2009) Standards of medical care in diabetes—2009. Diabetes Care 32:S13–S61
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
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
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
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
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
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
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
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
James AM, Smith RA, Murphy MP (2004) Antioxidant and prooxidant properties of mitochondrial Coenzyme Q. Arch Biochem Biophys 423:47–56
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
Szeto HH (2008) Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann N Y Acad Sci 1147:112–121
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
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
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
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
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
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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
DOI: https://doi.org/10.1007/978-1-4899-8035-9_5
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4899-8034-2
Online ISBN: 978-1-4899-8035-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)