Skip to main content

Advertisement

SpringerLink
Log in

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

  • Review Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

Diabetes mellitus type-2 (DMT-2) is a hyperglycemic syndrome with several characteristic features. It continues to rise unabatedly in all pockets of the world, parallels with affluence and can be controlled but not cured. It has a definite involvement of genetic component but environmental factors play overwhelmingly dominant role in etiopathogenesis. Insulin resistance (IR) and obesity are singular instigators of DMT-2. The various events cause critical defects in insulin signaling cascade followed by beta-cell dysfunction. Over a period of time, numerous other metabolic aberrations develop, resulting in diabetic complications which could be both vascular (cardiovascular complications, nephropathy, neuropathy, retinopathy and embryopathy) or a-vascular (cataract and glaucoma etc). It has been proposed that all these abnormal events are initiated or activated by a common mechanism of superoxide anion, which is accompanied with generation of a variety of reactive oxygen species (ROS), reactive nitrogen specie (RNS) and resultant heightened oxidative stress (OS). Provoked OS causes IR and altered gene expressions. Hyperglycemia induces OS through multiple routes: a)stimulated polyol pathway where in ≤ 30% glucose can be diverted to sorbitol and fructose, b)increased transcription of genes for proinflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1) c) activation of protein kinase-C (PKC) leading to several molecular changes d)increased synthesis of Advanced Glycation End Products (AGEs) e)changes in a receptor far AGEs and f) autooxidation of glucose with formation of ketoimines and AGEs. All these processes are accompanied with alteration in redox status, ROS, RNS and OS which trigger DMT-2 and its complications. Initial hurriedly planned and executed experimental and clinical studies showed promising results of antioxidant therapies, but recent studies indicate that excess intake/supplement may have adverse outcomes including increased mortality. It is advocated that antioxidants should be given only if preexisting deficiency is present. Selection of antioxidant is another important aspect. Lastly but most importantly the impact of OS is not obligatory but facultative. As such only those diabetic patients will be benefited by antioxidant therapies that have impelling punch of prooxidants.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Reference

  1. International Diabetes Federation. Atlas on Diabetes. Montreal, Canada 2009.

  2. Stymvoli M, Goldstecn B, Haeften TW. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005; 365: 1333–1345.

    Article  CAS  Google Scholar 

  3. Fajan SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity onset disease of the young. New Eng J Med 2001; 345: 971–980.

    Article  Google Scholar 

  4. Zimmet P, Albert KG, Shaw J. Global and societal implications in the diabetes epidemic. Nature 2001; 414: 782–787.

    Article  CAS  PubMed  Google Scholar 

  5. Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes and level of glycemia on all cause and cardiovascular mortality. The San Antonio Study. Diabetes Care 1998; 21: 1167–1172.

    Article  CAS  PubMed  Google Scholar 

  6. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes. Pediatrics 2005; 17: 534–541.

    Google Scholar 

  7. King H, Aubert RE, Herman WH. Global burden of diabetes 1995–2025, prevalence, numerical estimates and projections. Diabetes Care 1998; 21: 1414–1431.

    Article  CAS  PubMed  Google Scholar 

  8. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047–1053.

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  10. World Health Organization Expert Committee. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation, Part 1, diagnosis and classification of diabetes mellitus. Geneva: World Health Organization, 1999.

    Google Scholar 

  11. Stumvoli M, Tataranni PA, Stefan N, Vozarova B, Bogardus C. Glucose allostasis. Diabetes 2003; 52: 903–909.

    Article  Google Scholar 

  12. Dineen S, Gerich J, Rizza R. Carbohydrate metabolism in non-insulin dependent diabetes mellitus. New Eng J Med 1992; 327: 707–713.

    Google Scholar 

  13. Singh S, Farzana M, Singh PP. Insinuating role of free radicals and placating behaviour of antioxidants in diabetes mellitus. J Physiol 2009; 9: 35–38.

    Google Scholar 

  14. Singh PP, Gupta G, Barjatiya M, Mamtha GP, Adhikari D. Oxidant antioxidant dovetail hypothesis: Let us not sprint before we stand. In Free Radicals and Antioxidants in Health and Disease: Concordance and Discordance. Eds Singh et al 2007; 1–37.

  15. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Joshua T. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39: 44–84.

    Article  CAS  PubMed  Google Scholar 

  16. Aruoma OI, Neergheen VS, Bahorun T, Jen L. Free radicals, antioxidants and diabetes mellitus: Embryopathy, retinopathy, nuuropathy, nephropathy and cardiovascular complications. Neuroembryol Aging 2006/2007; 4: 117–137.

    Article  CAS  Google Scholar 

  17. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endo Rev 2002; 23: 599–622.

    Article  CAS  Google Scholar 

  18. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003; 52: 1–8.

    Article  CAS  PubMed  Google Scholar 

  19. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40: 405–412.

    Article  CAS  PubMed  Google Scholar 

  20. Patel C, Ghanin H, Ravishankar S, Sia CL, Vishwanathan P, Mohanty P, Dandona P. Prolonged reactive oxygen species generation and Nuclear Factor-kB activation after a high-fat, high-carbohydrate meal in obese. J Clin Endocrin Met 2007; 92: 4476–4479.

    Article  CAS  Google Scholar 

  21. Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction and metabolic consequences. Clin Chem 2008; 54: 945–955.

    Article  PubMed  CAS  Google Scholar 

  22. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 2008; 29: 42–61.

    Article  CAS  PubMed  Google Scholar 

  23. Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab 2006; 8: 136–145.

    Article  CAS  PubMed  Google Scholar 

  24. Qatanani M, Lazar MA. Mechanism of obesity associated insulin resistance: Many choices on the menu. Genes Dev 2007; 21: 1443–1455.

    Article  CAS  PubMed  Google Scholar 

  25. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin dependent diabetes mellitus: Problems and prospects. Endo Rev 1998; 19: 477–490.

    Article  CAS  Google Scholar 

  26. Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G. A promote genotype and oxidative stress potential link to human insulin resistance. Diabetes 2003; 52: 1611–1618.

    Article  CAS  PubMed  Google Scholar 

  27. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have causal role in multiple forms of insulin resistance. Nature 2006; 440: 944–948.

    Article  CAS  PubMed  Google Scholar 

  28. Buetler AE, Janson J, Bonner-Weir S, Ritzol R, Pizza RA, Butler PC. Beta cell deficit and increased beta cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110.

    Article  Google Scholar 

  29. Kaneto H, Nakatani Y, Kawamori D, Miyatsuka T, Matsuoka TA, Matsuchisa M, Yanasaki Y. Role of oxidative stress, endoplasmic reticulum stress and C-Jun N-terminal kinase in pancreatic beta cell dysfunction and insulin resistance. Int J Biochem Cell Biol 2006; 38: 782–793.

    Article  CAS  PubMed  Google Scholar 

  30. Ahmed N. Advanced glycation end products role in pathology of diabetic complications. Diab Res Clin Prac 2005; 67: 3–21.

    Article  CAS  Google Scholar 

  31. Lipinski B. Pathophysiology of oxidative stress in diabetes mellitus. J Diab Comp 2001; 15: 203–210.

    Article  CAS  Google Scholar 

  32. Rolo AP, Palmeira CM. Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006; 212: 167–178.

    Article  CAS  PubMed  Google Scholar 

  33. Willi C, Bodenmann P, Ghali WA, Farris PD, Cornuz J. Active smoking and the risk of type-2 diabetes: A systematic review and meta-analysis. JAMA 2007; 98: 654–664.

    Google Scholar 

  34. Agrawal R. Smoking, oxidative stress and inflammation: Impact on resting energy expenditure in diabetic nephropathy. BMC Nephrology 2005; 6: 13–21.

    Article  CAS  Google Scholar 

  35. Facchini FS, Hollenbeck CB, Jeppesen J, Chen YD, Reaven GM. Insulin resistance and cigarette smoking. Lancet 1992; 339: 1128–1130.

    Article  CAS  PubMed  Google Scholar 

  36. Canoy D, Warenham N, Luben R, Welch A, Bingham S, Day N, Khaw KT. Cigarette smoking and fat distribution in 21828 British men and women: A population based study. Obs Res 2005; 13: 1466–1475.

    Article  Google Scholar 

  37. Spector TD, Blake DR. Effect of cigarette smoking on Langerhan’s cells. Lancet 1988; 2: 1028.

    Article  CAS  PubMed  Google Scholar 

  38. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta cell mass and expression of oxidative stress-related DNA damage in the islets of Japanese Type II diabetic patients. Diabetologia 2002; 45: 85–96.

    Article  CAS  PubMed  Google Scholar 

  39. Maechler P, Jornot I, Wollheim CB. Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J Biol Chem 1999; 274: 27905–27914.

    Article  CAS  PubMed  Google Scholar 

  40. Wollhein CB. Beta cell mitochondria in the regulation of insulin secretion: A new culprit in type II diabetes. Diabetologia 2000; 43: 265–277.

    Article  Google Scholar 

  41. Robertson RP, Hamon J, Tran POT, Poit V. Beta cell glucose toxicity, lipotoxicity and chronic oxidative stress in type 2 diabetes. Diabetes 2004; 53(Supp I): S119–S124.

    Article  CAS  PubMed  Google Scholar 

  42. Cerillo A. Cardiovascular effects of acute hyperglycemia: pathophysiological underpinnings. Diab Vasc Dis Res 2008; 5: 260–268.

    Article  Google Scholar 

  43. Li X, Hu J, Zhang R, Sun X, Zhang Q, Guan X, Chen J, Zhu Q, Li S. Urocortin ameliorates diabetic nephropathy in obese db/db mice. PMCID: PMC 2009; 245: 1047–1052.

    Google Scholar 

  44. Joe MC, Arshag DM. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs 2000; 60: 95–113.

    Article  Google Scholar 

  45. Vats RK, Kumar V, Kothari A, Mittal A, Ramachandran U. Emerging targets for diabetes. Curr Sci 2005; 88: 241–248.

    CAS  Google Scholar 

  46. Johnson JS, Harns AK, Rychly DJ, Ergel A. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical pratice. Card Diabetol 2005; 4: 5–11.

    Article  CAS  Google Scholar 

  47. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813–820.

    Article  CAS  PubMed  Google Scholar 

  48. Halliwell B. Antioxidants and human disease. Nutr Rev 1997; 55: S44–S52.

    CAS  PubMed  Google Scholar 

  49. Halliwell B. Food derived antioxidants: How to evaluate their importance in food and in vivo. In Handbook of Antioxidants. Cadenas E, Packer L. Eds Marcel Dekker, Inc NY 2002; 1–45.

    Google Scholar 

  50. Valko M, Morris H, Cronin MTD. Metals toxicity and oxidative stress. Curr Med Chem 2005; 12: 1161–1208.

    Article  CAS  PubMed  Google Scholar 

  51. D’Autreaux B, Toledano M. ROS as signaling molecules: Mechanisms that generate specificity in ROS homeostasis. Mol Cell Biol 2007; 8: 813–824.

    Google Scholar 

  52. Theopold U. A bad boy comes good. Nature 2009; 461: 486–487.

    Article  CAS  PubMed  Google Scholar 

  53. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophilla hemaetopoitic progenitors for differentiation. Nature 2009; 461: 537–542.

    Article  CAS  PubMed  Google Scholar 

  54. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 3rd Ed Oxford University Press 1999.

  55. Singh PP, Pendse AK, Bomb BS, Barjatiya MK, Ghosh R. Free radicals and antioxidants: Sort out facts from fiction (Editorial). In Free Radicals and Antioxidants: Sort Out Facts from Fiction. 1999 P XV–XIX.

  56. Ferreira FML, Palmeira CM, Matos MJ, Seica R, Santos MS. Decreased susceptibility to lipid peroxidation of Goto-Kakizaki rats: Relationship to mitochondrial antioxidant capacity. Life Sci 1999; 65: 1013–1025.

    Article  CAS  PubMed  Google Scholar 

  57. Oliveira PJ, Sica R, Santos DL, Rolo AP, Sardo VA, Ferreira FML. Vitamin E or Coenzyme Q10 administrations are not fully advantageous for heart mitochondrial function in diabetic Croto-Kakizaki rats. Mitochondrion 2004; 3: 337–345.

    Article  CAS  PubMed  Google Scholar 

  58. Mootha UK, Lindgren CM, Errikson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately down regulated in human diabetes. Nat Genet 2003; 34: 267–273.

    Article  CAS  PubMed  Google Scholar 

  59. Patti ME, Buttle AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC-1 and NRF-1. Proc Natl Acad Sci USA 2003; 100: 8466–8471.

    Article  CAS  PubMed  Google Scholar 

  60. Russel JW, Golovoy D, Vinicent AM, Mahendru P, Olzmann JA, Mentzer A, Fieldman EL. High glucose induced oxidative stress and mitochondrial dysfunction in neuron. FASEB J 2002; 16: 1738–1748.

    Article  Google Scholar 

  61. Russel LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, et al. Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage dependent manner. Circ Res 2004; 94: 525–533.

    Article  CAS  Google Scholar 

  62. Nishikawa T, Edelstein D, Brownlee M. The missing link: A single unifying mechanism for diabetic complications. Kidney Int 2000; 58: S26–S30.

    Article  Google Scholar 

  63. Chabrashvili T, Tojo A, Onozato ML, Kitiyakara C, Quinn MT, Fujita T, et al. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension 2002; 39: 269–274.

    Article  CAS  PubMed  Google Scholar 

  64. Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47 phox: Role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Priol 2003; 23: 981–987.

    Article  CAS  Google Scholar 

  65. Babior BM. NADPH oxidase. Curr Opin Immunol 2004; 16: 42–47.

    Article  CAS  PubMed  Google Scholar 

  66. Bokoch GM, Zhao T. Regulation of the phagocyte NADPH oxidase by Ras GTPase. Antioxid Redox Signal 2006; 8: 1533–1548.

    Article  CAS  PubMed  Google Scholar 

  67. Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species and hypertension: Clinical implications and therapeutic possibilities. Diabetes Care 2008; 31: S170–S180.

    Article  CAS  PubMed  Google Scholar 

  68. Li JM, Shah AM. Intracellular localization and preassembly of NADPH oxidase complex endothelial cells. J Biol Chem 2002; 277: 19952–19990.

    Article  CAS  PubMed  Google Scholar 

  69. San Martin AS, Du P, Dikalova A, Lassegue B, Aleman M, Gongora MC, et al. Reactive oxygen species-selective regulation of aortic inflammatory gene expression in type 2 diabetes. Am J Physiol Heart Cir Physiol 2007; 292: H2073–H2082.

    Article  CAS  Google Scholar 

  70. Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, et al. Expression of a functionally active gp91 phox-containing neutrophil type NADPH oxidase in smooth muscle cells from human resistance arteries: Regulation by angiotensin II. Circ Res 2002; 90: 1205–1213.

    Article  CAS  PubMed  Google Scholar 

  71. Laisague B, Clempus RE. Vascular NADPH oxidases specific features, expression and regulation. Am J Physiol Reg Integ Comp Physiol 2003; 285: R277–R297.

    Google Scholar 

  72. Miller AA, Drummond GR, Sobey CG. Novel isoforms of NADPH oxidase in cerebral vascular control. Pharmacol Ther 2006; 111: 928–948.

    Article  CAS  PubMed  Google Scholar 

  73. Spinetti G, Kraenkel N, Emanuuel C, Madeddu P. Diabetes and vessel wall remodelling: From mechanistic insights to regenerative therapies. Cardiovas Res 2008; 78: 265–273.

    Article  CAS  Google Scholar 

  74. Butler R, Morris AD, Belch JJF, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 2000; 35: 746–751.

    CAS  PubMed  Google Scholar 

  75. Yanaoka T, Nishimura C, Yanashita K, Itakura M, Yamada T, Fujimoto J, et al. Acute onset of diabetic pathological changes in transgenic mice with human aldolase reductase cDNA. Diabetologia 1995; 38: 255–261.

    Article  Google Scholar 

  76. Lee AY, Chung SK, Chung SS. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldolase reductase gene in the lens. Proc Natl Acad Sci USA 1995; 92: 2780–2784.

    Article  CAS  PubMed  Google Scholar 

  77. Yagihashi S, Yamagishi S, Wada R, Suginoto K, Baba M, Wong HG, et al. Galactosemic neuropathy in transgenic mice for human aldolase reductase. Diabetes 1996; 45: 56–59.

    Article  CAS  PubMed  Google Scholar 

  78. Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J 1999; 13: 23–30.

    CAS  PubMed  Google Scholar 

  79. Schleicher E, Friess U. Oxidative stress Age and atherosclerosis. Kidney International 2007; 72: S17–S26.

    Article  CAS  Google Scholar 

  80. Mclain DA. Hexosamines as mediators of nutrient sensing and regulation in diabetes. J Diabetes Complications 2002; 16: 72–80.

    Article  Google Scholar 

  81. Veerababu G, Tang J, Hoffman RT, Daniels MC, Herbert Jr LF, Cook ED, et al. Overexpression of glutamic: fructose 6 phosphate aminotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity and impaired glucose tolerance. Diabetes 2000; 49: 2070–2078.

    Article  CAS  PubMed  Google Scholar 

  82. Schleicher ED, Weigert C. Role of hexosamine biosynthetic pathway in diabetic nephropathy. Kidney International 2000; 58(Suppl 77): S13–S18.

    Article  Google Scholar 

  83. Wolff SP, Dean RT. Glucose autooxidation and protein modification: The potential role of “autooxidative glycosylation: in diabetes mellitus. Biochem J 1987; 245: 243–250.

    CAS  PubMed  Google Scholar 

  84. Hunt JV, Bottons MA, Mitchinson MJ. Oxidative alterations in the experimental glycation model of diabetes mellitus are due to protein-glucose adduct oxidation. Biochem J 1993; 291: 529–535.

    CAS  PubMed  Google Scholar 

  85. Hammes HP, Weiss A, Hess S, Arak N, Horiuchi S, Brownlee M, et al. Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina. Lab Invest 1996; 75: 325–338.

    CAS  PubMed  Google Scholar 

  86. Howard EW, Benton R, Aheru-Moore J, Tomasek JJ. Cellular contraction of collagen lattices is inhibited by non-enzymatic glycation. Exp Cell Res 1996; 228: 132–137.

    Article  CAS  PubMed  Google Scholar 

  87. Newby AC. Matrix metalloproteinases regulate migration, proliferation and death of vascular smooth muscle cells by degrading matrix and non-matrix substances. Cardiovasc Res 2006; 69: 614–624.

    Article  CAS  PubMed  Google Scholar 

  88. Goldlin A, Beckman JA, Schimidt AM, Creager MA. Advanced glycation and products: Sparking the development of diabetic vascular injury. Circulation 2006; 114: 597–605.

    Article  CAS  Google Scholar 

  89. Yan S, Schimidt AM, Anderson GM, Zhang J, Brett J, Zou YS, et al. Enhanced cellular oxidative stress by interaction of advanced glycation end products with their receptors/ binding proteins. J Biol Chem 1994; 269: 9889–9897.

    CAS  PubMed  Google Scholar 

  90. Bergendi L, Benes L, Durackova Z, Ferencik M. Chemistry, physiology and pathology of free radicals. Life Sci 1999; 65: 1865–1874.

    Article  CAS  PubMed  Google Scholar 

  91. Rubbo H, Radi R. Antioxidant properties of nitric oxide. In Handbook of Antioxidants. Cadenas E, Packer L. Ed. Marcel Dekker Inc NY, 2002; 689–706.

  92. Ghafourifar p, Cadenas E. Mitochondrial nitric oxide synthase. Trend Pharmacol Sci 2005; 26: 190–195.

    Article  CAS  Google Scholar 

  93. Koshland DE. The molecule of the year. Science 1992; 258: 1861.

    Article  PubMed  Google Scholar 

  94. Sessa WC. Regulation of endothelial derived nitric oxide in health and disease. Men Inst Oswardo Cruz 2005; 100: 15–18.

    CAS  Google Scholar 

  95. Tinahone FJ, Murri-Pierri M, Garrido-Sanchez L, Garca-Almeida JM, Garcia-Serrano S, Garcia-Ames J, Garcia-Fuentes E. Oxidative stress in severely obese person is greater in those with insulin resistance. Obesity 2009; 17: 240–246.

    Google Scholar 

  96. Katakan PV, Domoki F, Snipes JA, Busija AR, Jarajapu YP, Bushija DW. Impaired mitochondria dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol 2009; 296: R289–R298.

    Google Scholar 

  97. Nathan C. Epidemic inflammation: Pondoring obesity. Molecular Med 2009; 14: 485–492.

    Google Scholar 

  98. Pandey V. Think you are slim? New norms may make you obese DNA, 2008. www.dnaindia.com

  99. Ogden CL, Caroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegel KM. Prevalence of overweight and obesity in United States 1999–2006. JAMA 2006; 295: 1594–1605.

    Article  Google Scholar 

  100. Wells GD, Noseworthing MD, Hamilton J, Tarnopolska M, Teir I. Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome. Con J News Sci 2008; 35: 31–40.

    Google Scholar 

  101. Farooqui IS, O’Rahilly S. Genetics of obesity in humans. End Rev 2006; 27: 710–718.

    Google Scholar 

  102. Foster-Schubert KE, Cummings DE. Emerging therapeutic strategies for obesity. Endo Rev 2006; 27: 779–793.

    Google Scholar 

  103. Chaturvedi N. The burden of diabetes and its complications: Trends and implications for intervention. Diabetes Res Clin Prac 2007; 76: S3–S12.

    Article  Google Scholar 

  104. Southern PA. Free radical in medicine. Involvement in human diseases. Mayo Clin Proc 1988; 63: 390–408.

    Google Scholar 

  105. Halliwell B, Cross CE, Gutteridge JMC. Free radicals, antioxidants and human disease: Where are we now? J Lab Clin Med 1992; 119: 598–620.

    CAS  PubMed  Google Scholar 

  106. Davi G, Falco A, Patrono C. Lipid peroxidation in diabetes mellitus. Antioxid Redox Sig 2005; 7: 256–268.

    Article  CAS  Google Scholar 

  107. Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sci 2009; 17: 460–466.

    Google Scholar 

  108. Piper GM, Gross GJ. Oxygen free radicals abolish endothelium dependent relaxation in diabetic rat aorta. Am J Physiol 1998; 255: H825–H833.

    Google Scholar 

  109. Gutteridge JMC, Halliwell B. Antioxidants: Elixirs of life or media hype? In-Antioxidants in Nutrition, Health and Disease. Oxford Univ Press NY 1996; 40–62.

  110. Cadenas E, Packer L. Hand book of Antioxidants Marcel Dekker Inc NY 2002.

  111. Singh PP, Gupta S. Antioxidants and cardiovascular system. In Free Radicals and Antioxidants in health and disease: Concordance and Discordance. Singh PP, Gupta G, Barjatia M, Mamtha GP, Adhikari D. Eds. Chowdhary Offset Pvt Ltd Udaipur, 2007.

  112. Tewari AK. Antioxidants: New generation therapeutic base for treatment of polygenic disorders. Curr Sci 2004; 86: 192–212.

    Google Scholar 

  113. Diplock AT. Antioxidant nutrients and disease prevention: An overview. Am J Clin Nutr 1991; 53: S189–S193.

    Google Scholar 

  114. Daga MK, Mohan A. Antioxidants and disease-current status. J Assoc Phys Ind 1996; 44: 703–714.

    CAS  Google Scholar 

  115. Pryor WA. Vitamin E and heart disease: Basic science to clinical intervention trials. Free Radic Biol Med 2000; 28: 141–164.

    Article  CAS  PubMed  Google Scholar 

  116. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 1989; 86: 6377–6381.

    Article  CAS  PubMed  Google Scholar 

  117. Franzini L, Ardigo D, Zavaroni I. Dietary antioxidants and glucose metabolism. Curr Opinion Clin Nutr Met Care 2008; 11: 471–476.

    Article  CAS  Google Scholar 

  118. Blomhoff R. Dietary antioxidants and cardiovascular disease. Curr Opinion Lipidology 2005; 16: 47–54.

    Article  CAS  Google Scholar 

  119. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High dosage vitamin E supplementation may increase all cause mortality. Ann Intern Med 2005; 142: 37–46.

    CAS  PubMed  Google Scholar 

  120. Bjelakovic G, Nikolova D, Gludd LL, Smonetti RG, Gludd C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta — analysis. JAMA 2007; 297: 842–857.

    Article  CAS  PubMed  Google Scholar 

  121. Lin J, Cook NR, Albert C, Zaharris E, Gaziano JM, Denberg MV, et al. Vitamin C and E and beta carotene: Supplementation and cancer risk: Arandomized controlled trial. J Natl Cancer Inst 2009; 101: 14–23.

    CAS  PubMed  Google Scholar 

  122. Liu S, Lee IM, Song Y, Denberg MV, Cook NR, Manson JE. Vitamin E and risk of type 2 diabetes in women health study randomized controlled trial. Diabetes 2006; 55: 2856–2862.

    Article  CAS  PubMed  Google Scholar 

  123. Clarke MW, Burnett JR. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008; 45: 417–450.

    Article  CAS  PubMed  Google Scholar 

  124. Bielakovic G, Nikolova D, Sinonetti RG, Gludd C. Antioxidant supplements for preventing cancers. The Cochrane Collaboration John Wiley & Sons Ltd USA 2008; 1–79.

  125. Dotan Y, Pinchuk I, Litchenberg D, Leshno M. Decision analysis supports the paradigm that indiscriminate supplementation of Vitamin E does more harm than good. Arterioscle Thromb Vasc Biol 2009; 29: 1304–1309.

    Article  CAS  Google Scholar 

  126. Montenen J, Knekt P, Jarvinen R, Reunanen A. Dietary antioxidants and risk of type 2 diabetes. Diabetes Care 2004; 27: 362–366.

    Article  Google Scholar 

  127. Reunannen A, Knekt P, Aaran RK, Aromaa A. Serum antioxidant and risk of non-insulin dependent diabetes mellitus. Eur J Clin Nutr 1998; 52: 89–93.

    Article  CAS  Google Scholar 

  128. Beckman JA, Goldfine AB, Gordon MB, Garret LA, Kenny JFJr, Cremager MA. Oral antioxidant therapy improves endothelial function in type 1 but not in type 2 diabetes mellitus. Am J Physiol 2003; 285: H2392–H2398.

    CAS  Google Scholar 

  129. Gaede P, Vedel P, Larsen N, Jensen GVH, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Eng J Med 2003; 348: 383–393.

    Article  Google Scholar 

  130. Yusuf S, Dagenairs G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New Eng J Med 2000; 342: 154–160.

    Article  CAS  PubMed  Google Scholar 

  131. Bjelakonc G, Nikolova D, Gludd LL, Simonetti RG, Gludd C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and metaanalysis. JAMA 2007: 297: 842–857.

    Article  Google Scholar 

  132. Holmes VA, McCame DR. Could antioxidant supplementation prevent pre-eclampsia? Proc Nutr Soc 2005; 64: 491–501.

    Article  CAS  PubMed  Google Scholar 

  133. Poston L, Briley AL, Seed PT, Kelly FJ, Snennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): Randomized placebo controlled trial. Lancet 2006; 367: 1145–1154.

    Article  CAS  PubMed  Google Scholar 

  134. Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C and vitamin E in relation to mortality. Am J Epidemiol 2009; 170: 472–483.

    Article  PubMed  Google Scholar 

  135. Singh PP, Sharma P. Antioxidant basket: Do not mix apples and oranges. Ind J Clin Biochem 2009; 24: 211–214.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Era’s Lucknow Medical College, Sarfarazganj, Lucknow, Uttar Pradesh, India

    P. P. Singh, Farzana Mahadi & Ajanta Roy

  2. Department of Biochemistry, SMS Medical College Jaipur, Rajasthan, India

    Praveen Sharma

  3. Department of Biochemistry, Era’s Lucknow Medical College, Sarfarazganj, Lucknow, 226003, India

    P. P. Singh

Authors
  1. P. P. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farzana Mahadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ajanta Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Praveen Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. P. Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, P.P., Mahadi, F., Roy, A. et al. Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2. Indian J Clin Biochem 24, 324–342 (2009). https://doi.org/10.1007/s12291-009-0062-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-009-0062-6

Key Words

Search

Navigation