Current Diabetes Reports

, Volume 13, Issue 4, pp 481–487 | Cite as

Antioxidants and Diabetic Retinopathy

  • Michael Williams
  • Ruth E. Hogg
  • Usha Chakravarthy
Microvascular Complications-Retinopathy (JK Sun, Section Editor)


The biochemical perturbations in diabetes mellitus (DM) create the conditions for the production of free radicals, the consequence of which is increased oxidative stress. Evidence has accrued over the past 2 decades that suggests that oxidative stress is an important pathogenetic factor in the development of diabetic retinopathy (DR). Experimental data show that the use of strategies that ameliorate oxidative stress can prevent and retard the development of DR in the animal model. Clinical observations also suggest that reducing oxidative stress may help to reverse pathological manifestations of DR. The present article constitutes an examination of the role of antioxidants in the management of DR and the current state of clinically relevant knowledge.


Oxidation Antioxidants Reactive oxygen species Retinopathy Diabetes 


Conflict of Interest

Michael Williams declares that he has no conflict of interest.

Ruth Hogg declares that she has no conflict of interest.

Usha Chakravarthy declares that she has no conflict of interest.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999;48:1–9.PubMedCrossRefGoogle Scholar
  2. 2.
    •• Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70. This narrative review gives an overview of the biochemical consequences of hyperglycaemia, outlining the clinical relevance for both micro- and macrovascular disease, and describing the central role of ROS.PubMedCrossRefGoogle Scholar
  3. 3.
    Betteridge DJ. What is oxidative stress? Metabolism. 2000;49:3–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Birben E, Sahiner UM, Sackesen C, et al. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012;5:9–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Pacifici RE, Davies KJ. Protein, lipid and DNA repair systems in oxidative stress: the free-radical theory of aging revisited. Gerontology. 1991;37:166–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Maritim AC, Sanders RA, Watkins III JB. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17:24–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Soufi FG, Vardyani M, Sheervalilou R, Mohammadi M, Somi MH. Long-term treatment with resveratrol attenuates oxidative stress pro-inflammatory mediators and apoptosis in streptozotocinnicotinamide- induced diabetic rats. Gen Physiol Biophys. 2012;31:431–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Hegde KR, Kowluru RA, Mohr S, Nagaraj RH, Petrash JM. New horizons in research on diabetic complications of the eye: special emphasis on diabetic cataracts and retinopathy. J Ophthalmol. 2010;2010:979040.PubMedGoogle Scholar
  9. 9.
    Kanwar M, Chan PS, Kern TS, Kowluru RA. Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase. Investig Ophthalmol Vis Sci. 2007;48:3805–11.CrossRefGoogle Scholar
  10. 10.
    Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Exp Diabetes Res. 2007;2007:43603.PubMedGoogle Scholar
  11. 11.
    Gupta SK, Kumar B, Nag TC, Agrawal SS, Agrawal R, Agrawal P, et al. Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant, and anti-inflammatory mechanisms. J Ocul Pharmacol Ther. 2011;27:123–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Izuta H, Matsunaga N, Shimazawa M, Sugiyama T, Ikeda T, Hara H. Proliferative diabetic retinopathy and relations among antioxidant activity, oxidative stress, and VEGF in the vitreous body. Mol Vis. 2010;16:130–6.PubMedGoogle Scholar
  13. 13.
    Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII: effect of long-term administration of antioxidants on the development of retinopathy. Diabetes. 2001;50:1938–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991;40:405–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S, Moller DE, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42:80–9.PubMedCrossRefGoogle Scholar
  17. 17.
    el-Remessy AB, Bartoli M, Platt DH, Fulton D, Caldwell RB. Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI3-kinase tyrosine nitration. J Cell Sci. 2005;118:243–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Wu M, Chen Y, Wilson K, Chirindel A, Ihnat MA, Yu Y, et al. Intraretinal leakage and oxidation of LDL in diabetic retinopathy. Investig Ophthalmol Vis Sci. 2008;49:2679–85.CrossRefGoogle Scholar
  19. 19.
    Lopes-Virella MF, Baker NL, Hunt KJ, Lyons TJ, Jenkins AJ, Virella G. High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. Diabetes Care. 2012;35:1333–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Rema M, Srivastava BK, Anitha B, Deepa R, Mohan V. Association of serum lipids with diabetic retinopathy in urban South Indians–the Chennai Urban Rural Epidemiology Study (CURES) Eye Study–2. Diabet Med. 2006;23:1029–36.PubMedCrossRefGoogle Scholar
  21. 21.
    Obrosova IG, Minchenko AG, Marinescu V, Fathallah L, Kennedy A, Stockert CM, et al. Antioxidants attenuate early up regulation of retinal vascular endothelial growth factor in streptozotocin-diabetic rats. Diabetologia. 2001;44:1102–10.PubMedCrossRefGoogle Scholar
  22. 22.
    Al-Shabrawey M, Bartoli M, El-Remessy AB, Platt DH, Matragoon S, Behzadian MA, et al. Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol. 2005;167:599–607.PubMedCrossRefGoogle Scholar
  23. 23.
    Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes. 2003;52:818–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang Y, Zang QS, Liu Z, Wu Q, Maass D, Dulan G, et al. Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol. 2011;301:C695–704.PubMedCrossRefGoogle Scholar
  25. 25.
    Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al-Shabrawey M. Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen induced retinopathy: role of NADPH oxidase. Investig Ophthalmol Vis Sci. 2009;50:878–84.CrossRefGoogle Scholar
  26. 26.
    Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol. 2003;75:95–108.PubMedCrossRefGoogle Scholar
  27. 27.
    Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998;101:1219–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.PubMedCrossRefGoogle Scholar
  29. 29.
    Bartlett HE, Eperjesi F. Nutritional supplementation for type 2 diabetes: a systematic review. Ophthalmic Physiol Opt. 2008;28:503–23.PubMedCrossRefGoogle Scholar
  30. 30.
    •• Lee CT, Gayton EL, Beulens JW, Flanagan DW, Adler AI. Micronutrients and diabetic retinopathy a systematic review. Ophthalmology. 2010;117:71–8. A systematic review, which although failing to find epidemiological evidence in support of use of micronutrients, including antioxidants, for DR provides an invaluable description of methodological considerations in the field.PubMedCrossRefGoogle Scholar
  31. 31.
    West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol. 2006;141:157–66.PubMedCrossRefGoogle Scholar
  32. 32.
    Wilkinson JT, Fraunfelder FW. Use of herbal medicines and nutritional supplements in ocular disorders: an evidence-based review. Drugs. 2011;71:2421–34.PubMedCrossRefGoogle Scholar
  33. 33.
    Lopes de Jesus CC, Atallah AN, Valente O, Moça Trevisani VF. Vitamin C and superoxide dismutase (SOD) for diabetic retinopathy. Cochrane Database Syst Rev. 2008;23(1):CD006695.Google Scholar
  34. 34.
    Blache D, Devaux S, Joubert O, Loreau N, Schneider M, Durand P, et al. Long-term moderate magnesium-deficient diet shows relationships between blood pressure, inflammation, and oxidant stress defense in aging rats. Free Radic Biol Med. 2006;41:277–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Johnson FC. The antioxidant vitamins. CRC Crit Rev Food Sci Nutr. 1979;11:217–309.PubMedCrossRefGoogle Scholar
  36. 36.
    Millen AE, Klein R, Folsom AR, Stevens J, Palta M, Mares JA. Relation between intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study. Am J Clin Nutr. 2004;79:865–73.PubMedGoogle Scholar
  37. 37.
    Mayer-Davis EJ, Bell RA, Reboussin BA, Rushing J, Marshall JA, Hamman RF. Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley Diabetes Study. Ophthalmology. 1998;105:2264–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Millen AE, Gruber M, Klein R, Klein BE, Palta M, Mares JA. Relations of serum ascorbic acid and alpha-tocopherol to diabetic retinopathy in the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2003;158:225–33.PubMedCrossRefGoogle Scholar
  39. 39.
    de Valk HW, Hardus PL, van Rijn HJ, Erkelens DW. Plasma magnesium concentration and progression of retinopathy. Diabetes Care. 1999;22:864–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417–36.Google Scholar
  41. 41.
    Kowluru RA, Zhong Q. Beyond AREDS: is there a place for antioxidant therapy in the prevention/treatment of eye disease? Investig Ophthalmol Vis Sci. 2011;52:8665–71.CrossRefGoogle Scholar
  42. 42.
    Avignon A, Hokayem M, Bisbal C, Lambert K. Dietary antioxidants: do they have a role to play in the ongoing fight against abnormal glucose metabolism? Nutrition. 2012;28:715–21.PubMedCrossRefGoogle Scholar
  43. 43.
    de Lemos ET, Oliviera J, Pinheiro JP, Reis F. Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev. 2012;2012:741545.Google Scholar
  44. 44.
    Biesenbach G, Grafinger P, Janko O, Zazgornik J. Influence of cigarette-smoking on the progression of clinical diabetic nephropathy in type 2 diabetic patients. Clin Nephrol. 1997;48:146–50.PubMedGoogle Scholar
  45. 45.
    Chuahirun T, Wesson DE. Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition. Am J Kidney Dis. 2002;39:376–82.PubMedCrossRefGoogle Scholar
  46. 46.
    Nilsson PM, Cederholm J, Eeg-Olofsson K, Eliasson B, Zethelius B, Fagard R, et al. Smoking as an independent risk factor for myocardial infarction or stroke in type 2 diabetes: a report from the Swedish National Diabetes Register. Eur J Cardiovasc Prev Rehabil. 2009;16:506–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Guillausseau PJ, Massin P, Charles MA, Allaguy H, Güvenli Z, Virally M, et al. Glycaemic control and development of retinopathy in type 2 diabetes mellitus: a longitudinal study. Diabet Med. 1998;15:151–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Moss SE, Klein R, Klein BE. Cigarette smoking and ten-year progression of diabetic retinopathy. Ophthalmology. 1996;103:1438–42.PubMedGoogle Scholar
  49. 49.
    Ulvik A, Ebbing M, Hustad S, Midttun Ø, Nygård O, Vollset SE, et al. Long- and short-term effects of tobacco smoking on circulating concentrations of B vitamins. Clin Chem. 2010;56:755–63.PubMedCrossRefGoogle Scholar
  50. 50.
    Ergüder IB, Ergüder T, Ozkan C, Bozkurt N, Soylu K, Devrim E, et al. Short-term effects of smoking cessation on blood antioxidant parameters and paraoxonase activity in healthy asymptomatic long-term cigarette smokers. Inhal Toxicol. 2006;18:575–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Kowluru RA, Kanwar M, Chan PS, Zhang JP. Inhibition of retinopathy and retinal metabolic abnormalities in diabetic rats with AREDS-based micronutrients. Arch Ophthalmol. 2008;126:1266–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Mustata GT, Rosca M, Biemel KM, Reihl O, Smith MA, Viswanathan A, et al. Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes. 2005;54:517–26.PubMedCrossRefGoogle Scholar
  53. 53.
    Hu BJ, Hu YN, Lin S, Ma WJ, Li XR. Application of lutein and zeaxanthin in nonproliferative diabetic retinopathy. Int J Ophthalmol. 2011;4:303–6.PubMedGoogle Scholar
  54. 54.
    Salvemini D, Wang ZQ, Zweier JL, Samouilov A, Macarthur H, Misko TP, et al. A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science. 1999;286:304–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Batinic-Haberle I, Reboucas JS, Spasojevic I. Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal. 2010;13:877–918.PubMedCrossRefGoogle Scholar
  56. 56.
    Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care. 1999;22:1245–51.PubMedCrossRefGoogle Scholar
  57. 57.
    Faure P, Benhamou PY, Perard A, Halimi S, Roussel AM. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Eur J Clin Nutr. 1995;49:282–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Michael Williams
    • 1
  • Ruth E. Hogg
    • 2
  • Usha Chakravarthy
    • 2
  1. 1.Medical Ophthalmology, Department of OphthalmologyRoyal Victoria Hospital, Belfast Health and Social Care TrustBelfastUK
  2. 2.Centre for Vision and Vascular ScienceQueen’s University of Belfast, Institute of Clinical Science Block A, Royal Victoria HospitalBelfastUK

Personalised recommendations