Current Diabetes Reports

, Volume 7, Issue 1, pp 8–13 | Cite as

Antioxidants and CVD in diabetes: Where do we stand now?



Diabetes is an oxidative stress disorder as a result of both hyperglycemia and increased levels of free fatty acids. Oxidative stress has been implicated in the pathogenesis of diabetes-related complications, and treatment with antioxidants seemed to be a promising therapeutic option. Although animal studies and preliminary human studies were initially encouraging, subsequent human studies have failed to show a clear benefit of antioxidants, whereas some studies have even suggested that they can be potentially harmful. Therefore, treatment with antioxidants cannot be currently recommended as a therapeutic option.


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References and Recommended Reading

  1. 1.
    King GL, Loeken MR: Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol 2004, 122:333–338.PubMedCrossRefGoogle Scholar
  2. 2.
    Nishikawa T, Edelstein D, Du XL, et al.: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404:787–790.PubMedCrossRefGoogle Scholar
  3. 3.
    Creager MA, Luscher TF, Cosentino F, Beckman JA: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 2003, 108:1527–1532.PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    Hofmann MA, Drury S, Fu C, et al.: RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999, 97:889–901.PubMedCrossRefGoogle Scholar
  6. 6.
    Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414:813–820.PubMedCrossRefGoogle Scholar
  7. 7.
    Craven PA, Studer RK, DeRubertis FR: Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response. J Clin Invest 1994, 93:311–320.PubMedGoogle Scholar
  8. 8.
    Kolm-Litty V, Sauer U, Nerlich A, et al.: High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest 1998, 101:160–169.PubMedGoogle Scholar
  9. 9.
    Du XL, Edelstein D, Dimmeler S, et al.: Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001, 108:1341–1348.PubMedCrossRefGoogle Scholar
  10. 10.
    Pacher P, Szabo C: Role of peroxynitrite in the pathogenesis of cardiovascular complications of diabetes. Curr Opin Pharmacol 2006, 6:136–141.PubMedCrossRefGoogle Scholar
  11. 11.
    Johansen JS, Harris AK, Rychly DJ, Ergul A: Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol 2005, 4:5.PubMedCrossRefGoogle Scholar
  12. 12.
    Maritim AC, Sanders RA, Watkins JB 3rd: Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 2003, 17:24–38.PubMedCrossRefGoogle Scholar
  13. 13.
    Stewart-Lee AL, Forster LA, Nourooz-Zadeh J, et al.: Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits. Arterioscler Thromb 1994, 14:494–499.PubMedGoogle Scholar
  14. 14.
    Cinar MG, Ulker S, Alper G, Evinc A: Effect of dietary vitamin E supplementation on vascular reactivity of thoracic aorta in streptozotocin-diabetic rats. Pharmacology 2001, 62:56–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Palmer AM, Thomas CR, Gopaul N, et al.: Dietary antioxidant supplementation reduces lipid peroxidation but impairs vascular function in small mesenteric arteries of the streptozotocin-diabetic rat. Diabetologia 1998, 41:148–156.PubMedCrossRefGoogle Scholar
  16. 16.
    Alper G, Olukman M, Irer S, et al.: Effect of vitamin E and C supplementation combined with oral antidiabetic therapy on the endothelial dysfunction in the neonatally streptozotocin injected diabetic rat. Diabetes Metab Res Rev 2006, 22:190–197.PubMedCrossRefGoogle Scholar
  17. 17.
    Gorbunov NV, Osipov AN, Sweetland MA, et al.: NO-redox paradox: direct oxidation of alpha-tocopherol and alpha-tocopherol-mediated oxidation of ascorbate. Biochem Biophys Res Commun 1996, 219:835–841.PubMedCrossRefGoogle Scholar
  18. 18.
    Moens AL, Kass DA: Tetrahydrobiopterin and cardiovascular Disease. Arterioscler Thromb Vasc Biol 2006, 26:2439–2444.PubMedCrossRefGoogle Scholar
  19. 19.
    Akamine EH, Kawamoto EM, Scavone C, et al.: Correction of endothelial dysfunction in diabetic female rats by tetrahydrobiopterin and chronic insulin. J Vasc Res 2006, 43:309–320.PubMedCrossRefGoogle Scholar
  20. 20.
    Meininger CJ, Marinos RS, Hatakeyama K, et al.: Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J 2000, 349:353–356.PubMedCrossRefGoogle Scholar
  21. 21.
    d’Uscio LV, Katusic ZS: Increased vascular biosynthesis of tetrahydrobiopterin in apolipoprotein E-deficient mice. Am J Physiol Heart Circ Physiol 2006, 290:H2466–H2471.PubMedCrossRefGoogle Scholar
  22. 22.
    Hammes HP, Du X, Edelstein D, et al.: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003, 9:294–299.PubMedCrossRefGoogle Scholar
  23. 23.
    Marchetti V, Menghini R, Rizza S, et al.: Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling. Diabetes 2006, 55:2231–2237.PubMedCrossRefGoogle Scholar
  24. 24.
    Beckman JA, Goldfine AB, Gordon MB, Creager MA: Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001, 103:1618–1623.PubMedGoogle Scholar
  25. 25.
    Timimi FK, Ting HH, Haley EA, et al.: Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998, 31:552–557.PubMedCrossRefGoogle Scholar
  26. 26.
    Ting HH, Timimi FK, Boles KS, et al.: Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996, 97:22–28.PubMedCrossRefGoogle Scholar
  27. 27.
    Schneider MP, Delles C, Schmidt BM, et al.: Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension. Am J Hypertens 2005, 18:1111–1117.PubMedCrossRefGoogle Scholar
  28. 28.
    Beckman JA, Goldfine AB, Gordon MB, et al.: Oral antioxidant therapy improves endothelial function in type 1 but not type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 2003, 285:H2392–H2398.PubMedGoogle Scholar
  29. 29.
    Chen H, Karne RJ, Hall G, et al.: High-dose oral vitamin C partially replenishes vitamin C levels in patients with type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol 2006, 290:H137–H145.PubMedCrossRefGoogle Scholar
  30. 30.
    Jackson TS, Xu A, Vita JA, Keaney JF Jr: Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998, 83:916–922.PubMedGoogle Scholar
  31. 31.
    Economides PA, Khaodhiar L, Caselli A, et al.: The effect of vitamin E on endothelial function of micro-and macro-circulation and left ventricular function in type 1 and type 2 diabetic patients. Diabetes 2005, 54:204–211.PubMedCrossRefGoogle Scholar
  32. 32.
    Stephens NG, Parsons A, Schofield PM, et al.: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996, 347:781–786.PubMedCrossRefGoogle Scholar
  33. 33.
    Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico [no authors listed]. Lancet 1999, 354:447–455.Google Scholar
  34. 34.
    Yusuf S, Dagenais G, Pogue J, et al.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:154–160.PubMedCrossRefGoogle Scholar
  35. 35.
    Lonn E, Bosch J, Yusuf S, et al.: Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005, 293:1338–1347.PubMedCrossRefGoogle Scholar
  36. 36.
    Eidelman RS, Hollar D, Hebert PR, et al.: Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 2004, 164:1552–1556.PubMedCrossRefGoogle Scholar
  37. 37.
    Shekelle PG, Morton SC, Jungvig LK, et al.: Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med 2004, 19:380–389.PubMedCrossRefGoogle Scholar
  38. 38.
    Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al.: Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005, 142:37–46.PubMedGoogle Scholar
  39. 39.
    Ihlemann N, Rask-Madsen C, Perner A, et al.: Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am J Physiol Heart Circ Physiol 2003, 285:H875–H882.PubMedGoogle Scholar
  40. 40.
    Heitzer T, Krohn K, Albers S, Meinertz T: Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 2000, 43:1435–1438.PubMedCrossRefGoogle Scholar
  41. 41.
    Stirban A, Negrean M, Stratmann B, et al.: Benfotiamine prevents macro-and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 2006, 29:2064–2071.PubMedCrossRefGoogle Scholar
  42. 42.
    Haupt E, Ledermann H, Kopcke W: Benfotiamine in the treatment of diabetic polyneuropathy—a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther 2005, 43:71–77.PubMedGoogle Scholar
  43. 43.
    Kushi LH, Folsom AR, Prineas RJ, et al.: Dietary antioxidant vitamins and death from coronary heart disease in post-menopausal women. N Engl J Med 1996, 334:1156–1162.PubMedCrossRefGoogle Scholar
  44. 44.
    Kris-Etherton P, Eckel RH, Howard BV, et al.: Lyon Diet Heart Study: benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association step I dietary pattern on cardiovascular disease. Circulation 2001, 103:1823–1825.PubMedGoogle Scholar
  45. 45.
    Perez-Jimenez F, Alvarez de Cienfuegos G, Badimon L, et al.: International conference on the healthy effect of virgin olive oil. Eur J Clin Invest 2005, 35:421–424.PubMedCrossRefGoogle Scholar
  46. 46.
    Esposito K, Marfella R, Ciotola M, et al.: Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004, 292:1440–1446.PubMedCrossRefGoogle Scholar
  47. 47.
    van Dam RM, Hu FB: Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA 2005, 294:97–104.PubMedCrossRefGoogle Scholar
  48. 48.
    Pereira MA, Parker ED, Folsom AR: Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women. Arch Intern Med 2006, 166:1311–1316.PubMedCrossRefGoogle Scholar
  49. 49.
    Kuriyama S, Shimazu T, Ohmori K, et al.: Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA 2006, 296:1255–1265.PubMedCrossRefGoogle Scholar
  50. 50.
    Iso H, Date C, Wakai K, et al.: The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006, 144:554–562.PubMedGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Microcirculation Laboratory, Palmer 321ABeth Israel Deaconess Medical Center, West CampusBostonUSA

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