Current Diabetes Reports

, Volume 6, Issue 2, pp 102–107 | Cite as

Mechanisms and strategies for prevention in diabetic retinopathy



Evidence converges from multiple directions to indicate that prevention or very early intervention is the correct approach to diabetic retinopathy. Preclinical studies are identifying promising drugs or classes of drugs to be added to antidiabetic treatment. Recent clinical trials were still initiated at such late stages of retinopathy that the results are not readily interpretable. The challenge for the next few years is to find ways faster than clinical trials to ascertain the relevance to human diabetic retinopathy of adjunct drugs successful in animal studies.


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References and Recommended Reading

  1. 1.
    Ramsay R, Goetz F, Sutherland D, et al.: Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1988, 318:208–214.PubMedCrossRefGoogle Scholar
  2. 2.
    Petersen M, Vine A: Progression of diabetic retinopathy after pancreas transplantation. Ophthalmology 1990, 97:496–502.PubMedGoogle Scholar
  3. 3.
    Kennedy W, Navarro X, Goetz F, et al.: Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990, 322:1031–1037.PubMedCrossRefGoogle Scholar
  4. 4.
    Fioretto P, Steffes M, Sutherland D, et al.: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998, 339:69–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Early worsening of diabetic retinopathy in the diabetes control and complications trial [no authors listed]. Arch Ophthalmol 1998, 116:874–886.Google Scholar
  6. 6.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus [no authors listed]. N Engl J Med 1993, 329:977–986.Google Scholar
  7. 7.
    Engerman R, Kern T: Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 1987, 36:808–812.PubMedCrossRefGoogle Scholar
  8. 8.
    Roy S, Sala R, Cagliero E, Lorenzi M: Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A 1990, 87:404–408.PubMedCrossRefGoogle Scholar
  9. 9.
    The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Effects of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002, 287:2563–2569.CrossRefGoogle Scholar
  10. 10.
    The Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy. The epidemiology of diabetes interventions and complications (EDIC) study. JAMA 2003, 290:2159–2167.CrossRefGoogle Scholar
  11. 11.
    Nathan DM, Lachin J, Cleary P, et al.: Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003, 348:2294–2303.PubMedCrossRefGoogle Scholar
  12. 12.
    Mizutani M, Kern T, Lorenzi M: Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996, 97:2883–2890.PubMedCrossRefGoogle Scholar
  13. 13.
    Mecham R, Whitehouse L, Wrenn D, et al.: Smooth muscle-mediated connective tissue remodeling in pulmonary hypertension. Science 1987, 237:423–426.PubMedCrossRefGoogle Scholar
  14. 14.
    Munsat T: Poliomyelitis—new problems with an old disease. N Engl J Med 1991, 324:1206–1208.PubMedCrossRefGoogle Scholar
  15. 15.
    Mohsin F, Craig M, Cusumano J, et al.: Discordant trends in microvascular complications in adolescents with type 1 diabetes from 1990 to 2002. Diabetes Care 2005, 28:1974–1980. Describes the changing rates of diabetic complications in adolescents with type 1 diabetes after the DCCT.PubMedCrossRefGoogle Scholar
  16. 16.
    Asnaghi V, Gerhardinger C, Hoehn T, et al.: A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat. Diabetes 2003, 52:506–511.PubMedCrossRefGoogle Scholar
  17. 17.
    Dagher Z, Park YS, Asnaghi V, et al.: Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes 2004, 53:2404–2411. Shows the effects of the polyol pathway on multiple features of diabetic retinopathy in the rat, and aspects relevant to human diabetic retinopathy.PubMedCrossRefGoogle Scholar
  18. 18.
    Mizutani M, Gerhardinger C, Lorenzi M: Müller cell changes in human diabetic retinopathy. Diabetes 1998, 47:445–449.PubMedCrossRefGoogle Scholar
  19. 19.
    Engerman R, Kern T: Retinopathy in animal models of diabetes. Diabetes Metab Rev 1995, 11:109–120.PubMedCrossRefGoogle Scholar
  20. 20.
    Hammes HP, Lin J, Renner O, et al.: Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51:3107–3112.PubMedCrossRefGoogle Scholar
  21. 21.
    Barber A, Antonetti D, Kern T, et al.: The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci 2005, 46:2210–2218.PubMedCrossRefGoogle Scholar
  22. 22.
    Gerhardinger C, Cost MB, Coulombe M, et al.: Expression of acute-phase response proteins in retinal Müller cells in diabetes. Invest Ophthalmol Vis Sci 2005, 46:349–357. Describes the complex reactive phenotype that Müller glial cells acquire in experimental diabetes.PubMedCrossRefGoogle Scholar
  23. 23.
    Stitt A, Gardiner T, Anderson N, et al.: The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 2002, 51:2826–2832.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    Zheng L, Szabo C, Kern T: Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB. Diabetes 2004, 53:2960–2967.PubMedCrossRefGoogle Scholar
  26. 26.
    Kern TS, Engerman R: Pharmacological inhibition of diabetic retinopathy. Aminoguanidine and aspirin. Diabetes 2001, 50:1636–1642.PubMedCrossRefGoogle Scholar
  27. 27.
    Sun W, Gerhardinger C, Dagher Z, et al.: Aspirin at lowintermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-plateletmediated effects. Diabetes 2005, 54:3418–3426. Compares the effects of aspirin, a selective antiplatelet agent, and an ARI on multiple outcomes in experimental diabetic retinopathy. Reports a hierarchy of effects, and beneficial effects of aspirin exerted at low-intermediate concentrations.PubMedCrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    Sochor M, Kunjara S, McLean P: The effect of aldose reductase inhibitor Statil (ICI 128436) on the glucose over-utilization in kidney of diabetic rats. Biochem Pharmacol 1988, 37:3349–3356.PubMedCrossRefGoogle Scholar
  30. 30.
    Cheng HM, Hirose K, Xiong H, González R: Polyol pathway activity in streptozotocin-diabetic rat lens. Exp Eye Res 1989, 49:87–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Wu G, Marliss EB: Enhanced glucose metabolism and respiratory burst in peritoneal macrophages from spontaneously diabetic BB rats. Diabetes 1993, 42:520–529.PubMedCrossRefGoogle Scholar
  32. 32.
    Chung SSM, Chung SK: Aldose reductase in diabetic microvascular complications. Curr Drug Targets 2005, 6:475–486. This is an updated and comprehensive review on the relationship of the polyol pathway with diabetic complications.PubMedCrossRefGoogle Scholar
  33. 33.
    A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy. Sorbinil Retinopathy Trial Research Group [no authors listed]. Arch Ophthalmol 1990, 108:1234–1244.Google Scholar
  34. 34.
    Pillinger M, Capodici C, Rosenthal P, et al.: Modes of action of aspirin-like drugs: salicylates inhibit Erk activation and integrin-dependent neutrophil adhesion. Proc Natl Acad Sci U S A 1998, 95:14540–14545.PubMedCrossRefGoogle Scholar
  35. 35.
    Mylari BL, Armento SJ, Beebe DA, et al.: A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2-H-pyridazin-3-one. J Med Chem 2003, 46:2283–2286.PubMedCrossRefGoogle Scholar
  36. 36.
    Hotta N, Toyota T, Matsuoka K, et al.: Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebocontrolled double-blind parallel group study. Diabetes Care 2001, 24:1776–1782.PubMedCrossRefGoogle Scholar
  37. 37.
    Bril V, Buchanan RA: Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 2004, 27:2369–2375.PubMedCrossRefGoogle Scholar
  38. 38.
    Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group [no authors listed]. Ophthalmology 1991, 98:757–765.Google Scholar
  39. 39.
    Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group [no authors listed]. Diabetes 1989, 38:491–498.Google Scholar
  40. 40.
    The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta inhibitor diabetic retinopathy study (PKC-DRS) multicenter randomized clinical trial. The PKC-DRS Study Group [no authors listed]. Diabetes 2005, 54:2188–2197. Reports the results of the clinical trial testing a selective PKC β inhibitor on progression of advanced retinopathy.Google Scholar
  41. 41.
    Wilkinson-Berka JL: Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol 2005, Sep 12; [Epub ahead of print].Google Scholar
  42. 42.
    Charbonnel B, Massin P: The Diabetic Retinopathy Candesartan Trials (DIRECT): rationale and design [abstract]. J Hypertens 2005, 23:A5.CrossRefGoogle Scholar
  43. 43.
    Cunningham ET Jr, Adamis AP, Altaweel M, et al.: A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005, 112:1747–1757. Reports the results of a clinical trial testing a VEGF inhibitor administered intravitreally on diabetic macular edema.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  1. 1.Schepens Eye Research InstituteHarvard Medical SchoolBostonUSA

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