Diabetic retinopathy: pathogenesis and therapeutic implications

Czech version

Authors: Terezie Pelikánová
Authors‘ workplace: Centrum diabetologie IKEM, Praha
Published in: Vnitř Lék 2016; 62(7-8): 620-628
Category: Reviews

Overview

Diabetic retinopathy (DR) develops in patients with both type 1 and type 2 diabetes and is the major cause of vision loss and blindness in the working population. The main risk factor of DR is hyperglycemia accompanied by enhanced mitochondrial production of reactive oxygen species and oxidative stress, formation of advanced glycation end products (AGE) and hexosamines, increase in polyol metabolism of glucose. The severity of vascular injury depends on the individual genetic background and is modified by other epigenetic, metabolic and haemodynamic factors, including hypertension, dyslipidemia and oxidative stress. In diabetes, damage to the retina occurs in the vasculature (endothelial cells and pericytes), neurons and glia, pigment epithelial cells and infiltrating immunocompetent cells: monocytes, granulocytes, lymfocytes. These activated cells change the production pattern of a number of mediators such as growth factors, proinflammatory cytokines, vasoactive molecules, coagulation factors and adhesion molecules resulting in increased blood flow, increased capillary permeability, proliferation of extracellular matrix and thickening of basal membranes, altered cell turnover (apoptosis, proliferation, hypertrophy), procoagulant and proaggregant pattern, and finally in angiogenesis and tissue remodelling. Brain, liver, adipose tissue, GUT, skeletal muscle and other tissues could be another source of mediators. Therapeutic approaches used for patients with or at risk for diabetic retinopathy include drug therapy to reduce modifiable risk factors, laser photocoagulation, intravitreous administration of anti-VEGF agents/steroids and intraocular surgery. Screening plays an important role in early detection and intervention to prevent the progression of diabetic retinopathy. Described insights into pathophysiological mechanisms responsible for DR, could help in the development of more targeted approach for prevention and treatment of diabetic retinopathy.

Key words:
anti-VEGF – diabetic dyslipidemia – growth factors – hyperglycemia – hypertension – microRNA – oxidative stress – retinopathy

Sources

1. Sosna T. Diabetická retinopatie – diagnostika, prevence, léčba. Axonite: Praha 2016. ISBN 978–80–88046–05–9.

2. Kalvodová B. Diabetická oftalmopatie. In: Škrha J (ed.) Diabetologie. Galén: Praha 2009: 177–188. ISBN 978–80–7262–607–6.

3. Singleton JR, Smith AG, Russell JW et al. Microvascular complications of impaired glucose tolerance. Diabetes 2003; 52(12): 2867–2873.

4. Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 2007; 14(4): 179–183.

5. Yau JW, Rogers SL, Kawasaki R et al. Meta-Analysis for Eye Disease Study G. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3): 556–564.

6. Kalvodová B, Kalvoda J. Diabetický makulární edém. In: Ernest J (ed.) Makulární edémy. Mladá fronta: Praha 2014: 120–155. ISBN 978–80–204–3472–2.

7. Hammes HP, Welp R, Kempe HP et al. [DPV Initiative—German BMBF Competence Network Diabetes Mellitus]. Risk Factors for Retinopathy and DME in Type 2 Diabetes-Results from the German/Austrian DPV Database. PLoS One 2015; 10(7): e0132492. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0132492>.

8. Cho H, Sobrin L. Genetics of diabetic retinopathy. Curr Diab Rep 2014; 14(8): 515.

9. Kuo JZ, Wong TY, Rotter JI. Challenges in elucidating the genetics of diabetic retinopathy. JAMA Ophthalmol 2014; 132(1): 96–107.

10. Agardh E, Lundstig A, Perfilyev A et al. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med 2015; 13: 182.

11. Novák J, Bienertová-Vašků J, Slabý O. Mikrorna a diabetes mellitus. In: Kvapil M (ed.) Diabetologie 2014. Triton: Praha 2014: 225–233. ISBN 9788073877552.

12. Yang TT, Song SJ, Xue HB et al. Regulatory t cells in the pathogenesis of type 2 diabetes mellitus retinopathy by mir-155. Eur Rev Med Pharmacol Sci 2015; 19(11): 2010–2015.

13. McAuley AK, Dirani M, Wang JJ et al. A genetic variant regulating mir-126 is associated with sight threatening diabetic retinopathy. Diab Vasc Dis Res 2015; 12(2): 133–138.

14. Zampetaki A, Willeit P, Burr S et al. Angiogenic micrornas linked to incidence and progression of diabetic retinopathy in type 1 diabetes. Diabetes 2016; 65(1): 216–227.

15. Pelikánová T. Patogeneza diabetické retinopatie. Vnitř Lék 2007; 53(5): 498–505.

16. Tarr JM, Kaul K, Chopra M et al. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol 2013; 2013: 343560. Dostupné z DOI: <http://dx.doi.org/10.1155/2013/343560>.

17. Wilkinson-Berka JL, Rana I, Armani R et al. Reactive oxygen species, nox and angiotensin ii in angiogenesis: Implications for retinopathy. Clin Sci (Lond) 2013; 124(10): 597–615.

18. Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta 2015; 1852(11): 2474–2483.

19. Coucha M, Elshaer SL, Eldahshan WS et al. Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets. Middle East Afr J Ophthalmol 2015; 22(2): 135–144.

20. [Uk prospective diabetes study (UKPDS) group]. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837–853. Erratum in Lancet 1999; 354(9178): 602.

21. [Diabetes Control and Complications Trial Research Group]. The effect of intensive diabetes treatment on the development and progression of long term complication in non-insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–986.

22. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ 2000; 321(7258): 405–412.

23. White NH, Sun W, Cleary PA et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the diabetes control and complications trial. Arch Ophthalmol 2008; 126(12): 1707–1715.

24. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577–1589.

25. Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic retinopathy. J Neuroinflammation 2015; 12: 141.

26. Soheilian M, Karimi S, Ramezani A et al. Intravitreal diclofenac versus intravitreal bevacizumab in naive diabetic macular edema: A randomized double-masked clinical trial. Int Ophthalmol 2015; 35(3): 421–428.

27. Chew EY, Klein ML, Ferris FL et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22.. Arch Ophthalmol 1996; 114(9): 1079–1084.

28. Keech AC, Mitchell P, Summanen PA et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (field study): A randomised controlled trial. Lancet 2007; 370(9600): 1687–1697.

29. Chew EY, Ambrosius WT, Davis MD et al. [ACCORD Study Group; ACCORD Eye Study Group]. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363: 233–244. Erratum in N Engl J Med 2011; 364(2): 190. N Engl J Med 2012; 367(25): 2458.

30. Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (cards): Multicentre randomised placebo-controlled trial. Lancet 2004; 364(9435): 685–696.

31. Holman RR, Paul SK, Bethel MA et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008; 359(15): 1565–1576.

32. Chaturvedi N, Sjolie AK, Stephenson JM et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The euclid study group. Eurodiab controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet 1998; 351(9095): 28–31.

33. Chew EY, Davis MD, Danis RP et al. [Action to Control Cardiovascular Risk in Diabetes Eye Study Research Group]. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: The action to control cardiovascular risk in diabetes (ACCORD) eye study. Ophthalmology 2014; 121(12): 2443–2451.

34. Do DV, Wang X, Vedula SS et al. Blood pressure control for diabetic retinopathy. Cochrane Database Syst Rev 2015; 1: CD006127. Dostupné z DOI: <http://dx.doi.org/10.1002/14651858.CD006127.pub2>.

35. Bonadonna R, Cucinotta D, Fedele D et al. [Metascreen Writing Committee]. The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: Results from metascreen, a multicenter diabetes clinic-based survey. Diabetes Care 2006; 29(12): 2701–2707.

36. Costa LA, Canani LH, Lisboa HR et al. Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabet Med 2004; 21(3): 252–255.

37. Hammes HP, Feng Y, Pfister F et al. Diabetic retinopathy: Targeting vasoregression. Diabetes 2011; 60(1): 9–16.

38. Semeraro F, Cancarini A, dell‘Omo R et al. Diabetic retinopathy: Vascular and inflammatory disease. J Diabetes Res 2015; 2015: 582060. Dostupné z DOI: <http://dx.doi.org/10.1155/2015/582060>.

39. Arden GB. The absence of diabetic retinopathy in patients with retinitis pigmentosa: Implications for pathophysiology and possible treatment. Br J Ophthalmol 2001; 85(3): 366–370.

40. de Gooyer TE, Stevenson KA, Humphries P et al. Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci 2006; 47(12): 5561–5568.

41. Kern TS, Berkowitz BA. Photoreceptors in diabetic retinopathy. J Diabetes Investig 2015; 6(4): 371–380.

42. Du Y, Veenstra A, Palczewski K et al. Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci USA 2013; 110(41): 16586–16591. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.1314575110>.

43. Boehm BO, Lang G, Volpert O et al. Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (pedf) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 2003; 46(3): 394–400.

44. Watanabe D, Suzuma K, Matsui S et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 2005; 353(8): 782–792.

45. Hernandez C, Fonollosa A, Garcia-Ramirez M et al. Erythropoietin is expressed in the human retina and it is highly elevated in the vitreous fluid of patients with diabetic macular edema. Diabetes Care 2006; 29 (9): 2028–2033.

46. Simo R, Hernandez C. [European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR)]. Neurodegeneration in the diabetic eye: New insights and therapeutic perspectives. Trends Endocrinol Metab 2014; 25(1): 23–33.

47. Studnička J. Indikace ranibizumabu v oftalmologii. Remedia 2012; 22(5): 341–344.

48. Yanagida Y, Ueta T. Systemic safety of ranibizumab for diabetic macular edema: Meta-analysis of randomized trials. Retina 2014; 34(4): 629–635.

49. Wells JA, Glassman AR, Ayala AR et al. [Diabetic Retinopathy Clinical Research Network]. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372(13): 1193–1203.

50. Brown DM, Schmidt-Erfurth U, Do DV et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology 2015; 122(10): 2044–2052.

51. Korobelnik JF, Do DV, Schmidt-Erfurth U et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014; 121(11): 2247–2254.

52. Evans M, Katz TA, Crane M. Effects of baseline haemoglobin a1c and on-treatment blood pressure on outomes in the vivid-dme and vista-dme studies. EASD 2015. Abstract #235. Dostupné z WWW: <http://www.easdvirtualmeeting.org/resources/effects-of-baseline-haemoglobin-a1c-and-on-treatment-blood-pressure-on-outcomes-in-the-vivid-dme-and-vista-dme-studies--2>.

53. Kalvodová B, Sosna T, Ernest J et al. Doporučené postupy pro diagnostiku a léčbu diabetické retinopatie. Doporučení české diabetologické společnosti, české oftalmologické společnosti a české vitreoretinální společnosti. DMEV 2016; 19(2): 64–71.