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Abstract
Diabetic Retinopathy (RD) is the main cause of blindness in people of productive age worldwide. Poor control of hyperglycemia and blood pressure are essential risk factors for the development of RD. This condition will trigger the occurrence of biomolecular mechanisms that cause damage to vessels and cells in the retina and develop into RD. The early stages of RD are generally asymptomatic, so it is recommended to perform RD screening as soon as the patient is diagnosed with type 2 DM and every 5 years for type 1 DM patients. RD therapy can be carried out with a non-pharmacological and pharmacological approach that is applied based on the level of severity to minimize the progression of RD. Apart from conventional therapy, there are potential therapies in the future, which include oral pharmacological therapy, genetic therapy, stem cell therapy, and CRISPR-Cas-Based therapy.
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This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
Ulfayani, N., & Haitsam, M. (2023). Diabetic Retinopathy: Pathogenesis, Diagnosis, Present and Future Management . Jurnal Klinik Dan Riset Kesehatan, 3(1), 18-32. https://doi.org/10.11594/jk-risk.03.1.4
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2. Flaxel CJ, Adelman RA, Bailey ST, Fawzi A, Lim JI, Vemulakonda GA, et al. Diabetic Retinopathy Preferred Practice Pattern®. Vol. 127, American Academy of Ophthalmology. Elsevier Inc.; 2020. 66–145 p.
3. PERDAMI. Pedoman Nasional Pelayanan Kedokteran: RETINOPATI DIABETIKA PERSATUAN. Dameria D, Andayani G, Rahman K, Soedarman S, editors. 2018.
4. Kementrian Kesehatan RI. InfoDATIN: Situasi dan Analisi Diabetes. 2014. p. 1–2.
5. Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R. Pathophysiology of Diabetic Retinopathy. ISRN Ophthalmol. 2013 Jan 15;2013:1–13.
6. Whitehead M, Wickremasinghe S, Osborne A, Van Wijngaarden P, Martin KR. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. Expert Opin Biol Ther. 2018 Dec 2;18(12):1257–70.
7. Ansari P, Tabasumma N, Snigdha NN, Siam NH, Panduru RVNRS, Azam S, et al. Diabetic Retinopathy: An Overview on Mechanisms, Pathophysiology and Pharmacotherapy. Diabetology. 2022 Feb 15;3(1):159–75.
8. Lechner J, O’Leary OE, Stitt AW. The pathology associated with diabetic retinopathy. Vision Res. 2017 Oct;139:7–14.
9. Shukla U V, Tripathy K. Diabetic Retinopathy. StatPearls [Internet]. 2023 Jan [cited 2023 Jun 13]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK560805/
10. Firdous SM, Dhang P, Koley A, Khan H. Diabetes and diabetic complications : current status and future perspectives. In: Diabetes and Diabetic Complications . Nova Science Publishers, Inc; 2021.
11. Wang W, Lo ACY. Diabetic retinopathy: Pathophysiology and treatments. Vol. 19, International Journal of Molecular Sciences. MDPI AG; 2018.
12. Solomon SD, Chew E, Duh EJ, Sobrin L, Sun JK, VanderBeek BL, et al. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Mar 1;40(3):412–8.
13. Sun JK, Radwan SH, Soliman AZ, Lammer J, Lin MM, Prager SG, et al. Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema. Diabetes. 2015 Jul 1;64(7):2560–70.
14. Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS Bin. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Vol. 2014, BioMed Research International. Hindawi Publishing Corporation; 2014.
15. Firdous SM. Diabetic retinopathy: Pathogenesis and Therapeutic Management. In: Diabetes and Diabetic Complications. 2021. p. 123–40.
16. Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020 Oct;37:101799.
17. Pan D, Xu L, Guo M. The role of protein kinase C in diabetic microvascular complications. Front Endocrinol (Lausanne). 2022 Aug 17;13.
18. Elvira EES. Retinopati Diabetes. CDK. 2019;46(3):220–4.
19. Falcão M, Falcão-Reis F, Rocha-Sousa A. Diabetic Retinopathy: Understanding Pathologic Angiogenesis and Explor-ing its Treatment Options. Vol. 3, The Open Circulation and Vascular Journal. 2010.
20. Gupta N, Mansoor S, Sharma A, Sapkal A, Sheth J, Falatoonzadeh P, et al. Diabetic Retinopathy and VEGF. Open Ophthalmol J. 2013;7:4–10.
21. Saini D, Kochar A, Poonia R. Clinical correlation of diabetic retinopathy with nephropathy and neuropathy. Indian J Ophthalmol. 2021;69(11):3364.
22. Samsu N. Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. Biomed Res Int. 2021 Jul 8;2021:1–17.
23. Trevisan R, Vedovato M, Mazzon C, Coracina A, Iori E, Tiengo A, et al. Concomitance of Diabetic Retinopathy and Proteinuria Accelerates the Rate of Decline of Kidney Function in Type 2 Diabetic Patients. Diabetes Care. 2002 Nov 1;25(11):2026–31.
24. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia. 2013 Mar 12;56(3):457–66.
25. Pavkov ME, Harding JL, Chou CF, Saaddine JB. Prevalence of Diabetic Retinopathy and Associated Mortality Among Diabetic Adults With and Without Chronic Kidney Disease. Am J Ophthalmol. 2019 Feb;198:200–8.
26. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia. 2013 Mar 12;56(3):457–66.
27. Dervišević M, Rebic D, Dervisevic E. Correlation between diabetic nephropathy and diabetic retinopathy as a long term complications of diabetes mellitus. 2023 May 21;1.
28. Jeng CJ, Hsieh YT, Yang CM, Yang CH, Lin CL, Wang IJ. Diabetic Retinopathy in Patients with Diabetic Nephropathy: Development and Progression. PLoS One. 2016 Aug 26;11(8):e0161897.
29. World Health Organization. Diabetic retinopathy screening: a short guide. Increase effectiveness, maximize benefits and minimize harm. Copenhagen; 2020.
30. Muqit M. ICO Guidelines For Diabetic Eye Care 2017. ICO Guidelines for Diabetic Eye Care. 2017 Jan;
31. World Health Organization. Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. New Delhi; 2020. 46 p.
32. Antonetti DA, Silva PS, Stitt AW. Current understanding of the molecular and cellular pathology of diabetic retinopathy. Vol. 17, Nature Reviews Endocrinology. Nature Research; 2021. p. 195–206.
33. Early Treatment Diabetic Retinopathy Study Research Group. Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs — An Extension of the Modified Airlie House Classification. Ophthalmology. 2020 Apr;127(4):S99–119.
34. Wu L, Fernandez-Loaiza P, Sauma J, Hernandez-Bogantes ,Erick, Masis M. Classification of diabetic retinopathy and diabetic macular edema. World J Diabetes. 2013;4(6):290.
35. Lechner J, Medina RJ, Lois N, Stitt AW. Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina. Stem Cell Res Ther. 2022 Dec 30;13(1):388.
36. Diabetic Retinopathy Clinical Research Network. Relationship between Optical Coherence Tomography–Measured Central Retinal Thickness and Visual Acuity in Diabetic Macular Edema. Ophthalmology. 2007 Mar;114(3):525–36.
37. Gardner TW, Larsen M, Girach A, Zhi X. Diabetic macular oedema and visual loss: relationship to location, severity and duration. Acta Ophthalmol. 2009 Nov;87(7):709–13.
38. Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine. 1993 Sep 30;329(14):977–86.
39. Do D V, Wang X, Vedula SS, Marrone M, Sleilati G, Hawkins BS, et al. Blood pressure control for diabetic retinopathy. Cochrane Database of Systematic Reviews. 2015 Jan 31;
40. Aro A, Kauppinen A, Summanen P, Kivinen N, Selander T, Kinnunen K, et al. Life Style Intervention Improves Retinopathy Status—The Finnish Diabetes Prevention Study. Nutrients. 2019 Jul 23;11(7):1691.
41. Bryl A, Mrugacz M, Falkowski M, Zorena K. The Effect of Diet and Lifestyle on the Course of Diabetic Retinopathy—A Review of the Literature. Nutrients. 2022 Mar 16;14(6):1252.
42. Arevalo JF, Wu L, Sanchez JG, Maia M, Saravia MJ, Fernandez CF, et al. Intravitreal bevacizumab (avastin) for proliferative diabetic retinopathy: 6-months follow-up. Eye. 2009 Jan 21;23(1):117–23.
43. Diabetic Retinopathy Clinical Research Network. A Phase II Randomized Clinical Trial of Intravitreal Bevacizumab for Diabetic Macular Edema. Ophthalmology. 2007 Oct;114(10):1860-1867.e7.
44. Vaziri K, Schwartz SG, Relhan N, Kishor KS, Flynn Jr HW. New Therapeutic Approaches in Diabetic Retinopathy. The Review of Diabetic Studies. 2015;12(1–2):196–210.
45. Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS. A Phase 2/3, Multicenter, Randomized, Double-Masked, 2-Year Trial of Pegaptanib Sodium for the Treatment of Diabetic Macular Edema. Ophthalmology. 2011 Jun;118(6):1107–18.
46. Patz A, Fine S, Finkelstein D, Prout T, Aiello L, Bradley R, et al. Photocoagulation Treatment of Proliferative Diabetic Retinopathy: The Second Report of Diabetic Retinopathy Study Findings. Ophthalmology. 1978 Jan;85(1):82–106.
47. Kupis M, Samelska K, Szaflik J, Skopiński P. Novel therapies for diabetic retinopathy. Central European Journal of Immunology. 2022;47(1):102–8.
48. Everett LA, Paulus YM. Laser Therapy in the Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Curr Diab Rep. 2021 Sep 6;21(9):35.
49. The Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine. 1993 Sep 30;329(14):977–86.
50. Tomita Y, Lee D, Tsubota K, Kurihara T. PPARα Agonist Oral Therapy in Diabetic Retinopathy. Biomedicines. 2020 Oct 19;8(10):433.
51. Liu Q, Zhang F, Zhang X, Cheng R, Ma J xing, Yi J, et al. Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. Mol Cell Biochem. 2018 Aug 21;445(1–2):105–15.
52. Lee JH, Wang JH, Chen J, Li F, Edwards TL, Hewitt AW, et al. Gene therapy for visual loss: Opportunities and concerns. Prog Retin Eye Res. 2019 Jan;68:31–53.
53. Wang JH, Ling D, Tu L, van Wijngaarden P, Dusting GJ, Liu GS. Gene therapy for diabetic retinopathy: Are we ready to make the leap from bench to bedside? Pharmacol Ther. 2017 May;173:1–18.
54. Wang JH, Roberts GE, Liu GS. Updates on Gene Therapy for Diabetic Retinopathy. Curr Diab Rep. 2020 Jul 16;20(7):22.
55. Ideno J, Mizukami H, Kekehashi A, Saito Y, Okada T, Urabe M, et al. Prevention of diabetic retinopathy by intraocular soluble flt-1gene transfer in a spontaneously diabetic rat model. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE . 2006 Oct 2;75–9.
56. Lai CM, Shen WY, Brankov M, Lai YKY, Barnett NL, Lee SY, et al. Long-term Evaluation of AAV-Mediated sFlt-1 Gene Therapy for Ocular Neovascularization in Mice and Monkeys. Molecular Therapy. 2005 Oct;12(4):659–68.
57. Altiok EI, Browne S, Khuc E, Moran EP, Qiu F, Zhou K, et al. sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo. PLoS One. 2016;11(6):e0155990.
58. Zhang X, Das SK, Passi SF, Uehara H, Bohner A, Chen M, et al. AAV2 Delivery of Flt23k Intraceptors Inhibits Murine Choroidal Neovascularization. Molecular Therapy. 2015 Feb;23(2):226–34.
59. Whitehead M, Wickremasinghe S, Osborne A, Van Wijngaarden P, Martin KR. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. Expert Opin Biol Ther. 2018 Dec 2;18(12):1257–70.
60. Haurigot V, Villacampa P, Ribera A, Bosch A, Ramos D, Ruberte J, et al. Long-Term Retinal PEDF Overexpression Prevents Neovascularization in a Murine Adult Model of Retinopathy. PLoS One. 2012 Jul 20;7(7):e41511.
61. Ao H, Liu B, Li H, Lu L. Egr1 mediates retinal vascular dysfunction in diabetes mellitus via promoting p53 transcription. J Cell Mol Med. 2019 May 19;23(5):3345–56.
62. Fiori A, Terlizzi V, Kremer H, Gebauer J, Hammes HP, Harmsen MC, et al. Mesenchymal stromal/stem cells as potential therapy in diabetic retinopathy. Immunobiology. 2018 Dec;223(12):729–43.
63. Kestane S. Diabetic Retinopathy and Stem Cell Therapy. In: Diabetic Eye Disease - From Therapeutic Pipeline to the Real World. IntechOpen; 2022.
64. Gaddam S, Periasamy R, Gangaraju R. Adult Stem Cell Therapeutics in Diabetic Retinopathy. Int J Mol Sci. 2019 Sep 30;20(19):4876.
65. Li XJ, Li CY, Bai D, Leng Y. Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis. Neural Regen Res. 2021;16(1):172.
66. Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell. 2021 Oct;28(10):1708–25.
67. Sun F, Sun Y, Zhu J, Wang X, Ji C, Zhang J, et al. Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4. Stem Cell Res Ther. 2022 Dec 15;13(1):293.
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