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Diabetic retinopathy: new therapeutic perspectives based on pathogenic mechanisms

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Abstract

Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness and represents a significant socioeconomic cost for healthcare systems worldwide. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR (mainly blood glucose and blood pressure). The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new treatments for the early stages of DR are needed. However, in early stages of DR invasive treatments such as intravitreal injections are too aggressive, and topical treatment seems to be an emerging route. In the present review, therapeutic strategies based on the main pathogenic mechanisms involved in the development of DR are reviewed. The main gap in the clinical setting is the treatment of early stages of DR and, therefore, this review emphasizes in this issue by giving an overview of potential druggable targets. By understanding of disease-specific pathogenic mechanisms, biological heterogeneity and progression patterns in early and advanced DR a more personalised approach to patient treatment will be implemented.

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References

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

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lee LJ, Yu AP, Cahill KE, Oglesby AK, Tang J, Qiu Y, Birnbaum HG (2008) Direct and indirect costs among employees with diabetic retinopathy in the United States. Curr Med Res Opin 24:1549–1559

    Article  PubMed  Google Scholar 

  3. Pelletier EM, Shim B, Ben-Joseph R, Caro JJ (2009) Economic outcomes associated withmicrovascular complications of type 2 diabetes mellitus: results from a US claims data analysis. Pharmacoeconomics 27:479–490

    Article  PubMed  Google Scholar 

  4. Heintz E, Wirehn AB, Peebo BB, Rosenqvist U, Levin LA (2010) Prevalence and healthcare costs of diabetic retinopathy: a population-based register study in Sweden. Diabetologia 53:2147–2154

    Article  CAS  PubMed  Google Scholar 

  5. Guariguata L, Nolan T, Beagley J, Linnenkamp U, Jacqmain O, International Diabetes Federation (2014) Diabetes atlas. International Diabetes Federation, Brussels

  6. Simó R, Hernández C (2015) Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retin Eye Res 48:160–180

    Article  PubMed  Google Scholar 

  7. Stitt AW, Curtis TM, Chen M, Medina RJ, McKay GJ, Jenkins A, Gardiner TA, Lyons TJ, Hammes HP, Simó R, Lois N (2016) The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res 51:156–186

    Article  PubMed  Google Scholar 

  8. Eljarrat-Binstock E, Pe’er J, Domb AJ (2010) New techniques for drug delivery to the posterior eye segment. Pharm Res 27:530–543

    Article  CAS  PubMed  Google Scholar 

  9. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414 (6865):813–20

    Article  CAS  PubMed  Google Scholar 

  10. Simó-Servat O, Hernández C, Simó R (2013) Genetics in diabetic retinopathy: current concepts and new insights. Curr Genom 14:289–299

    Article  CAS  Google Scholar 

  11. Kador PF, Wyman M, Oates PJ (2016) Aldose reductase, ocular diabetic complications and the development of topical Kinostat®. Prog Retin Eye Res 54:1–29

    Article  CAS  PubMed  Google Scholar 

  12. Aiello LP, Bursell S-E, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LEH, King GL (1997) Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform–selective inhibitor. Diabetes 46:1473–1480

    Article  CAS  PubMed  Google Scholar 

  13. PKC-DRS Study Group (2005) 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. Diabetes 54(7):2188–2197

    Article  Google Scholar 

  14. Jakus V, Rietbrock N (2004) Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res 53(2):131–142

    CAS  PubMed  Google Scholar 

  15. van Norren D, Gorgels TG (2011) The action spectrum of photochemical damage to the retina: a review of monochromatic threshold data. Photochem Photobiol 87(4):747–753

    Article  PubMed  CAS  Google Scholar 

  16. Yülek F, Or M, Ozoğul C, Isik AC, Ari N, Stefek M, Bauer V, Karasu C (2007) Effects of stobadine and vitamin E in diabetes-induced retinal abnormalities, involvement of oxidative stress. Arch Med Res 38(5):503–511

    Article  PubMed  CAS  Google Scholar 

  17. Rosales MA, Silva KC, Lopes de Faria JB, Lopes de Faria JM (2010) Exogenous SOD mimetic tempol ameliorates the early retinal changes reestablishing the redox status in diabetic hypertensive rats. Invest Ophthalmol Vis Sci 51(8):4327–4336

    Article  PubMed  Google Scholar 

  18. Faria AM, Papadimitriou A, Silva KC, Lopes de Faria JM, Lopes de Faria JB (2012) Uncoupling endothelial nitric oxide synthase is ameliorated by green tea in experimental diabetes by re-establishing tetrahydrobiopterin levels. Diabetes 61:1838–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kowluru RA, Zhong Q, Santos JM, Thandampallayam M, Putt D, Gierhart DL (2014) Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. Nutr Metab (Lond) 11:8

    Article  CAS  Google Scholar 

  20. Duarte DA, Rosales MA, Papadimitriou A, Silva KC, Amancio VH, Mendonça JN, Lopes NP, de Faria JB, de Faria JM (2015) Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway. J Nutr Biochem 26:64–74

    Article  CAS  PubMed  Google Scholar 

  21. Mayer-Davis EJ, Bell RA, Reboussin BA, Rushing J, Marshall JA, Hamman RF (1998) Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley Diabetes Study. Ophthalmology 105:2264–2270

    Article  CAS  PubMed  Google Scholar 

  22. Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, Laffel L, King GL (1999) High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 22:1245–1251

    Article  CAS  PubMed  Google Scholar 

  23. Millen AE, Klein R, Folsom AR, Stevens J, Palta M, Mares JA (2004) Relation between intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 79:865–873

    CAS  PubMed  Google Scholar 

  24. Haritoglou C, Gerss J, Hammes HP, Kampik A, Ulbig MW, Group RS (2011) Alpha-lipoic acid for the prevention of diabetic macular edema. Ophthalmologica 226:127–137

    Article  CAS  PubMed  Google Scholar 

  25. Brownlee M (2005) The pathobiology of diabetic complications. A unifying mechanism. Diabetes 54(6):1615–1625

    Article  CAS  PubMed  Google Scholar 

  26. Antonetti DA, Klein R, Gardner TW (2012) Diabetic retinopathy. N Engl J Med 366:1227–1239

    Article  CAS  PubMed  Google Scholar 

  27. Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2012) Neurodegeneration is an early event in diabetic retinopathy, therapeutic implications. Br J Ophthalmol 96:1285–1290

    Article  PubMed  Google Scholar 

  28. Abcouwer SF, Gardner TW (2014) Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci 1311:174–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2014) Neurodegeneration in the diabetic eye, new insights and therapeutic perspectives. Trends Endocrinol Metab 25:23–33

    Article  PubMed  CAS  Google Scholar 

  30. Jackson GR, Barber AJ (2010) Visual dysfunction associated with diabetic retinopathy. Curr Diab Rep 10:380–384

    Article  PubMed  Google Scholar 

  31. Di Leo MA, Caputo S, Falsini B, Porciatti V, Greco AV, Ghirlanda G (1994) Presence and further development of retinal dysfunction after 3-year follow up in IDDM patients without angiographically documented vasculopathy. Diabetologia 37:911–916

    Article  CAS  PubMed  Google Scholar 

  32. Frost-Larsen K, Larsen HW, Simonsen SE (1981) Value of electroretinography and dark adaptation as prognostic tools in diabetic retinopathy. Dev Ophthalmol 2:222–234

    Article  CAS  PubMed  Google Scholar 

  33. Reis A, Mateus C, Melo P, Figueira J, Cunha-Vaz J, Castelo-Branco M (2014) Neuroretinal dysfunction with intact blood-retinal barrier and absent vasculopathy in type 1 diabetes. Diabetes 63:3926–3937

    Article  CAS  PubMed  Google Scholar 

  34. Han Y, Schneck ME, Bearse MA.r et al (2004) Formulation and evaluation of a predictive model to identify the sites of future diabetic retinopathy. Invest Ophthalmol Vis Sci 45:4106–4112

    Article  PubMed  Google Scholar 

  35. Harrison WW, Bearse MA Jr, Ng JS, Jewell NP, Barez S, Burger D, Schneck ME, Adams AJ (2011) Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. Invest Ophthalmol Vis Sci 52:772–777

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ng JS, Bearse MA Jr, Schneck ME, Barez S, Adams AJ (2008) Local diabetic retinopathy prediction by multifocal ERG delays over 3 years. Invest Ophthalmol Vis Sci 49:1622–1628

    Article  PubMed  Google Scholar 

  37. Carrasco E, Hernández C, Miralles A, Huguet P, Farrés J, Simó R (2007) Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 30:2902–2908

    Article  CAS  PubMed  Google Scholar 

  38. Garcia-Ramírez M, Hernández C, Villarroel M, Canals F, Alonso MA, Fortuny R, Masmiquel L, Navarro A, García-Arumí J, Simó R (2009) Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy. Diabetologia 52:2633–2641

    Article  PubMed  CAS  Google Scholar 

  39. Valverde AM, Miranda S, García-Ramírez M, González-Rodriguez A, Hernández C, Simó R (2013) Proapoptotic and survival signaling in the neuroretina at early stages of diabetic retinopathy. Mol Vis 19:47–53

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Grant MB, Mames RN, Fitzgerald C, Hazariwala KM, Cooper-DeHoff R, Caballero S, Estes KS (2000) The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 2000 23(4):504–549.

    Article  CAS  PubMed  Google Scholar 

  41. Grant MB, Caballero S (2002) Somatostatin analogues as drug therapies for retinopathies. Drugs Today (Barc) 38(11):783–791.

    Article  CAS  Google Scholar 

  42. Grant MB, Caballero S Jr (2005) The potential role of octreotide in the treatment of diabetic retinopathy. Treat Endocrinol 4(4):199–203

    Article  CAS  PubMed  Google Scholar 

  43. Hernández C, Simó R, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2013) Somatostatin replacement: a new strategy for treating diabetic retinopathy. Curr Med Chem 20(26):3251–3257

    Article  PubMed  CAS  Google Scholar 

  44. Wang Q, Dills D, Klein R, Klein B, Moss S (1995) Does insulin-like growth factor 1 predict incidence and progression of diabetic retinopathy? Diabetes 44(2):161–164

    Article  CAS  PubMed  Google Scholar 

  45. Gerhardinger C, McClure KD, Romeo G, Podestà F, Lorenzi M (2000) IGF-I mRNA and signaling in the diabetic retina. Diabetes 50(1):175–183

    Article  Google Scholar 

  46. Simó R, Lecube A, Sararols L, García-Arumí J, Segura RM, Casamitjana R, Hernández C (2002) Deficit of somatostatin-like immunoreactivity in the vitreous fluid of diabetic patients: possible role in the development of proliferative diabetic retinopathy. Diabetes Care 25(12):2282–2286

    Article  PubMed  Google Scholar 

  47. Hernández C, Carrasco E, Casamitjana R, Deulofeu R, García-Arumí J, Simó R (2005) Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and non-diabetic control subjects. Diabetes Care 28(8):1941–1947

    Article  PubMed  Google Scholar 

  48. Simó R, Carrasco E, Fonollosa A, García-Arumí J, Casamitjana R, Hernández C (2007) Deficit of somatostatin in the vitreous fluid of patients with diabetic macular edema. Diabetes Care 30(3):725–727

    Article  PubMed  CAS  Google Scholar 

  49. Carrasco E, Hernández C, Miralles A, Huguet P, Farrés J, Simó R (2007) Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 30(11):2902–2908

    Article  CAS  PubMed  Google Scholar 

  50. Hernández C, García-Ramírez M, Corraliza L, Fernández-Carneado J, Farrera-Sinfreu J, Ponsati B, González-Rodríguez A, Valverde AM, Simó R (2013) Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes. Diabetes 62(7):2569–2578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hölscher C (2012) Potential role of glucagon-like peptide (GLP-1) in neuroprotection. CNS Drugs 26:871–882

    Article  PubMed  Google Scholar 

  52. Heppner KM, Perez-Tilve D (2015) GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front Neurosci 9:92

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yarchoan M, Arnold SE (2014) Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63:2253–2261

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hernández C, Bogdanov P, Corraliza L, García-Ramírez M, Solà-Adell C, Arranz JA, Arroba AI, Valverde AM, Simó R (2016) Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes 65:172–187

    PubMed  Google Scholar 

  55. Zhang Y, Zhang J, Wang Q, Lei X, Chu Q, Xu GT, Ye W (2011) Intravitreal injection of exendin-4 analogue protects retinal cells in early diabetic rats. Invest Ophthalmol Vis Sci 52:278–285

    Article  CAS  PubMed  Google Scholar 

  56. Fan Y, Liu K, Wang Q, Ruan Y, Zhang Y, Ye W (2014) Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis. Mol Vis 20:1557–1568

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, LEADER Steering Committee, LEADER Trial Investigators (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375(4):311–322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T, SUSTAIN-6 Investigators (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med (Epub ahead of print)

  59. Aronis KN, Chamberland JP, Mantzoros CS (2013) GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. Metabolism 62:1279–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pujadas G, Drucker DJ (2016) Vascular biology of glucagon receptor superfamily peptides: mechanistic and clinical relevance. Endocr Rev 37(6):554–583

    Article  PubMed  Google Scholar 

  61. Kang HM, Sohn I, Jung J, Jeong JW, Park C (2015) Exendin-4 protects hindlimb ischemic injury by inducing angiogenesis. Biochem Biophys Res Commun 465:758–763

    Article  CAS  PubMed  Google Scholar 

  62. Sheu JJ, Chang MW, Wallace CG, Chiang HJ, Sung PH, Tsai TH, Chung SY, Chen YL, Chua S, Chang HW, Sun CK, Lee FY, Yip HK (2015) Exendin-4 protected against critical limb ischemia in obese mice. Am J Transl Res 15(7):445–459

    Google Scholar 

  63. Tong G, Kim TH, Kim TH, Ma N, Niu G, Cao F, Chen X (2015) PEGylated exendin-4, a modified GLP-1 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction. Theranostics 5:240–250.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Du J, Zhang L, Wang Z, Yano N, Zhao YT, Wei L, Dubielecka-Szczerba P, Liu PY, Zhuang S, Qin G, Zhao TC (2016) Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts. Am J Physiol Cell Physiol 310:C270–C283

    Article  PubMed  PubMed Central  Google Scholar 

  65. Federici TJ (2011) The non-antibiotic properties of tetracyclines: clinical potential in ophthalmic disease. Pharmacol Res 64:614–623

    Article  CAS  PubMed  Google Scholar 

  66. Scott IU, Jackson GR, Quillen DA, Klein R, Liao J, Gardner TW (2014) Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in mild to moderate nonproliferative diabetic retinopathy: a randomized proof-of-concept clinical trial. JAMA Ophthalmol 132:1137–1142

    Article  PubMed  CAS  Google Scholar 

  67. Cheung SS, Leung JW, Lam AK, Lam KS, Chung SS, Lo AC, Chung SK (2011) Selective over-expression of endothelin-1 in endothelial cells exacerbates inner retinal edema and neuronal death in ischemic retina. PLoS One 6:e26184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Adamis AP (2002) Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol 86:363–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kern TS (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Tang J, Kern TS (2011) Inflammation in diabetic retinopathy. Prog Retin Eye Res 30(5):343–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. El-Asrar AM, Nawaz MI, Kangave D, Geboes K, Ola MS, Ahmad S, Al-Shabrawey M (2011) High-mobility group box-1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy. Mol Vis 17:1829–1838

    PubMed  PubMed Central  Google Scholar 

  72. Hernández C, Segura RM, Fonollosa A, Carrasco E, Francisco G, Simó R (2005) Interleukin-8, monocyte chemoattractant protein-1 and IL-10 in the vitreous fluid of patients with proliferative diabetic retinopathy. Diabet Med 22:719–722

    Article  PubMed  Google Scholar 

  73. Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP (2001) Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 158:147–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. McLeod DS, Lefer DJ, Merges C, Lutty GA (1995) Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 147:642–653

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Rangasamy S, McGuire PG, Franco Nitta C, Monickaraj F, Oruganti SR, Das A (2014) Chemokine mediated monocyte trafficking into the retina, role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy. PLoS One 9(10):e108508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Simó-Servat O, Hernández C, Simó R (2012) Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy. Mediators Inflamm 2012:872978

    Article  PubMed  PubMed Central  Google Scholar 

  77. Kowluru RA, Odenbach S (2004) Role of interleukin-1beta in the pathogenesis of diabetic retinopathy. Br J Ophthalmol 88(10):1343–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu X, Ye F, Xiong H, Hu DN, Limb GA, Xie T, Peng L, Zhang P, Wei Y, Zhang W, Wang J, Wu H, Lee P, Song E, Zhang DY (2015) IL-1β Induces IL-6 production in retinal Müller cells predominantly through the activation of P38 MAPK/NF-κB signaling pathway. Exp Cell Res 331(1):223–231

    Article  CAS  PubMed  Google Scholar 

  79. Vincent J, Mohr S (2007) Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56(1):224–230

    Article  CAS  PubMed  Google Scholar 

  80. Wang Y, Lu Q, Gao S, Zhu Y, Gao Y, Xie B, Shen X (2015) Pigment epithelium-derived factor regulates glutamine synthetase and l-glutamate/l-aspartate transporter in retinas with oxygen-induced retinopathy. Curr Eye Res 40(12):1232–1244

    Article  CAS  PubMed  Google Scholar 

  81. Stahel M, Becker M, Graf N, Michels S (2016) Systemic Interleukin 1β inhibition in Proliferative Diabetic Retinopathy: A Prospective Open-Label Study Using Canakinumab. Retina 36(2):385–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Aveleira CA, Lin CM, Abcouwer SF, Ambrósio AF, Antonetti DA (2010) TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes 59:2872–2882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kitaoka Y, Kwong JM, Ross-Cisneros FN, Wang J, Tsai RK, Sadun AA, Lam TT (2006) TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65. Invest Ophthalmol Vis Sci 47:1448–1457

    Article  PubMed  Google Scholar 

  84. Madigan MC, Sadun AA, Rao NS, Dugel PU, Tenhula WN, Gill PS (1996) Tumor necrosis factor-alpha (TNF-alpha)-induced optic neuropathy in rabbits. Neurol Res 18:176–184

    Article  CAS  PubMed  Google Scholar 

  85. Huang L, Zhang R, Wu J, Chen J, Grosjean F, Satlin LH, Klein JD, Sands JM, Striker GE, Tan J, Zheng F (2011) Increased susceptibility to acute kidney injury due to endoplasmic reticulum stress in mice lacking tumor necrosis factor-α and its receptor 1. Kidney Int 79(6):613–623

    Article  CAS  PubMed  Google Scholar 

  86. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Döhmen S, Adamis AP (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 16:438–440

    CAS  PubMed  Google Scholar 

  87. Joussen AM, Doehmen S, Le ML, Koizumi K, Radetzky S, Krohne TU, Poulaki V, Semkova I, Kociok N (2009) TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol Vis 15:1418–1428

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Behl Y, Krothapalli P, Desta T, Roy S, Graves DT (2009) FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats. Diabetes 58:917–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hong KH, Ryu J, Han KH (2005) Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 105:1405–1407

    Article  CAS  PubMed  Google Scholar 

  90. The DAMAD Study Group (1989) Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes 38(4):491–498

    Article  Google Scholar 

  91. Early Treatment Diabetic Retinopathy Study Research Group (1991) Effects of aspirin treatment on diabetic retinopathy: ETDRS report number 8. Ophthalmology 98(suppl):757–765

    Google Scholar 

  92. Simó R, Hernández C (2012) Prevention and treatment of diabetic retinopathy, evidence from large, randomized trials. The emerging role of fenofibrate. Rev Recent Clin Trials 7(1):71–80

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Chew EY, Ambrosius WT, Davis MD et al (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363:233–244

    Article  PubMed  CAS  Google Scholar 

  95. Simó R, Hernández C (2007) Fenofibrate for diabetic retinopathy. Lancet 370(9600):1667–1668

    Article  PubMed  Google Scholar 

  96. Simó R, Roy S, Behar-Cohen F, Keech A, Mitchell P, Wong TY (2013) Fenofibrate, a new treatment for diabetic retinopathy. Molecular mechanisms and future perspectives. Curr Med Chem 20(26):3258–3266

    Article  PubMed  CAS  Google Scholar 

  97. Wilkinson-Berka JL (2006) Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol 38:752–765

    Article  CAS  PubMed  Google Scholar 

  98. Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjølie AK, Group DPS (2008) Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372:1394–1402

    Article  CAS  PubMed  Google Scholar 

  99. Sjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Chaturvedi N, DIRECT Programme Study Group (2008) Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2), a randomised placebo-controlled trial. Lancet 372:1385–1393

    Article  PubMed  CAS  Google Scholar 

  100. Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572

    Article  CAS  PubMed  Google Scholar 

  101. Leite EB, Mota MC, de Abreu JR, Cunha-Vaz JG (1990) Effect of calcium dobesilate on the blood-retinal barrier in early diabetic retinopathy. Int Ophthalmol 14:81–88

    Article  CAS  PubMed  Google Scholar 

  102. Ribeiro ML, Seres AI, Carneiro AM, Stur M, Zourdani A, Caillon P, Cunha-Vaz JG, DX-Retinopathy Study Group (2006) Effect of calcium dobesilate on progression of early diabetic retinopathy, a randomised double-blind study. Graefes Arch Clin Exp Ophthalmol 244:1591–1600

    Article  CAS  PubMed  Google Scholar 

  103. Haritoglou C, Gerss J, Sauerland C, Kampik A, Ulbig MW, Group Cs (2009) Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial. Lancet 373:1364–1371

    Article  CAS  PubMed  Google Scholar 

  104. Zhang X, Liu W, Wu S, Jin J, Li W, Wang N (2015) Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis. Sci China Life Sci 58(1):101–107

    Article  CAS  PubMed  Google Scholar 

  105. Simó R, Ballarini S, Cunha-Vaz J, Ji L, Haller H, Zimmet P, Wong TY (2015) Non-traditional systemic treatments for diabetic retinopathy: an evidence-based review. Curr Med Chem 22(21):2580–2589

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Solà-Adell C, Bogdanov P, Hernández C, Corraliza L, Valeri M, Pasquali C, Simó R (2016) Calcium dobesilate prevents neurodegeneration and vascular leakage in experimental diabetes. Diabetes 65(Suppl 1):A158

    Google Scholar 

  107. Simunovic MP (2015) Anti-Vascular endothelial growth factor therapy for proliferative diabetic retinopathy: a systematic review and meta-analysis. Retina 10:1931–1942

    Article  CAS  Google Scholar 

  108. American Academy of Ophthalmology/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. American Academy of Ophthalmology, San Francisco. http://www.aao.org/ppp. Accessed 27 Jan 2017

  109. Writing Committee for the Diabetic Retinopathy Clinical Research Network (2015) Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA 314:2137–2146

    Article  CAS  Google Scholar 

  110. Tan GS, Cheung N, Simó R, Cheung GC, Wong TY (2016) Diabetic macular oedema. Lancet Diabetes Endocrinol (pii: S2213-8587(16)30052-3)

  111. Bandello F, Preziosa C, Querques G, Lattanzio R (2014) Update of intravitreal steroids for the treatment of diabetic macular edema. Ophthalmic Res 52:89–96

    Article  CAS  PubMed  Google Scholar 

  112. Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, Maker MP, Jampol LM, Melia M (2015) Diabetic Retinopathy Clinical Research Network. Topical nepafenec in eyes with noncentral diabetic macular edema. Retina 35(5):944–956

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ohira A, Hara K, Jóhannesson G, Tanito M, Ásgrímsdóttir GM, Lund SH, Loftsson T, Stefánsson E (2015) Topical dexamethasone γ-cyclodextrin nanoparticle eye drops increase visual acuity and decrease macular thickness in diabetic macular oedema. Acta Ophthalmol 93(7):610–615

    Article  CAS  PubMed  Google Scholar 

  114. Sahoo S, Barua A, Myint KT, Haq A, Abas AB, Nair NS (2015) Topical non-steroidal anti-inflammatory agents for diabetic cystoid macular oedema. Cochrane Database Syst Rev 2:CD010009

    Google Scholar 

  115. Semeraro F, Russo A, Gambicorti E, Duse S, Morescalchi F, Vezzoli S, Costagliola C (2015) Efficacy and vitreous levels of topical NSAIDs. Expert Opin Drug Deliv 12(11):1767–1782

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. CIBERDEM (CIBER de Diabetes y Enfermedades Metabólicas Asociadas) and Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autónoma de Barcelona, Pg. Vall d’Hebron 119-129, 08035, Barcelona, Spain

    C. Hernández, P. Bogdanov & R. Simó

  2. Servicio de Endocrinología y Nutrición, Hospital Universitario de Bellvitge, Universitat de Barcelona, L’Hospitalet del LLobregat, Barcelona, Spain

    A. Simó-Servat

Authors
  1. C. Hernández
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  2. A. Simó-Servat
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  3. P. Bogdanov
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  4. R. Simó
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Correspondence to R. Simó.

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This study was supported by grants from the Ministerio de Economía y Competitividad (SAF2016-77784 and PI16/00541).

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Hernández, C., Simó-Servat, A., Bogdanov, P. et al. Diabetic retinopathy: new therapeutic perspectives based on pathogenic mechanisms. J Endocrinol Invest 40, 925–935 (2017). https://doi.org/10.1007/s40618-017-0648-4

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  • DOI: https://doi.org/10.1007/s40618-017-0648-4

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