Abstract
Diabetic retinopathy (DR), a leading cause of acquired vision loss, is a microvascular complication of diabetes. While traditional risk factors for diabetic retinopathy including longer duration of diabetes, poor blood glucose control, and dyslipidemia are helpful in stratifying patient’s risk for developing retinopathy, many patients without these traditional risk factors develop DR; furthermore, there are persons with long diabetes duration who do not develop DR. Thus, identifying biomarkers to predict DR or to determine therapeutic response is important. A biomarker can be defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Incorporation of biomarkers into risk stratification of persons with diabetes would likely aid in early diagnosis and guide treatment methods for those with DR or with worsening DR. Systemic biomarkers of DR include serum measures including genomic, proteomic, and metabolomics biomarkers. Ocular biomarkers including tears and vitreous and retinal vascular structural changes have also been studied extensively to prognosticate the risk of DR development. The current studies on biomarkers are limited by the need for larger sample sizes, cross-validation in different populations and ethnic groups, and time-efficient and cost-effective analytical techniques. Future research is important to explore novel DR biomarkers that are non-invasive, rapid, economical, and accurate to help reduce the incidence and progression of DR in people with diabetes.
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•• Ting DSW, Cheung CM, Wong TY. Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clin Exp Ophthalmol. 2016;44(4):260–77. This study provides the updated DR epidemiology (incidence and progression) and risk factors; various screening practices using different imaging modalities.
Diabetes Atlas, 3rd Edition. Brussels: International Diabetes Federation. [database on the Internet]2014. Available from: http://www.diabetesatlas.org/content/diabetes-and-impaired-glucose-tolerance. Accessed 3 Feb 2011.
Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol. 2007;14(4):179–83. doi:10.1080/09286580701396720.
Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124–36. doi:10.1016/S0140-6736(09)62124-3.
International Diabetes Federation. Diabetes atlas. 6th ed. Brussels: International Diabetes Federation; 2015.
Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov. 2003;2(7):566–80. doi:10.1038/nrd1130.
Steyerberg EW, Pencina MJ, Lingsma HF, Kattan MW, Vickers AJ, Van Calster B. Assessing the incremental value of diagnostic and prognostic markers: a review and illustration. Eur J Clin Invest. 2012;42(2):216–28. doi:10.1111/j.1365-2362.2011.02562.x.
Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology. 1995;102(4):647–61.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381–9. doi:10.1056/NEJM200002103420603.
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):837–53.
Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 2007;298(8):902–16. doi:10.1001/jama.298.8.902.
Song J, Chen S, Liu X, Duan H, Kong J, Li Z. Relationship between C-reactive protein level and diabetic retinopathy: a systematic review and meta-analysis. PLoS One. 2015;10(12):e0144406. doi:10.1371/journal.pone.0144406.
Xu C, Wu Y, Liu G, Liu X, Wang F, Yu J. Relationship between homocysteine level and diabetic retinopathy: a systematic review and meta-analysis. Diagn Pathol. 2014;9:167. doi:10.1186/s13000-014-0167-y.
Roy MS, Janal MN, Crosby J, Donnelly R. Inflammatory biomarkers and progression of diabetic retinopathy in African Americans with type 1 diabetes. Invest Ophthalmol Vis Sci. 2013;54(8):5471–80. doi:10.1167/iovs.13-12212.
Sharma S, Purohit S, Sharma A, Hopkins D, Steed L, Bode B, et al. Elevated serum levels of soluble TNF receptors and adhesion molecules are associated with diabetic retinopathy in patients with type-1 diabetes. Mediat Inflamm. 2015;2015:279393. doi:10.1155/2015/279393.
van Hecke MV, Dekker JM, Nijpels G, Moll AC, Heine RJ, Bouter LM, et al. Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn Study. Diabetologia. 2005;48(7):1300–6. doi:10.1007/s00125-005-1799-y.
Simo R, Masmiquel L, Garcia-Pascual L, Burgos R, Mateo C, Segura RM, et al. Serum concentrations of laminin-P1 in diabetes mellitus: usefulness as an index of diabetic microangiopathy. Diabetes Res Clin Pract. 1996;32(1–2):45–53.
Masmiquel L, Segura RM, Mateo C, Calatayud M, Marti R, Mesa J, et al. Serum laminin as a marker of diabetic retinopathy development: a 4-year follow-up study. Am J Ophthalmol. 2000;129(3):347–52.
Zhou W, Hu W. Serum and vitreous pentraxin 3 concentrations in patients with diabetic retinopathy. Genet Test Mol Biomarkers. 2016;20(3):149–53. doi:10.1089/gtmb.2015.0238.
Dong N, Shi H, Xu B, Cai Y. Increased plasma S100A12 levels are associated with diabetic retinopathy and prognostic biomarkers of macrovascular events in Type 2 diabetic patients. Invest Ophthalmol Vis Sci. 2015;56(8):4177–85. doi:10.1167/iovs.15-16470.
Sinha S, Saxena S, Das S, Prasad S, Bhasker SK, Mahdi AA, et al. Antimyeloperoxidase antibody is a biomarker for progression of diabetic retinopathy. J Diabetes Complicat. 2016;30(4):700–4. doi:10.1016/j.jdiacomp.2016.01.010.
Huang Q, Shang G, Deng H, Liu J, Mei Y, Xu Y. High mannose-binding lectin serum levels are associated with diabetic retinopathy in chinese patients with Type 2 diabetes. PLoS One. 2015;10(7):e0130665. doi:10.1371/journal.pone.0130665.
Li ZZ, Lu XZ, Liu JB, Chen L. Serum retinol-binding protein 4 levels in patients with diabetic retinopathy. J Int Med Res. 2010;38(1):95–9.
Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin Endocrinol Metab. 2007;92(7):2712–9. doi:10.1210/jc.2006-1249.
Domingueti CP, Fuzatto JA, Foscolo RB, Reis JS, Dusse LM, Carvalho MD, et al. Association between Von Willebrand factor, disintegrin and metalloproteinase with thrombospondin type 1 motif member 13, d-Dimer and cystatin C levels with retinopathy in type 1 diabetes mellitus. Clin Chim Acta. 2016;459:1–4. doi:10.1016/j.cca.2016.05.011.
Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, McCarren M, et al. Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2014;37(2):501–6. doi:10.2337/dc13-1193.
Boehm BO, Schilling S, Rosinger S, Lang GE, Lang GK, Kientsch-Engel R, et al. Elevated serum levels of N(epsilon)-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema. Diabetologia. 2004;47(8):1376–9. doi:10.1007/s00125-004-1455-y.
Wautier MP, Massin P, Guillausseau PJ, Huijberts M, Levy B, Boulanger E, et al. N(carboxymethyl)lysine as a biomarker for microvascular complications in type 2 diabetic patients. Diabetes Metab. 2003;29(1):44–52.
Lopes-Virella MF, Hunt KJ, Baker NL, Lachin J, Nathan DM, Virella G, et al. Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes. Diabetes. 2011;60(2):582–9. doi:10.2337/db10-0915.
Lin Y, Xiao YC, Zhu H, Xu QY, Qi L, Wang YB, et al. Serum fibroblast growth factor 21 levels are correlated with the severity of diabetic retinopathy. J Diabetes Res. 2014;2014:929756. doi:10.1155/2014/929756.
Fan X, Wu Q, Li Y, Hao Y, Ning N, Kang Z, et al. Association between adiponectin concentrations and diabetic retinopathy in patients with type 2 diabetes: a meta analysis. Chin Med J (Engl). 2014;127(4):765–71.
Wong CW, Teo BW, Lamoureux E, Ikram MK, Wang JJ, Tai ES, et al. Serum cystatin C, markers of chronic kidney disease, and retinopathy in persons with diabetes. J Diabetes Res. 2015;2015:404280. doi:10.1155/2015/404280.
He R, Shen J, Zhao J, Zeng H, Li L, Zhao J, et al. High cystatin C levels predict severe retinopathy in type 2 diabetes patients. Eur J Epidemiol. 2013;28(9):775–8. doi:10.1007/s10654-013-9839-2.
Gopalakrishnan V, Purushothaman P, Bhaskar A. Proteomic analysis of plasma proteins in diabetic retinopathy patients by two dimensional electrophoresis and MALDI-Tof-MS. J Diabetes Complicat. 2015;29(7):928–36. doi:10.1016/j.jdiacomp.2015.05.021.
Lu CH, Lin ST, Chou HC, Lee YR, Chan HL. Proteomic analysis of retinopathy-related plasma biomarkers in diabetic patients. Arch Biochem Biophys. 2013;529(2):146–56. doi:10.1016/j.abb.2012.11.004.
Liu YP, Hu SW, Wu ZF, Mei LX, Lang P, Lu XH. Proteomic analysis of human serum from diabetic retinopathy. Int J Ophthalmol. 2011;4(6):616–22. doi:10.3980/j.issn.2222-3959.2011.06.08.
Chen L, Cheng CY, Choi H, Ikram MK, Sabanayagam C, Tan GS, et al. Plasma metabonomic profiling of diabetic retinopathy. Diabetes. 2016;65(4):1099–108. doi:10.2337/db15-0661.
Xia JF, Wang ZH, Liang QL, Wang YM, Li P, Luo GA. Correlations of six related pyrimidine metabolites and diabetic retinopathy in Chinese type 2 diabetic patients. Clin Chim Acta. 2011;412(11–12):940–5. doi:10.1016/j.cca.2011.01.025.
Garcia de la Torre N, Fernandez-Durango R, Gomez R, Fuentes M, Roldan-Pallares M, Donate J, et al. Expression of angiogenic MicroRNAs in endothelial progenitor cells from type 1 diabetic patients with and without diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015;56(6):4090–8. doi:10.1167/iovs.15-16498.
Qing S, Yuan S, Yun C, Hui H, Mao P, Wen F, et al. Serum miRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy. Cell Physiol Biochem. 2014;34(5):1733–40. doi:10.1159/000366374.
Zampetaki A, Willeit P, Burr S, Yin X, Langley SR, Kiechl S, et al. Angiogenic microRNAs linked to incidence and progression of diabetic retinopathy in type 1 diabetes. Diabetes. 2016;65(1):216–27. doi:10.2337/db15-0389.
Zeng J, Xiong Y, Li G, Liu M, He T, Tang Y, et al. MiR-21 is overexpressed in response to high glucose and protects endothelial cells from apoptosis. Exp Clin Endocrinol Diabetes. 2013;121(7):425–30. doi:10.1055/s-0033-1345169.
Sobrin L, Green T, Sim X, Jensen RA, Tai ES, Tay WT, et al. Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). Invest Ophthalmol Vis Sci. 2011;52(10):7593–602. doi:10.1167/iovs.11-7510.
Zitman-Gal T, Green J, Pasmanik-Chor M, Golan E, Bernheim J, Benchetrit S. Vitamin D manipulates miR-181c, miR-20b and miR-15a in human umbilical vein endothelial cells exposed to a diabetic-like environment. Cardiovasc Diabetol. 2014;13:8. doi:10.1186/1475-2840-13-8.
Looker HC, Nelson RG, Chew E, Klein R, Klein BE, Knowler WC, et al. Genome-wide linkage analyses to identify Loci for diabetic retinopathy. Diabetes. 2007;56(4):1160–6. doi:10.2337/db06-1299.
Hietala K, Forsblom C, Summanen P, Groop PH, FinnDiane Study G. Heritability of proliferative diabetic retinopathy. Diabetes. 2008;57(8):2176–80. doi:10.2337/db07-1495.
Arar NH, Freedman BI, Adler SG, Iyengar SK, Chew EY, Davis MD, et al. Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest Ophthalmol Vis Sci. 2008;49(9):3839–45. doi:10.1167/iovs.07-1633.
Salman AG, Mansour DE, Swelem AH, Al-Zawahary WM, Radwan AA. Pentosidine - a new biochemical marker in diabetic retinopathy. Ophthalmic Res. 2009;42(2):96–8. doi:10.1159/000225661.
Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT, et al. Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS One. 2008;3(10):e3583. doi:10.1371/journal.pone.0003583.
Musunuru K, Lettre G, Young T, Farlow DN, Pirruccello JP, Ejebe KG, et al. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet. 2010;3(3):267–75. doi:10.1161/CIRCGENETICS.109.882696.
Fu YP, Hallman DM, Gonzalez VH, Klein BE, Klein R, Hayes MG, et al. Identification of diabetic retinopathy genes through a genome-wide association study among Mexican-Americans from Starr County, Texas. J Ophthalmol. 2010. doi:10.1155/2010/861291.
Huang YC, Lin JM, Lin HJ, Chen CC, Chen SY, Tsai CH, et al. Genome-wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology. 2011;118(4):642–8. doi:10.1016/j.ophtha.2010.07.020.
Grassi MA, Tikhomirov A, Ramalingam S, Below JE, Cox NJ, Nicolae DL. Genome-wide meta-analysis for severe diabetic retinopathy. Hum Mol Genet. 2011;20(12):2472–81. doi:10.1093/hmg/ddr121.
Sheu WH, Kuo JZ, Lee IT, Hung YJ, Lee WJ, Tsai HY, et al. Genome-wide association study in a Chinese population with diabetic retinopathy. Hum Mol Genet. 2013;22(15):3165–73. doi:10.1093/hmg/ddt161.
Awata T, Yamashita H, Kurihara S, Morita-Ohkubo T, Miyashita Y, Katayama S, et al. A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA. PLoS One. 2014;9(11):e111715. doi:10.1371/journal.pone.0111715.
Burdon KP, Fogarty RD, Shen W, Abhary S, Kaidonis G, Appukuttan B, et al. Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene. Diabetologia. 2015;58(10):2288–97. doi:10.1007/s00125-015-3697-2.
Kwak SH, Park KS. Genetic studies on diabetic microvascular complications: focusing on genome-wide association studies. Endocrinol Metab (Seoul). 2015;30(2):147–58. doi:10.3803/EnM.2015.30.2.147.
Hosseini SM, Boright AP, Sun L, Canty AJ, Bull SB, Klein BE, et al. The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy. Hum Genet. 2015;134(2):247–57. doi:10.1007/s00439-014-1517-2.
Zeng Y, Dai F, Yang K, Tang Y, Xu M, Zhou Y. Association between a vascular endothelial growth factor gene polymorphism (rs2146323) and diabetic retinopathy: a meta-analysis. BMC Ophthalmol. 2015;15:163. doi:10.1186/s12886-015-0155-3.
Lu Y, Ge Y, Shi Y, Yin J, Huang Z. Two polymorphisms (rs699947, rs2010963) in the VEGFA gene and diabetic retinopathy: an updated meta-analysis. BMC Ophthalmol. 2013;13:56. doi:10.1186/1471-2415-13-56.
Qiu M, Xiong W, Liao H, Li F. VEGF -634G>C polymorphism and diabetic retinopathy risk: a meta-analysis. Gene. 2013;518(2):310–5. doi:10.1016/j.gene.2013.01.018.
Han L, Zhang L, Xing W, Zhuo R, Lin X, Hao Y, et al. The associations between VEGF gene polymorphisms and diabetic retinopathy susceptibility: a meta-analysis of 11 case–control studies. J Diabetes Res. 2014;2014:805801. doi:10.1155/2014/805801.
Gong JY, Sun YH. Association of VEGF gene polymorphisms with diabetic retinopathy: a meta-analysis. PLoS One. 2013;8(12):e84069. doi:10.1371/journal.pone.0084069.
Ding Y, Hu Z, Yuan S, Xie P, Liu Q. Association between transcription factor 7-like 2 rs7903146 polymorphism and diabetic retinopathy in type 2 diabetes mellitus: a meta-analysis. Diab Vasc Dis Res. 2015;12(6):436–44. doi:10.1177/1479164115598274.
Fan WY, Liu NP. Meta-analysis of association between K469E polymorphism of the ICAM-1 gene and retinopathy in type 2 diabetes. Int J Ophthalmol. 2015;8(3):603–7. doi:10.3980/j.issn.2222-3959.2015.03.30.
Zhang J, Liu H, Yan H, Huang G, Wang B. Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: a meta-analysis. Gene. 2013;518(2):405–11. doi:10.1016/j.gene.2012.12.086.
Zhou M, Zhang P, Xu X, Sun X. The relationship between aldose reductase C106T polymorphism and diabetic retinopathy: an updated meta-analysis. Invest Ophthalmol Vis Sci. 2015;56(4):2279–89. doi:10.1167/iovs.14-16279.
Liu L, Jiao J, Wang Y, Wu J, Huang D, Teng W, et al. TGF-beta1 gene polymorphism in association with diabetic retinopathy susceptibility: a systematic review and meta-analysis. PLoS One. 2014;9(4):e94160. doi:10.1371/journal.pone.0094160.
Wang J, Yang MM, Rong SS, Ng TK, Li YB, Liu XM. Association of paraoxonase gene polymorphisms with diabetic nephropathy and retinopathy. Mol Med Rep. 2013;8(6):1845–51. doi:10.3892/mmr.2013.1710.
Zhang T, Pang C, Li N, Zhou E, Zhao K. Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis. BMC Med. 2013;11:1. doi:10.1186/1741-7015-11-1.
Ma J, Li Y, Zhou F, Xu X, Guo G, Qu Y. Meta-analysis of association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene and diabetic retinopathy in Caucasians and Asians. Mol Vis. 2012;18:2352–60.
Zhao S, Li T, Zheng B, Zheng Z. Nitric oxide synthase 3 (NOS3) 4b/a, T-786C and G894T polymorphisms in association with diabetic retinopathy susceptibility: a meta-analysis. Ophthalmic Genet. 2012;33(4):200–7. doi:10.3109/13816810.2012.675398.
Tian C, Fang S, Du X, Jia C. Association of the C47T polymorphism in SOD2 with diabetes mellitus and diabetic microvascular complications: a meta-analysis. Diabetologia. 2011;54(4):803–11. doi:10.1007/s00125-010-2004-5.
Suzuki Y, Nakazawa M, Suzuki K, Yamazaki H, Miyagawa Y. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion. Jpn J Ophthalmol. 2011;55(3):256–63. doi:10.1007/s10384-011-0004-8.
Simo R, Vidal MT, Garcia-Arumi J, Carrasco E, Garcia-Ramirez M, Segura RM, et al. Intravitreous hepatocyte growth factor in patients with proliferative diabetic retinopathy: a case–control study. Diabetes Res Clin Pract. 2006;71(1):36–44. doi:10.1016/j.diabres.2005.05.017.
Katsura Y, Okano T, Noritake M, Kosano H, Nishigori H, Kado S, et al. Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care. 1998;21(10):1759–63.
Simo R, Hernandez C, Segura RM, Garcia-Arumi J, Sararols L, Burgos R, et al. Free insulin-like growth factor 1 in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy: a case–control study. Clin Sci (London, England : 1979). 2003;104(3):223–30. doi:10.1042/cs20020278.
Simo R, Lecube A, Segura RM, Garcia Arumi J, Hernandez C. Free insulin growth factor-I and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2002;134(3):376–82.
Burgos R, Mateo C, Canton A, Hernandez C, Mesa J, Simo R. Vitreous levels of IGF-I, IGF binding protein 1, and IGF binding protein 3 in proliferative diabetic retinopathy: a case-control study. Diabetes Care. 2000;23(1):80–3.
You JJ, Yang CM, Chen MS, Yang CH. Elevation of angiogenic factor Cysteine-rich 61 levels in vitreous of patients with proliferative diabetic retinopathy. Retina (Philadelphia, Pa). 2012;32(1):103–11. doi:10.1097/IAE.0b013e318219e4ad.
Zhang X, Yu W, Dong F. Cysteine-rich 61 (CYR61) is up-regulated in proliferative diabetic retinopathy. Graefe’s Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2012;250(5):661–8. doi:10.1007/s00417-011-1882-7.
You JJ, Yang CH, Chen MS, Yang CM. Cysteine-rich 61, a member of the CCN family, as a factor involved in the pathogenesis of proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2009;50(7):3447–55. doi:10.1167/iovs.08-2603.
Praidou A, Klangas I, Papakonstantinou E, Androudi S, Georgiadis N, Karakiulakis G, et al. Vitreous and serum levels of platelet-derived growth factor and their correlation in patients with proliferative diabetic retinopathy. Curr Eye Res. 2009;34(2):152–61. doi:10.1080/02713680802585920.
Praidou A, Papakonstantinou E, Androudi S, Georgiadis N, Karakiulakis G, Dimitrakos S. Vitreous and serum levels of vascular endothelial growth factor and platelet-derived growth factor and their correlation in patients with non-proliferative diabetic retinopathy and clinically significant macula oedema. Acta Ophthalmol. 2011;89(3):248–54. doi:10.1111/j.1755-3768.2009.01661.x.
Li JK, Wei F, Jin XH, Dai YM, Cui HS, Li YM. Changes in vitreous VEGF, bFGF and fibrosis in proliferative diabetic retinopathy after intravitreal bevacizumab. Int J Ophthalmol. 2015;8(6):1202–6. doi:10.3980/j.issn.2222-3959.2015.06.22.
Simo R, Carrasco E, Garcia-Ramirez M, Hernandez C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev. 2006;2(1):71–98.
Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles. Exp Eye Res. 2006;82(5):798–806.
Watanabe D, Suzuma K, Suzuma I, Ohashi H, Ojima T, Kurimoto M, et al. Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2005;139(3):476–81. doi:10.1016/j.ajo.2004.10.004.
Loukovaara S, Robciuc A, Holopainen JM, Lehti K, Pessi T, Liinamaa J, et al. Ang-2 upregulation correlates with increased levels of MMP-9, VEGF, EPO and TGFbeta1 in diabetic eyes undergoing vitrectomy. Acta Ophthalmol. 2013;91(6):531–9. doi:10.1111/j.1755-3768.2012.02473.x.
Xu Y, Cheng Q, Yang B, Yu S, Xu F, Lu L, et al. Increased sCD200 levels in vitreous of patients with proliferative diabetic retinopathy and its correlation with VEGF and proinflammatory cytokines. Invest Ophthalmol Vis Sci. 2015;56(11):6565–72. doi:10.1167/iovs.15-16854.
Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res. 2006;82(5):798–806. doi:10.1016/j.exer.2005.10.002.
Spranger J, Osterhoff M, Reimann M, Mohlig M, Ristow M, Francis MK, et al. Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes. 2001;50(12):2641–5.
Ogata N, Tombran-Tink J, Nishikawa M, Nishimura T, Mitsuma Y, Sakamoto T, et al. Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment. Am J Ophthalmol. 2001;132(3):378–82.
Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol. 2002;134(3):348–53.
Boehm BO, Lang G, Feldmann B, Kurkhaus A, Rosinger S, Volpert O, et al. Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study. Horm Metab Res = Hormon Stoffwechselforschung = Horm Metab. 2003;35(6):382–6. doi:10.1055/s-2003-41362.
Spranger J, Meyer-Schwickerath R, Klein M, Schatz H, Pfeiffer A. Deficient activation and different expression of transforming growth factor-beta isoforms in active proliferative diabetic retinopathy and neovascular eye disease. Exp Clin Endocrinol Diabetes. 1999;107(1):21–8. doi:10.1055/s-0029-1212068.
Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137–48. doi:10.1016/j.phrs.2015.05.013.
Praidou A, Androudi S, Brazitikos P, Karakiulakis G, Papakonstantinou E, Dimitrakos S. Angiogenic growth factors and their inhibitors in diabetic retinopathy. Curr Diabetes Rev. 2010;6(5):304–12.
Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992;189(2):824–31.
Hata Y, Nakagawa K, Ishibashi T, Inomata H, Ueno H, Sueishi K. Hypoxia-induced expression of vascular endothelial growth factor by retinal glial cells promotes in vitro angiogenesis. Virchows Arch Int J Pathol. 1995;426(5):479–86.
Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem. 1999;274(33):23463–7.
Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes. 1998;47(12):1953–9.
Campochiaro PA, Hackett SF, Vinores SA, Freund J, Csaky C, LaRochelle W, et al. Platelet-derived growth factor is an autocrine growth stimulator in retinal pigmented epithelial cells. J Cell Sci. 1994;107(Pt 9):2459–69.
Vinores SA, Henderer JD, Mahlow J, Chiu C, Derevjanik NL, Larochelle W, et al. Isoforms of platelet-derived growth factor and its receptors in epiretinal membranes: immunolocalization to retinal pigmented epithelial cells. Exp Eye Res. 1995;60(6):607–19.
Carrington L, McLeod D, Boulton M. IL-10 and antibodies to TGF-beta2 and PDGF inhibit RPE-mediated retinal contraction. Invest Ophthalmol Vis Sci. 2000;41(5):1210–6.
Yokota T, Ma RC, Park JY, Isshiki K, Sotiropoulos KB, Rauniyar RK, et al. Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes. 2003;52(3):838–45.
Burgos R, Simo R, Audi L, Mateo C, Mesa J, Garcia-Ramirez M, et al. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia. 1997;40(9):1107–9. doi:10.1007/s001250050794.
King GL, Goodman AD, Buzney S, Moses A, Kahn CR. Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985;75(3):1028–36. doi:10.1172/jci111764.
Grant MB, Mames RN, Fitzgerald C, Ellis EA, Aboufriekha M, Guy J. Insulin-like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia. 1993;36(4):282–91.
Grant MB, Caballero S, Millard WJ. Inhibition of IGF-I and b-FGF stimulated growth of human retinal endothelial cells by the somatostatin analogue, octreotide: a potential treatment for ocular neovascularization. Regul Pept. 1993;48(1–2):267–78.
Danis RP, Bingaman DP. Insulin-like growth factor-1 retinal microangiopathy in the pig eye. Ophthalmology. 1997;104(10):1661–9.
Tombran-Tink J, Chader GG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res. 1991;53(3):411–4.
Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science (New York, NY). 1999;285(5425):245–8.
Holtkamp GM, De Vos AF, Peek R, Kijlsta A. Analysis of the secretion pattern of monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-beta 2 (TGF-beta2) by human retinal pigment epithelial cells. Clin Exp Immunol. 1999;118(1):35–40.
Eichler W, Yafai Y, Kuhrt H, Grater R, Hoffmann S, Wiedemann P, et al. Hypoxia: modulation of endothelial cell proliferation by soluble factors released by retinal cells. Neuroreport. 2001;12(18):4103–8.
Katsura MK, Mishima HK, Minamoto A, Ishibashi F, Yamashita H. Growth regulation of bovine retinal pericytes by transforming growth factor-beta2 and plasmin. Curr Eye Res. 2000;20(3):166–72.
Kawai S, Nakajima T, Hokari S, Komoda T, Kawai K. Apolipoprotein A-I concentration in tears in diabetic retinopathy. Ann Clin Biochem. 2002;39(Pt 1):56–61.
Zhao Z, Liu J, Shi B, He S, Yao X, Willcox MD. Advanced glycation end product (AGE) modified proteins in tears of diabetic patients. Mol Vis. 2010;16:1576–84.
Moschos MM, Rouvas AA, Papadimitriou S, Kotsolis A, Sitaras N, Apostolopoulos M. Quantitative determination of glycosaminoglycans in tears of diabetic patients. Clin Ophthalmol. 2008;2(3):581–4.
Yu L, Chen X, Qin G, Xie H, Lv P. Tear film function in type 2 diabetic patients with retinopathy. Ophthalmologica. 2008;222(4):284–91. doi:10.1159/000140256.
Herber S, Grus FH, Sabuncuo P, Augustin AJ. Two-dimensional analysis of tear protein patterns of diabetic patients. Electrophoresis. 2001;22(9):1838–44. doi:10.1002/1522-2683(200105)22:9<1838::AID-ELPS1838>3.0.CO;2-7.
Zhou L, Beuerman RW, Foo Y, Liu S, Ang LP, Tan DT. Characterisation of human tear proteins using high-resolution mass spectrometry. Ann Acad Med Singapore. 2006;35(6):400–7.
Li N, Wang N, Zheng J, Liu XM, Lever OW, Erickson PM, et al. Characterization of human tear proteome using multiple proteomic analysis techniques. J Proteome Res. 2005;4(6):2052–61. doi:10.1021/pr0501970.
Sack RA, Conradi L, Krumholz D, Beaton A, Sathe S, Morris C. Membrane array characterization of 80 chemokines, cytokines, and growth factors in open- and closed-eye tears: angiogenin and other defense system constituents. Invest Ophthalmol Vis Sci. 2005;46(4):1228–38. doi:10.1167/iovs.04-0760.
Lei Z, Beuerman RW, Chew AP, Koh SK, Cafaro TA, Urrets-Zavalia EA, et al. Quantitative analysis of N-linked glycoproteins in tear fluid of climatic droplet keratopathy by glycopeptide capture and iTRAQ. J Proteome Res. 2009;8(4):1992–2003. doi:10.1021/pr800962q.
Csosz E, Boross P, Csutak A, Berta A, Toth F, Poliska S, et al. Quantitative analysis of proteins in the tear fluid of patients with diabetic retinopathy. J Proteomics. 2012;75(7):2196–204. doi:10.1016/j.jprot.2012.01.019.
Kim HJ, Kim PK, Yoo HS, Kim CW. Comparison of tear proteins between healthy and early diabetic retinopathy patients. Clin Biochem. 2012;45(1–2):60–7. doi:10.1016/j.clinbiochem.2011.10.006.
Glasgow BJ, Marshall G, Gasymov OK, Abduragimov AR, Yusifov TN, Knobler CM. Tear lipocalins: potential lipid scavengers for the corneal surface. Invest Ophthalmol Vis Sci. 1999;40(13):3100–7.
Shamaei-Tousi A, Stephens JW, Bin R, Cooper JA, Steptoe A, Coates AR, et al. Association between plasma levels of heat shock protein 60 and cardiovascular disease in patients with diabetes mellitus. Eur Heart J. 2006;27(13):1565–70. doi:10.1093/eurheartj/ehl081.
Esposito G, Michelutti R, Verdone G, Viglino P, Hernandez H, Robinson CV, et al. Removal of the N-terminal hexapeptide from human beta2-microglobulin facilitates protein aggregation and fibril formation. Protein Sci. 2000;9(5):831–45. doi:10.1110/ps.9.5.831.
Haritoglou C, Kernt M, Neubauer A, Gerss J, Oliveira CM, Kampik A, et al. Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy. Retina (Philadelphia, Pa). 2014;34(1):157–64. doi:10.1097/IAE.0b013e318295f6de.
Ribeiro ML, Nunes SG, Cunha-Vaz JG. Microaneurysm turnover at the macula predicts risk of development of clinically significant macular edema in persons with mild nonproliferative diabetic retinopathy. Diabetes Care. 2013;36(5):1254–9. doi:10.2337/dc12-1491.
Klein R, Myers CE, Knudtson MD, Lee KE, Gangnon R, Wong TY, et al. Relationship of blood pressure and other factors to serial retinal arteriolar diameter measurements over time: the beaver dam eye study. Arch Ophthalmol. 2012;130(8):1019–27. doi:10.1001/archophthalmol.2012.560.
Cheung N, Rogers SL, Donaghue KC, Jenkins AJ, Tikellis G, Wong TY. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care. 2008;31(9):1842–6. doi:10.2337/dc08-0189.
•• Silva PS, Cavallerano JD, Tolls D, Omar A, Thakore K, Patel B, et al. Potential efficiency benefits of nonmydriatic ultrawide field retinal imaging in an ocular telehealth diabetic retinopathy program. Diabetes Care. 2014;37(1):50–5. doi:10.2337/dc13-1292. This study suggests that ultrawide-field imaging is a more effective way to screen for DR and this could potentially change the screening practice guidelines in the future.
Wessel MM, Aaker GD, Parlitsis G, Cho M, D’Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina (Philadelphia, Pa). 2012;32(4):785–91. doi:10.1097/IAE.0b013e3182278b64.
Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014;132(11):1309–16. doi:10.1001/jamaophthalmol.2014.2350.
• 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;64(7):2560–70. doi:10.2337/db14-0782. This is a novel OCT imaging biomarker that is highly clinically relevant to predict the visual outcome in patients with diabetic macular edema.
Diabetic Retinopathy Clinical Research N, Bressler NM, Miller KM, Beck RW, Bressler SB, Glassman AR, et al. Observational study of subclinical diabetic macular edema. Eye (Lond). 2012;26(6):833–40. doi:10.1038/eye.2012.53.
Bearse Jr MA, Adams AJ, Han Y, Schneck ME, Ng J, Bronson-Castain K, et al. A multifocal electroretinogram model predicting the development of diabetic retinopathy. Prog Retin Eye Res. 2006;25(5):425–48. doi:10.1016/j.preteyeres.2006.07.001.
Manolio T. Novel risk markers and clinical practice. N Engl J Med. 2003;349(17):1587–9. doi:10.1056/NEJMp038136.
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Daniel S.W. Ting, Kara-Anne Tan, Val Phua, Gavin Tan, and Chee Wai Wong declare that they have no conflict of interest.
Tien Yin Wong reports personal fees from Abbott, Novartis, Pfizer, Allergan, and Bayer.
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This article is part of the Topical Collection on Microvascular Complications—Retinopathy
Chee Wai Wong and Tien Yin Wong contributed equally to this work.
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Ting, D.S.W., Tan, KA., Phua, V. et al. Biomarkers of Diabetic Retinopathy. Curr Diab Rep 16, 125 (2016). https://doi.org/10.1007/s11892-016-0812-9
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DOI: https://doi.org/10.1007/s11892-016-0812-9