Proliferative diabetic retinopathy (PDR) the sequel of diabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is the leading cause of blindness in the working-age population. The current screening process for the DR risk is not sufficiently effective such that often the disease is undetected until irreversible damage occurs. Diabetes-associated small vessel disease and neuroretinal changes create a vicious cycle resulting in the conversion of DR into PDR with characteristic ocular attributes including excessive mitochondrial and retinal cell damage, chronic inflammation, neovascularisation, and reduced visual field. PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke. A "domino effect" is highly characteristic for the cascading DM complications in which DR is an early indicator of impaired molecular and visual signaling. Mitochondrial health control is clinically relevant in DR management, and multi-omic tear fluid analysis can be instrumental for DR prognosis and PDR prediction. Altered metabolic pathways and bioenergetics, microvascular deficits and small vessel disease, chronic inflammation, and excessive tissue remodelling are in focus of this article as evidence-based targets for a predictive approach to develop diagnosis and treatment algorithms tailored to the individual for a cost-effective early prevention by implementing the paradigm shift from reactive medicine to predictive, preventive, and personalized medicine (PPPM) in primary and secondary DR care management.

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Histology and Embryology and Biomedical Centre Faculty of Medicine in Plzen Charles University Prague Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Neurology University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Neurology University Hospital Plzen and Faculty of Medicine in Plzen Charles University 100 34 Prague Czech Republic

Division of Experimental Ophthalmology Department of Clinical Neurosciences University of Geneva University Hospitals 1205 Geneva Switzerland

Max Planck Institute for Plant Breeding Research Carl Von Linne Weg 10 50829 Cologne Germany

Ophthalmology Department University Hospitals of Geneva 1205 Geneva Switzerland

Predictive Preventive and Personalised Medicine Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

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Avogaro A, Fadini GP. Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol. 2019;291:29–35. doi: 10.1016/j.ijcard.2019.02.030. PubMed DOI

Bourne RRA, Jonas JB, Bron AM, Cicinelli MV, Das A, Flaxman SR, et al. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe in 2015: magnitude, temporal trends and projections. Br J Ophthalmol. 2018;102:575–585. doi: 10.1136/bjophthalmol-2017-311258. PubMed DOI PMC

Jackson W. Improving diabetic retinopathy screening. Diabetes Care. 2002;25:1477–1478. doi: 10.2337/diacare.25.8.1477. PubMed DOI

Kashim RM, Newton P, Ojo O. Diabetic retinopathy screening: a systematic review on patients’ non-attendance. Int J Environ Res Public Health. 2018;15:157. doi: 10.3390/ijerph15010157. PubMed DOI PMC

Bebu I, Lachin JM. Optimal screening schedules for disease progression with application to diabetic retinopathy. Biostatistics. 2018;19:1–13. doi: 10.1093/biostatistics/kxx009. PubMed DOI PMC

Miller DJ, Cascio MA, Rosca MG. Diabetic retinopathy: the role of mitochondria in the neural retina and microvascular disease. Antioxidants (Basel) 2020;9:905. doi: 10.3390/antiox9100905. PubMed DOI PMC

Al-Shabrawey M, Smith S. Prediction of diabetic retinopathy: role of oxidative stress and relevance of apoptotic biomarkers. EPMA J. 2010;1:56–72. doi: 10.1007/s13167-010-0002-9. PubMed DOI PMC

Hendrick AM, Gibson MV, Kulshreshtha A. Diabetic retinopathy. Prim Care. 2015;42:451–464. doi: 10.1016/j.pop.2015.05.005. PubMed DOI

Golubnitschaja O, Potuznik P, Polivka J, Pesta M, Kaverina O, Pieper CC, et al. Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach. EPMA J. 2022;13:535–545. doi: 10.1007/s13167-022-00307-z. PubMed DOI PMC

Wang Z, Cao D, Zhuang X, Yao J, Chen R, Chen Y, et al. Diabetic retinopathy may be a predictor of stroke in patients with diabetes mellitus. J Endocr Soc. 2022;6:bvac097. 10.1210/jendso/bvac097. PubMed PMC

Eriksson MI, Summanen P, Gordin D, Forsblom C, Shams S, Liebkind R, et al. Cerebral small-vessel disease is associated with the severity of diabetic retinopathy in type 1 diabetes. BMJ Open Diabetes Res Care. 2021;9:e002274. doi: 10.1136/bmjdrc-2021-002274. PubMed DOI PMC

Wat N, Wong RL, Wong IY. Associations between diabetic retinopathy and systemic risk factors. Hong Kong Med J. 2016;22:589–599. doi: 10.12809/hkmj164869. PubMed DOI

Animaw W, Seyoum Y. Increasing prevalence of diabetes mellitus in a developing country and its related factors. PLoS One. 2017;12:e0187670. doi: 10.1371/journal.pone.0187670. PubMed DOI PMC

Tinajero MG, Malik VS. An update on the epidemiology of type 2 diabetes: a global perspective. Endocrinol Metab Clin North Am. 2021;50:337–355. doi: 10.1016/j.ecl.2021.05.013. PubMed DOI

Lin X, Xu Y, Pan X, Xu J, Ding Y, Sun X, et al. Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Sci Rep. 2020;10:14790. doi: 10.1038/s41598-020-71908-9. PubMed DOI PMC

Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al KJ. Epidemiology of type 2 diabetes - global burden of disease and forecasted trends. J Epidemiol Glob Health. 2020;10:107–111. doi: 10.2991/jegh.k.191028.001. PubMed DOI PMC

International Diabetes Federation IDF Diabetes Atlas 10th, Brussels, Belgium, International Diabetes Federation 2021.

Khalid M, Petroianu G, Adem A. Advanced glycation end products and diabetes mellitus: mechanisms and perspectives. Biomolecules. 2022;12:542. doi: 10.3390/biom12040542. PubMed DOI PMC

Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol. 2003;75:95–108. doi: 10.1016/s0014-4800(03)00035-2. PubMed DOI

Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88:1322–1335. doi: 10.2522/ptj.20080008. PubMed DOI PMC

Ling W, Huang Y, Huang Y-M, Fan R-R, Sui Y, Zhao H-L. Global trend of diabetes mortality attributed to vascular complications, 2000–2016. Cardiovasc Diabetol. 2020;19:182. doi: 10.1186/s12933-020-01159-5. PubMed DOI PMC

Tönnies T, Röckl S, Hoyer A, Heidemann C, Baumert J, Du Y, et al. Projected number of people with diagnosed type 2 diabetes in Germany in 2040. Diabet Med. 2019;36:1217–1225. doi: 10.1111/dme.13902. PubMed DOI

Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. 10.1016/j.diabres.2019.107843. PubMed

Pradeepa R, Mohan V. Epidemiology of type 2 diabetes in India. Indian J Ophthalmol. 2021;69:2932–2938. doi: 10.4103/ijo.IJO_1627_21. PubMed DOI PMC

Jacobs E, Hoyer A, Brinks R, Icks A, Kuß O, Rathmann W. Healthcare costs of type 2 diabetes in Germany. Diabet Med. 2017;34:855–861. doi: 10.1111/dme.13336. PubMed DOI

Lynch JL, Barrientos-Pérez M, Hafez M, Jalaludin MY, Kovarenko M, Rao PV, et al. Country-specific prevalence and incidence of youth-onset type 2 diabetes: a narrative literature review. Ann Nutr Metab. 2020;76:289–296. doi: 10.1159/000510499. PubMed DOI

Shukla UV, Tripathy K. Diabetic retinopathy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. PubMed

Alemu Mersha G, Alimaw YA, Woredekal AT. Prevalence of diabetic retinopathy among diabetic patients in Northwest Ethiopia-a cross sectional hospital based study. PLoS One. 2022;17:e0262664. doi: 10.1371/journal.pone.0262664. PubMed DOI PMC

Romero-Aroca P, López-Galvez M, Martinez-Brocca MA, Pareja-Ríos A, Artola S, Franch-Nadal J, et al. Changes in the epidemiology of diabetic retinopathy in Spain: a systematic review and meta-analysis. Healthcare (Basel) 2022;10:1318. doi: 10.3390/healthcare10071318v. PubMed DOI PMC

Teo ZL, Tham Y-C, Yu M, Chee ML, Rim TH, Cheung N, et al. Global Prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128:1580–1591. doi: 10.1016/j.ophtha.2021.04.027. PubMed DOI

Pradeepa R, Surendar J, Indulekha K, Chella S, Anjana RM, Mohan V. Relationship of diabetic retinopathy with coronary artery disease in Asian Indians with type 2 diabetes: the Chennai Urban Rural Epidemiology Study (CURES) Eye Study–3. Diabetes Technol Ther. 2015;17:112–118. doi: 10.1089/dia.2014.0141. PubMed DOI

Tan GS, Gan A, Sabanayagam C, Tham YC, Neelam K, Mitchell P, et al. Ethnic differences in the prevalence and risk factors of diabetic retinopathy: the Singapore Epidemiology of Eye Diseases Study. Ophthalmology. 2018;125:529–536. doi: 10.1016/j.ophtha.2017.10.026. PubMed DOI

Yang Q-H, Zhang Y, Zhang X-M, Li X-R. Prevalence of diabetic retinopathy, proliferative diabetic retinopathy and non-proliferative diabetic retinopathy in Asian T2DM patients: a systematic review and Meta-analysis. Int J Ophthalmol. 2019;12:302–311. doi: 10.18240/ijo.2019.02.19. PubMed DOI PMC

Cheloni R, Gandolfi SA, Signorelli C, Odone A. Global prevalence of diabetic retinopathy: protocol for a systematic review and meta-analysis. BMJ Open. 2019;9:e022188. doi: 10.1136/bmjopen-2018-022188. PubMed DOI PMC

The world report on vision, World Health Organization (WHO), 2019.

Wykoff CC, Khurana RN, Nguyen QD, Kelly SP, Lum F, Hall R, et al. Risk of blindness among patients with diabetes and newly diagnosed diabetic retinopathy. Diabetes Care. 2021;44:748–756. doi: 10.2337/dc20-0413. PubMed DOI PMC

Wang LZ, Cheung CY, Tapp RJ, Hamzah H, Tan G, Ting D, et al. Availability and variability in guidelines on diabetic retinopathy screening in Asian countries. Br J Ophthalmol. 2017;101:1352–1360. doi: 10.1136/bjophthalmol-2016-310002. PubMed DOI

Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82:844–51. PubMed PMC

Pandova MG. Diabetic Retinopathy and Blindness: an epidemiological overview. In: Giudice GL, Catalá A, editors. Visual impairment and blindness – what we know and what we have to know. IntechOpen; 2019. 10.5772/intechopen.88756.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858. 10.1016/S0140-6736(18)32279-7. PubMed PMC

Lin K-Y, Hsih W-H, Lin Y-B, Wen C-Y, Chang T-J. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. J Diabetes Investig. 2021;12:1322–1325. doi: 10.1111/jdi.13480. PubMed DOI PMC

Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BEK. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008;115:1859–1868. doi: 10.1016/j.ophtha.2008.08.023. PubMed DOI PMC

Scanlon PH. The English National Screening Programme for diabetic retinopathy 2003–2016. Acta Diabetol. 2017;54:515–525. doi: 10.1007/s00592-017-0974-1. PubMed DOI PMC

Scanlon PH, Nevill CR, Stratton IM, Maruti SS, Massó-González EL, Sivaprasad S, et al. Prevalence and incidence of diabetic retinopathy (DR) in the UK population of Gloucestershire. Acta Ophthalmol. 2022;100:e560–e570. doi: 10.1111/aos.14927. PubMed DOI PMC

Xie J, Ikram MK, Cotch MF, Klein B, Varma R, Shaw JE, et al. Association of diabetic macular edema and proliferative diabetic retinopathy with cardiovascular disease: a systematic review and meta-analysis. JAMA Ophthalmol. 2017;135:586–593. doi: 10.1001/jamaophthalmol.2017.0988. PubMed DOI PMC

Ong Y-T, De Silva DA, Cheung CY, Chang H-M, Chen CP, Wong MC, et al. Microvascular structure and network in the retina of patients with ischemic stroke. Stroke. 2013;44:2121–2127. doi: 10.1161/STROKEAHA.113.001741. PubMed DOI

Kramer CK, Rodrigues TC, Canani LH, Gross JL, Azevedo MJ. Diabetic retinopathy predicts all-cause mortality and cardiovascular events in both type 1 and 2 diabetes: meta-analysis of observational studies. Diabetes Care. 2011;34:1238–1244. doi: 10.2337/dc11-0079. PubMed DOI PMC

Zhou J-B, Zhu X-R, Zhao W, Yin L, Li H-B, Qi L, et al. Prediction of proliferative diabetic retinopathy to asymptomatic obstructive coronary artery disease in Chinese type 2 diabetes individuals: an exploratory study. Metab Syndr Relat Disord. 2019;17:367–373. doi: 10.1089/met.2018.0140. PubMed DOI PMC

Külahçıoğlu Ş, Karagöz IK, Bilen Y, Kültürsay B, Akbaş RB, Yücel E, et al. Evaluation of the relationship between diabetic retinopathy and left atrial deformation parameters. Egypt Heart J. 2022;74:30. doi: 10.1186/s43044-022-00265-x. PubMed DOI PMC

Shityakov S, Nagai M, Ergün S, Braunger BM, Förster CY. The protective effects of neurotrophins and microRNA in Diabetic retinopathy, nephropathy and heart failure via regulating endothelial function. Biomolecules. 2022;12:1113. doi: 10.3390/biom12081113. PubMed DOI PMC

Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson CS, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol. 2019;18:394–405. doi: 10.1016/S1474-4422(18)30500-3. PubMed DOI

Hu K, Jiang M, Zhou Q, Zeng W, Lan X, Gao Q, et al. Association of diabetic retinopathy with stroke: a systematic review and meta-analysis. Front Neurol. 2021;12:626996. doi: 10.3389/fneur.2021.626996. PubMed DOI PMC

Callaghan BC, Price RS, Chen KS, Feldman EL. The importance of rare subtypes in diagnosis and treatment of peripheral neuropathy: a review. JAMA Neurol. 2015;72:1510–1518. doi: 10.1001/jamaneurol.2015.2347. PubMed DOI PMC

Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5:41. doi: 10.1038/s41572-019-0092-1. PubMed DOI

Hafeez M, Achar P, Neeralagi M, Naik GT. Correlation between diabetic retinopathy and diabetic peripheral neuropathy in patients with type II diabetes mellitus. J Pharm Bioallied Sci. 2022;14:S658–S661. doi: 10.4103/jpbs.jpbs_138_22. PubMed DOI PMC

Abougalambou SSI, Abougalambou AS. Explorative study on diabetes neuropathy among type II diabetic patients in Universiti Sains Malaysia Hospital. Diabetes Metab Syndr. 2012;6:167–172. doi: 10.1016/j.dsx.2012.09.002. PubMed DOI

Won JC, Kwon HS, Kim CH, Lee JH, Park TS, Ko KS, et al. Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea. Diabet Med. 2012;29:e290–296. doi: 10.1111/j.1464-5491.2012.03697.x. PubMed DOI

Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am. 2004;88(1001–36):xi. doi: 10.1016/j.mcna.2004.04.012. PubMed DOI

Skyler JS. Microvascular complications. Retinopathy and nephropathy. Endocrinol Metab Clin North Am. 2001;30:833–56. doi: 10.1016/s0889-8529(05)70218-8. PubMed DOI

Saini DC, Kochar A, Poonia R. Clinical correlation of diabetic retinopathy with nephropathy and neuropathy. Indian J Ophthalmol. 2021;69:3364–3368. doi: 10.4103/ijo.IJO_1237_21. PubMed DOI PMC

Singh SK, Behre A, Singh MK. Diabetic retinopathy and microalbuminuria in lean type 2 diabetes mellitus. J Assoc Physicians India. 2001;49:439–441. PubMed

Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: part I. Pathophysiology and prevention. J Am Acad Dermatol. 2014;70:1.e1–18; quiz 19–20. 10.1016/j.jaad.2013.06.055. PubMed

Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005;366:1719–1724. doi: 10.1016/S0140-6736(05)67698-2. PubMed DOI

Hwang DJ, Lee KM, Park MS, Choi SH, Park JI, Cho JH, et al. Association between diabetic foot ulcer and diabetic retinopathy. PLoS One. 2017;12:e0175270. doi: 10.1371/journal.pone.0175270. PubMed DOI PMC

Karam T, Kamath YS, Rao LG, Rao KA, Shenoy SB, Bhandary SV. Diabetic retinopathy in patients with diabetic foot syndrome in South India. Indian J Ophthalmol. 2018;66:547–550. doi: 10.4103/ijo.IJO_1000_17. PubMed DOI PMC

Shahbazian H, Yazdanpanah L, Latifi SM. Risk assessment of patients with diabetes for foot ulcers according to risk classification consensus of International Working Group on Diabetic Foot (IWGDF) Pak J Med Sci. 2013;29:730–734. doi: 10.12669/pjms.293.3473. PubMed DOI PMC

Madonna R, Balistreri CR, Geng Y-J, De Caterina R. Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches. Vascul Pharmacol. 2017;90:1–7. doi: 10.1016/j.vph.2017.01.004. PubMed DOI

Koklesova L, Mazurakova A, Samec M, Kudela E, Biringer K, Kubatka P, et al. Mitochondrial health quality control: measurements and interpretation in the framework of predictive, preventive, and personalized medicine. EPMA J. 2022;13:177–193. doi: 10.1007/s13167-022-00281-6. PubMed DOI PMC

Koklesova L, Samec M, Liskova A, Zhai K, Büsselberg D, Giordano FA, et al. Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine. EPMA J. 2021;12:27–40. doi: 10.1007/s13167-021-00237-2. PubMed DOI PMC

De Lorenzo A, Romano L, Di Renzo L, Di Lorenzo N, Cenname G, Gualtieri P. Obesity: a preventable, treatable, but relapsing disease. Nutrition. 2020;71:110615. doi: 10.1016/j.nut.2019.110615. PubMed DOI

Zhu W, Wu Y, Meng Y-F, Xing Q, Tao J-J, Lu J. Association of obesity and risk of diabetic retinopathy in diabetes patients: a meta-analysis of prospective cohort studies. Medicine (Baltimore). 2018;97:e11807. doi: 10.1097/MD.0000000000011807. PubMed DOI PMC

Tawfik A, Mohamed R, Elsherbiny NM, DeAngelis MM, Bartoli M, Al-Shabrawey M. Homocysteine: a potential biomarker for diabetic retinopathy. J Clin Med. 2019;8:121. doi: 10.3390/jcm8010121. PubMed DOI PMC

Kowluru RA. Diabetic retinopathy: mitochondria caught in a muddle of homocysteine. J Clin Med. 2020;9:3019. doi: 10.3390/jcm9093019. PubMed DOI PMC

Koklesova L, Mazurakova A, Samec M, Biringer K, Samuel SM, Büsselberg D, et al. Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J. 2021;12:477–505. doi: 10.1007/s13167-021-00263-0. PubMed DOI PMC

Lei X, Zeng G, Zhang Y, Li Q, Zhang J, Bai Z, et al. Association between homocysteine level and the risk of diabetic retinopathy: a systematic review and meta-analysis. Diabetol Metab Syndr. 2018;10:61. doi: 10.1186/s13098-018-0362-1. PubMed DOI PMC

Kowluru RA, Mohammad G, Sahajpal N. Faulty homocysteine recycling in diabetic retinopathy. Eye Vis (Lond) 2020;7:4. doi: 10.1186/s40662-019-0167-9. PubMed DOI PMC

Torres Crigna A, Link B, Samec M, Giordano FA, Kubatka P, Golubnitschaja O. Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine. EPMA J. 2021;12:265–305. doi: 10.1007/s13167-021-00248-z. PubMed DOI PMC

Chang W, Lajko M, Fawzi AA. Endothelin-1 is associated with fibrosis in proliferative diabetic retinopathy membranes. PLoS One. 2018;13:e0191285. doi: 10.1371/journal.pone.0191285. PubMed DOI PMC

Kang HM, Hasanuzzaman M, Kim SW, Koh HJ, Lee SC. Elevated aqueous endothelin-1 concentrations in advanced diabetic retinopathy. PLoS One. 2022;17:e0268353. doi: 10.1371/journal.pone.0268353. PubMed DOI PMC

Zhan X, Li J, Guo Y, Golubnitschaja O. Mass spectrometry analysis of human tear fluid biomarkers specific for ocular and systemic diseases in the context of 3P medicine. EPMA J. 2021;12:449–475. doi: 10.1007/s13167-021-00265-y. PubMed DOI PMC

Umemura T, Kawamura T. Retinopathy: a sign of cerebral small vessel disease in diabetes? J Diabetes Investig. 2017;8:428–430. doi: 10.1111/jdi.12602. PubMed DOI PMC

Wong TY, Sabanayagam C. Strategies to tackle the global burden of diabetic retinopathy: from epidemiology to artificial intelligence. Ophthalmologica. 2020;243:9–20. doi: 10.1159/000502387. PubMed DOI

Singh C. Metabolism and vascular retinopathies: current perspectives and future directions. Diagnostics (Basel) 2022;12:903. doi: 10.3390/diagnostics12040903. PubMed DOI PMC

Mounirou BAM, Adam ND, Yakoura AKH, Aminou MSM, Liu YT, Tan LY. Diabetic retinopathy: an overview of treatments. Indian J Endocrinol Metab. 2022;26:111–118. doi: 10.4103/ijem.ijem_480_21. PubMed DOI PMC

Hammer SS, Beli E, Kady N, Wang Q, Wood K, Lydic TA, et al. The Mechanism of diabetic retinopathy pathogenesis unifying key lipid regulators, sirtuin 1 and liver X receptor. EBioMedicine. 2017;22:181–190. doi: 10.1016/j.ebiom.2017.07.008. PubMed DOI PMC

Hou X-W, Wang Y, Pan C-W. Metabolomics in diabetic retinopathy: a systematic review. Invest Ophthalmol Vis Sci. 2021;62:4. doi: 10.1167/iovs.62.10.4. PubMed DOI PMC

Singh C. Metabolism and vascular retinopathies: current perspectives and future directions. Diagnostics. Multidisciplinary Digital Publishing Institute; 2022;12:903. 10.3390/diagnostics12040903. PubMed PMC

The Diabetes Control and Complications Trial Research Group Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116:874–886. doi: 10.1001/archopht.116.7.874. PubMed DOI

ACCORD Study Group, ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233–44. 10.1056/NEJMoa1001288. PubMed PMC

Chang Y-C, Wu W-C. Dyslipidemia and diabetic retinopathy. Rev Diabet Stud. 2013;10:121–132. doi: 10.1900/RDS.2013.10.121. PubMed DOI PMC

Hammes H-P. Optimal treatment of diabetic retinopathy. Ther Adv Endocrinol Metab. 2013;4:61–71. doi: 10.1177/2042018813477886. PubMed DOI PMC

Chatziralli IP. The role of dyslipidemia control in the progression of diabetic retinopathy in patients with type 2 diabetes mellitus. Diabetes Ther. 2017;8:209–12. doi: 10.1007/s13300-017-0240-0. PubMed DOI PMC

Ola MS, Nawaz MI, Khan HA, Alhomida AS. Neurodegeneration and neuroprotection in diabetic retinopathy. Int J Mol Sci. Multidisciplinary Digital Publishing Institute; 2013;14:2559–72. 10.3390/ijms14022559. PubMed PMC

Yun JH, Kim J-M, Jeon HJ, Oh T, Choi HJ, Kim B-J. Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients. PLoS One. 2020;15:e0241365. doi: 10.1371/journal.pone.0241365. PubMed DOI PMC

Pradeepa R, Mohan V. Prevalence of type 2 diabetes and its complications in India and economic costs to the nation. Eur J Clin Nutr. 2017;71:816–824. doi: 10.1038/ejcn. PubMed DOI

Tarboush NA, Abu-Yaghi NE, Al Ejeilat LH, Wahed RKA, Jeris IN. Association of Irisin circulating level with diabetic retinopathy: a case-control study. Exp Clin Endocrinol Diabetes. 2021;129:36–42. doi: 10.1055/a-0723-3749. PubMed DOI

Castro-Sánchez AE, Ávila-Ortíz MN. Changing dietary habits in persons living with type 2 diabetes. J Nutr Educ Behav. 2013;45:761–766. doi: 10.1016/j.jneb.2013.04.259. PubMed DOI

Khandekar R. Screening and public health strategies for diabetic retinopathy in the Eastern Mediterranean region. Middle East Afr J Ophthalmol. 2012;19:178–184. doi: 10.4103/0974-9233.95245. PubMed DOI PMC

Martin CG, Pomares ML, Muratore CM, Avila PJ, Apoloni SB, Rodríguez M, et al. Level of physical activity and barriers to exercise in adults with type 2 diabetes. AIMS Public Health. 2021;8:229–239. doi: 10.3934/publichealth.2021018. PubMed DOI PMC

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;14:1252. doi: 10.3390/nu14061252. PubMed DOI PMC

Gudlavalleti AG, Gilbert C, Shukla R, Gajiwala U, Shukla A, Murthy GVS, et al. Establishing peer support groups for diabetic retinopathy in India: lessons learned and way ahead. Indian J Ophthalmol. 2020;68:S70–S73. doi: 10.3390/nu14061252. PubMed DOI PMC

Vashist P, Singh S, Gupta N, Saxena R. Role of early screening for diabetic retinopathy in patients with diabetes mellitus: an overview. Indian J Community Med. 2011;36:247–252. doi: 10.4103/0970-0218.91324. PubMed DOI PMC

Aro A, Kauppinen A, Kivinen N, Selander T, Kinnunen K, Tuomilehto J, et al. Life style intervention improves retinopathy status—the Finnish Diabetes Prevention Study. Nutrients. 2019;11:1691. doi: 10.3390/nu11071691. PubMed DOI PMC

Eliasson B. Cigarette smoking and diabetes. Prog Cardiovasc Dis. 2003;45:405–413. doi: 10.1053/pcad.2003.00103. PubMed DOI

Swade TF, Emanuele NV. Alcohol & diabetes. Compr Ther. 1997;23:135–140. PubMed

Gupta P, Fenwick EK, Sabanayagam C, Gan ATL, Tham Y-C, Thakur S, et al. Association of alcohol intake with incidence and progression of diabetic retinopathy. Br J Ophthalmol. 2021;105:538–542. doi: 10.1136/bjophthalmol-2020-316360. PubMed DOI

Bukht MS, Ahmed KR, Hossain S, Masud P, Sultana S, Khanam R. Association between physical activity and diabetic complications among Bangladeshi type 2 diabetic patients. Diabetes Metab Syndr. 2019;13:806–809. doi: 10.1016/j.dsx.2018.11.069. PubMed DOI

Dirani M, Crowston JG, van Wijngaarden P. Physical inactivity as a risk factor for diabetic retinopathy? A review. Clin Exp Ophthalmol. 2014;42:574–581. doi: 10.1111/ceo.12306. PubMed DOI

Ren C, Liu W, Li J, Cao Y, Xu J, Lu P. Physical activity and risk of diabetic retinopathy: a systematic review and meta-analysis. Acta Diabetol. 2019;56:823–837. doi: 10.1007/s00592-019-01319-4. PubMed DOI

Wang YX, Wei WB, Xu L, Jonas JB. Physical activity and eye diseases. The Beijing Eye Study. Acta Ophthalmologica. 2019;97:325–331. doi: 10.1111/aos.13962. PubMed DOI

Frith E, Loprinzi PD. Physical activity, muscle-strengthening activities, and systemic inflammation among retinopathy patients. Diabetes Spectr. 2019;32:16–20. doi: 10.2337/ds18-0002. PubMed DOI PMC

Tikkanen-Dolenc H, Wadén J, Forsblom C, Harjutsalo V, Thorn LM, Saraheimo M, et al. Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes. Acta Diabetol. 2020;57:527–534. doi: 10.1007/s00592-019-01454-y. PubMed DOI PMC

Yan X, Han X, Wu C, Shang X, Zhang L, He M. Effect of physical activity on reducing the risk of diabetic retinopathy progression: 10-year prospective findings from the 45 and Up Study. PLoS One. 2021;16:e0239214. doi: 10.1371/journal.pone.0239214. PubMed DOI PMC

Frith E, Loprinzi PD. The association between bouted and non-bouted physical activity on retinopathy prevalence. Eur J Intern Med. 2018;47:32–35. doi: 10.1016/j.ejim.2017.08.012. PubMed DOI

Kuwata H, Okamura S, Hayashino Y, Tsujii S, Ishii H, Diabetes Distress and Care Registry at Tenri Study Group. Higher levels of physical activity are independently associated with a lower incidence of diabetic retinopathy in Japanese patients with type 2 diabetes: a prospective cohort study, Diabetes Distress and Care Registry at Tenri (DDCRT15). PLoS One. 2017;12:e0172890. 10.1371/journal.pone.0172890. PubMed PMC

Preguiça I, Alves A, Nunes S, Gomes P, Fernandes R, Viana SD, et al. Diet-induced rodent models of diabetic peripheral neuropathy, retinopathy and nephropathy. Nutrients. 2020;12:E250. doi: 10.3390/nu12010250. PubMed DOI PMC

Cheng Y, Yu X, Zhang J, Chang Y, Xue M, Li X, et al. Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-Ay/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes. Diabetologia. 2019;62:1074–1086. doi: 10.1007/s00125-019-4838-9. PubMed DOI PMC

Pyo Y-H, Lee K-W. Preventive effect of Monascus-fermented products enriched with ubiquinones on type 2 diabetic rats induced by a high-fructose plus high-fat diet. J Med Food. 2014;17:826–829. doi: 10.1089/jmf.2013.3001. PubMed DOI PMC

Alcubierre N, Navarrete-Muñoz EM, Rubinat E, Falguera M, Valls J, Traveset A, et al. Association of low oleic acid intake with diabetic retinopathy in type 2 diabetic patients: a case-control study. Nutr Metab (Lond) 2016;13:40. doi: 10.1186/s12986-016-0099-5. PubMed DOI PMC

Sasaki M, Kawasaki R, Rogers S, Man REK, Itakura K, Xie J, et al. The associations of dietary intake of polyunsaturated fatty acids with diabetic retinopathy in well-controlled diabetes. Invest Ophthalmol Vis Sci. 2015;56:7473–7479. doi: 10.1167/iovs.15-17485. PubMed DOI

Dow C, Mancini F, Rajaobelina K, Boutron-Ruault M-C, Balkau B, Bonnet F, et al. Diet and risk of diabetic retinopathy: a systematic review. Eur J Epidemiol. 2018;33:141–156. doi: 10.1007/s10654-017-0338-8. PubMed DOI

Tanaka S, Yoshimura Y, Kawasaki R, Kamada C, Tanaka S, Horikawa C, et al. Fruit intake and incident diabetic retinopathy with type 2 diabetes. Epidemiology. 2013;24:204–211. doi: 10.1097/EDE.0b013e318281725e. PubMed DOI

Mahoney SE, Loprinzi PD. Influence of flavonoid-rich fruit and vegetable intake on diabetic retinopathy and diabetes-related biomarkers. J Diabetes Complications. 2014;28:767–771. doi: 10.1016/j.jdiacomp.2014.06.011. PubMed DOI

Shi C, Wang P, Airen S, Brown C, Liu Z, Townsend JH, et al. Nutritional and medical food therapies for diabetic retinopathy. Eye and Vision. 2020;7:33. doi: 10.1186/s40662-020-00199-y. PubMed DOI PMC

Rossino MG, Casini G. Nutraceuticals for the treatment of diabetic retinopathy. Nutrients. 2019;11:771. doi: 10.3390/nu11040771. PubMed DOI PMC

Hsu S-K, Cheng K-C, Mgbeahuruike MO, Lin Y-H, Wu C-Y, Wang H-MD, et al. New insight into the effects of metformin on diabetic retinopathy, aging and cancer: nonapoptotic cell death, immunosuppression, and effects beyond the AMPK pathway. Int J Mol Sci. Multidisciplinary Digital Publishing Institute; 2021;22:9453. 10.3390/ijms22179453. PubMed PMC

Li Y, Gappy S, Liu X, Sassalos T, Zhou T, Hsu A, et al. Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium. PLoS One. 2022;17:e0268451. doi: 10.1371/journal.pone.0268451. PubMed DOI PMC

Song S, Bao S, Zhang C, Zhang J, Lv J, Li X, et al. Stimulation of AMPK prevents diabetes-induced photoreceptor cell degeneration. Oxid Med Cell Longev. 2021;2021:5587340. doi: 10.1155/2021/5587340. PubMed DOI PMC

Silva C, Rodrigues I, Andrade S, Costa R, Soares R. Metformin reduces vascular assembly in high glucose-treated human microvascular endothelial cells in an AMPK-independent manner. Cell J. 2021;23:174–183. doi: 10.22074/cellj.2021.7212. PubMed DOI PMC

Nahar N, Mohamed S, Mustapha NM, Lau S, Ishak NIM, Umran NS. Metformin attenuated histopathological ocular deteriorations in a streptozotocin-induced hyperglycemic rat model. Naunyn Schmiedebergs Arch Pharmacol. 2021;394:457–467. doi: 10.1007/s00210-020-01989-w. PubMed DOI

Yan Y, Li T, Li Z, He M, Wang D, Xu Y, et al. Metformin suppresses the progress of diabetes-accelerated atherosclerosis by inhibition of vascular smooth muscle cell migration through AMPK-Pdlim5 pathway. Front Cardiovasc Med. 2021;8:690627. doi: 10.3389/fcvm.2021.690627. PubMed DOI PMC

Han J, Li Y, Liu X, Zhou T, Sun H, Edwards P, et al. Metformin suppresses retinal angiogenesis and inflammation in vitro and in vivo. PLoS One. 2018;13:e0193031. doi: 10.1371/journal.pone.0193031. PubMed DOI PMC

Kim YS, Kim M, Choi MY, Lee DH, Roh GS, Kim HJ, et al. Metformin protects against retinal cell death in diabetic mice. Biochem Biophys Res Commun. 2017;492:397–403. doi: 10.1016/j.bbrc.2017.08.087. PubMed DOI

Hassan N, Abd El-kader M, Sherif R, Saleh D. Does metformin protect against diabetic retinopathy in albino rats? An immunohistochemical study. Cytol Histol Rep. 2019;2:110. doi: 10.29011/2688-6421.100010. DOI

Ge X, Wang L, Fei A, Ye S, Zhang Q. Research progress on the relationship between autophagy and chronic complications of diabetes. Front Physiol. 2022;13:956344. doi: 10.3389/fphys.2022.956344. PubMed DOI PMC

Niu C, Chen Z, Kim KT, Sun J, Xue M, Chen G, et al. Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway. Autophagy. 2019;15:843–870. doi: 10.1080/15548627.2019.1569913. PubMed DOI PMC

Lu G, Wu Z, Shang J, Xie Z, Chen C, Zhang C. The effects of metformin on autophagy. Biomed Pharmacother. 2021;137:111286. 8 10.1016/j.biopha.2021.111286. PubMed

Oubaha M, Miloudi K, Dejda A, Guber V, Mawambo G, Germain M-A, et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med. 2016;8:362ra144. 10.1126/scitranslmed.aaf9440. PubMed

Velmurugan BK, Rathinasamy B, Lohanathan BP, Thiyagarajan V, Weng C-F. Neuroprotective role of phytochemicals. Molecules. 2018;23:2485. doi: 10.3390/molecules23102485. PubMed DOI PMC

Khameneh B, Iranshahy M, Soheili V, Fazly Bazzaz BS. Review on plant antimicrobials: a mechanistic viewpoint. Antimicrob Resist Infect Control. 2019;8:118. doi: 10.1186/s13756-019-0559-6. PubMed DOI PMC

Mazurakova A, Koklesova L, Samec M, Kudela E, Sivakova J, Pribulova T, et al. Flavonoids exert potential in the management of hypertensive disorders in pregnancy. Pregnancy Hypertens. 2022;29:72–85. doi: 10.1016/j.preghy.2022.06.007. PubMed DOI

Kubatka P, Mazurakova A, Samec M, Koklesova L, Zhai K, AL-Ishaq R, et al. Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression—3PM pathways. EPMA J. 2021;12:559–87. 10.1007/s13167-021-00257-y. PubMed PMC

Mazurakova A, Koklesova L, Samec M, Kudela E, Kajo K, Skuciova V, et al. Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. EPMA J. 2022;2:315–334. doi: 10.1007/s13167-022-00277-2. PubMed DOI PMC

Koklesova L, Liskova A, Samec M, Zhai K, Abotaleb M, Ashrafizadeh M, et al. Carotenoids in cancer metastasis-status quo and outlook. Biomolecules. 2020;10:1653. doi: 10.3390/biom10121653. PubMed DOI PMC

Abotaleb M, Samuel S, Varghese E, Varghese S, Kubatka P, Liskova A, et al. Flavonoids in cancer and apoptosis. Cancers. 2018;11:28. doi: 10.3390/cancers11010028. PubMed DOI PMC

Kapinova A, Kubatka P, Liskova A, Baranenko D, Kruzliak P, Matta M, et al. Controlling metastatic cancer: the role of phytochemicals in cell signaling. J Cancer Res Clin Oncol. 2019;145:1087–1109. doi: 10.1007/s00432-019-02892-5. PubMed DOI PMC

Gilbert C, Gordon I, Mukherjee CR, Govindhari V. Guidelines for the prevention and management of diabetic retinopathy and diabetic eye disease in India: a synopsis. Indian J Ophthalmol. 2020;68:S63–S66. doi: 10.4103/ijo.IJO_1917_19. PubMed DOI PMC

Zhang T, Mei X, Ouyang H, Lu B, Yu Z, Wang Z, et al. Natural flavonoid galangin alleviates microglia-trigged blood-retinal barrier dysfunction during the development of diabetic retinopathy. J Nutr Biochem. 2019;65:1–14. doi: 10.1016/j.jnutbio.2018.11.006. PubMed DOI

Matos AL, Bruno DF, Ambrósio AF, Santos PF. The benefits of flavonoids in diabetic retinopathy. Nutrients. 2020;12:E3169. doi: 10.3390/nu12103169. PubMed DOI PMC

Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products. Circulation American Heart Association. 2006;114:597–605. doi: 10.1161/CIRCULATIONAHA.106.621854. PubMed DOI

Al-Dosary DI, Alhomida AS, Ola MS. Protective effects of dietary flavonoids in diabetic induced retinal neurodegeneration. Curr Drug Targets. 2017;18:1468–1476. doi: 10.2174/1389450117666161003121304. PubMed DOI

Bikbova G, Oshitari T, Yamamoto S. Neuronal cell death and regeneration in diseases associated with advanced glycation end-products accumulation. Neural Regen Res. 2014;9:701–702. doi: 10.4103/1673-5374.131569. PubMed DOI PMC

Chai G-R, Liu S, Yang H-W, Chen X-L. Quercetin protects against diabetic retinopathy in rats by inducing heme oxygenase-1 expression. Neural Regen Res. 2021;16:1344–1350. doi: 10.4103/1673-5374.301027. PubMed DOI PMC

Kim J, Kim C-S, Moon MK, Kim JS. Epicatechin breaks preformed glycated serum albumin and reverses the retinal accumulation of advanced glycation end products. Eur J Pharmacol. 2015;748:108–114. doi: 10.1016/j.ejphar.2014.12.010. PubMed DOI

Liskova A, Koklesova L, Samec M, Smejkal K, Samuel SM, Varghese E, et al. Flavonoids in cancer metastasis. Cancers (Basel) 2020;12:1498. doi: 10.3390/cancers12061498. PubMed DOI PMC

Al-Dosari DI, Ahmed MM, Al-Rejaie SS, Alhomida AS, Ola MS. Flavonoid naringenin attenuates oxidative stress, apoptosis and improves neurotrophic effects in the diabetic rat retina. Nutrients. 2017;9:E1161. doi: 10.3390/nu9101161. PubMed DOI PMC

Ola MS, Ahmed MM, Shams S, Al-Rejaie SS. Neuroprotective effects of quercetin in diabetic rat retina. Saudi J Biol Sci. 2017;24:1186–1194. doi: 10.1016/j.sjbs.2016.11.017. PubMed DOI PMC

Arikan S, Ersan I, Karaca T, Kara S, Gencer B, Karaboga I, et al. Quercetin protects the retina by reducing apoptosis due to ischemia-reperfusion injury in a rat model. Arq Bras Oftalmol. 2015;78:100–104. doi: 10.5935/0004-2749.20150026. PubMed DOI

Wu W, Xie Z, Zhang Q, Ma Y, Bi X, Yang X, et al. Hyperoside ameliorates diabetic retinopathy via anti-oxidation, inhibiting cell damage and apoptosis induced by high glucose. Front Pharmacol. 2020;11:797. doi: 10.3389/fphar.2020.00797. PubMed DOI PMC

Fu Y, Li Z, Xiao S, Zhao C, Zhou K, Cao S. Ameliorative effects of chickpea flavonoids on redox imbalance and mitochondrial complex I dysfunction in type 2 diabetic rats. Food Funct. Royal Society of Chemistry; 2022;13:8967–76. 10.1039/d2fo00753c. PubMed

Ma H, Li J. The ginger extract could improve diabetic retinopathy by inhibiting the expression of e/iNOS and G6PDH, apoptosis, inflammation, and angiogenesis. J Food Biochem. 2022;46:e14084. doi: 10.1111/jfbc.14084. PubMed DOI

Bungau S, Abdel-Daim MM, Tit DM, Ghanem E, Sato S, Maruyama-Inoue M, et al. Health benefits of polyphenols and carotenoids in age-related eye diseases. Oxid Med Cell Longev. 2019;2019:9783429. doi: 10.1155/2019/9783429. PubMed DOI PMC

Sharavana G, Baskaran V. Lutein downregulates retinal vascular endothelial growth factor possibly via hypoxia inducible factor 1 alpha and X-box binding protein 1 expression in streptozotocin induced diabetic rats. Journal of Functional Foods. 2017;31:97–103. doi: 10.1016/j.jff.2017.01.023. DOI

McClinton KJ, Aliani M, Kuny S, Sauvé Y, Suh M. Differential effect of a carotenoid-rich diet on retina function in non-diabetic and diabetic rats. Nutr Neurosci. 2020;23:838–848. doi: 10.1080/1028415X.2018.1563664. PubMed DOI

Moschos MM, Dettoraki M, Tsatsos M, Kitsos G, Kalogeropoulos C. Effect of carotenoids dietary supplementation on macular function in diabetic patients. Eye Vis (Lond) 2017;4:23. doi: 10.1186/s40662-017-0088-4. PubMed DOI PMC

Chiosi F, Rinaldi M, Campagna G, Manzi G, De Angelis V, Calabrò F, et al. Effect of a fixed combination of Curcumin, Artemisia, Bromelain, and black pepper oral administration on optical coherence tomography angiography indices in patients with diabetic macular edema. Nutrients. 2022;14:1520. doi: 10.3390/nu14071520. PubMed DOI PMC

Septembre-Malaterre A, Lalarizo Rakoto M, Marodon C, Bedoui Y, Nakab J, Simon E, et al. Artemisia annua, a traditional plant brought to light. Int J Mol Sci. 2020;21:4986. doi: 10.3390/ijms21144986. PubMed DOI PMC

Hou H, Feng X, Li Y, Meng Z, Guo D, Wang F, et al. Suboptimal health status and psychological symptoms among Chinese college students: a perspective of predictive, preventive and personalised health. EPMA J. 2018;9:367–377. doi: 10.1007/s13167-018-0148-4. PubMed DOI PMC

Madsen-Bouterse SA, Zhong Q, Mohammad G, Ho Y-S, Kowluru RA. Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase. Free Radic Res. 2010;44:313–321. doi: 10.3109/10715760903494168. PubMed DOI PMC

Hagan S, Martin E, Enríquez-de-Salamanca A. Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine. EPMA J. 2016;7:15. doi: 10.1186/s13167-016-0065-3. PubMed DOI PMC

The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation