Melatonin as a potential biomarker in diabetic retinopathy
Medical hypothesis, discovery & innovation in optometry,
Vol. 6 No. 2 (2025),
31 July 2025
,
Page 74-82
https://doi.org/10.51329/mehdioptometry225
Abstract
Background: Diabetic retinopathy (DR) is a major complication of diabetes mellitus (DM). Melatonin protects against inflammation and oxidative stress. This review focuses on the literature comparing melatonin levels in patients with and without DR.Methods: A thorough search of the PubMed/MEDLINE, Web of Science, and Embase databases was performed for articles published until April 2025. The inclusion criteria were studies reporting melatonin levels in patients with DR and control groups; studies involving human participants of any age, gender, or ethnicity; and investigations documented in scholarly publications. The exclusion criteria were as follows: animal studies; review articles; case reports; editorials; and conference abstracts; studies not available in English or lacking an English translation; and studies focusing on interventions altering melatonin levels rather than comparing levels between patients with DR and controls. Furthermore, we manually checked the reference lists of the included papers to identify any earlier series that were not initially found in our core search. The Newcastle-Ottawa Scale was used to evaluate study quality.
Results: Eight studies with 1004 participants published from 2011 to 2022 were included. The mean age of participants ranged from 39.9 to 72 years. Three studies assessed urinary melatonin excretion, three examined blood melatonin concentrations, one evaluated melatonin concentration in the aqueous humor, and one measured salivary melatonin levels. All samples were collected at night, except for three studies. All studies utilized enzyme-linked immunosorbent assay to measure melatonin concentration, except for the one study, which employed high-performance liquid chromatography. Numerous studies have indicated that patients with DM exhibit reduced melatonin levels relative to healthy controls, and that individuals with DR show lower levels than those without DR. Patients with proliferative DR exhibit reduced nocturnal urinary excretion of 6-sulfatoxymelatonin. Melatonin levels in the aqueous humor were elevated in patients with proliferative DR. Melatonin levels were negatively correlated with both the duration of DM and glycated hemoglobin levels.
Conclusions: The findings of this review suggest that patients with DM, particularly those with DR, exhibit altered melatonin production. Reduced systemic melatonin levels may correlate with increased risk and severity of DR. However, the majority of included studies had a case-control design, which hinders the ability to draw causal conclusions regarding the association between melatonin levels and DR. Moreover, confounding factors, including age, duration of DM, medication use, and lifestyle characteristics of participants, were not uniformly considered, and the limited sample sizes restrict the applicability of the results. Future investigations should emphasize longitudinal studies to clarify the temporal dynamics between melatonin levels and DR progression Additional investigations are required to clarify the function of melatonin in the pathogenesis of DR and its viability as a therapeutic target.
Keywords:
- diabetic retinopathies
- melatonin
- chronobiology phenomenon
- eyes
- pineal-retinal relationships
- retina-SCN-pineal pathway
- retina-SCN-pineal axis
- suprachiasmatic nucleus (SCN)
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2. Yang Z, Tan TE, Shao Y, Wong TY, Li X. Classification of diabetic retinopathy: Past, present and future. Front Endocrinol (Lausanne). 2022 Dec 16;13:1079217. doi: 10.3389/fendo.2022.1079217. PMID: 36589807; PMCID: PMC9800497.
3. Hussain A, Ashique S, Afzal O, Altamimi MA, Malik A, Kumar S, Garg A, Sharma N, Farid A, Khan T, Altamimi ASA. A correlation between oxidative stress and diabetic retinopathy: An updated review. Exp Eye Res. 2023 Nov;236:109650. doi: 10.1016/j.exer.2023.109650. Epub 2023 Sep 19. PMID: 37734426.
4. Kropp M, Golubnitschaja O, Mazurakova A, Koklesova L, Sargheini N, Vo TKS, de Clerck E, Polivka J Jr, Potuznik P, Polivka J, Stetkarova I, Kubatka P, Thumann G. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications-risks and mitigation. EPMA J. 2023 Feb 13;14(1):21-42. doi: 10.1007/s13167-023-00314-8. PMID: 36866156; PMCID: PMC9971534.
5. Rodríguez ML, Pérez S, Mena-Mollá S, Desco MC, Ortega ÁL. Oxidative Stress and Microvascular Alterations in Diabetic Retinopathy: Future Therapies. Oxid Med Cell Longev. 2019 Nov 11;2019:4940825. doi: 10.1155/2019/4940825. PMID: 31814880; PMCID: PMC6878793.
6. Shukla UV, Tripathy K. Diabetic Retinopathy. 2023 Aug 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 32809640.
7. Samanta S. Physiological and pharmacological perspectives of melatonin. Arch Physiol Biochem. 2022 Oct;128(5):1346-1367. doi: 10.1080/13813455.2020.1770799. Epub 2020 Jun 10. PMID: 32520581.
8. Felder-Schmittbuhl MP, Hicks D, Ribelayga CP, Tosini G. Melatonin in the mammalian retina: Synthesis, mechanisms of action and neuroprotection. J Pineal Res. 2024 Apr;76(3):e12951. doi: 10.1111/jpi.12951. PMID: 38572848.
9. Jiang T, Chang Q, Cai J, Fan J, Zhang X, Xu G. Protective Effects of Melatonin on Retinal Inflammation and Oxidative Stress in Experimental Diabetic Retinopathy. Oxid Med Cell Longev. 2016;2016:3528274. doi: 10.1155/2016/3528274. Epub 2016 Apr 6. PMID: 27143993; PMCID: PMC4837288.
10. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016 Oct;61(3):253-78. doi: 10.1111/jpi.12360. Epub 2016 Sep 1. PMID: 27500468.
11. Boga JA, Caballero B, Potes Y, Perez-Martinez Z, Reiter RJ, Vega-Naredo I, Coto-Montes A. Therapeutic potential of melatonin related to its role as an autophagy regulator: A review. J Pineal Res. 2019 Jan;66(1):e12534. doi: 10.1111/jpi.12534. Epub 2018 Nov 26. PMID: 30329173.
12. Tsai MH, Wei IH, Jiang-Shieh YF, Jou MJ, Ko MH, Chen HM, Wu CH. Expression of protein gene product 9.5, tyrosine hydroxylase and serotonin in the pineal gland of rats with streptozotocin-induced diabetes. Neurosci Res. 2008 Mar;60(3):233-43. doi: 10.1016/j.neures.2007.11.003. Epub 2007 Nov 19. PMID: 18155792.
13. Amin M, Rafla B, Wu R, Postolache TT, Gragnoli C. The role of melatonin receptor 1B gene (MTNR1B) in the susceptibility to depression and type 2 diabetes comorbidity. Genes Dis. 2023 Aug 4;11(3):101067. doi: 10.1016/j.gendis.2023.06.036. PMID: 38292205; PMCID: PMC10825273.
14. Nwaji AR, Bisong SA, Antai AB, Okakpu CM, Okechukwu MP, Igwe EO, Okafor CS, Odoh PC, Chukwu MC, Esinulo JI, Simon T. Impact of Melatonin on Brain Metabolism in Diabetes: A Narrative Review. Natural Product Communications. 2025 May;20(5):1934578X251340772. doi: 10.1177/1934578X251340772.
15. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2011). 'The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses'. Ottawa, ON: Ottawa Hospital Research Institute. Available at: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (Accessed: February 20, 2025)
16. Wan WC, Long Y, Wan WW, Liu HZ, Zhang HH, Zhu W. Plasma melatonin levels in patients with diabetic retinopathy secondary to type 2 diabetes. World J Diabetes. 2021 Feb 15;12(2):138-148. doi: 10.4239/wjd.v12.i2.138. PMID: 33594333; PMCID: PMC7839166.
17. Ba-Ali S, Brøndsted AE, Andersen HU, Sander B, Jennum PJ, Lund-Andersen H. Assessment of diurnal melatonin, cortisol, activity, and sleep-wake cycle in patients with and without diabetic retinopathy. Sleep Med. 2019 Feb;54:35-42. doi: 10.1016/j.sleep.2018.10.018. Epub 2018 Oct 31. PMID: 30529775.
18. Reutrakul S, Siwasaranond N, Nimitphong H, Saetung S, Chirakalwasan N, Chailurkit LO, Srijaruskul K, Ongphiphadhanakul B, Thakkinstian A. Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes. Chronobiol Int. 2017;34(3):382-392. doi: 10.1080/07420528.2016.1278382. Epub 2017 Jan 27. PMID: 28128991.
19. Chen W, Cao H, Lu QY, Wang N, Zhao SZ, Xu X, Zheng Z. Urinary 6-sulfatoxymelatonin level in diabetic retinopathy patients with type 2 diabetes. Int J Clin Exp Pathol. 2014 Jun 15;7(7):4317-22. PMID: 25120815; PMCID: PMC4129050.
20. Hikichi T, Tateda N, Miura T. Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Clin Ophthalmol. 2011;5:655-60. doi: 10.2147/OPTH.S19559. Epub 2011 May 19. PMID: 21629571; PMCID: PMC3104794.
21. Tanaka K, Okada Y, Maiko H, Mori H, Tanaka Y. Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes. J Diabetes Investig. 2021 Apr;12(4):601-609. doi: 10.1111/jdi.13374. Epub 2020 Aug 25. PMID: 33460308; PMCID: PMC8015816.
22. Saeed WM, Al-Sehli A, Al-Alawi B, Al-Raheili R. Melatonin Levels in Saudi Female with Type 2 Diabetes Mellitus. Journal of Pharmaceutical Negative Results. 2022 Oct 7;13: 339-44. doi: 10.47750/pnr.2022.13.S06.048.
23. Aydin E, Sahin S. Increased melatonin levels in aqueous humor of patients with proliferative retinopathy in type 2 diabetes mellitus. Int J Ophthalmol. 2016 May 18;9(5):721-4. doi: 10.18240/ijo.2016.05.15. PMID: 27275429; PMCID: PMC4886868.
24. Benloucif S, Burgess HJ, Klerman EB, Lewy AJ, Middleton B, Murphy PJ, Parry BL, Revell VL. Measuring melatonin in humans. J Clin Sleep Med. 2008 Feb 15;4(1):66-9. PMID: 18350967; PMCID: PMC2276833.
25. Baskett JJ, Cockrem JF, Antunovich TA. Sulphatoxymelatonin excretion in older people: relationship to plasma melatonin and renal function. J Pineal Res. 1998 Jan;24(1):58-61. doi: 10.1111/j.1600-079x.1998.tb00366.x. PMID: 9468119.
26. Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, Baik HH. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006 Aug;41(1):67-72. doi: 10.1111/j.1600-079X.2006.00334.x. PMID: 16842543.
27. Contreras-Alcantara S, Baba K, Tosini G. Removal of melatonin receptor type 1 induces insulin resistance in the mouse. Obesity (Silver Spring). 2010 Sep;18(9):1861-3. doi: 10.1038/oby.2010.24. Epub 2010 Feb 18. PMID: 20168308; PMCID: PMC2929321.
28. Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes. 2011 Jun 15;2(6):82-91. doi: 10.4239/wjd.v2.i6.82. PMID: 21860691; PMCID: PMC3158876.
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