Melatonin as a potential biomarker in diabetic retinopathy

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 ۲۰۲۵. 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 ۱۰۰۴ participants published from ۲۰۱۱ to ۲۰۲۲ were included. The mean age of participants ranged from ۳۹.۹ to ۷۲ 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 ۶-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)