Role of Trace Elements in Diabetic Retinopathy: A Systematic Review

Diabetic retinopathy (DR) is a leading cause of vision impairment worldwide and a major microvascular complication of type 2 diabetes mellitus (T2DM). While chronic hyperglycemia remains the principal driver of DR, growing evidence suggests that dysregulation of essential trace elements, including magnesium, zinc, manganese, chromium, selenium, and iron, may contribute to retinal microvascular injury through oxidative stress and impaired endothelial function. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, with a comprehensive search of PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Google Scholar for studies published between January 2000 and June 2024. Search terms included "diabetic retinopathy," "trace elements," "magnesium," "zinc," "manganese," "chromium," "selenium," and "iron." Eligible studies comprised observational studies (cross-sectional, case-control, cohort), randomized controlled trials, and meta-analyses reporting serum, plasma, or dietary levels of trace elements in patients with T2DM, with and without DR. Data extraction was performed independently by two reviewers with consensus resolution. A total of 15 studies met the inclusion criteria. Patients with DR consistently demonstrated lower serum levels of magnesium, zinc, manganese, and chromium compared to diabetic controls without retinopathy. Selenium exhibited a U-shaped relationship, with both low and high levels associated with increased DR risk. Dysregulation of iron, particularly deficiency and evidence of iron-driven ferroptosis, was linked to retinal hypoxia, neurodegeneration, and elevated oxidative stress. These findings demonstrate that trace element imbalances are strongly associated with the risk and progression of DR. Assessment of serum trace elements may serve as a cost-effective biomarker panel for early risk stratification. However, heterogeneity across studies and the predominance of observational designs limit causal inference, underscoring the need for well-designed prospective cohorts and randomized controlled trials to determine whether targeted micronutrient supplementation can reduce DR incidence or delay progression.