Tear Fluid Biomarkers in Diabetic Ocular Surface Disease: A Systematic Review

Background: Diabetic eye surface disease, including dry eye syndrome, corneal neuropathy, and diabetic retinopathy, is a common complication of diabetes. Tear fluid biomarkers may aid in early diagnosis and disease monitoring. The objective of this systematic review was to identify and evaluate tear fluid biomarkers in diabetic ocular surface disease according to PRISMA guidelines. Methods: PubMed, Scopus, and Embase databases were searched through June 2025. Eligible studies included clinical and observational studies measuring proteins, lipids, cytokines, trace elements, or nucleic acids in tear fluids in patients with diabetes. Results: The search identified 198 studies, and of those, 30 studies were included, comprising 14 original investigations with 871 participants (133 with type 1 diabetes, 453 with type 2 diabetes, 16 with pre-diabetes, and 269 healthy controls). The main biomarker categories were cytokines (IL-6, IL-8, TNF-α, and MMP-9), neuropeptides (substance P, NPY), proteins (IGFBP-3, progranulin), lipids, glycans, microRNAs, circRNAs, and trace elements. Conclusions: More than a dozen biomarkers in the tear fluid have been identified that may reflect diabetes-related changes in the ocular surface. Tear fluid analysis may be a valuable tool in personalizing the diagnosis and treatment of diabetic ocular surface diseases, but further studies are needed to confirm its clinical significance.