Circulating netrin-1 levels in type 2 diabetes mellitus: A systematic review and meta-analysis

Netrin-1, a laminin-related guidance cue protein with emerging immunomodulatory roles, has shown conflicting associations with type 2 diabetes mellitus (T2DM) in human studies. We conducted a systematic review and meta-analysis to evaluate circulating netrin-1 levels in individuals with T2DM compared to healthy controls.

A comprehensive search of MEDLINE/PubMed, Scopus, and Europe PMC up to March 17, 2025, was performed for studies reporting netrin-1 levels in T2DM patients. Eligible studies were observational and provided extractable quantitative data. Study quality was assessed using the Newcastle-Ottawa Scale and JBI checklist. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity, subgroup, sensitivity, and publication bias analyses were performed using R software.

Twenty studies involving 1,798 articles were included. Pooled analysis revealed significantly elevated netrin-1 levels in T2DM (SMD = 0.57; 95% CI: 0.03-1.11; p = 0.0393), with substantial heterogeneity (I² = 96.4%). Subgroup analyses indicated geographic and diagnostic criteria as key moderators. Egyptian studies and those using ADA guidelines reported increased netrin-1, while Indian and WHO-based studies reported reductions. The 95% prediction interval (-2.03 to 3.18) reflected wide variability. No significant publication bias was detected (LFK index = -0.49).

This meta-analysis supports a potential link between netrin-1 and T2DM, suggesting its role as a biomarker of metabolic inflammation. However, substantial heterogeneity and study-level differences necessitate further standardized, longitudinal research to clarify its clinical relevance.