Netrin-1: A potential biomarker for diabetic neuropathy

Aims: To explore the relationship between serum netrin-1 levels and small nerve fibre damage in diabetic neuropathy (DN), measured using corneal confocal microscopy (CCM).

Methods: 72 participants with type 2 diabetes, comprising 42 without DN (DN-) and 30 with DN (DN+), alongside 45 healthy controls, underwent a comprehensive physical and sensory assessment, including vibration (VPT), warm and cold (WPT and CPT) perception thresholds.  CCM was used to quantify small nerve fibres and serum netrin-1 levels were measured using an enzyme-linked immune sorbent assay (ELISA) to investigate the association with neuropathy.

Results: VPT, CPT and WPT were significantly worse in both DN- and DN+ groups compared to healthy controls, with worse VPT in DN+ compared to DN-. Corneal nerve fibre density (CNFD), branch density (CNBD), and fibre length (CNFL), progressively declined in DN+ compared to DN- and healthy controls. Serum netrin-1 levels also exhibited lower levels in the DN- and DN+ groups compared to healthy controls, displaying the most substantial reduction in the DN+.  Multiple regression analysis confirmed that netrin-1 is a significant predictor for DN (P<0.04), with receiver operating characteristic (ROC) analysis indicating a moderate to good diagnostic accuracy (AUC 0.85) with 76% sensitivity and 74% specificity at a 599.6 pg/mL cut-off level for differentiating DN+ from DN-.

Conclusions: These findings show a progressive decline in netrin-1 levels corresponding with increased small nerve fibre damage in patients with diabetes, suggesting that netrin-1 could be a potential biomarker for early DN detection.

Comments. The role of netrin-1 in DN and related complications has been complex and sometimes controversial. Previous meta-analysis by Behnoush AH et al (Endocrine. 2024;84(2):328-344) suggested no significant difference in netrin-1 levels between healthy individuals and those with diabetes, however other studies reported elevated netrin-1 levels in diabetic nephropathy cases, particularly among patients with albuminuria. This is particularly interesting, as netrin-1 is known to inhibit inflammatory processes and is synthesized in the pancreas, playing potential roles in diabetic complications. Moreover, Zhu K et al (Neural Regen Res. 2025;20(4):960-972) highlighted the protective role of netrin-1 in both peripheral nerve regeneration and central neuronal survival, underscoring its potential as a biomarker and potential therapeutic target in peripheral neuropathy and neurodegenerative diseases. The current study by Mondal et al aligns with these findings, offering further evidence of netrin-1’s association with small nerve fibre damage. The observed reduction in serum netrin-1 levels with increasing corneal nerve fibre loss offers valuable insights. While promising, this study has its limitations, including the cross-sectional nature, the absence of neurophysiology and skin biopsy assessments, and lack of age-matching between the DN+, DN- and control groups. Despite these limitations, it is the first study to report on netrin-1’s role in DN. Future research with larger studies would be needed to validate the netrin-1’s role as a diagnostic tool in DN.  This opens the door for potential applications of netrin-1 as a biomarker for small nerve fibre loss and possibly offering insight into intervention strategies.

Alise Kalteniece

Reference. Mondal A, Bose C, Pramanik S, Dash D, Mukherjee B, Malik RA, Mukhopadhyay S. Circulating netrin-1 levels are reduced and related to corneal nerve fiber loss in patients with diabetic neuropathy. J Diabetes Investig. 2024 Aug;15(8):1068-1074. doi: 10.1111/jdi.14197. Epub 2024 May 9. PMID: 38725153; PMCID: PMC11292387.

https://onlinelibrary.wiley.com/doi/10.1111/jdi.14197