Clinical Diabetic Peripheral Neuropathy: Can It Be Reversed? Arguments for and Against From a NEUROdiab Debate.

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, yet whether established clinical DPN is reversible remains debated. At the 35th Annual Meeting of NEUROdiab, a formal debate examined arguments 'for' and 'against' the proposition that clinical DPN can be reversed. This review summarises both perspectives and considers their implications for clinical practice and future research. Evidence supporting the reversibility of clinical DPN draws on four main observations. Therapies for hereditary transthyretin amyloidosis demonstrate that substantial improvement in a progressive length-dependent neuropathy is biologically achievable, providing a proof-of-concept in a different disease. Pancreatic transplantation in Type 1 diabetes leads to measurable improvements in large- and small-fibre indices. Structured lifestyle interventions and bariatric surgery improve intraepidermal nerve fibre density, suggesting that metabolic correction can promote neural repair. Finally, emerging agents such as topical oxybutynin show early promise in improving surrogate outcomes, reinforcing the argument that clinical DPN may be partially reversible. Arguments opposing reversibility emphasise that DPN resembles other microvascular complications, in which early abnormalities may regress but established clinical disease is not reversed. Heterogeneity in diagnostic thresholds, phenotype variability and inconsistent outcome measures complicates defining what constitutes true reversal. Long-term studies and major trials, including DCCT/EDIC and BARI 2D, demonstrate slowing of progression rather than restoration of normal nerve function. Moreover, numerous mechanistically promising agents have failed in human trials despite strong pre-clinical results. Collectively, these limitations support the view that established clinical neuropathy remains largely irreversible to date. Overall, the debate underscores that reversibility depends on timing, definitions and outcome thresholds. While early-stage dysfunction is more likely to be modifiable, complete restoration of established clinical DPN (such as full restoration of protective sensation) remains unproven. Future research should prioritise developing validated biomarkers and standardised endpoints in addition to searching for new therapeutics.