Corneal nerve morphological differences across Ahlqvist-based diabetes subtypes: a multicenter cross-sectional study

Diabetic neuropathy is a common chronic complication of diabetes, and damage to corneal small nerve fibers represents an early manifestation of small fiber neuropathy within the visual system. However, whether corneal nerve injury differs across diabetes subtypes remains unclear. This study aimed to investigate subtype-specific variations in corneal nerve morphology based on the Ahlqvist classification in a Chinese diabetic population and to explore their associations with microvascular complications. This multicenter cross-sectional study enrolled 516 patients with diabetes aged 18–80 years. Diabetes subtypes were classified using a modified Ahlqvist-based hierarchical clustering approach, with additional sensitivity analysis using six-variable k-means clustering. Corneal nerve parameters were quantified using in vivo confocal microscopy, and their associations with neuropathic signs, median nerve motor conduction velocity, and microvascular complications were analyzed. Statistical analyses included analysis of variance or Kruskal–Wallis tests, Spearman correlation analyses, and multivariable logistic regression, as appropriate. CNFD showed an overall between-subtype difference, with numerically lower values in the SAID subgroup and higher values in the MOD subgroup. However, corrected post hoc comparisons did not confirm significant pairwise differences. Associations between CCM parameters and median motor nerve conduction velocity showed an unexpected inverse direction and were therefore interpreted cautiously. No significant associations were observed between NDS and CCM parameters. In the overall cohort, lower standardized CCM parameters were consistently associated with higher odds of DR, and these associations remained significant in sensitivity models with additional adjustment for diabetes duration, HbA1c, and BMI. In contrast, no significant associations were observed between CCM parameters and DKD. Subtype-specific regression findings were considered exploratory because of limited event numbers in some subgroups. CCM parameters showed subtype-related heterogeneity among patients classified using a modified Ahlqvist-based framework. Lower CCM parameters were more consistently associated with DR than with DKD, suggesting a potential relationship between corneal small-fiber imaging markers and retinal microvascular involvement. Associations with median motor nerve conduction velocity showed an unexpected inverse direction and require further validation. Longitudinal studies with comprehensive NCS-based DSPN definitions are needed to confirm these exploratory findings. This observational study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2500100007 https://www.chictr.org.cn/ ) on April 1, 2025.