Metabolomic risk predictors of diabetic foot complications: A longitudinal observational study in type 1 diabetes

Diabetic foot complications are a growing challenge for both individuals and society, underscoring the need for medical treatments and reliable risk markers. This study aimed to identify circulating metabolites associated with the prevalence and incidence of diabetic foot complications in individuals with type 1 diabetes (T1D).

A non-targeted panel of 75 serum metabolites was measured via mass spectrometry in 637 individuals with T1D from the Steno Diabetes Center Copenhagen, with a median follow-up of 10 years. Associations with diabetic foot complications (foot ulcers and lower extremity amputations) were assessed using linear regression for prevalent and Cox models for incident outcomes. Metabolites with significant crude associations (after multiple testing correction) were further adjusted for key confounders including demographics, clinical variables, lipid profile and renal function, using R statistics.

Participants had a median (interquartile range) age of 55 (47, 64) years, diabetes duration of 35 (25, 44) years and HbA1c levels of 64 (8%) (56, 72 (7.3%, 8.7%)) mmol/mol. In crude models, six metabolites were associated with prevalent amputations and 11 with incident ulcers. After adjustment, threonine and succinic acid remained associated with prevalent amputations (p < 0.05). Ribonic acid (Hazard Ratio [HR] per percentage-increase: 1.02; 95% CI: 1.00-1.04) and nonanoic acid (HR: 0.96; 95% CI: 0.94-0.99) remained significantly associated with incident ulcers. The association between ribonic acid and incident diabetic foot ulcers was replicated in an independent cohort (p < 0.05).

This study identified novel circulating metabolites, particularly those of the pentose phosphate pathway, associated with the risk of diabetic foot complications.