Metabolomic risk predictors of diabetic foot ulcers

Abstract
Background and aims: Diabetic foot ulcers (DFUs) are among the most severe complications associated with diabetes. The severity is highlighted by the evidence of increased mortality and morbidity and more than 70% of all amputations being preceded by a DFU. In recent years, the main strategy of dealing with DFUs has shifted towards prevention. Even though prevention has been successful in lowering the incidence of DFUs, the lifetime risk of DFUs for individuals with diabetes is still 15-33% warranting research on risk markers with the potential of predicting DFUs. In this study, we investigated the association between circulating plasma metabolites and DFUs in subjects with type 1 diabetes (T1D).
Materials and methods: Plasma metabolites (n=75) and clinical characteristics from 637 individuals with T1D recruited from Steno Diabetes Center Copenhagen as part of a cross-sectional study were assessed. Baseline characteristics, DFU diagnoses at baseline and longitudinal data on development of DFU were retrieved from electronic patient journals. Associations between single metabolites and DFU were evaluated by linear regression analyses at baseline and by Cox proportional hazards model at follow-up. Models were fitted with and without adjustments (age, gender, body mass index, systolic blood pressure, cholesterol, HbA1c, smoking, statin, triglycerides, eGFR and urinary albumin excretion) and corrected for multiple testing.
Results: Participants had a mean age of 54 (IQR 46, 62) years, 55% were male (n=348), diabetes duration 35 (25, 44) years, HbA1c 64 (56, 72) mmol/mol and eGFR 85 (64, 102) ml/min/1.73m2. In total 19 participants had DFU at baseline, and a further 108 developed DFU during a median follow-up of 10 years. In the crude model, 11 metabolites at baseline were associated with future risk of DFU. After adjustment, higher levels of ribonic acid exhibited a significantly elevated risk of future DFUs (HR 1.38(1.06-1.8) p<0.05). Figure 1 shows DFU-free survival of participants stratified by ribonic acid at baseline measurement.
Conclusion: In this study, we identified several circulating metabolites associated with future risk of DFU in individuals with T1D. After adjustment for potential confounders and multiple testing, a sugar derivate (i.e. ribonic acid) retained significant association to future development of DFUs. Previous studies have demonstrated that ribonic acid is related to other complications (i.e. kidney disease and retinopathy) and this study adds to theses findings as well as the growing evidence of predicting DFUs via measurements of plasma metabolites.