Metabolomic Risk Predictors of Diabetic Foot Complications: a longitudinal observational study

Diabetic foot complications (DFCs) comprising diabetic foot ulcer (DFU), charcots neuroarthropathy and amputations are a collective term used for the ailments of the foot that individuals with diabetes incur. Despite implementation of national and international guidelines, DFCs are still a growing challenge to the individual and society. Novel markers for the treatment and prevention of DFCs are thus needed. The aim of this study was to investigate circulating metabolites associated with the prevalence and incidence of DFCs in persons with type 1 diabetes (T1D). A panel of non-targeted serum metabolites (n=75) were analyzed using mass spectrometry in 637 individuals with T1D with a median follow up time of 10 years. Cross sectional associations between metabolites and DFCs were analysed by linear regression models at baseline, Cox proportional hazards model at follow-up and adjusted for relevant confounders (age, sex, HbA1c, systolic blood pressure, bmi, smoking, statin use, total cholesterol, plasma triglycerides, and renal function). The median (interquartile range) age was 55 (47, 64) years, diabetes duration of 35 (25, 44) years and HbA1c levels 64 (8%) (56, 72(7.3%, 8.7%)) mmol/mol. In the adjusted model, four amino acids (Proline, Threonine, Valine, and Leucine) were associated with a decreased incidence of Charcots arthropathy at baseline (p<0.05). In addition, circulating ribonic acid levels were associated with an increased risk of DFUs during follow-up (HR 1.38(1.06-1.8); p<0.05) which were validated in an independent cross-sectional T1D cohort (p<0.05). This study identifies novel circulating metabolites, as potential biomarkers for risk stratification of diabetic foot complications.