Metabolomic Risk Predictors of Diabetic Foot Complications: a longitudinal observational study in Type 1 Diabetes

Diabetic foot complications (DFCs) comprising diabetic foot ulcer (DFU), charcot’s 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 Charcot’s 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. ### Competing Interest Statement None of the authors have any competing interest connected to this study. Outside of this study: PR has received consultancy and/or speaking fees (to SDCC) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Eli Lilly, MSD, Novo Nordisk and Sanofi Aventis, and research grants from Novo Nordisk and Astra Zeneca. MFM has received speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi ### Funding Statement This study PI was funded by the Novo Nordisk Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted according to the Helsinki Declaration on ethical principles for medical research. The study was approved by the Danish Ethical Committee, Danish Patient Safety Authorities and Danish Data Protection Agency. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes