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

Diabetic foot complications is a collective term used for the ailments of the foot that individuals with diabetes incur. The different entities of the term diabetic foot complications are closely linked to each other and several of the other complications of diabetes. Despite implementation of national and international preventive guidelines, diabetic foot complications are still a growing challenge to the individual and society in general. This highlights the need for new strategies in the treatment and prevention of diabetic foot complications. The aim of the study was to investigate associations between plasma metabolites and diabetic foot complications (diabetic foot ulcer (DFU), amputations and Charcot’s Arthropathy) in individuals with diabetes type 1. Non targeted plasma metabolites (n=75) were analyzed using mass spectrometry in a cohort comprising 637 individuals (55% male) with diabetes type 1. Cross sectional associations between metabolites and diabetic foot complications was analysed by linear regression at baseline and by Cox proportional hazards model at follow-up and adjusted for relevant confounders. The median follow up time was 10 years, age 55 (47, 64) years, diabetes duration 35 (25, 44) years and HbA1c 64 (56, 72) mmol/mol. In the adjusted model, four amino acids (proline, threonine, valine, and leucine) were associated with decreased incidence of Charcot’s arthropathy at baseline ( p adjusted < 0 . 5 ). In addition, the plasma levels of ribonic acid was associated with an increased risk of diabetic foot ulcers during follow-up (HR 1.38(1.06-1.8) p < 0 . 05) . This study identifies novel circulating metabolites, as potential biomarkers for risk of diabetic foot complications. One Sentence Summary Several plasma metabolites show promise as risk markers of diabetic foot complications. ### Competing Interest Statement The authors have declared no competing interest. ### 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 All data produced in the present study are available upon reasonable request to the authors