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Background and Aims: Longer diabetic foot ulcer (DFU) healing time is associated with a 10 to 20 times higher risk of foot amputations in people with diabetes than in nondiabetic subjects, however no biomarkers for DFU healing exist. We investigated foot ulcer swap proteins associated with DFU healing time. Material and Methods: Untargeted proteomics profiling of DFU surface swaps was conducted on 112 diabetic individuals at the Steno Diabetes Center Copenhagen outpatient clinic with follow-up of 6 months. Proteomics was performed using Liquid Chromatography Mass Spectrometry workflow with quantification (MaxQuant), and annotation (Perseus). Two data preprocessing workflows (WFs) were compared, WF1: Missing values were either imputed from normal distribution after filtering 30% non-missing data, and WF2: Compositionality-based Bayesian multiplicative replacement was applied. Longitudinal analysis was conducted using cox proportional hazards regression adjusting for covariates (age, gender, BMI, diabetes type and duration, HbA1c, and triglyceride levels) with false detection rate (FDR) applied, with significance PFDR0.1 in R Studio. A lower hazards ratio (HR) indicated longer healing time. Results: Study participants had a mean (± SD) age 50.7(11.9), and diabetes duration 26.9(14.6) years, HbA1c 64.8(15.3) mmol/mol, BMI 29.9(5.5) kg/m2, TBI 0.48 (0.22), 83.9% had neuropathy and 62.5% had type 2 diabetes. Of 256 (WF1) and 1092 (WF2) unique proteins remaining post preprocessing, 6 and 46 proteins remained significantly associated (PFDR0.1) with ulcer healing time. Top proteins included S100A8 (HR: 0.81), and Myeloblastin (HR: 0.74) associating with longer healing and IL16 and MMP1 (HR:1.28) with faster healing. Both WFs were highly correlated (R=0.7). Conclusions: We identify tissue proteomic signatures for DFU wound healing time particularly proteins indicating increased inflammation and granulocyte infiltration in DFU wound bed and poor healing. Disclosure T. Ahluwalia: None. S. Jain: None. M. Petkovic: None. J.A. Raguz: None. G. Kaur: None. R.R. Jersie-Christensen: None. K. Kirketerp-Møller: None. J.H. Andersen: None. A.G. Pedersen: None. A. Veves: None. A. Rasmussen: None. L.T. Dalgaard: None. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. Funding Novo Nordisk Foundation (NNF 23OC0084081)
Ahluwalia et al. (2024) studied this question.