Metabolomic profiling and vitamin D pathway investigation in diabetic foot ulcer patients

INTRODUCTION: Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus (DM) characterized by chronic inflammation, impaired wound repair, and systemic metabolic imbalance. This study aimed to identify plasma metabolite signatures associated with DFU and investigate altered metabolic pathways that may serve as potential biomarker. OBJECTIVE: The study aims to identify metabolic alterations and potential biomarkers associated with diabetic foot ulcers, with a focus on the role of vitamin D. METHODS: We performed an LC/MS/MS-based untargeted metabolomic profiling on plasma sample from DFU patients (n = 22), DM patients without foot ulcers (n = 22), and healthy controls (n = 10). The mean age group was 54years, with comparable gender (male = 9; female = 13) distribution in DFU and DM groups. RESULTS: PLS-DA showed clear metabolic separation between DFU and DM groups. DFU group showed elevated levels of aspartic acid, glutamic acid, taurine, and D-fructose, indicating altered hyperglycemia induced metabolic stress. In contrast, calcitriol and glutathione were significantly reduced (P < 0.01), suggesting compromised antioxidant capacity and immune metabolic regulation. Downregulation of sphingosine-1-phosphate (SIP), L-palmitoylcarnitine, and docosahexaenoic acid (DHA) suggest disruptions in mitochondrial dynamics, and wound healing. Elevated taurine, potentially regulated by the vitamin D receptor (VDR), links vitamin D to tissue homeostasis. CONCLUSIONS: This study reveals coordinated disturbances in lipid metabolism, antioxidant defense, and vitamin D signaling in DFU. The identified metabolite signatures highlight pathway-level metabolic alterations associated with impaired wound healing. Our findings suggest that the biological impact of vitamin D in DFU may depend not only on supplementation, but also on its downstream conversion to calcitriol.