Cross-Species Comparison of Diabetic Skin at Single-Cell Resolution: db/db and STZ Mouse Models Versus Human Diabetic Foot Patients

Background: Research on diabetes-related skin conditions relies primarily on rodent models, including genetic and chemically induced models of diabetes. However, criteria for selecting the most appropriate model remain unclear, and comparative studies at the cellular level are lacking. Methods: Full-thickness skin samples were collected from patients with diabetic foot disease, db/db mice, and C57BL/6J mice with streptozotocin (STZ)-induced diabetes. Histological analysis was performed using hematoxylin and eosin staining to assess tissue architecture. Single-cell RNA sequencing (scRNA-seq) was used to characterize cellular composition and transcriptional profiles. Results: Human skin was significantly thicker and more stratified than mouse skin. scRNA-seq revealed that human tissue contained a higher proportion of endothelial cells but lacked the adipocyte population observed in STZ-treated mice. Human cells showed greater enrichment in the G1 phase, whereas mouse cells exhibited higher proliferative activity. Transcriptional profiling revealed that human fibroblasts were enriched for markers of chronic inflammation and fibrosis, whereas human keratinocytes and endothelial cells showed increased expression of immune-related genes and decreased expression of metabolic genes. These patterns differed from those observed in the murine models. Conclusions: Although the db/db and STZ models reproduce hyperglycemia, they do not fully recapitulate the inflammatory, cell-cycle, and metabolic features observed in human diabetic foot skin. These species-specific differences underscore the need for caution when extrapolating findings from mouse models to human diabetic skin pathology.