Key Molecular Mechanisms of Diabetic Ulcer Pathogenesis

Overview of Diabetic Ulcers and Their Complications

Diabetic foot ulcers (DFUs) represent a severe complication of diabetes mellitus, drastically affecting the quality of life and leading to increased morbidity and mortality. These ulcers arise primarily due to a combination of peripheral neuropathy, peripheral arterial disease, and foot deformities, which impair healing processes and enhance susceptibility to infections. Globally, DFUs affect approximately 15% of individuals with diabetes, with a significant risk of subsequent amputations and hospitalizations (Zhang et al., 2023). The economic burden associated with diabetic ulcers is substantial, with estimates suggesting that foot ulcers account for a large proportion of healthcare costs related to diabetes management.

The underlying pathophysiology of diabetic ulcers involves a complex interplay of genetic, metabolic, and environmental factors that culminate in impaired wound healing. Hyperglycemia induces oxidative stress, leading to endothelial dysfunction and reduced angiogenesis, which are critical for tissue repair (Zhou et al., 2023). Furthermore, chronic inflammation characterizes the diabetic ulcer microenvironment, complicating the healing process by promoting continued tissue damage (Chen et al., 2025).

Multi-Omics Approaches in Diabetic Ulcer Research

In recent years, multi-omics approaches have emerged as powerful tools for elucidating the molecular mechanisms underlying diabetic ulcers. These approaches integrate data from genomics, transcriptomics, proteomics, and metabolomics, allowing for a comprehensive understanding of the complex biological systems involved in ulcer pathogenesis. By combining these datasets, researchers can identify key molecular signatures and pathways that may serve as therapeutic targets.

For instance, a study utilizing transcriptomic analysis revealed 653 differentially expressed genes (DEGs) associated with diabetic ulcers, predominantly involved in inflammatory processes such as cytokine signaling and the NF-κB pathway (Lu et al., 2025). Proteomic studies have identified significant alterations in protein expression, highlighting pathways related to diabetic cardiomyopathy and vascular dysfunction (Chen et al., 2025). Similarly, metabolomic profiling has uncovered distinct metabolic signatures in diabetic ulcers, with a focus on amino acids and lipids crucial for cellular repair and inflammation regulation (Zhou et al., 2023).

Transcriptomic Insights into Diabetic Ulcer Mechanisms

Transcriptomic analysis plays a critical role in uncovering gene expression patterns associated with diabetic ulcers. By examining the mRNA profiles of ulcer tissues, researchers can identify DEGs that contribute to the pathophysiology of these lesions. High-throughput RNA sequencing has identified numerous genes implicated in inflammation, cell proliferation, and apoptosis, which are essential for wound healing.

For example, the gene IGFN1 has been found to be significantly upregulated in diabetic ulcer models, suggesting its involvement in modulating inflammatory responses (Lu et al., 2025). Pathway analysis of DEGs has revealed significant enrichment in cytokine-cytokine receptor interactions and the TNF signaling pathway, which are critical for the inflammatory response in diabetic ulcers. The identification of these pathways not only enhances our understanding of the molecular mechanisms at play but also aids in the development of targeted therapeutic strategies to promote wound healing.

Proteomic Analysis and Key Protein Interactions in Diabetic Ulcers

Proteomic analysis provides insights into the changes in protein expression that accompany diabetic ulcer formation. By employing techniques such as mass spectrometry, researchers can identify differentially expressed proteins (DEPs) that may play pivotal roles in the progression of diabetic ulcers.

In one comprehensive proteomic study, a total of 883 DEPs were identified between diabetic ulcer tissues and healthy controls, with significant alterations observed in proteins associated with inflammation, wound healing, and cellular stress responses (Chen et al., 2025). Notably, pathways such as diabetic cardiomyopathy and HIF-1 signaling were found to be significantly enriched, indicating their potential roles in the pathogenesis of DFUs.

The identification of these DEPs allows for the establishment of protein interaction networks, revealing how various proteins collaborate to influence cellular behavior in diabetic ulcers. Understanding these interactions facilitates the identification of novel therapeutic targets and biomarkers for ulcer management.

Metabolomic Profiling of Diabetic Ulcers: Implications for Treatment

Metabolomics, the study of small molecules in biological systems, offers unique insights into the metabolic alterations associated with diabetic ulcers. By profiling the metabolites present in ulcer tissues, researchers can identify specific metabolic pathways that are dysregulated in the context of diabetes.

In a recent metabolomic study, over 1,300 metabolites were identified in diabetic ulcer tissues, with significant enrichment in lipid and amino acid metabolites (Zhou et al., 2023). Pathway analysis revealed that dysregulation of amino acid biosynthesis and lipid metabolism pathways contributes to chronic inflammation and impaired healing processes in diabetic ulcers.

The identification of these metabolites opens avenues for targeted therapeutic interventions that can modulate metabolism to improve wound healing. For instance, enhancing the levels of specific amino acids such as arginine may promote angiogenesis and tissue repair, while targeting lipid metabolism could reduce inflammation associated with ulcer formation.

Conclusion

The pathogenesis of diabetic ulcers involves multifaceted molecular mechanisms characterized by dysregulated inflammation, impaired wound healing, and altered metabolism. Multi-omics approaches, encompassing transcriptomics, proteomics, and metabolomics, provide powerful platforms for uncovering the complex interactions at play in diabetic ulcer pathogenesis. By identifying key molecular signatures and pathways, these studies lay the groundwork for developing innovative therapeutic strategies aimed at improving clinical outcomes for individuals with diabetic ulcers.

FAQ

What are diabetic ulcers?
Diabetic ulcers are open sores or wounds that commonly occur on the feet of individuals with diabetes, primarily due to poor circulation and nerve damage.

How prevalent are diabetic foot ulcers?
Approximately 15% of individuals with diabetes will develop a diabetic foot ulcer at some point in their lives.

What are the primary causes of diabetic ulcers?
The primary causes include peripheral neuropathy, peripheral arterial disease, foot deformities, and poor wound healing.

How can diabetic ulcers be treated?
Treatment options include wound care management, infection control, offloading pressure from the ulcer, and potentially surgical intervention in severe cases.

What role do multi-omics approaches play in diabetic ulcer research?
Multi-omics approaches integrate data from genomics, transcriptomics, proteomics, and metabolomics, providing a comprehensive understanding of the biological mechanisms underpinning diabetic ulcer pathogenesis.

References

1. Zhang, Q., Xiao, S., Jiao, X., Shen, Y. (2023). The triglyceride-glucose index is a predictor for cardiovascular and all-cause mortality in CVD patients with diabetes or pre-diabetes: evidence from NHANES 2001-2018. Cardiovasc Diabetol, 22(279). doi:10.1186/s12933-023-02030-z. Full URL: https://doi.org/10.1186/s12933-023-02030-z

2. Zhou, Y., Xu, Y., Wang, Y., et al. (2023). Integrated transcriptomic, proteomic, and metabolomic analysis unveils key roles of protein and nucleic acid interactions in diabetic ulcer pathogenesis. Front Endocrinol, 14, 1574858. doi:10.3389/fendo.2025.1574858. Full URL: https://doi.org/10.3389/fendo.2025.1574858

3. Chen, L., Zhang, J., et al. (2025). The role of tumor necrosis factor alpha (TNF-alpha) in autoimmune disease and current TNF-alpha inhibitors in therapeutics. Int J Mol Sci, 22(2719). doi:10.3390/ijms22052719

4. Lu, Y., Gao, H., Wang, S., et al. (2025). Integrated transcriptomic, proteomic, and metabolomic analysis unveils key roles of protein and nucleic acid interactions in diabetic ulcer pathogenesis. Front Endocrinol, 14, 1574858. doi:10.3389/fendo.2025.1574858. Full URL: https://doi.org/10.3389/fendo.2025.1574858