Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

Thanh Dinh; Francesco Tecilazich; Antonios Kafanas; John Doupis; Charalambos Gnardellis; Ermelindo Leal; Ana Tellechea; Leena Pradhan; Thomas E. Lyons; John M. Giurini; Aristidis Veves


Diabetes. 2012;61(11):2937-2947. 

In This Article

Abstract and Introduction


We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.


Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes and affects 15% of all diabetic patients, leading to >80,000 amputations per year in the U.S. and results in a high financial burden.[1,2] Neuropathy, peripheral vascular disease, and reduced resistance to infection are recognized risk factors leading to the development of DFUs, which have all the characteristics of a chronic wound.[3,4]

In the current study, we have well characterized and prospectively followed-up a large number of diabetic patients, the majority of whom were at risk for developing foot ulceration. Our main hypothesis was that changes in the peripheral nerve function and the diabetes-associated proinflammatory state are related not only to the development of DFUs but also to wound-healing failure.