Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

  1. Aristidis Veves1
  1. 1Microcirculation Laboratory and Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
  2. 2Technological Educational Institute of Messolonghi, Messolonghi, Greece
  1. Corresponding author: Aristidis Veves, aveves{at}
  1. T.D. and F.T. contributed equally to this article as first authors.


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.


  • Received February 24, 2012.
  • Accepted April 24, 2012.

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  1. Diabetes vol. 61 no. 11 2937-2947
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