Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

Admin2 · Jun 14, 2012

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Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration.
Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, Tellechea A, Pradhan L, Lyons TE, Giurini JM, Veves A.
Diabetes. 2012 Jun 13

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.
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Admin2 · Jun 14, 2012

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NewsBot · Dec 21, 2013

Role of endothelial progenitor cells and inflammatory cytokines in healing of diabetic foot ulcers.
Tecilazich F et al
PLoS One. 2013 Dec 16;8(12):e83314.

BACKGROUND:
To evaluate changes in endothelial progenitor cells (EPCs) and cytokines in patients with diabetic foot ulceration (DFU) in association with wound healing.
METHODS:
We studied healthy subjects, diabetic patients not at risk of DFU, at risk of DFU and with active DFU. We prospectively followed the DFU patients over a 12-week period. We also investigated similar changes in diabetic rabbit and mouse models of wound healing.
RESULTS:
All EPC phenotypes except the kinase insert domain receptor (KDR)(+)CD133(+) were reduced in the at risk and the DFU groups compared to the controls. There were no major EPC differences between the control and not at risk group, and between the at risk and DFU groups. Serum stromal-cell derived factor-1 (SDF-1) and stem cell factor (SCF) were increased in DFU patients. DFU patients who healed their ulcers had lower CD34(+)KDR(+) count at visits 3 and 4, serum c-reactive protein (CRP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at visit 1, interleukin-1 (IL-1) at visits 1 and 4. EPCs tended to be higher in both diabetic animal models when compared to their non-diabetic counterparts both before and ten days after wounding.
CONCLUSIONS:
Uncomplicated diabetes does not affect EPCs. EPCs are reduced in patients at risk or with DFU while complete wound healing is associated with CD34(+)KDR(+) reduction, suggesting possible increased homing. Low baseline CRP, IL-1α and GM-CSF serum levels were associated with complete wound healing and may potentially serve as prognostic markers of DFU healing. No animal model alone is representative of the human condition, indicating the need for multiple experimental models.
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NewsBot · Mar 14, 2014

Prognostic significance of circulating and endothelial progenitor cell markers in type 2 diabetic foot.
Sambataro M, Seganfreddo E, Canal F, Furlan A, Del Pup L, Niero M, Paccagnella A, Gherlinzoni F, Dei Tos AP.
Int J Vasc Med. 2014;2014:589412.

Objective. We studied circulating precursor cells (CPC) in type 2 diabetes mellitus (T2DM) with neuropathic foot lesions with or without critical limb ischemia and relationships between endothelial precursor cells (EPC) and peripheral neuropathy.

Methods and Subjects. We measured peripheral blood CD34, CD133, and CD45 markers for CPC and KDR, CD31 markers for EPC by citofluorimetry and systemic neural nociceptor CGRP (calcitonin gene related protein) by ELISA in 8 healthy controls (C) and 62 T2DM patients: 14 with neuropathy (N), 20 with neuropathic foot lesions (N1), and 28 with neuroischemic recent revascularized (N2) foot lesions. Timing of lesions was: acute (until 6 weeks), healed, and not healed.

Results. CD34+ and CD133+ were reduced in N, N1, and N2 versus C, and CD34+ were lower in N2 versus N1 (P = 0.03). In N2 CD34+KDR+ remain elevated in healed versus chronic lesions and, in N1 CD133+31+ were elevated in acute lesions. CGRP was reduced in N2 and N1 versus C (P < 0.04 versus C 26 ± 2 pg/mL). CD34+KDR+ correlated in N2 with oximetry and negatively in N1 with CGRP.

Conclusions. CD34+ CPC are reduced in diabetes with advanced complications and diabetic foot. CD34+KDR+ and CD31+133+ EPC differentiation could have a prognostic and therapeutic significance in the healing process of neuropathic and neuroischemic lesions.
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drdebrule · Mar 18, 2014

Although these types of studies are important, this just seems like alphabet soup to me. There are too many abbreviations and no immediate implications for how we should change our treatments.

NewsBot · Mar 22, 2014

Promising Role of ANGPTL4 Gene in Diabetic Wound Healing
Awadhesh K. Arya, Kamlakar Tripathi, Parimal Das
International Journal of Lower Extremity Wounds March 2014 vol. 13 no. 1 58-63

Diabetes mellitus (DM) is one of the severe metabolic disorders of carbohydrate metabolism worldwide. Developing countries are at higher risk of DM, and there is significant evidence that it is epidemic in many economically developing and newly industrialized countries. Among all other complications associated with DM, delayed wound healing is a major concern in diabetic patients. Wound healing is a natural healing process that starts immediately after injury. This involves interaction of a complex cascade of cellular events that generates resurfacing, reconstitution, and restoration of the tensile strength of injured skin. There are multiple factors responsible for delayed wound healing among which the contribution of DM has been well documented. The wound healing process is also delayed by the metabolic, vascular, neurological, and inflammatory alterations, which are well known in both type 1 and type 2 diabetes. Keratinocytes are crucial for wound re-epithelialization, and defects in directed migration of keratinocytes due to DM are associated with the delayed wound healing process. Many factors responsible for re-epithelialization have been identified, characterized, and well described; however, the genes responsible for the healing process have only partially been illustrated. This article will therefore focus on the efficacy of ANGPTL4 (angiopoietin-like 4) gene, which plays a novel role in keratinocyte migration during wound healing.
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NewsBot · Apr 11, 2015

Circulating endothelial progenitor cells and angiogenic factors in diabetes complicated diabetic foot and without foot complications
Arleta Kulwas et al
Journal of Diabetes and its Complications; In Press

Introduction
Data about angiogenic factors in diabetic foot syndrome (DFS) are insufficient. Therefore, in the present study we focus on circulating endothelial progenitor cells (EPCs) and two major angiogenic factors: vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF-2) in patients with DFS.

Materials and methods
We included 75 subjects: 45 patients with type 2 diabetes and 30 controls. The study group was divided into 2 subgroups: 23 patients with diabetic foot and 22 patients without diabetic complications. The concentration of VEGF-A, soluble VEGF receptor 2 (sVEGF-R2) and FGF-2 were measured in plasma samples. The number of circulating EPCs was determined in peripheral venous blood. The number of endothelial progenitor cells was measured with FACSCalibur flow cytometer using monoclonal antibodies directed against antigens specific for EPCs.

Results
In our study we observed significant higher levels of VEGF-A and FGF-2 and lower sVEGF-R2 concentration in patients with T2DM compared to healthy subjects. The conducted analysis showed decreased levels of VEGF -A and elevated levels of FGF-2 in patients with DM complicated DFS compared to diabetic patients without DFS. Increased circulating EPCs number was reported in patients with DFS, and the difference was almost statistical significant.

Conclusions
The high concentration of VEGF-A and FGF-2, and a positive correlation between them indicate their participation in the process of angiogenesis in T2DM. Decreased sVEGF-R2 may result from inactivation of VEGF-A during complexes formation.
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NewsBot · Mar 8, 2017

An Overview on Current Issues and Challenges of Endothelial Progenitor Cell-Based Neovascularization in Patients with Diabetic Foot Ulcer.
Das SK et al
Cell Reprogram. 2017 Mar 7. doi: 10.1089/cell.2016.0050.

Diabetic foot ulcer's impaired wound healing, which leads to the development of chronic non-healing wounds and ultimately amputation, is a major problem worldwide. Although recently endothelial progenitor cell-derived cell therapy has been used as a therapeutic intervention to treat diabetic wounds, thereby promoting neovascularization, the results, however, are not satisfactory. In this article, we have discussed the several steps that are involved in the neovascularization process, which might be impaired during diabetes. In addition, we have also discussed the reported possible interventions to correct these impairments. Thus, we have summarized neovascularization as a process with a coordinated sequence of multiple steps and thus, there is the need of a combined therapeutic approach to achieve better treatment outcomes
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NewsBot · Oct 3, 2022

Circulating endothelial precursor cells are associated with a healed diabetic foot ulcer evaluated in a prospective cohort study
David J Margolis et al
Wound Repair Regen. 2022 Sep 30.

The goal of this multicenter study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects and 40.0% (28.4,41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+ CD45dim , the univariate odds ratio was 1.19(95% confidence interval: 0.88,1.61) and after adjustment for wound area and wound duration the odds ratio was 1.67(1.16,2.42) p=0.006). A prognostic model using CD34+ CD45dim , wound area, and wound duration had an area under the curve of 0.75(0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multi-centered prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care.
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NewsBot · Nov 9, 2022

Distal symmetrical polyneuropathy is present in all individuals with diabetes and foot ulcers - and does not associate with healing time
Hatice IsikMizrak et al
Journal of Diabetes and its Complications; 7 November 2022, 108353

Highlights
•All individuals with a diabetic foot ulcer had distal symmetrical polyneuropathy evaluated by one or more of the tested modalities
•None of the examined tests for distal symmetrical polyneuropathy or cardiovascular autonomic neuropathy were associated with healing time of the diabetic foot ulcer
•The DPNCheckTM device seems to have limited usability in individuals with a diabetic foot ulcer
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We estimated the occurrence of diabetic neuropathy using six different diagnostic modalities in individuals with newly diagnosed diabetic foot ulcers (DFU) and assessed the association with DFU healing time. All individuals with DFU had distal symmetrical polyneuropathy. Presence of neuropathy did not associate with ulcer healing time (p ≥ 0.12).
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