Immune Mediators in Patients with Acute Diabetic Foot Syndrome

SLR - April 2010 - Sarnarendra Miranpuri

Reference: 
Weigelt C, Rose B, Poschen U et al. (2009).   Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care, 32, 1491-1496.

Scientific Literature Reviews

Reviewed by:  Sarnarendra Miranpuri, DPM
Residency Program: Detroit Medical Center

Podiatric Relevance:
With the increase in worldwide incidence of diabetes, the diabetic foot syndrome has become a significant complication.  Foot ulcerations are a leading cause of lower-limb amputations, with a subsequent decrease in quality of life and increase in risk of mortality.  Despite the correlation between systemic inflammation and microvascular and macrovascular complications of diabetes, there is little published data on the role of immune system activation and foot ulcers.  Because inflammatory processes are critical in the various phases of wound healing, it is possible that immune system disturbances may interfere with tissue homeostasis which may lead to chronic nonhealing wounds, characteristic of diabetic foot syndrome.

Methods:
The authors evaluated the association between foot ulcers and immune status in a cross-sectional study in diabetic patients with (170) and without (140) acute foot ulcers.  They measured several immune mediators to represent the immune system:  C-reactive protein (CRP), fibrinogen, interleukin (IL)-6, macrophage migration inhibitory factor (MIF), regulated on activation normal T-cell expressed and secreted (RANTES), IL-8, IL-18, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and interferon-γ-inducible protein-10 (IP-10).  Using multivariate regression models, they analyzed the associations between circulating concentrations of immune mediators and the presence of a foot ulcer.

Results: 
In diabetic patients with a foot ulcer, several immune mediators were elevated:  CRP, fibrinogen, IL-6, MIF, IP-10, and MIP-1α, whereas no significant differences were found for IL-8, IL-18, and MCP-1.  Serum levels of RANTES, however, were significantly lower in patients with an ulcer compared with those without an ulcer.  To adjust for imbalances between both groups, the association of immune mediators with foot ulcer persisted after adjustment for age, sex, diabetes type, metabolic factors and comorbidities.  Additionally, according to the University of Texas classification for foot ulcers but not the grade of infection, the size of the ulcer was independently associated with three inflammatory markers:  CRP, IL-6 and fibrinogen.

Conclusions:
The authors demonstrated that acute foot ulcers and their severity are associated with an upregulation of circulating levels of several acute-phase proteins, cytokines and chemokines, and lower levels of chemokine RANTES compared with diabetic patients without a history of foot ulcer.  These results indicate a specific and nonrandom alteration of the immune system in patients with foot ulcers.  A parallel upregulation of IL-6, CRP and fibrinogen is of biologic significance because IL-6 is known to increase the release of both acute-phase proteins.  Chemokines are involved in the recruitment of leukocytes to injured sites and migration of other cells (keratinocytes, endothelial cells and fibroblasts) necessary for wound healing.  The results indicate a combination of normal and abnormal wound repair mechanisms, combined with an activation of acute-phase proteins by the acute foot ulcer.