Neutrophils and macrophages are the foot soldiers asserting first major line of defense against most bacterial and fungal infections.

In diabetic patients with higher than normal blood glucose levels (prolonged hyperglycemia) often seen in individuals with inadequately controlled diabetes, this critical element of host defense becomes less effective in prevention and containment of infections. It is important to note that such impairment in host immune defenses makes it more likely for infections to spread locally and systemically (throughout the body) leading to a potential for life-threatening illness, especially if not recognized promptly and managed with appropriate care.

This compromise in neutrophil and macrophage function occurs at various levels of white blood cells’ ability to combat invading bacteria and fungi.

Prominent features in antimicrobial function of neutrophils and macrophages that may be impaired due to prolonged exposure to high blood glucose levels in diabetic patients are mainly due to “altered glucose metabolism” and “oxidative stress“, which is an imbalance between the production of free radicals and body’s ability to detoxify the harmful effects of these free radicals by antioxidants.

Following are the salient known defects in neutrophil and macrophage’s handling of invading pathogens in patients with poorly controlled diabetes:

 

[]  Adhesion of neutrophils to the endothelium (sticking to the inner lining of blood vessels) and migration (leaving the blood vessel and entering the tissue to access the infected area), which is triggered by release of pro-inflammatory signals (cytokine and chemokine, including leukotrienes) by cells that commonly reside in the tissue (Natural killer cells, macrophages, dendritic cells). This initial important step in combating infection becomes less effective in diabetic patients with persistently high blood glucose levels.

 

[] Engulfing (entrapment) of pathogens by neutrophils and macrophages requires “expenditure of cellular energy”. Metabolic changes (such as glycolytic and glutaminolytic pathways) in patients with diabetes impairs such critical function by lowering expendable cellular energy levels and thereby leading to a compromised capacity to effectively ingest invading bacteria and fungi.

 

[] Once the bacteria are ingested (taken inside the cell) the killing mechanisms (intracellular killing) are of utmost significance. Effective “intracellular killing” ensures that ingested pathogens DO NOT find a secure residence inside the cell, which may than make these disease-fighting-cells unwittingly act as “Trojan horse” providing safe (intracellular) sanctuary to pathogens. Production of the key elements for effective intracellular killing of bacteria and fungi include bursts (high level production) of “reactive oxygen radicals”, a response that appears to be stunted in patients with poorly controlled diabetes.

 

[] The natural killer cells provide an important stimulus for neutrophils and more importantly, macrophages for a robust antibacterial response against the ingested pathogens. In patients with poorly controlled diabetes, ineffective activation of natural killer cells in response to invading bacteria and fungi results in suboptimum “chemical signaling” via inadequate release of gamma interferon. The resulting low gamma interferon levels in tissue with bacterial and fungal invasion, weakens white blood cells’ ability to effectively neutralize these potential threats.

 

[] Furthermore, convergence of aforementioned factors and other conditions in such patients may promote “programed cell death” or “apoptosis” among the white blood cells, resulting in premature self-destruction of this sentinel component of a persons’ immune defense.  An important, recently recognized mechanism includes a state of chronic, unimpeded low-grade inflammation in patients with diabetes mellitus resulting from the formation of “advanced glycation endproducts” which by way of RAGE (receptor for advanced glycation endproducts) activation yields to the highly undesirable condition of “sustained low-grade inflammation”. The microenvironment or milieu yielded due to “sustained low-grade inflammation” has been implicated in fostering shortened lifespan (premature self-destruction) of the white blood cells.

 

 

Please take note,

Diabetes is associated with a number of complications and among which, infections are of serious concern. 

Better control of diabetes by a) a significant change in life-style; b) appropriate diet modifications and adjustments; c) and an effective, multifaceted approach towards anti-diabetic therapy can significantly ameliorate these potential complications.

 

 

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