SPMs and Diabetic Wound Healing

Approximately 29.1 million Americans, or 9.3% of the population, have diabetes with Type 2 Diabetes (T2DM) representing 90-95% of all diabetes cases, according to the American Diabetes Association. Many co-morbidities are associated with diabetes, including hypertension and cardiovascular disease, blindness, and kidney disease. Poor wound healing is also associated with diabetes and may sometimes lead to amputation.

Diabetes and Inflammation

It is well known that people with diabetes also have elevated concentrations of pro-inflammatory mediators. An early cohort study on the topic, published in The Lancet in 1999, studied the markers of inflammation in a population of over 12 thousand men and women between the ages of 45 and 64 years. Markers of inflammation like elevated white-cell count, low serum albumin, raised fibrinogen, raised orosomucoid, and sialic acid were associated with the development of diabetes. Since then, researchers have identified other inflammatory markers like tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are also elevated in obesity and type 2 diabetes.

The prevailing hypothesis of the metabolic and inflammatory signaling revolves around the pathways of adipocytes or macrophages. Inflammatory pathways are initiated by intracellular or extracellular mechanisms and then converge on inflammatory signaling pathways. Then, additional inflammatory mediators are produced. In general, cells must balance metabolism and inflammation. Finding that balance is difficult in obesity and diabetes because the process required for response to nutrients can also induce inflammation.

Poor Wound Healing in Diabetes

In all people, wound healing is a complex process that requires alignment of inflammation resolution, growth factors, and cytokines. There are four phases associated with wound healing: hemostasis, inflammation, proliferation, and remodeling. The poor resolution of inflammation among diabetes patients makes the complex process of wound healing even more difficult. Poor wound healing is associated with defective clearance of apoptotic cells, increased risk of infection, and poor genesis of new blood vessels.

 Improving Diabetic Wound Healing With SPMs

Poor wound healing among diabetic patients is due to macrophage dysfunction. Chronic inflammation that is prevalent among diabetic and obese patients is also associated with altered biosynthesis of bioactive lipid mediators that promote inflammation resolution.

A recent review found that using SPMs to stimulate resolution of inflammation improves the metabolic parameters in diabetic patients. SPMs also accelerate wound healing and restore macrophage function in animal models of diabetes. Similarly, another animal model demonstrated that treatment with SPMs “enhanced resolution of peritonitis, decreased accumulation of apoptotic thymocytes in diabetic mice, and stimulated diabetic macrophage phagocytosis.” It accelerated wound closure. These findings indicate that stimulating resolution with SPMs could be an effective treatment of chronic non-healing wounds in diabetic patients.

References

Dandona P, Aljada A, Bandyopadhyay A. Inflammation: The Link Between Insulin Resistance, Obesity, and Diabetes. Trends in Immunology. 2004:25(1);4-7.

Falanga V. Wound Healing and its Impairment in the Diabetic Foot. The Lancet. 2005:366(9498);1736-1743.

Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2010:89(3); 219-229.

Hellman J, Tang Y, Spite M. Proresolving Lipid Mediators and Diabetic Wound Healing. Current Opinion in Endocrinology, Diabetes & Obesity. 2012: 19(2); 104-108.

Schmidt MI, Duncan BB, Scharrett AR, et al. Markers of Inflammation and Prediction of Diabetes Mellitus in Adults (Atherosclerosis Risk in Communities Study): A Cohort Study. The Lancet. 1999:353(9156);1649-1652.

Tang Y, Zhang MJ, Hellmann J, et al. Proresolution Therapy for the Treatment of Delayed Healing of Diabetic Wounds. Diabetes. 2013:62(2); 618-627.

Wellen KE, Hotamisligil GS. Inflammation, Stress, and Diabetes. The Journal of Clinical Investigation. 2005:115(5);1111-1119.

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