Impaired wound healing in diabetes: a target for nutritional intervention?

Abstract

Skin provides the body with a protective barrier against the environment. When this barrier is damaged a tightly regulated set of coordinated cellular and molecular pathways begin the process of repair. Wound healing is a dynamic process consisting of three major phases, inflammation, proliferation, and remodelling. A synchronous overlapping of these phases occurs to restore the integrity of the skin quickly and efficiently. Acute wounds heal rapidly to produce a small scar with near to normal tissue function. Chronic wounds heal slowly or not at all due to a loss of synchronicity between the wound healing phases. Patients with diabetes are prone to chronic wounds which are primarily initiated by trauma but fail to heal due to predisposing factors. The most common factor of the chronic wound is that of a prolonged inflammatory state. Therefore nutrient modulation of inflammation could be a strategy to improve wound healing in patients with diabetes. Omega-3 fatty acids are known to be anti-inflammatory and arginine has roles in immune regulation and as a substrate for nitric oxide involved in vascular responses and inflammation. A wound healing model was developed in C57BL/6 and db/db mice and used to establish an integrated view of the healing process between mouse types. Two controlled wounds were made on the dorsum of each mouse and collected at 1, 3, 5, 7, 10 and 14 days post-wounding. The model allowed for assessment of weight change, wound closure, protein and gene expression of key mediators, nitric oxide metabolites (NOx), skin morphology, and immune cell infiltration over fourteen days. Nutritional intervention was incorporated into this model with the development of omega-3 and arginine, alone and in combination, enriched diets. Mice were assessed for weight change and wound closure over fourteen days. Wound tissue and spleens were collected fourteen days post-wounding for assessment of protein and gene expression, NOx levels, skin morphology, immune cell infiltration, and fatty acid content. Blood glucose levels and body weights were higher in the db/db mice compared to the C57BL/6 mice. The wounds of diabetic mice healed at a significantly slower rate than those of the nondiabetic mice (p < 0.0001). Diabetic mice also showed an increased number of infiltrating immune cells and an over expression of matrix metalloproteinase-2, transforming growth factor β1 and β2, and vascular endothelial growth factor. Nutritional intervention improved the inflammatory profile of wounds in the diabetic mice. A reduced number of immune cells were present in the wound tissue and levels of localised and systemic inflammatory markers were reduced in those fed on diets enriched with omega-3 fatty acids and arginine, when compared to those fed on the control diet. These findings indicate that both omega-3 and arginine improved the health of the wounds in db/db mice by reducing the prolonged inflammatory effects caused by hyperglycaemia. The addition of both nutrients however did not have a compounded effect on wound healing in either mouse type.

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