Diabetes medications: Impact on inflammation and wound healing

Abstract

Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.

Keywords: DPP-4 inhibitor; Insulin; Metformin; Sulfonylurea; Thiazolidinedione; Wound healing.

Figure 1. Diabetes Medications Associated Mechanisms of Action Involved in Wound Healing

The figure shows signaling pathway that may be targeted by diabetic medications on epithelial cells (keratinocytes), vascular endothelial cells, “classically activated” M1-like macrophages, and “alternative activated” M2-like macrophages present in chronic wounds. Classically activated M1-like macrophages produce pro-inflammatory gene products that maintain wounds on a persistent inflammatory state. Alternative activated M2-like macrophages produce more pro-healing gene products that allow wound to resolve the inflammatory state and proceed to healing. All receptors (Insulin R, PPARγ R and GLP-1 R) and cell targets are present in both types of macrophages.