Working Toward New Therapies for Diabetic Wound Healing

Research background: Diabetes and its complications

The number of people suffering from diabetes is increasing in the United States and worldwide, and the number of cases is estimated to rise to more than 500 million by 2030. The obesity epidemic is a major contributor to the rise in diabetes.

Over time, elevated blood sugar damages blood vessels. Macrovascular complications of diabetes include atherosclerosis, high blood pressure and cardiovascular disease. Microvascular complications include retinopathy, nephropathy and neuropathy.

Nerve damage and poor blood flow impair wound healing following tissue injury in patients with diabetes. Wounds that do not heal could ultimately require toe, foot or leg amputation. In 2010, more than 70,000 amputations were performed in patients with diabetes.

Diabetic ulcers on the feet or legs precede 84% of all diabetic lower extremity amputations and are the primary cause of hospitalization among patients with diabetes. The annual cost of diabetic ulcers alone exceeds $1.5 billion.

Chronic wounds in patients with diabetes result in:

• Long hospitalizations
• Prolonged exposure to antibiotics
• Acute and chronic pain
• Need for cumbersome wound care
• Restricted mobility

Despite the burden of chronic wounds for patients with diabetes and for society, effective therapies are lacking. Large clinical trials have demonstrated that treatments aimed at controlling blood glucose reduce the risk of macrovascular complications, but they do not improve microvascular complications, including impaired wound healing.

Research methods: Diabetic wounds and blood vessel formation

In diabetic wounds, the process of angiogenesis is defective. New blood vessels are required to supply wounded skin with the nutrients and oxygen that are crucial for the influx and growth of cells required to repair the wound.

Diabetic wounds have decreased production of growth factors (VEGF and HIF-1-alpha) that stimulate blood vessel formation. The wounds also have increased production of damaging reactive oxygen species and inflammatory factors that further impair the healing process.

Therapies that have been clinically used to restore angiogenesis in skin wounds include:

• Topical application of VEGF or other growth factors
• High-pressure oxygen chambers
• Tissue-engineered dressings
• Tissue reconstruction with blood vessel stem cells

These approaches, however, have demonstrated limited results in improving the healing of diabetic foot ulcers.

Research results: MicroRNAs, especially miR-26a

MicroRNAs (miRs, pronounced "meers") are small bits of genetic material (RNA) that "turn off" the expression of certain genes at the level of protein production.

The miR-26 family, composed of three different miRs, regulates a variety of signaling pathways and cellular processes. One particular member, miR-26a, has been demonstrated to have a wide variety of roles:

• Expression reduced in cardiac diseases
• Required for skeletal muscle differentiation (maturation) in vivo
• Required for skeletal muscle regeneration in vivo
• Component of obesity-induced cartilage inflammation

miR-26a also plays multiple roles in diabetes, as it targets genes that regulate insulin signaling and glucose metabolism. Findings indicate:

• Reduced expression in the liver in obese individuals and mouse models
• Overexpression prevents obesity-associated metabolic complications in mice fed a high-fat diet
• Inhibition dysregulates insulin sensitivity and increases glucose production in mice fed a conventional diet

Research discussion: The role of miR-26a and diabetic wound healing

Several studies have explored a potential role for miR-26a in diabetic wound healing, especially in the process of angiogenesis.

One study analyzed the levels of miR-26a and the effects of inhibiting miR-26a in multiple cell lines and in a mouse model of diabetes. The study demonstrated, both in vitro and in vivo, that overexpression of miR-26a significantly inhibited angiogenesis by blocking the proliferation, migration and tube formation of the endothelial cells that form blood vessels.

Other studies have demonstrated that the effects of miR-26a depend on the cell type. In glioma (brain cancer) cells, miR-26a promotes angiogenesis. In liver cancer cells, it suppresses angiogenesis. In an acute heart attack model, blocking miR-26a increased angiogenesis and reduced scarring.

Other miRs have also been identified as having roles in wound healing at the level of angiogenesis.

Research conclusion: Implications for treatment of diabetes and diabetic wounds

The evidence that miR-26a has roles in diabetes and in angiogenesis, as well as increased expression in diabetic wounds, make it an intriguing target for diabetes and diabetic wound treatment.

Studies have demonstrated that it is possible to manipulate miR expression. Controlling miRs may represent a new frontier in regulating and fine-tuning gene expression to combat diabetes and its complications, particularly diabetic wounds.

The editorial was authored by Ken Liechty, MD, former Director of Pediatric Surgery Basic and Translational Research at Children's Hospital Colorado, and Carlos Zgheib, PhD, postdoctoral fellow and instructor of surgery at the University of Colorado School of Medicine.