ADA 2008: Reducing excess iron levels encourages diabetic wound healing

Researchers at Stanford University are reporting positive results in healing diabetic wounds with a pharmaceutical agent already approved by the FDA?but only in mice so far.

The drug, deferoxamine, is a potent iron-chelating agent that is usually used to treat hemochromatosis, or iron overload, caused by excess iron levels. Depleting iron levels also encourages wound healing in diabetic patients by reversing inhibition of pathways that lead to neovascularization. Topical application of deferoxamine increases wound healing in diabetic mice to levels typical of non-diabetic mice.

"We are able to salvage wounds by up-regulating the end product that is reduced in diabetes," said Geoffrey Gurtner, MD, Stanford University, Palo Alto, CA. "This accelerates wound healing."

Most of Dr. Gurtner's work has been in murine models. In both mice and humans, an ischemic event such as a wound to normal tissue mobilizes endothelial precursor cells (EPCs) from bone marrow. EPCs migrate to the ischemic area where they form cords that coalesce into hollow tubes and become functional, fully perfused vessels.

In diabetic tissue, EPC migration is impaired, which impairs neovascularization and wound healing, Dr. Gurtner explained. EPC levels in ischemic tissue in diabetic mice is about ten times lower than in normal mice. Similar differences in EPC levels have been observed in diabetic human tissue, he added.

"We clearly need to reintroduce angiogenesis in diabetic tissue," Dr. Gurtner said.

Hyperglycemia acts to blunt the normal response to hypoxia, which is an increase in hypoxia inducible factor 1 (HIF-1). HIF-1 upregulates vascular endothelial growth factor (VEGF), which increases angiogenesis. Modulation of VEGF and EPC mobilization leading to neovascularization and wound healing.

Hyperglycemia appears to inhibit the activity of HIF-1, Dr. Gurtner said. Down-regulating HIF-1 inhibits the growth of new blood vessels, new tissue, and wound healing. The enzymes that degrade HIF-1 are all dependent on iron, he continued. Depleting available iron stores with deferoxamine reduces HIF-1 degradation.

Inhibiting degradation effectively increases HIF-1 levels, which increases HIF-1 activity. Increasing HIF-1 activity, in turn, upregulates neovascularization and wound healing. Whether the same mechanism works in diabetic humans has yet to be tested.