A drug used to remove iron from the body could help doctors fight one of diabetes’ cruelest complications — poor wound healing — which can lead to infection and amputation.
The drug deferoxamine helped diabetic mice heal small cuts 10 days faster than those who did not receive treatment, according to researchers from Stanford University School of Medicine and the Albert Einstein College of Medicine. The team is now working to arrange human trials for deferoxamine. If the results translate, it could help doctors combat such diabetic complications as foot ulcers, an “unmet medical need of gigantic proportions,” Geoffrey Gurtner, MD, professor of surgery and senior author on the paper was quoted as saying.
Blisters, cuts or pressure sores on diabetic patients’ lower limbs often heal slowly or not at all, putting patients at risk for infection and amputation. Internal injuries are an issue, as well. More than 40% of patients hospitalized for heart attacks have clinical diabetes, and they are less likely to recover fully than their non-diabetic counterparts.
The reason, say researchers, is that diabetic tissue fails to reconnect oxygen-deprived areas to the bloodstream with new vessels.
Gurtner and colleagues say the culprit is a transcription factor that cannot thrive in the high-sugar environment of diabetic tissue. Their potential treatment, deferoxamine, is already Food and Drug Administration-approved for the management of chronic iron-overload disorders.
To tease out a treatment, the researchers first focused on the mechanisms of healing. They isolated fibroblasts, cells that secrete fibers to heal wounds and bind cells together. Normally, fibroblasts trigger production of a protein called vascular endothelial growth factor in response to low oxygen. This factor prompts the formation of new blood vessels. In diabetic cells, however, growth factor production remained flat.
The researchers grew healthy fibroblasts in low and high glucose environments for four weeks, mimicking healthy and diabetic tissue. They then exposed the cells to low oxygen.
Cells grown in high-glucose produced growth factor by only 20%, compared with 200% in cells grown in low glucose. Similar experiments with diabetic and non-diabetic mice confirmed the findings.
The team next looked at a protein that acts as a “second-to-second oxygen sensor” in the cell. When oxygen gets low, this protein binds to DNA to trigger a cellular response, including production of vascular endothelial growth factor. To work efficiently, the protein (HIF-1a) must bind with a molecule called p300. That’s where the system broke down, the researchers found. When cells were grown in high-sugar environments, the two molecules failed to bind properly.
Michael Brownlee, MD, a molecular cell biologist at the Einstein College of Medicine in New York and co-author on the paper, stated that high glucose inside cells results in the creation of free radicals, which oxidize iron. The iron then interacts with other molecules to form DNA-damaging hydroxyl radicals, causing a cascade of problems. “What you need to do is interrupt this cascade,” Brownlee said. Enter deferoxamine — an off-patent drug that binds to and removes iron from the environment. Experiments in cell cultures suggested that deferoxamine brought the HIF-1a protein and the p300 molecule back together.
To find out if this would translate to better wound healing, the researchers gave diabetic mice small cuts. Rodents, unlike people, have a thin muscle layer under their skin that allows them to pull the edges of wounds together, making it difficult to compare a mouse’s healing process to a human’s. To solve this problem, the researchers glued a tiny stent around the wounds to prevent muscle contraction. They then treated some of the mice with deferoxamine cream.
Mice treated with deferoxamine healed in 13 days, compared with 23 days in untreated mice. Treated mice also produced almost three times more vascular endothelial growth factor. “By understanding the science of why is it that diabetics generate wounds more readily and don’t heal wounds, we’re able to start to target those mechanisms,” Gurtner said.
The next step, say Gurtner and Brownlee, is to test the drug on human wounds.
Proceedings of the National Academy of Sciences, July 27, 2009