(Ivanhoe Newswire) -- 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, M.D.,
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 percent of patients
hospitalized for heart attacks have clinical diabetes, and they are less likely
to recover fully than their non-diabetic counterparts. The reason, researchers
say, 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 FDA-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 percent, compared
with 200 percent 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, Gurtner said, 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.
The problem, Michael Brownlee, M.D., a molecular cell biologist at the Einstein
College of Medicine in New York and co-author on the paper, says, is 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," Dr. Gurtner said.
The next step, say Dr. Gurtner and Dr. Brownlee, is to test the drug on human
wounds.
SOURCE: Proceedings of the National Academy of Sciences, July 27, 2009
