In Depth
Feeding the Diabetic Brain
In late 1999, Simpson left NIH to take an academic position in the neuroscience and anatomy department at Penn State College of Medicine. "I'm still getting used to how much time students take up," he smiles. Three o r four gargoyles perch on shelves around his office—"to ward away evil spirits," he says, still smiling—and next to his computer leans a colorful cross-stitch of an old woman in a bathrobe on a scale, made by his secretary at NIH. It reads, "Brain cells may come and go, but fat cells live forever."
At Penn State, Simpson has continued his fundamental studies of the bloodbrainbarrier. His work was helped considerably when one of his collaborators, Richard A. Hawkins at the University of Chicago Medical School, developed a method for separating the two membranes of the endothelial cells and counting the number of transporters in both. "There is a specific radioactive tag that will bind exclusively to transporters," Simpson explains. The tags allow researchers to count how many transporters are in each membrane.
Using this technique, Simpson and his colleagues are taking apart brain cells and looking at how transporters migrate between the two membranes of the blood-brain barrier. "We want to try to understand the mechanism by which transporters are recruited to one side of the membrane or the other," he explains. "If we can understand the mechanism responsible, we might be able to come up with a way of triggering that movement," an intervention which could help diabetics better regulate the balance of glucose in both the blood and the brain.
Simpson has also become interested in the relationship between diabetes and stroke. According to the National Institutes of Health, diabetics are two to four times more likely than non-diabetics to suffer a stroke. And, diabetic brains have a much harder time repairing the damage a stroke can cause.
Stroke is the third leading cause of death and the leading cause of disability in the U.S. Sixteen million Americans have diabetes, Simpson notes. The stakes are high. Still, the details of how diabetes exacerbates stroke have yet to be sorted out.
Recently, he and Vannucci (now at Columbia University) received support from the American Diabetes Association to study how diabetic brains deal with this catastrophic event. Part of the reason diabetics are more susceptible to stroke, Simpson acknowledges, is that they tend to be overweight and have high blood pressure and heart problems. Beyond these well-known risk factors, however, "there's something else," he argues. "Something that puts diabetics at higher risk. But we haven't figured it out yet."
Right now, Simpson is most interested in what happens after a stroke. "The combined effects of both diabetes and stroke on the brain haven't been looked at as closely as the effects of stroke on the brain," he says. "But we know that recovery from stroke in diabetics is far worse than it is in non-diabetics. This is becoming more of an issue, as there are more and more diabetics."
During recovery from a stroke the tissue surrounding the area where the blockage occurred needs to obtain a supply of glucose and oxygen in order to repair the damage. Knowing this, "We have started focusing on the process of wound healing,"Simpson says. "Maybe it's the same process that happens in other parts of the body when there's a wound." In diabetics, this process is seriously impaired, which is one reason why diabetics who incur minor foot wounds, for example are at higher risk for gangrene and amputation.
"If the same proces of impaired wound-healing applies to the brain, then we need to know which cells are involved. It's probably a complex problem of which the blood brain barrier is just one part," he speculates.
During recovery from stroke in the "normal" brain, animal models show, there's an increase in the number of transporters both at the blood-brain barrier and in the astrocytes around the damaged area. "The astrocytes and microglia, which are trying to clean up all of the mess, require more energy, too," Simpson explains.
If the same thing happens in a diabetic brain, Simpson suggests, then the same sorts of therapies that are used to promote wound healing in other parts of the body might work in the brain. Drugs containing growth factors might help the cells surrounding the wound get the extra nutrients they need.
"But first," Simpson says, "we have to show that impaired wound-healing is indeed what is happening."
Ian Simpson, Ph.D., is professor of neural and behavioral sciences in the College of Medicine; ixs10@psu.edu. His research is funded by the National Institutes of Health and the American Diabetes Association. He is also a member of the Penn State University Juvenile Diabetes Research Foundation Diabetic Retinopathy Center.