In Depth
Feeding the Diabetic Brain
Simpson himself is diabetic—late-onset, Type I—but he insists that's not exactly why he has spent his entire career studying diabetes. "The story is a little more interesting than that," he says, chuckling.
He was in his late twenties—about to get married, finishing his doctorate in bio-chemistry back in his native England, and seeking new scientific challenges. Then came the diagnosis of diabetes. "The physician who diagnosed me, a very well known researcher in Britain, said to me, 'Why don't you contribute something useful and study your disease?'"
Instead, Simpson moved to Germany to study adrenaline receptors in red blood cells at the University of Würzburg. "It was paradise for a diabetic," Simpson says. "It's the one place in Germany where they don't make sweet wine."
Still Simpson's physician, Harry Keen, persisted. "He told me there were many more opportunities and better funding for diabetes researchers." Keen put Simpson in contact with a colleague in the United States at the National Institutes of Health. Two years after his diagnosis, Simpson held a post-doc position at the NIH's National Institute of Diabetes, Digestive, and Kidney Diseases in Bethesda, Maryland. He stayed there for 20 years, eventually becoming associate chief of the Experimental Diabetes, Metabolism and Nutrition Section.
He spent his first decade at NIH focusing on the role of the insulin in the transport of glucose in muscle and fat cells. His transition into neuroscience began one day in the early 1990s over a beer with colleague Dick Hennerberry. "We'd go to the pub after work. He'd been complaining about the neurons he was growing in the lab. They would grow beautifully for nine days, and on the tenth day they would die," Simpson remembers.
Simpson asked Hennerberry if the neurons were getting enough glucose. Simpson speculated that the cells were using up all the glucose in the growth medium in the first nine days. On day ten, with no sugar to sustain them, they died. "At the time, very little was known about how the brain obtained its glucose," he explains.
This much was known: All cells—brain, muscle, liver, or otherwise—have to work for their food. Glucose cannot simply diffuse from the bloodstream into cells; specialized proteins are needed to transport it across cellular membranes. In muscle, heart and fat cells, insulin recruits these transporters to the cell membrane. What those cells can't use is stored as fat or glycogen.
The brain works differently. No insulin. No fat storage. And a tighter border to cross. The blood brain barrier is just that—a physical barrier meant to protect the brain from potential toxins in the blood. The tiny blood vessels that snake through the brain are made up of tightly linked endothelial cells that form a two-ply membrane. Somehow, glucose molecules have to navigate both of these layers to get into the brain,where neurons—the 10 percent of nerve cells that actually transmit signals to and from the brain—and glial cells—often called the "glue" that makes up the remaining 90 percent—are waiting to be fed.
Soon after their conversation, Simpson joined Hennerberry and began growing neurons and studying their eating habits. "We published a paper together showing that these neurons had two different types of glucose transporters," he says. Hennerberry had known about one type, called GLUT1, but not the other—"the one that was really responsible for transporting all the glucose," Simpson says. That particular transporter, called GLUT3, is unique to cells that need a tremendous amount of energy very quickly, like platelets, sperm cells, and, of course, neurons.
"I thought, 'geez these transporters are different,' and I got interested," says Simpson. "That was truly my first venture into the brain."
Next page: "Six months later..."