In Depth
Feeding the Diabetic Brain
Six months later, a post-doctoral researcher named Susan Vannucci joined Simpson's group at NIH. Vannucci had studied diabetic fat cells for her Ph.D. at Penn State, and was prepared to continue these studies at NIH. Before she earned her Ph.D., she had spent many years doing brain research with her husband, Robert Vannucci, a pediatric neurologist at Penn State College of Medicine.
"Susan and I made the switch from the study of fat cells to the study of glucose transport into brain cells together," says Simpson. Thus began a ten-year research partnership that continues today. "Our families have become good friends, and we always spend Christmas together," he says. "And if you look at my publication list you'll see lots of Vannucci and Simpson papers."
One of their first joint ventures was to characterize all the different kinds of glucose transporters that exist in the brain. "We wanted to know what the brain had to work with," Simpson says. In addition to the transporters that Simpson had previously identified in the blood-brain barrier, they found others in the neurons and glial cells.
As Simpson explains it, the two membranes that make up the blood-brain barrier are very different. The inside surface, against which blood flows, is called the luminal side. The outside surface, which faces the brain, is called the abluminal side. Specialized transporters are embedded in both membranes. To enter the brain, sugar molecules bind to transporters on the luminal side and are pumped across the luminal membrane and into the endothelial cell. There, another transporter, positioned in the abluminal membrane, grabs the sugar molecule and ferries it into the brain. To deal with contingencies, Simpson continues, there is a sort of auxiliary crew of transporters floating around between the membranes—inside the endothelial cells—that can be recruited to either side of the membrane in response to a sugar imbalance.
At NIH, Simpson and Vannucci did experiments to see how abnormal levels of glucose in the blood affect the number of transporter cells the brain makes. First, they looked at what happens in the case of hypo-glycemia, or low blood sugar. They gave healthy rats a constant high dose of insulin, which caused the muscle cells to take up all of the glucose, leaving very little for the brain. Soon, Simpson reports, the rats showed the classic signs of low blood sugar: They were woozy and couldn't function very well. They "bonked"—like people sometimes do during a long run or an intense workout at the gym. After about two or three days, however, something interesting happened: The rats recovered. They started running around like nothing was wrong. Their blood glucose levels were still very low—at the same level that was originally making them sick—but, "somehow they were getting enough glucose into their brains that they could function normally,"says Simpson. "There was compensation."
Turns out the blood-brain barrier, over time, was able to sense the deficiency in blood glucose in these otherwise healthy rats. In response, the endothelial cells began to create more glucose transporters: 25 percent more. Half of those new transporters were assigned to the luminal side of the membrane to help transport as much glucose as possible from the blood.
This change in the number of transporters, Simpson stresses, happened only in the endothelial cells. He and Vannucci looked at other cells inside the brain—at neurons and astrocytes, a type of glial cell—and saw no increase. "That was a little bit of a surprise to us," says Simpson. It meant the blood-brain barrier alone was responsible for regulating the amount of sugar going to cells inside the brain.
Next they looked at the case of diabetes, where the level of sugar in the blood is abnormally high. After inducing diabetes in rats with a drug called Streptozoticin, they expected to see a decrease in the number of transporters produced in the rats' brain cells.
"We expected the cells to say, 'We don't need to transport as much because we sense we already have too much glucose,'" Simpson remembers. Instead, there was no change in the number of glucose transporters. "We still don't understand this," Simpson says. "We were just trying to confirm the work of other groups—who suggested that too much glucose caused a reduction in the number of transporters—but we couldn't confirm it.
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