NIDDK's Cushman Wins Banting Medal
By Anna Maria Gillis
Dr. Samuel W. Cushman, chief of NIDDK's experimental diabetes, metabolism, and nutrition section, received the Banting Medal for Scientific Achievement at the recent American Diabetes Association meeting in San Francisco. The award is ADA's highest research honor, and it recognizes significant, long-term contributions to the understanding, treatment or prevention of diabetes.
Cushman was honored for basic science findings that were pivotal to explaining the relationship between insulin and glucose transporters. In the late 1970s, he and his then colleague L.J. Wardzala showed that insulin promotes the translocation of glucose transporters from intracellular space to the plasma membrane in insulin-sensitive cells. K. Suzuki and T. Kono at Vanderbilt University made the same finding independently.
When Cushman and Wardzala started their experiments, Cushman said researchers didn't know just how pervasive glucose transporters are. In an early experiment using fat cells, they asked whether an increase in insulin would raise either the number or the activity of glucose transporters in the plasma membrane that surrounds the cell. "We had no idea glucose transporters were anywhere else," Cushman says.
In 1978, the researchers claimed that insulin increased the number of transporters in the plasma membrane. They thought the transporters were somehow hidden and that insulin was needed to make them appear. "We wanted to know how 'cryptic transporters' could be seen. When we failed, we decided to see if they came from somewhere else."
Cushman and Wardzala next worked on intracellular membranes and found that they actually contained most of the glucose transporters. Finally, when they treated intact fat cells with insulin, they discovered that plasma membrane levels of glucose transporters increased. At the same time, the level of glucose transporters in the intracellular membranes decreased, which strongly suggested that intracellular glucose transporters moved outward in response to insulin.
Initially, most scientists thought this translocation hypothesis unlikely. But because Kono's lab at Vanderbilt was getting the same result using different techniques, "we thought we were on the right track," says Cushman. His and Wardzala's results were published in 1980 on a fast track in the Journal of Biological Chemistry. The reviewers' comments and criticisms were so extensive, says Cushman, "the review letter defined what we did for the next 10 years."
Another key finding by Cushman's lab showed that G proteins controlled glucose transporter functioning at the plasma membrane. During translocation of glucose transporters from the inside to the outside of cells, vesicles containing the transporters bind to and then fuse with the plasma membrane. Depending on the specific G protein and its activating agent, vesicle fusion either speeds up or slows down. When vesicle fusion speeds up, the number of glucose transporters increases at the plasma membrane, which in turn increases glucose uptake into cells. When fusion slows, glucose uptake declines.
According to ADA, "the discovery of intracellular glucose transporters, subsequently shown to be GLUT4, turned out to be not only a major breakthrough in understanding the molecular mechanism of action of insulin on glucose transport, but (also) of key importance to understanding the pathophysiology of insulin resistance and type 2 diabetes." GLUT4 is the dominant glucose transporter in white and brown fat and skeletal muscle. In people who are resistant to insulin, fat tissue loses some of its internal GLUT4 transporters, so there are fewer to go to the cell surface, says Cushman. In contrast, insulin resistance in skeletal muscle is caused by a defect in the translocation mechanisms, which are responsible for the movement of the vesicles that carry the glucose transporters.
There's still a lot to be understood about trafficking, the two-way traveling of glucose transporters, says Cushman, who especially wants to understand the process in insulin-resistant people. He is now doing studies that rely on antibodies and fluorescent probes to track exactly where individual glucose transporters go in fat and muscle cells in normal and insulin-resistant animal models of human metabolic states, especially type 2 diabetes and obesity.
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