Key to this are glucose transporters, a class of proteins that shuttles glucose molecules through the membrane and into the body of the cell. The first glucose transporter was discovered in 1985 in Lodish's lab. Several others, including GLUT4, have been discovered since then. While most glucose transporters reside at the cell surface, GLUT4 is usually deep inside the cell, only moving to the surface when insulin sends a signal. It is the only transporter that responds exclusively to the presence of insulin.

For the study, Bogan engineered GLUT4 proteins so that they contained two distinct fluorescent tags, and studied them in cultured fat cells. One tag glowed only when GLUT4 appeared at the cell surface. The other was detectable at any location in the cell, enabling Bogan to measure GLUT4 distribution within the cells. He then tested a collection of approximately 2.4 million proteins to see which ones had an effect on GLUT4 distribution.

"By using the tags," Bogan says, "we were able to sift through all the cells and find this needle in a haystack."

Bogan found that one protein, TUG, had a significant effect on GLUT4, acting as a tether that binds GLUT4 inside the cell. When insulin reaches the cell surface, it signals TUG to release GLUT4, which then moves to the cell surface to allow glucose absorption. These study results suggest that excess tethering may somehow contribute to insulin resistance.

Lodish proposes that discovering this key component of the GLUT4 pathway is a significant clue for possibly identifying a diabetes drug target. "Insulin shots just overwhelm the cell and hopefully make it respond to insulin," he says. "But so far, there aren't any drugs that act directly o
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Contact: David Cameron
newsroom@wi.mit.edu
617-258-5183
Whitehead Institute for Biomedical Research
15-Oct-2003