ANN ARBOR—One of the enduring mysteries of Type 2 diabetes lies in the condition that precedes it—the body’s growing loss of sensitivity to its own hormone, insulin, which regulates blood sugar levels. Reversing or at least controlling this desensitization before it becomes full-blown diabetes might be an effective therapy, but the many variables at play in the process of desensitization are not well understood. A University of Michigan study published in the April 10 issue of Nature sheds further light on how insulin regulates the machinery that fat cells use to take glucose out of the blood stream immediately after a meal. Rather than just being a simple signal to the fat cell to start or stop glucose uptake, insulin appears to regulate five or six different steps in the machinery the cell uses in glucose-uptake. Each of these steps regulated by insulin may offer an opportunity to understand diabetes a bit better, says study co-author Alan R. Saltiel, director of the U-M Life Sciences Institute. “We’ve learned that there are many different ways to regulate insulin sensitivity, potentially giving us multiple chances to intervene,” Saltiel said. Glucose uptake in fat and muscle relies on a transport molecule called Glut4, which captures the sugar molecule at the surface of the cell and then drags it in. In the latest research, a team led by U-M postdoctoral fellow Mayumi Inoue has identified a protein complex called the Exocyst that helps Glut4 dock on the cell surface where it can grab a passing glucose.
Insulin signals one of the proteins in this complex, called Exo70, to go to the cell membrane and to assemble the docking complex for Glut4. A mutant form of Exo70 that Saltiel’s team made still allowed Glut4 to travel to the cell membrane, but interfered with the transporter’s ability to capture glucose. "This complex of proteins that helps Glut4 dock on the cell membrane offers diabetes researchers a chance to evaluate new candidates for the genes that cause insulin resistance, one of the primary defects that give rise to Type 2 diabetes,” Saltiel said. “The Exocyst complex represents a new pathway to explore for potential problems in insulin action.” There are eight molecules in the Exocyst targeting assembly that Exo70 builds, each of which is made by a gene, and then folded into shape and linked to the other seven to form the functioning complex. Still to be learned is how those units assemble, how they recognize the other members of the complex and how they interact with the cell membrane to form a targeting site for Glut4. "This is a pretty big finding, because we have to understand all these steps in the process to develop other ways to intervene," said Jeffrey Pessin, professor of pharmacology at State University of New York, Stony Brook. Fortunately, yeast will be a useful model for some of this work, Saltiel added. “The fundamental part of the process is shared in yeast, giving us a head start on how to move forward.” This work was supported by grants from the National Institutes of Health. The Life Sciences Institute is a new unit of the University of Michigan dedicated to interdisciplinary research in genomics and proteomics, molecular and cellular biology and structural and chemical biology. Its 230,000 square foot laboratory facility opens this fall.

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