For quite some time now, scientists suspected the so-called hexosamine pathway - a small side business of the main sugar processing enterprise inside a cell - to be involved in the development of insulin resistance.
But they could never quite put their finger on the underlying mechanism.
Now, researchers at the Salk Institute for Biological Studies have uncovered the long-missing molecular link: the enzyme OGT (short for O-linked ß-N-acetylglucosamine transferase), the last in a line of enzymes that shuttle sugars through the hexosamine pathway.
Their study revealed that OGT slams the brake on insulin signaling soon after insulin fires up the machinery that pulls glucose from the blood stream and squirrels it away inside liver or stashes the surplus energy in fat pads.
“For the first time we have a real understanding of how the insulin signaling system is turned on and off,” says Howard Hughes Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk Institute's Gene Expression Laboratory, who led the study that appears in the Feb. 21 issue of Nature.
He hopes that “this could lead to a new class of insulin-sensitizing drugs that loosen the brake and let insulin work a little bit longer.”
When insulin binds its receptor on the cell surface it sets off a cascade of intracellular signals resulting in the production of PIP3, a specialized lipid molecule that masterminds a whole army of molecules that work together to synthesize and store carbohydrates, lipids and proteins. “But turning on a physiological process is only half the story,” explains Evans. “You also need instructions that tell the cell to get off the accelerator and put on the brake.”
Postdoctoral researcher and first author Xiaoyong Yang, Ph.D., discovered that PIP3 oversees both. His experiments revealed that within minutes activation of the insulin signaling network coaxes OGT out of the nucleus and into the cytoplasm. It travels to the plasma membrane and hooks up with PIP3.
“It uses a novel PIP3 binding domain to interact with the same lipid that just turned on the system,” describes Xiaoyong. “After OGT is recruited to the plasma membrane it starts turning off the system.”
It accomplishes this task by tagging key members of the insulin signaling network with sugar molecules, specifically O-linked ß-N-acetylglucosamine or O-GlcNAc, which are produced by the hexosamine pathway.