Molecular Link Between Excessive Nutrient Levels, Insulin Resistance Identified

A long-missing molecular link between excessive nutrient levels and insulin resistance has been unearthed by scientists at the Salk Institute of Biological Studies.

The researchers say that their study basically elaborates how excessive quantities of nutrients causes the hexosamine pathway to trigger a relentless progression of insulin resistance.

Scientifically, the hexosamine pathway is described as a small side business of the main sugar processing enterprise inside a cell. Although scientists have suspected it to be involved in the development of insulin resistance for quite some time, the underlying mechanism remained undiscovered to date.

Now, Salk researchers have found that the enzyme OGT (O-linked ß-N-acetylglucosamine transferase)—the last in a line of enzymes that shuttle sugars through the hexosamine pathway—puts the break on insulin signalling 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,” Nature magazine quoted Howard Hughes Medical Investigator Ronald M. Evans, a professor in the Salk Institute’s Gene Expression Laboratory, as saying.

He expressed hope that “this could lead to a new class of insulin-sensitising drugs that loosen the brake and let insulin work a little bit longer.”

As 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. You also need instructions that tell the cell to get off the accelerator and put on the brake,” says Evans

Postdoctoral researcher Xiaoyong Yang, who is also the first author of the study, has found that within minutes of its activation, the insulin-signalling 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. After OGT is recruited to the plasma membrane it starts turning off the system,” says Xiaoyong

The researcher says that it accomplishes this task by tagging key members of the insulin signalling network with sugar molecules, specifically O-linked ß-N-acetylglucosamine (O-GlcNAc), which are produced by the hexosamine pathway—a small side business of the main sugar processing enterprise inside a cell.

Given the direct link between the amount of O-GlcNAc with the availability of glucose, lipids and other nutrients in the bloodstream, the researchers believe that the hexosamine pathway acts as fuel gauge, protecting the body’s cells against the toxic effects of too much glucose and other high-energy molecules.

According to them, excessive quantities of nutrients drive O-GlcNAc levels up, which in turn dampen the insulin response, paving the way for a relentless progression of insulin resistance.

When Xiaoyong put OGT into overdrive in the livers of mice, the animals developed insulin resistance and abnormal blood lipid levels. The researchers says that the finding emphasised the importance of the hexosamine pathway for the development of insulin resistance, the first step towards full-blown type 2 diabetes.

Source-ANI
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