ER stress response is major driver of insulin resistance, say researchers

Biologists have long known that an enzyme called the PI 3-kinase is a crucial actor in the main molecular pathway for insulin signaling in cells. Researchers at Joslin Diabetes Center now have uncovered startling evidence that one of the proteins in this enzyme also drives a pathway with an opposite result-triggering a stress response that leads to insulin resistance.

Studies in cells and genetically modified mice show that the regulatory subunit of the PI 3-kinase, a protein called p85, works both ways, says C. Ronald Kahn, M.D., Head of the Joslin Section on Integrative Physiology and Metabolism, and senior author on a Nature Medicine paper reporting the discovery on March 28.

"The p85 protein has kind of a yin-yang effect, functioning both as an important link in insulin action and an important link to insulin resistance," he says.

PI 3-kinase is made up of two protein subunits, one being p85 and the other called p110, explains Dr. Kahn, who is also Mary K. Iacocca Professor of Medicine at Harvard Medical School.

"The p85 molecule is like Dr. Jekyll and Mr. Hyde," he remarks. "One end of the molecule binds to p110, forming a key pathway that is needed for the metabolic effects of insulin on glucose metabolism. The other end of p85 is doing mischief."

That end of p85 interacts with a protein known as XBP-1, helping XBP-1 journey to the cell nucleus, where it activates genes that promote a cell response known as the endoplasmic reticulum (ER) stress response.

Other studies have shown that the ER stress response, also called the unfolded protein response, is a major driver of insulin resistance, a precursor to type 2 diabetes.

"The result is that p85, a protein that is central to insulin action, also is playing a role in creating insulin resistance," says Dr. Kahn. "It's the balance of this protein with other proteins that allows it to be either optimal for insulin sensitivity or bad for insulin sensitivity."

"Up until now, nobody had ever found a link between the ER stress response and insulin action," he adds. "Nobody ever envisioned that it was really a molecule in the insulin action pathway that was so critical to creating its own resistance!"

Understanding this interaction may provide novel targets for developing drugs that minimize insulin resistance, or that address the negative role that ER stress plays in many other diseases.

Among his lab's next steps, Dr. Kahn says, "we'll reduce the amount of p85 in cells, aiming to improve insulin sensitivity and protect against diabetes. p85 also is present in insulin-producing pancreatic beta cells, and we also will see if changing the level of p85 in beta cells will make them more resilient when stressed with high insulin demands like those from early type 2 diabetes."