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Novel Method for Normalizing Blood Sugar

A potential new method of normalizing blood sugar levels in diabetes has been discovered by U.S. researchers….

The Children’s Hospital Boston team identified a cellular pathway that fails because of obesity. Artificial activation of this pathway normalized glucose levels in severely obese and diabetic mice, according to the published report. 

Previously, the researchers found that the brain, liver and fat cells of obese mice have increased stress in the endoplasmic reticulum (ER), which produces proteins. Obesity overwhelms the ER and causes it to malfunction. This so-called “ER stress” triggers a series of events that suppresses the body’s response to insulin, making ER stress an important link between obesity and Type 2 diabetes.

In this new study, the researchers found that a transcription factor that normally helps relieve ER stress — called X-box binding protein 1 (XBP-1) — can’t function in obese mice. They also found that obesity affects a protein fragment called p85 that plays a key role in the ability of XBP-1 to relieve ER stress.

The study’s senior author, Dr. C. Ronald Kahn, head of the integrative physiology and metabolism section at Joslin Diabetes Center, said in a news release from the center, “The p85 molecule is like Dr. Jekyll and Mr. Hyde…. One end of the molecule binds to p110, forming a key pathway that is needed for the metabolic effect of insulin on glucose metabolism. The other end of p85 is doing mischief” by interacting with a protein that causes a stress response that’s a major factor in insulin resistance.

According to Dr. Umut Ozcan and colleagues, insulin signaling that would normally increase the levels of free p85 is impaired in obesity. This leads to an increase in ER stress and more insulin resistance, which eventually causes Type 2 diabetes. However, increasing levels of free p85 may prevent this from occurring, the researchers said.

“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.” 

Nature Medicine, March 28, 2010