A new strategy normalizes blood sugars in diabetes

March 28, 2010

Researchers at Children's Hospital Boston have identified a new strategy for treating type 2 diabetes, identifying a cellular pathway that fails when people become obese. By activating this pathway artificially, they were able to normalize blood glucose levels in severely obese and diabetic mice. Their findings will be published online by Nature Medicine on March 28.

Epidemiologists have long known that obesity contributes to type 2 diabetes. In previous work, researcher Umut Ozcan, MD, in Division of Endocrinology at Children's, showed that the brain, liver and of obese mice have increased stress in the endoplasmic reticulum (ER), a structure in the cell where proteins are assembled, folded into their proper shapes, and dispatched to do jobs for the cell. In the presence of obesity, the ER is overwhelmed and its operations break down. This so-called "ER stress" activates a cascade of events that suppress the body's response to insulin, and is a key link between obesity and type 2 diabetes.

Until now, however, researchers haven't known precisely why obesity causes ER stress to develop. Ozcan and colleagues now show that a transcription factor that normally helps relieve ER stress, called X-box binding protein 1 (XBP-1), is unable to function in obese mice. Instead of traveling to the cell nucleus and turning on genes called chaperones, necessary for proper ER function, XBP-1 becomes stranded.

Probing further, the researchers found the reason: XBP-1 fails to interact with a protein fragment called p85, part of an important protein that mediates insulin's effect of lowering levels (phosphotidyl inositol 3 kinase or PI3K). Ozcan's group identified a new complex of p85 proteins in the cell, and showed that normally, when stimulated by insulin, p85 breaks off and binds to XBP-1, helping it get to the nucleus.

"What we found is, in conditions of obesity, XBP1 cannot go to the nucleus and there is a severe defect in the up-regulation of chaperones," says Ozcan. "But when we increase levels of free p85 in the liver of obese, severely diabetic mice, we see a significant increase in XBP1 activity and chaperone response and, consequently, improved glucose tolerance and reduced blood glucose levels."

When people are obese, the insulin signaling that normally increases free p85 is impaired, leading to more ER stress and more insulin resistance, ultimately leading to type 2 diabetes. But Ozcan thinks this vicious cycle can be circumvented through strategies that increase levels of free p85. His group is taking further steps to activate this novel pathway to create new treatment strategies for .

More information: Sang Won Park, Yingjiang Zhou, Justin Lee, Allen Lu, Cheng Sun, Jason Chung, Kohijiro Ukei and Umut Ozcan. The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nature Medicine advance online publication, March 28, 2010. DOI:10.1038/nm.2099

Related Stories

Recommended for you

'Human chronobiome' study informs timing of drug delivery, precision medicine approaches

December 13, 2017
Symptoms and efficacy of medications—and indeed, many aspects of the human body itself—vary by time of day. Physicians tell patients to take their statins at bedtime because the related liver enzymes are more active during ...

Study confirms link between the number of older brothers and increased odds of being homosexual

December 12, 2017
Groundbreaking research led by a team from Brock University has further confirmed that sexual orientation for men is likely determined in the womb.

Potassium is critical to circadian rhythms in human red blood cells

December 12, 2017
An innovative new study from the University of Surrey and Cambridge's MRC Laboratory of Molecular Biology, published in the prestigious journal Nature Communications, has uncovered the secrets of the circadian rhythms in ...

Estrogen discovery could shed new light on fertility problems

December 12, 2017
Estrogen produced in the brain is necessary for ovulation in monkeys, according to researchers at the University of Wisconsin-Madison who have upended the traditional understanding of the hormonal cascade that leads to release ...

Time of day affects severity of autoimmune disease

December 12, 2017
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between ...

3-D printed microfibers could provide structure for artificially grown body parts

December 12, 2017
Much as a frame provides structural support for a house and the chassis provides strength and shape for a car, a team of Penn State engineers believe they have a way to create the structural framework for growing living tissue ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.