A new strategy normalizes blood sugars in diabetes

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 fat cells 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 blood glucose 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 type 2 diabetes.

The study was funded the National Institutes of Health, a Translational Research award from Children's Hospital Boston, and Timothy Murphy funds.

Citation: Sang Won Park, Yingjiang Zhou, Justin Lee, Allen Lu, Cheng Sun, Jason Chung, Kohijiro Ukei and Umut Ozcan. The regulatory subunits of PI3K, p85á and p85â, interact with XBP-1 and increase its nuclear translocation. Nature Medicine advance online publication, March 28, 2010. DOI 10.1038/nm.2099.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School.