Heavy burden. Obese people are at a higher risk of type II diabetes.

Protein Links Diabetes and Obesity

A newly discovered protein may help explain why the overweight often suffer from type II diabetes. The protein, dubbed resistin, is produced by fat cells and seems to keep cells from responding to insulin. Discoveries of new proteins often suggest a therapeutic payoff, but in an unusual twist, the researchers made their discovery by using a class of drugs already popular with diabetes patients. Scientists say the finding should help explain how and why the drugs work so well--and may lead to even more effective treatments for the disease.

One of the health hazards of obesity is an increased risk of type II diabetes, also known as adult-onset diabetes. The disease starts when the body mysteriously becomes unable to respond to insulin, a key hormone that regulates blood sugar after meals. Patients' cells fail to take up glucose, sending blood levels of glucose to dangerous levels. Over decades, this can lead to a host of complications including nerve damage, kidney failure, and blindness.

Some of the most effective treatments for type II diabetes belong to a class of drugs called thiazolidinediones (TZDs), which improve patients' insulin response. Scientists were puzzled, because the drugs seem to turn on a gene involved in the development of fat cells. Why a diabetes drug would also increase fat cell production was a mystery--and a bit of a paradox, because the fat cells seem to be the cause of diabetes, says endocrinologist Mitchell Lazar of the University of Pennsylvania School of Medicine in Philadelphia. This connection led Lazar to speculate that the drugs might shed light on what goes wrong in diabetes in the first place.

Lazar and his colleagues guessed that the drugs might be turning off a gene that interferes with insulin response, so they looked for genes that become less active in the presence of TZDs. In tomorrow's issue of Nature, they describe just such a gene, which makes a previously unknown protein. They named the protein resistin, because it appears to cause insulin resistance.

The researchers found that fat cells in mice produce resistin and then excrete it into the bloodstream. Overweight mice had significantly higher levels of resistin in their blood--and higher blood sugar levels--than did healthy mice. Blocking the resistin seems to help animals respond more effectively to insulin. The researchers also found a human gene that is similar to the mouse resistin. They are planning experiments to find out whether human cells respond the same way as mouse cells.

The work "makes quite an appealing story," says endocrinologist Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston. Why mice and humans would have a gene that causes insulin resistance is still a mystery, but Lazar speculates that evolution has favored organisms with "thrifty genes" that help store and use energy efficiently to help them survive lean times. When there's plenty of food, however, such genes may backfire.

Related sites

Mitchell Lazar's home page

NIDDK information on diabetes