Protein may tie obesity to diabetes.

The high incidence of obesity among people with type II diabetes suggests a connection between the two conditions. Scientists have sought a link by studying insulin resistance, the trademark symptom of type II, or adult-onset, diabetes. But they still don't know why cells in people with insulin resistance ignore insulin's signals to process blood glucose for use by muscles and other tissues.

Researchers working with mice have now identified a hormone, called resistin, that is secreted by fat cells and appears to play a direct role in type II diabetes. Healthy mice given doses of extra resistin for 2 days develop insulin resistance, researchers at the University of Pennsylvania in Philadelphia report in the Jan. 18 NATURE.

Interestingly, obese mice naturally produce copious resistin, says study coauthor Mitchell A. Lazar, a molecular endocrinologist at Pennsylvania. When given drugs that inhibit the effects of resistin, these overweight mice process glucose more efficiently, he says.

The Pennsylvania researchers have identified the human gene that encodes resistin, but they haven't yet gauged the hormone's effects in people.

Roughly four out of five people with type II diabetes are obese. The new findings "indicate that resistin may form at least part of the missing link between obesity and diabetes," says Jeffrey S. Flier of Beth Israel Deaconess Medical Center in Boston in the same issue of NATURE.

Lazar's team found resistin in mice while monitoring the effects of a diabetes medication in the family of drugs called TZDs, or thiazolidinediones. Earlier studies in rodents had shown that TZDs slow type II diabetes even though they spur the creation of fat cells, a seemingly contradictory action. The drugs work by activating a receptor molecule, called PPAR-gamma, in fat cells.

When PPAR-gamma becomes active, production rates change for some proteins in the cells. Although most of these rates rise in the presence of TZDs, the researchers focused on the few protiens having rates that dropped. Among these, Lazar and his colleagues identified one that they dubbed resistin.

Further tests showed that TZDs indeed reduce the concentration of resistin in the blood of mice.

"This is a big deal," says Allen M. Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md. Measuring resistin concentrations in blood could help physicians diagnose type II diabetes, both Spiegel and Lazar say.

Resistin shares some qualities with another protein secreted by fat cells and associated with obesity, the hormone leptin. This hormone, discovered in 1995, seems to regulate food intake.

Establishing that fat cells secrete resistin and leptin confirms that these cells are more than just "oily stuff in the body," Spiegel says. Fat in the body "is an endocrine gland, a hormone-producing substance involved in a dialogue with the brain, liver, and muscle in a complex [process] of nutrient metabolism," he says.

Leptin doesn't appear to have a straightforward association with diabetes. In rodents, a leptin deficiency causes severe insulin resistance, but people with type II diabetes actually have high concentrations of leptin in their blood. Some research points instead to a compound called tumor necrosis factor alpha as a trigger for insulin resistance, Flier says.

Resistin "is almost certainly a piece of the puzzle," Lazar says. "Resistin may actually play a big role in explaining why having too many fat cells can induce insulin resistance."

The Pennsylvania researchers have already devised an antibody to resistin, which they used in the mouse tests to inhibit the newfound substance's effects. However, they still haven't found the molecular receptor that allows resistin to bind to cells. Identifying this molecule could give drug makers a target by which to chemically block the effects of resistin, Spiegel says.