Risk profile for diabetes

Study finds link to high levels of the protein fetuin-A

Elderly people with excess amounts of the protein fetuin-A are more likely than others to develop type 2 diabetes, a new study finds. Because earlier work showed that the protein may interfere with the action of insulin, the new findings potentially implicate fetuin-A in diabetes and suggest the protein may make a good target for drug therapy.

Scientists have found fetuin-A tantalizing ever since lab experiments showed it competed with insulin to bind to receptor proteins on cells. By doing so, fetuin-A seems to crowd out insulin and prevent it from making glucose available to muscle cells.

“We don’t understand why one person who’s obese develops diabetes and another doesn’t,” says Joachim Ix, a nephrologist at the University of California, San Diego and coauthor on the study. Fetuin-A may play a role since it seems to operate irrespective of weight, he notes. That could help doctors to identify people at hidden risk of developing diabetes. “Ultimately that might lead to different therapies in these two different kinds of people,” Ix says.

Further research in mice genetically engineered to lack fetuin-A showed that the animals were the mirror opposites of mice with diabetes. “They were lean, mean mice machines,” Ix says.

Those early findings led Ix and his colleagues to assess the protein’s role in people. The researchers identified healthy elderly individuals who had participated in a medical study starting in the late 1990s while they were all still in their 70s. Each volunteer had given a blood sample at the start of the study. Ix and his team identified 135 people in the study who had developed type 2 diabetes during the six-year study period and another 384 who hadn’t.

High levels of fetuin-A in the blood increased the risk of diabetes by 70 percent.

The researchers accounted for differences between the groups in age, gender, obesity, lifestyle, blood pressure, blood sugar, cholesterol and proteins associated with inflammation. The study appears in the July 9 Journal of the American Medical Association.

“We think fetuin-A is a bad guy,” says Suresh Mathews, a molecular biologist at AuburnUniversity in Alabama. He and his colleagues did much of the initial work establishing fetuin-A’s link to the insulin receptor.

Mathews says the new study breaks ground. A link to diabetes in a longitudinal study in which people are tracked over time hadn’t been shown before, he says.

Several groups are currently studying fetuin-A’s actions in the body. While there is keen interest in developing a drug that neutralizes fetuin-A, a drug doesn’t exist yet. “I think that has a lot for potential to be useful, but it’s not quite ready for prime time,” Ix says.

Mathews’ working hypothesis is that the protein serves as a brake for insulin, to keep people from becoming hypoglycemic if the hormone doesn’t shut off appropriately.

But treatment may not be as simple as turning off the fetuin-A spigot, Mathews says. The protein also seems to regulate calcium levels in the blood. Disturbing that role could cause crystallization of calcium in blood vessels and other part of the body, causing other health problems. Ideally, he says, a drug would disable fetuin-A’s ability to crowd out insulin at the receptor sites while not disrupting its blood-calcium duties.

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