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For Walt...

Researchers in Boston have pinpointed a primary trigger for the most common form of diabetes and have uncovered evidence that simple, inexpensive aspirin-like drugs could keep the disease that affects millions in check.

The researchers, from Joslin Diabetes Center in Boston, discovered a genetic "master switch" in the liver that is turned on when people become obese. Obesity has long been linked to diabetes, but the reason, until now, has been unknown. Joslin researchers found that once on, this switch produces low-level inflammation, which disrupts the body's ability to process insulin, causing type 2 diabetes.

But the researchers took the finding one step further. Reasoning that aspirin-like drugs are used to quell inflammation, they successfully used the drugs, called salicylates, to eliminate the symptoms of type 2 diabetes in mice. Human tests are already underway in Boston, though no results have been published.

"These drugs, among the safest drugs known, can do a surprisingly good job of toning down this inflammation," said Joslin researcher Dr.

Steven E. Shoelson, lead author of the paper. "These are hopeful ideas for the future."

Shoelson warned against rushing out to get salicylates. Their effectiveness has been proved thus far only in mice.

"No one should go out and take these drugs," said Shoelson. He said losing weight, exercising, and eating healthy are the obvious things to do.

Nonetheless, researchers at Joslin were excited about their findings and are preparing federal grant requests to fund a major, multicity trial of salicylate therapy for type 2 diabetes. And there are indications that the drugs could also help stave off heart disease.

"There is good reason to believe that this could develop into a therapy for diabetes. The evidence is quite good," said Dr. Gokhan Hotamisligil, professor of genetics and metabolism at Harvard School of Public Health, who was not involved in the study. "I'm fully convinced this is where the key therapies for diabetes will emerge from."

The findings appeared Sunday in the online version of the journal Nature Medicine. The work was funded by the federal government and the American Diabetes Association.

About 18 million Americans have diabetes, and most have type 2 diabetes.

In type 2 diabetes, the body's cells become resistant to insulin, which transports sugar from the bloodstream into cells, giving cells energy to function. In diabetes, this feeding is blocked, causing sugar to build up in blood.

Those afflicted grow excessively thirsty, exhausted, and confused if the condition goes untreated, and are at high risk for heart disease, stroke, blindness, and amputations. About three-quarters of sufferers are obese or overweight.

Shoelson's team began the experiment seeking the biological connections between weight gain and diabetes. They knew that the livers of obese people accumulate fat faster than any other organ, and that many overweight diabetic patients had high levels of proteins - particularly one called NF-kB - in their livers that normally trigger inflammation.

They zeroed in on it and were stunned to discover its role in diabetes.

The scientists were able to trigger inflammation and the symptoms of diabetes in lean, previously healthy mice by using genetic techniques to turn on the gene that makes NF-kB.

Normally, in response to an infection, the liver produces massive amounts of NF-kB, which triggers a biological process that sends white blood cells to an injury site to fight off infections, causing inflammation in the process. NF-kB acts as a master switch, triggering this complex and life-saving reaction.

But in obese mice, Shoelson's team found that a fatty liver - for reasons still unknown - also flipped on NF-kB, though at far lower levels.

The proteins secreted when this low-level inflammation occurs disrupt the body's ability to process insulin, leading to diabetes.

"We previously knew that in obesity, the liver becomes fatty and that it accumulates fat faster than other organs and tissues," said Shoelson.

"But until now, we didn't know fat in the liver could orchestrate the entire inflammatory process that results in insulin resistance, both locally and throughout the body."

Shoelson's team decided to use salicylates, already used as anti-inflammatory, to try to stop low-level inflammation and diabetes symptoms triggered by NF-kB - and was successful. As long as the mice got adequate doses, their diabetes was held in check. Aspirin is the best known of this family of drugs. But Shoelson found that it would take more than 20 aspirins daily to suppress NF-kB in human diabetics, which would cause severe gastrointestinal bleeding.

In human trials, Shoelson is using a milder, commercially available prescription salicylate called salsalate, used safely by thousands to treat joint pain. He is negotiating with the National Institutes of Health to fund a large-scale national trial.

Another intriguing finding emerged from the study: Within the complex cascade of biological events triggered by NF-kB, Shoelson found that C-reactive protein levels were elevated. C-reactive protein, or CRP, has been found to be a strong risk marker for heart disease.

Shoelson is preparing an experiment to test if salicylates also can reduce CRP and thus heart disease risk.

Yes, but...

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