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[tvoivozhd <tvoivozd AT infionline.net>]

Diabetes is a huge component of Medicare, Medicaid and medical insurance 
costs---wiping it out or keeping it under control with a drug cheap as 
aspirin would take a huge load off taxpayers.

Boston.com      THIS STORY HAS BEEN FORMATTED FOR EASY PRINTING

The Boston Globe <http://www.boston.com/news/globe/>


 Researchers find diabetes trigger, possible fix

By Raja Mishra, Globe Staff  |  January 31, 2005

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 yesterday 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-inflammatories, 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.

Raja Mishra can be reached at rmishra AT globe.com. 

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The New York Times Company