Insulin Resistance / Type 2 Diabetes / Salicylate

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Date: 02/01/05 

Date: 1 Feb 2005 05:53:50 -0800

January 30, 2005 01:00 PM US Eastern Timezone

Joslin Diabetes Center Scientists Discover 'Master Switch' that
Triggers Insulin Resistance and Type 2 Diabetes; Salicylate Blocks the
Inflammatory Cascade

BOSTON--(BUSINESS WIRE)--Jan. 30, 2005--Scientists at Joslin Diabetes
Center have discovered why excess weight leads to low-grade
inflammation, which hampers the body's ability to use insulin. They
found that the "master switch" of this inflammation is activated in the
liver by weight gain. And they showed it can be turned off by
salicylates, a class of drugs that includes aspirin.

The Joslin study, published in the February edition of Nature Medicine,
is a major milestone in understanding why being overweight can lead to
a host of health problems, including type 2 diabetes and heart disease.
An estimated 18 million Americans have type 2 diabetes, including an
increasing number of young people. They are two to four times more
likely to have cardiovascular disease.

"We zeroed in on a factor called NF-kB," said principal investigator
Steven E. Shoelson, M.D., Ph.D., Helen and Morton Adler Chair and head
of the Section on Cellular and Molecular Physiology at Joslin, and
Professor of Medicine at Harvard Medicine School. Other researchers
included Dongsheng Cai, M.D., Ph.D., Minsheng Yuan, Daniel F. Frantz,
Peter A. Melendez, Lone Hansen and Jongsoon Lee. This study was funded
by the National Institutes of Health and the American Diabetes
Association.

"When we activated this factor in the liver of laboratory animals, it
stimulated a cascade of inflammatory responses," said Dr. Shoelson.
"The result was dramatic -- including insulin resistance consistent
with type 2 diabetes.

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

The researchers were inspired by previous clinical studies of human
patients at Joslin, driving them to seek answers in the laboratory.
Those studies had shown that overweight people who have insulin
resistance had slightly higher activity levels of NF-kB and other
substances normally found in inflammation. Intrigued that fatty tissue
may activate a small but measurable level of inflammation, they set out
to discover the cellular pathway.

They focused on healthy lean mice -- with no weight problems
predisposing them to type 2 diabetes. Using genetic techniques, the
research team turned on the gene that expresses NF-kB. They then
measured the insulin levels in the bloodstream; if higher than normal,
it's a telltale sign of insulin resistance because the body is not
using the available insulin. They also measured blood glucose levels to
see if they were higher, consistent with diabetes. And they looked for
substances produced along the inflammation pathway.

"Unlike in an acute infection, when NF-kB levels shoot up about
50-fold, the inflammation seen in these mice just simmered -- only
about 3-fold," said Dr. Shoelson. "But their insulin levels and blood
glucose levels were high, what we'd expect in type 2 diabetes. In
effect, we had induced diabetes by turning on low-grade inflammation."
Among the markers in the cascade was C-reactive protein, now the focus
of considerable interest in cardiovascular research.

The Joslin researchers also found that the NF-kB "master switch" could
be inhibited by the salicylate family of drugs. "These drugs -- among
the safest drugs known -- can do a surprisingly good job of toning down
this inflammation," said Dr. Shoelson.

"But more studies need to be done before we can make recommendations to
patients," he cautions. "For now, the best advice for preventing the
onset of type 2 diabetes is to shed those extra pounds, eat a healthy
diet and exercise regularly."

Contacts

Joslin Communications
Marge Dwyer or Jenny Eriksen, 617-732-2415
Marjorie.dwyer@joslin.harvard.edu,
jenny.eriksen@joslin.harvard.edu

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Tom
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