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'Junk' Gene Tied to Both Diabetes and Obesity

Mouse study opens door to one therapy for both conditions

THURSDAY, Nov. 21, 2002 (HealthDayNews) -- Researchers have identified a gene involved in both diabetes and obesity, a finding that helps explain how the conditions are linked and that may also present a new target for drugs to combat them.

The JNK gene (known as "junk") was shown to be overly active in obese mice and in mice that were fed a high-fat diet. Mice without the gene were thinner and had less insulin resistance.

"This points to a central mechanism, really the heart of the disease," says Dr. Gökhan S. Hotamisligil, an associate professor of nutrition at the Harvard School of Public Health and senior author of the paper, which appears in today's issue of Nature.

Together, obesity and Type II diabetes affect more than half of the adults in the United States. Obesity is a leading risk factor for this form of diabetes.

At the center of both obesity and diabetes is a phenomenon called insulin resistance. Insulin, a hormone produced by the pancreas, is responsible for guiding glucose out of the bloodstream and helping to store it so it can be used later for energy. People with Type II diabetes are resistant to insulin, meaning that although they produce the hormone, their bodies don't respond the way they should.

Scientists have long been seeking to unravel the mechanisms that link the two metabolic diseases of obesity and diabetes.

In this study, Hotamisligil and his colleagues at Harvard, in collaboration with researchers at the University of California at San Diego, bred three sets of mice: one set with normal genes; one that lacked the JNK1 version of the gene (the gene comes in three "flavors"); and one that lacked the JNK2 version of the gene. They then tried to make the rodents obese by feeding them a high-fat, high-calorie diet or by cross-breeding with a genetic model of obesity and diabetes.

JNK activity turned out to be much higher in the high-fat tissue (liver, muscle, and fat) when compared with lean tissue.

Obese mice with the JNK1 gene also developed mild hyperglycemia (excess glucose in the blood) and their bodies also stopped responding to insulin. The group of mice without the JNK1 gene had significantly lower insulin and blood glucose levels and were less obese.

Apparently, obesity and diabetes produce inflammation in fatty tissues. This triggers the JNK gene, which, in turn, interferes with insulin sensitivity. "What this research shows is that the cellular stress and the resulting inflammation due to obesity is translated by this protein into insulin resistance in diabetes," Hotamisligil says.

The finding that the pathway was central not only to diabetes but also to obesity was a bonus, Hotamisligil reveals. "We have been chasing this activity for many years and all of this was based on the hypothesis that this pathway, if we discovered it, would be central to diabetes," he says. "But that it was also central to obesity. That was a surprise. This is a very exciting discovery."

"It seems that if you have this protein you're worse off than if you don't," says Dr. Steven Heymsfield, deputy director of the Obesity Research Center at St. Luke's-Roosevelt Hospital in New York City. "This could be that little missing piece. This could partially explain why one person is insulin-resistant and one isn't and why some get diabetes and some don't."

The finding is also, Heymsfield points out, "a drug company's dream." "Now they have a protein that seems pivotal in insulin and glucose metabolism. They can make antagonists or agonists to those genes or to the receptor which might then be a treatment for diabetes," he says. "The therapeutics could be quite interesting."

In fact, Hotamisligil reports, compounds that can block JNK pathways are already in development, although they haven't yet been tested on humans. Preliminary analyses may therefore happen relatively quickly. "This is the song of the optimistic," Hotamisligil says.

What To Do

For more information on diabetes, visit the American Diabetes Association or the National Institute of Diabetes and Digestive and Kidney Diseases.

SOURCES: Gökhan S. Hotamisligil, M.D., Ph.D., associate professor, nutrition, Harvard School of Public Health, Boston; Steven Heymsfield, M.D., deputy director, Obesity Research Center, St. Luke's-Roosevelt Hospital, New York City; Nov. 21, 2002, Nature
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