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Cu Team Discovers Crucial Clue to Diabetes ; Health Sciences Scientists Find Proof of Trigger in Type 1

Posted on: Thursday, 12 May 2005, 09:00 CDT

Denver researchers have identified a crucial target in the immune- system attack that leads to Type 1 diabetes, which afflicts more than 1.3 million Americans.

In Type 1 diabetes the body turns against itself and destroys insulin-producing cells in the pancreas. For years, researchers have tried to determine what prompts this autoimmune assault.

Disrupting the first steps could lead to therapies that block the disease, formerly known as juvenile-onset diabetes.

Now a University of Colorado Health Sciences Center team working with genetically altered mice has uncovered the strongest evidence to date that insulin itself triggers the onslaught.

Working independently, Harvard Medical School researchers also have shown that insulin likely plays an essential role in human cases.

Both teams report their results in today's edition of the the British journal Nature.

"This study says there is a crucial target, and it's a piece of insulin," said Dr. George Eisenbarth, head of the CU team and executive director of the Barbara Davis Center for Childhood Diabetes at Fitzsimons.

"And if you can stop the attack on a crucial target, you can stop disease," he said. There is currently no treatment to prevent Type 1 diabetes.

In the Denver study, researchers used mice that usually develop Type 1 diabetes, called nonobese diabetic (NOD) mice.

They eliminated the mouse genes that make insulin and inserted modified genes that produce a slightly altered, disguised form of insulin. Immune cells in the NOD mice failed to recognize the altered insulin and didn't attack. The mice remained healthy.

"It's a beautifully elegant experiment that proves a key principle," said Dr. Gerald Nepom, director of the Benaroya Research Institute in Seattle.

More than 100 research papers over the past decade have suggested that insulin itself is a likely target in Type 1 diabetes. But the Eisenbarth team's experiment is the first to provide "the molecular proof," said Nepom, who was not involved in the work.

"It's really the strongest evidence to date," said Dr. Matthias von Herrath, an immunologist at the La Jolla Institute for Allergy and Immunology in San Diego.

Type 1 diabetes accounts for 5 to 10 percent of the diagnosed diabetes cases in the United States. It develops most often in children and young adults but can appear at any age.

Type 2 diabetes is far more common. It is associated with older age, obesity and physical inactivity. Both types involve defects in insulin production or insulin activity.

Insulin is a hormone produced by the pancreas, a large gland behind the stomach. It regulates blood-sugar levels so that energy from food can be used by the body's cells.

In Type 1 diabetes, immune-system white blood cells attack insulin-producing beta cells in the pancreas, destroying them.

To stay alive, people with Type 1 diabetes must take multiple insulin injections daily or have the hormone delivered through a pump.

Several experimental therapies have used the strategy of providing extra insulin - through injections or orally - to high- risk patients in hopes of preventing the disease.

The goal of those trials was to train the immune system to tolerate insulin, instead of attacking it. So far, the approach has not succeeded.

But the results of the Eisenbarth study "provide the rationale for continuing to do the human studies, emphasizing the use of insulin," said Dr. Robert Goldstein, chief scientific officer at the Juvenile Diabetes Research Foundation.

Another approach would be to eliminate or suppress immune-system cells that recognize and attack insulin, said John Hutton, a cell biologist at the CU child diabetes center.

"If insulin is the prime target, then it's really the Achilles heel," he said. "It raises the prospect that new therapeutic measures simply targeted at this molecule might be sufficient."

Hutton said the experiment reported in Nature is the culmination of 10 years of mouse breeding and gene-splicing work.

The lead author of the CU Nature paper is Maki Nakayama. The other authors are Eisenbarth, Hutton, Norio Abiru, Hiroaki Moriyama, Naru Babaya, Edwin Liu, Dongmei Miao, Liping Yu, Dale Wegmann and John Elliott.

INFOBOX

Type 1 diabetes

* Also known as: Insulin-dependent diabetes mellitus; Juvenile onset diabetes

* Definition: A chronic (lifelong) disease that occurs when the pancreas does not produce enough insulin to regulate levels of blood sugar (glucose). Without adequate insulin, glucose builds up in the bloodstream instead of entering cells to be burned for energy.

* Incidence: Type 1 diabetes can occur at any age, but it usually starts in people younger than 30. Symptoms are usually severe and occur rapidly.

3% of all new cases of diabetes diagnosed each year are Type 1.

1.3 million Americans are afflicted by Type 1 diabetes.

* In Type 2 diabetes (adult onset), the body produces insulin but can't use it effectively. It is often accompanied by obesity and high cholesterol.

Source: National Library Of Medicine/National Institutes Of Health

Source: Rocky Mountain News

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