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Type 2 diabetes, like Type 1, may be an autoimmune disease, researchers say

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April 18, 2011|By Thomas H. Maugh II, Los Angeles Times

Type 2 diabetes, like Type 1, may be an autoimmune disease, but the immune system's target cells are different, Stanford researchers said Sunday. The discovery sheds new light on how obesity contributes to the onset of Type 2 diabetes and could lead to new types of treatment for the disorder, the researchers reported in the journal Nature Medicine.

Diabetes is a growing problem in the United States, triggered in large part by the obesity epidemic. An estimated 27 million Americans are now thought to have diabetes, with the vast majority of them -- all but about a million -- afflicted with Type 2 diabetes. That disorder strikes in adulthood and is marked by a growing inability of cells to respond to insulin in the bloodstream, which necessitates using drugs to increase the output of the hormone by the pancreas. Intriguingly, not everyone who becomes obese develops diabetes, however, and researchers have never been sure why.

Dr. Daniel Winer, an endocrine pathologist now at the University of Toronto, and his twin, Dr. Shawn Winer of the University of Toronto's Hospital for Sick Children, reasoned that the death of excess fat cells might trigger an autoimmune reaction. In an earlier study with senior author Dr. Edgar Engleman of the Stanford University School of Medicine, they demonstrated in mice that, as fat accumulates in the tissues surrounding organs, it outstrips its blood supply, leading to the death of cells on the periphery of the fat deposits. When that occurs, the body mobilizes its immune system to break down and carry off the dead cells. But that produces antibodies against the cells and many of the proteins normally found only inside the cells.

In the new study, the team turned its attention to B cells, the lymphocytes or white blood cells that manufacture antibodies against foreign invaders. They genetically engineered mice so that they could not produce B cells and found that the rodents never became diabetic, no matter how fat they became. They next looked at normal mice that were prone to becoming diabetic when they became obese. One group they treated with a biological drug called anti-CD20 that binds to B cells and blocks their activity. The second group received no treatment. The mice that received the drug did not become diabetic when they became obese, while those that did not receive it did become diabetic. The effect lasted only about 40 days, however, and then needed to be repeated.

The group finally studied a group of 32 obese men, half of whom were diabetic and half who were not. They found that the diabetic men had a distinct group of antibodies against cellular proteins that were not present in the healthy men, suggesting that an unusual autoimmune reaction was taking place. The findings suggest that some people are genetically more susceptible to the immune reaction, which is typical of autoimmune diseases.

"We are in the process of redefining one of the most common diseases in America as an autoimmune disease, rather than a purely metabolic disease," Daniel Winer said in a statement. "This work will change the way people think about obesity, and will likely impact medicine for years to come as physicians begin to switch their focus to immune-modulating treatments for Type 2 diabetes." The researchers speculated, for example, that a form of anti-CD20 already used in humans might block the onset of diabetes, particularly if treatment is begun early in the course of the disease. The drug is sold under the brand names Rituxan and MabThera for the treatment of leukemias, lymphomas, transplant rejection and certain autoimmune disease. But they cautioned that the drug has some strong adverse side effects and that it can leave the patient susceptible to a variety of infections. Other approaches to modulating the immune system might thus be safer, they said.

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