Insulin Itself May Cause Diabetes

Scientists have come a step closer to understanding the cause of childhood diabetes, a disease in which the body's immune system destroys its own insulin-producing cells. A paper in the September issue of Nature Medicine suggests that insulin itself, on the surface of the cells that produce it, triggers the destruction. The study may help devise strategies to prevent the disease.

Previous studies had shown that T cells, immune cells that normally fight infections, are responsible for attacking--and destroying--the so-called islet b cells, the insulin factories in the pancreas. The attack can rob patients of the ability to produce insulin for the rest of their lives. Many scientists are trying to pinpoint which protein in the b cells serves as the antigen that triggers the attack, hoping that it may be used somehow to "teach" the immune system that it's not a foe.

A great deal of research has implicated the CD4 or "helper" T cells, which cooperate with other immune cells to trigger antibody production and other immune responses, as contributing to diabetes development. But immunologists Susan Wong, Charles Janeway, and colleagues at Yale University were more interested in a different class of T cell, the so-called CD8 or killer T cells. In 1996, they had isolated an aggressive CD8 cell from mice with a disease very similar to human diabetes and showed that, when transplanted into other mice, it causes diabetes in less than a week. Because the cells came from young mice that weren't sick yet but developed diabetes later on, the researchers figured that the cells might play a role in the earliest phase of the disease, perhaps even initiating the immune attack on the islet cells.

In the current study, the team set out to find what the CD8 cells might recognize on the islet cells. First, they took rapidly multiplying tumor cells and genetically engineered them to mass-produce hundreds of pancreatic proteins. Next, they inserted a gene into their CD8 T cells that causes the cells to turn blue when they latch on to the particular antigen that activates them. This way, they were able to identify insulin as the antigen; they could even pinpoint a specific sequence of nine amino acids in the hormone that the T cells recognized.

Wong says it's the first time researchers have identified a trigger for CD8 cells in an autoimmune disease. "It's a beautiful study," agrees immunologist George Eisenbarth of the Barbara Davis Center for Childhood Diabetes at the University of Colorado in Denver. "This new insight into insulin's role is exciting."

In addition, Wong says, the finding that insulin is the likely culprit bolsters the rationale for an idea that is already being tested. For reasons not well understood, some disease-triggering antigens, when taken orally, can suppress the immune reactions that would otherwise be directed at them, and clinical trials are now under way to see if oral insulin can inhibit the development of diabetes in children at risk of the disease. The results suggest another possibility as well, Eisenbarth says. If insulin-reactive CD8 cells are at the root of the disease, researchers may be able to find ways to disarm them.

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