Issue 214 Item 8 Why Some People Develop Type 1 Rapidly And Others Don’t

Joslin researchers identify a key molecule in the progression of Type 1 diabetes. Why do some people seem to develop type 1 diabetes rapidly while in others it may take years to develop? A new study by Joslin Diabetes Center researchers reveals one of the key biochemical pathways that determines whether type 1 diabetes will remain in its early stages or progress to full-blown disease, possibly explaining why some people develop type 1 diabetes more rapidly than others.

For many years scientists have known that type 1 diabetes is an autoimmune disease in which the body’s immune system mistakenly launches an attack on the insulin-producing beta cells of the pancreas. At an early stage in this process, white blood cells called T-cells invade the islets of Langerhans of the pancreas, where the beta cells reside (a condition known as "insulitis"). Yet, in both mice and humans, insulitis does not always progress to full-blown type 1 diabetes. For years, researchers have been trying to determine why insulitis sometimes leads to diabetes (so-called "destructive" insulitis) and sometimes does not ("respectful" insulitis). They know that certain T-cells called T effector cells promote destructive insulitis, and other T-cells called regulatory T-cells favor respectful insulitis. Yet, no one knows exactly what causes the balance of power to shift between these two types of cells to cause diabetes.

To study this question, Anne E. Herman, Ph.D., Diane Mathis, Ph.D., and Christophe Benoist, M.D., Ph.D., of the Section on Immunology and Immunogenetics at Joslin Diabetes Center in Boston studied insulitis lesions in a certain strain of genetically engineered mice called BCD2.5 mice. These mice develop insulitis, but a very respectful form, such that diabetes does not follow until months later, or, in some, never. The researchers discovered that both effector and regulatory T-cells co-existed and thrived in these insulitis lesions, and they wondered what kept these lesions respectful.

They looked specifically at a molecule called inducible co-stimulator (or ICOS), which was expressed at an unusually high level on regulatory T cells. Using monoclonal antibodies (man-made versions of natural antibodies, which target individual proteins like guided missiles), the researchers blocked the action of ICOS to see what would happen. Blocking ICOS disrupted the balance between T effector and T regulatory cells, and provoked insulitis to immediately convert to diabetes. The researchers concluded that ICOS plays an important role in keeping insulitis lesions from becoming destructive.

"Understanding the molecular and cellular basis of the immune regulation in the lesion might some day lead to the development of therapies that favor regulatory T-cells and respectful insulitis, preventing the development of full-blown diabetes even after insulitis has developed," Herman explains. The Journal of Experimental Medicine June 2004

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FACT: About half of all woman ages 20 to 74 are overweight or obese, according to an NBC 5 health report. The percentage increases are among African-American, American Indian and Mexican-American women.