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Protein Could Lead to Diabetes Treatments

By Nancy Touchette

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A new study in mice provides the strongest evidence yet that a protein that helps the body fight infection may also contribute to type 1 diabetes. Mice born without the protein are protected from diabetes, and a drug that blocks the protein could potentially prevent or reverse at least some forms of type 1 diabetes in humans, according to the researchers.

Type 1 diabetes, also known as juvenile diabetes or autoimmune diabetes, occurs when a person’s own immune cells attack the insulin-producing cells of the pancreas. Without insulin, cells in the body cannot use glucose. If untreated, the condition can lead to coma, seizures, and death.

A genetically modified mouse (bottom) develops diabetes, but a mouse missing the Stat-4 gene (top) is protected from the disease.
The mice in the study had been genetically modified to develop an autoimmune disease similar to type 1 diabetes in humans. But if the mice were also missing a gene called Stat4, they did not develop the disease, according to the new study by Zandong Yang and his colleagues at the University of Virginia in Charlottesville.

“If we can suppress Stat4, then we can suppress the cells that attack the pancreas,” says Yang. “That could be beneficial in delaying or preventing diabetes.”

Yang and his colleagues have studied a drug called lisofylline as a possible treatment for autoimmune diabetes. The drug was originally developed as an anticancer therapy, but it was not effective in clinical trials for cancer treatment.

In a study published last year, Yang found that the drug prevents diabetes in mice that normally develop the disease. It appears to work by blocking the activation of the Stat4 protein in the same type of immune cells that attack the pancreas in diabetes.

Taken together, the studies suggest that Stat4 may play a key role in autoimmune diabetes, at least in mice. The next step will be to see if the drug is effective in treating people with the disease and whether it causes any side effects.

To keep blood glucose at normal levels, people with type 1 diabetes must take insulin several times a day for their entire lives. Even with insulin treatment, devastating complications such as blindness, heart disease, and stroke often develop at an early age.

Researchers would like to find ways to thwart the immune attack that destroys the insulin-producing cells. Many doctors and patients are optimistic that stem cells—immature cells that have the potential to become replacement cells for people with disease—could restore function to the pancreas. But stem cells might be destroyed by the same process that causes the disease.

Yang predicts that lisofylline or similar drugs could prevent or reverse the autoimmune attack that causes type 1 diabetes and restore function to the pancreas. He hopes to test the drug in clinical trials, but that could take several years.

In the meantime, Yang is trying to develop a form of lisofylline that can be taken orally, because the drug in its current form must be given intravenously over the course of several hours, which is not practical for patients. And in his search for possible diabetes treatments, he will also be testing compounds related to lisofylline that might also block the Stat4 protein.

Yang, Z. et al. Autoimmune diabetes is blocked in Stat4-deficient mice. J. Autoimmunity 22, 191-200 (May 2004).
Yang, Z. et al. Inhibition of STAT4 activation by Lisofylline is associated with the protection of autoimmune diabetes. Ann. NY Acad. Sci. 1005, 409-411 (November 2003).

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