Disruption of a gene may prevent type 1 diabetes, UVa researchers find

May 06, 2004

CHARLOTTESVILLE, Va., May 6 - Disrupting a gene called Stat-4 suppresses the activation of white blood cells involved in the development of type 1 diabetes, say researchers from the University of Virginia Health System in the May issue of "The Journal of Autoimmunity." U.Va. researchers discovered for the first time that disrupting Stat-4 completely prevented the development of spontaneous diabetes in a mouse model, revealing an important role for the Stat-4 gene in the pathogenesis of type 1, also known as autoimmune diabetes. Type 1 diabetes occurs when the body's immune system goes haywire and attacks the insulin-making beta cells of the pancreas. People with type 1 normally need insulin by pump or injection to survive.

"We should not fully eliminate the function of Stat-4 in humans, because it is important to the body's immune response to infections," said Dr. Zandong Yang, assistant professor of research at the Health System's division of endocrinology and metabolism. "However, down the road, it may be possible to use a pharmacological approach to design specific drugs to minimize Stat-4 protein function, which may be helpful to prevent type 1 diabetes," Yang said. Stat-4 is a type of "signal transducer and activator of transcription" protein, activated by the body in response to cytokines (proteins produced by white blood cells), growth factors and hormones.

"This research opens up additional areas for identifying new, small molecular targets to prevent immune damage to insulin-producing cells," explained Dr. Jerry Nadler, a study co- author and chief of the division of endocrinology and metabolism at U.Va. "The results could form the basis for new ways to prevent type 1 diabetes and possibly advance the field of islet replacement therapy to reverse established diabetes. This study also represents a key collaboration between investigators in the Diabetes and Hormone Center of Excellence at U.Va. and Dr. Marcia McDuffie in the department of microbiology," Nadler said.

Previously, Yang and his colleagues used a new anti-inflammatory compound called Lisofylline (LSF) to prevent type 1 diabetes and autoimmune reaction. Their studies have shown that LSF inhibits the signaling of interleukin-12 (IL-12), a molecule that helps cells maintain defenses against infection. Yang and Nadler's LSF studies acted as a trigger in investigating the role of Stat-4 activation in type 1 diabetes.

"If you don't have a functional Stat-4 protein," Yang said, "IL-12 cannot express its biological function in many types of immune cells. LSF mainly inhibits Stat-4 protein function, leading to suppression of IL-12 biological action in cells. This is one mechanism explaining why LSF has prevented diabetes in our previous studies."

Both IL-12 cells and T helper type 1 cells are believed to actively participate in the development of type 1 diabetes. Yang hopes to test the therapeutic effects of LSF against diabetes in humans in the next few years.
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This research was supported by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation International and Paul and Diane Manning. The U.Va. Diabetes Center also supported this research.

University of Virginia Health System

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