Early trigger for type-1 diabetes found in mice, Stanford scientists report

August 27, 2008

STANFORD, Calif. - Scientists at the Stanford University School of Medicine are shedding light on how type-1 diabetes begins.

Doctors have known the disease is caused by an autoimmune attack on the pancreas, but the exact trigger of the attack has been unclear. Now, a new study in mice implicates the immune signal interferon-alpha as an early culprit in a chain of events that upend sugar metabolism and make patients dependent on lifelong insulin injections.

"We never considered that interferon-alpha could be a major player in early type-1 diabetes," said Qing Li, MD, PhD, a postdoctoral scholar in microbiology and immunology who was the primary author of a paper describing the new result. The study is published in today's issue of Proceedings of the National Academy of Sciences. "This was a pretty surprising finding."

Interferon-alpha normally helps the body fight viruses. Synthetic interferon-alpha is injected as a drug for treating hepatitis C and some forms of cancer, Li noted.

"Everybody's been wondering what process initiates type-1 diabetes," said Hugh McDevitt, MD, professor of microbiology and immunology and the study's senior author.

Type-1 diabetes is caused by complete deficiency of insulin, a hormone that helps the body store and burn sugar. About 1 million Americans have the disease, also known as juvenile diabetes because it tends to be diagnosed in children and young adults, for which there is no effective prevention or cure. Diabetes is a leading cause of heart disease, blindness, limb amputations and kidney failure.

The early pathology of type-1 diabetes is hard to study in humans, McDevitt said, because it's almost impossible to predict who will get the disease and when it will develop. Scientists have relied on animal models, such as diabetic mice, because they predictably develop high blood sugar and other features of the human disease.

To pinpoint interferon-alpha, Li and McDevitt worked backwards from what they knew about how type-1 diabetes starts. Prior studies in diabetic mice showed a pathogenic role for immune cells called CD4+ T cells. These cells are an early player in the immune attack on the body's insulin factories, pancreatic beta cells. The scientists used silicon gene-chip technology to measure which genes are revved up in the CD4+ T cells just before they assault the pancreas. The measurements fell into a pattern: many of the upregulated genes were known to be controlled by interferon-alpha.

To confirm the signal's nefarious role, the researchers gave mice an antibody that blocks interferon-alpha activity several weeks before the animals were expected to develop diabetes. Thwarting interferon-alpha delayed the start of the disease by an average of four weeks, and, in 60 percent of treated mice, it prevented diabetes entirely.

The finding confirmed the importance of interferon-alpha and helped the scientists connect the dots between normal mouse physiology and early diabetes. Mice are born with more pancreatic beta cells than they need, Li noted. The extras soon undergo programmed cell death, leaving plenty of working beta cells to pump out insulin. However, in mice that develop diabetes, debris left behind by the dying cells triggers an inappropriate immune response, with lots of interferon-alpha. The interferon-alpha cues immune destruction of more and more beta cells, causing insulin deficiency and diabetes.

The mechanism may be more complex in humans, the scientists cautioned, explaining that while their new finding goes a long way toward explaining the beginnings of diabetes in the mice, additional genetic and environmental factors influence the human disease. But the basic principle of disease is likely the same in diabetic mice and humans, they said.

"A normal process - programmed cell death - causes a normal response," McDevitt said. "But it does this in such a way that, in a small subset of the population, it starts them on the road to type-1 diabetes."

Stanford University Medical Center

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