A new insight into how type-1 diabetes begins has been revealed by researchers at the Stanford University School of Medicine. An autoimmune attack on the pancreas causes type-1 diabetes, but the exact trigger of the attack has not been unclear.
Now, a new study in mice implicates that 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 jabs.
"We never considered that interferon-alpha could be a major player in early type-1 diabetes. This was a pretty surprising finding," said Qing Li, MD, PhD, a postdoctoral scholar in microbiology and immunology who was the primary author of the new study.
Li noted that 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.
Hugh McDevitt, MD, professor of microbiology and immunology and the study's senior author, said that the early pathology of type-1 diabetes is hard to study in humans because it's almost impossible to predict who will get the disease and when it will develop.
Therefore, the researchers relied on animal models, such as diabetic mice, because they predictably develop high blood sugar and other features of the human disease.
Previous 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.
In order 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 researchers connect the dots between normal mouse physiology and early diabetes. Li noted that the mice are born with more pancreatic beta cells than they need.
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.
"A normal process - programmed cell death - causes a normal response. 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," McDevitt said.
The study is published in today's issue of Proceedings of the National Academy of Sciences.