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An early signpost for type 1 diabetes

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Type 1 diabetes is one of the most common serious diseases to strike young children, but how does it start? It’s a question that has bedeviled scientists for years. Now, a new study pinpoints a warning sign in healthy babies as young as 6 months old. The work could advance prevention efforts and might help explain the genesis of the autoimmune disease.Type 1 diabetes hits when the body destroys insulin-producing cells in the pancreas. By the time people—many of them children—are diagnosed, most of those cells are gone. Forty thousand new type 1 diabetes cases are recorded each year in the United States, and the disease is on the rise for reasons not well understood. A dream for diabetes researchers is to treat kids earlier, when they are headed down the diabetes road but aren’t yet there. About 3 decades ago, scientists discovered a collection of signposts: antibodies directed at certain proteins in the body, including insulin. As they studied these children more intensively, they learned that those with two or more different kinds of these autoantibodies will eventually develop diabetes, though sometimes not for many years. Many clinical trials have since focused on trying to slow disease onset in these individuals. But what happens before these autoantibodies arise? Ezio Bonifacio, a biologist at the Technische Universität Dresden in Germany, had the means to tackle this question. He and his colleagues had for years been following children since birth whose genetics and family history put them at increased risk. Beginning in 2000, the researchers began to collect and store blood cells from a subset of these children. Recently, technology had advanced to the point that scientists could analyze single cells in those samples.“We decided that it was time to start to see if there was something happening at the level of the T cells,” Bonifacio says. Commonly referred to as the sentries of our immune system, T cells are the villains in diabetes. They for some reason go rogue, leading the attack on insulin-producing cells in the pancreas.Bonifacio and his colleagues performed sophisticated analysis on T cells from 12 babies who didn’t develop autoantibodies later—suggesting they were in the clear—and 16 babies who did. Probing the T cells in the lab, they saw that cells from the children who continued down the path toward type 1 diabetes were not normal. Essentially, when the T cells were exposed to a substance called an antigen, which in this case could trigger a response against insulin-producing cells, some of those T cells got activated. This is a faint echo of what happens inside the body of someone developing diabetes: Their T cells are activated against cells in the pancreas much as they would be against a foreign invader, like a virus.“These T cells have somehow already learnt to get halfway” toward becoming autoreactive cells, says Bonifacio, whose team reports its findings today in Science Translational Medicine.Bonifacio cautions that the findings are still preliminary. For one, samples like these from infancy are rare, and thus the number of children whose T cells were studied is modest. For another, although the unusual T cell behavior was entirely absent in kids who didn’t get autoantibodies later on, it was recorded in only about half who did.Still, the work breaks ground by identifying likely signs of type 1 diabetes studies earlier than ever, says Kevan Herold, an endocrinologist at Yale University, who studies ways to prevent the condition. “The value of this paper is that there’s stuff that can be measured even before” the autoantibodies, agrees Gerald Nepom, director of the Immune Tolerance Network and former director of the Benaroya Research Institute in Seattle, Washington.One central mystery is what’s causing the changes in these cells so early in life. Bonifacio and others have looked exhaustively for environmental drivers of type 1 diabetes; although there have been hints of various influences, like certain infections, “the punch line here is that the data’s inconsistent” across all the studies, says Carla Greenbaum, who chairs Type 1 Diabetes TrialNet, which oversees type 1 diabetes treatment and prevention trials, and directs the diabetes program at the Benaroya Research Institute.So diabetes experts like Greenbaum have their eyes on prevention. Bonifacio is co-leading a study called Pre-POINT-Early, which offers oral insulin to children between 6 months and 2 years old; results are expected sometime next year. An oral insulin prevention study by TrialNet, in people with autoantibodies, will be reported in June. Herold hopes to report data in the near future on a study of an antibody called anti-CD3; he has tested it in newly diagnosed patients and is now trying it as a preventive. An early signpost for type 1 diabetes? 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