A ten-year study of more than 220,000 children in Germany found that screening during routine paediatric visits identified most of those who later developed clinical type 1 diabetes. Most came from families with no history of the disease, showing why screening only those already considered at increased risk would miss many early cases.
It is every parent’s nightmare – suddenly, your energetic two-year-old is listless and hard to rouse, perhaps even unresponsive. This can happen when undiagnosed type 1 diabetes develops into diabetic ketoacidosis. Without enough insulin, glucose cannot move efficiently from the blood into the body’s cells. Blood sugar rises, while the body burns fat for fuel and produces acidic substances called ketones. If enough ketones accumulate, the blood becomes dangerously acidic, which can lead to coma and, in severe cases, death. But how can a disease reach that point before parents or doctors realise anything is wrong?
“At least three children out of a thousand have the disease without their parents or doctors knowing,” says Christiane Winkler, who leads research on early diagnosis and staging of type 1 diabetes at Helmholtz Munich. About one third of children with type 1 diabetes are not diagnosed until the disease has developed into diabetic ketoacidosis.
Christiane Winkler and colleagues tested whether type 1 diabetes could be found before symptoms appeared in children from the general population—not only in families already known to be at increased risk. Across more than 220,000 children in Bavaria, a two-step blood screen looked for islet autoantibodies, signs that the immune system had begun attacking structures in and around the insulin-producing beta cells of the pancreas.
The study, published in the Journal of the American Medical Association, identified early-stage type 1 diabetes in about 0.3% of the children. During a median follow-up of 5.7 years, 260 children developed clinical diabetes. The first screen had already identified 212 of them—about 81%—before symptoms appeared.
Just as importantly, progression to clinical diabetes was similar in children with and without a parent or sibling with type 1 diabetes. The findings therefore support screening beyond families already known to be at increased risk, although questions about cost and implementation remain. “We are entering a new era of treatments,” says Peter Achenbach, Deputy Director of the Institute of Diabetes Research at Helmholtz Munich. “It is not just insulin now.”
Family history would miss most early cases
Type 1 diabetes develops when the immune system turns against beta cells in the pancreas—the cells that produce insulin, the hormone that helps glucose move from the bloodstream into the body’s cells. Genes influence the risk, but most children who develop the disease do not have a parent or sibling with it. “About 80% to 90% of newly diagnosed children do not have a first-degree relative with type 1 diabetes,” explains Christiane Winkler.
Restricting screening to children with a first-degree family history would have identified only 17% of the early-stage cases. Once early-stage disease had been detected, children without a family history also progressed to clinical diabetes at much the same rate as those with an affected close relative.
That leaves most families with no reason to watch for the disease. Early symptoms such as thirst, frequent urination, tiredness and weight loss can also be easy to overlook until a child becomes seriously ill.
Earlier studies had shown that islet autoantibodies can appear years before symptoms. One autoantibody alone may disappear or remain without further progression. But when two or more are confirmed in separate blood samples, the child is diagnosed with early-stage type 1 diabetes. This is not merely an increased risk of developing the disease: the immune disease has already begun, even though blood sugar may still be normal and the child may feel entirely well.
Previous studies have also linked early detection, education and monitoring with fewer cases of ketoacidosis and milder illness when type 1 diabetes eventually becomes symptomatic.
To determine whether the approach could work in the wider population, 716 paediatricians across Bavaria screened more than 220,000 apparently healthy children from 2015 to 2025, most aged between 20 months and six years at their first test. The blood was collected by finger prick during routine paediatric care and sent to a central laboratory for analysis.
One routine screen found four in five children before symptoms
A central laboratory first used a sensitive test that could flag any of three major islet autoantibodies. Only about 2% of samples required more specific testing for four antibodies. Children with at least two were then asked to provide a second blood sample to confirm the diagnosis.
The first screening identified 590 children with early-stage type 1 diabetes—an adjusted frequency of 0.3%. Because 98% of samples required no specialised second-line testing, the two-step system concentrated the more demanding analyses on a small group, although the study did not include a full cost-effectiveness analysis.
The programme also offered repeat screening because autoantibodies do not always emerge at the same age. About 11,700 children returned for a second test a median of 3.3 years later, and 29 additional cases were confirmed—an adjusted frequency of 0.27%.
“That was actually surprising to me,” says Anette-Gabriele Ziegler, Director of the Institute of Diabetes Research at Helmholtz Munich. “I had expected a lower rate.”
Because autoantibodies often first appear very early in life, the researchers had expected that one test around age three would capture many cases. The repeat screening showed that some children only developed detectable autoantibodies later. “There are others who appear to completely start anew after the age of three years,” says Ezio Bonifacio, Professor of Preclinical Stem Cell Therapy and Diabetes at TU Dresden.
The finding suggests that repeat testing may be useful, particularly for children screened very young. But only about 5% of eligible children returned, and they differed somewhat from the wider study population. The study does not establish the ideal age or interval for a second test, although earlier studies suggest that screening at around ages two and six may provide an efficient way to identify most cases.
Once the disease begins, family history does not appear to speed it up
The researchers also followed what happened after early-stage type 1 diabetes had been detected. At stage 1, at least two autoantibodies are present, but the remaining beta cells still keep blood sugar normal. At stage 2, that control begins to falter, although the child may still feel well. Stage 3 is clinical type 1 diabetes, with or without obvious symptoms.
Five years after an early-stage diagnosis, 36% of the children had progressed to stage 3. Progression was not significantly different between children with and without a first-degree family history: once the disease was underway, having an affected parent or sibling did not appear to make it advance faster.
Among children who began at stage 1, 69% had reached stage 2 or 3 within five years. More unexpectedly, movement from stage 1 to a later stage occurred at roughly the same annual rate as progression from stage 2 to stage 3. The disease may therefore advance more steadily than previously assumed, rather than accelerating only shortly before symptoms, although the study cannot reveal why.
“That brings up the question—should we already use immune modulation and other therapies before dysglycaemia develops?” notes Anette-Gabriele Ziegler.
Although family history was not associated with how quickly the disease progressed, the antibody pattern offered some clues. Different combinations were associated with five-year risks of clinical diabetes ranging from about 17% to 59%, suggesting that the tests may help estimate not only whether the disease has begun but also how quickly it may advance.
Teplizumab has already shown why detecting this silent phase can matter. The antibody drug dampens part of the immune attack and can postpone clinical diabetes by a median of two to three years in selected people with stage 2 disease. It delays rather than prevents the disease and is approved in Europe for certain people aged eight years or older. No drug has yet been approved for stage 1.
“This is the first drug that we now have in hand that really changes the course of the disease by modifying the immune response,” says Anette-Gabriele Ziegler. Other immune-targeting treatments are now in clinical trials.
Who should be screened—and who should be screened twice?
The findings suggest that screening can be considered in the wider childhood population rather than being confined to families already considered at increased risk.
A separate question is who should be screened again. The team is examining whether weaker antibody signals in the first samples, combined with genetic information, could identify a smaller group for retesting.
“Some of those who had early-stage type 1 diabetes at rescreening had single antibodies or weak signals in the assays that did not meet the diagnostic criteria,” says Anette-Gabriele Ziegler. “Maybe we could somehow stratify and select a more limited group for the second screening.”
That approach still needs to be tested in other populations to determine whether it could reduce the number of repeat tests without missing too many children.
Even without a preventive drug, early detection can change how a child reaches clinical diagnosis. Families receive education, while doctors can monitor blood sugar as the disease progresses. Earlier studies have found that children identified and followed before symptoms develop are less likely to experience ketoacidosis, spend fewer days in hospital and retain more insulin-producing capacity when clinical diabetes is diagnosed.
Screening could matter most where medical care is hardest to reach
The authors think that screening could be especially valuable when children have difficulty reaching medical care. “In places without regular medical care, or where people live remotely, many children present with severe ketoacidosis or even die because they do not get to the doctor when they have type 1 diabetes,” says Ezio Bonifacio.
The study nevertheless leaves important implementation questions open. While the study provided data on costs and possible harms of screening, in a previous analysis, a cost-benefit efficacy analysis is still missing and participation was voluntary. The screened children represented about 17% of the eligible population in Bavaria, while only a small, selected subgroup underwent repeat screening. The results may therefore not transfer directly to older children, regions with lower rates of type 1 diabetes or healthcare systems organised differently from Bavaria.
“For many children, type 1 diabetes begins years before thirst, weight loss or ketoacidosis appear. Screening allows us to find and monitor the disease before the child becomes ill,” concludes Peter Achenbach.
Routine screening found most of the children who later developed clinical diabetes—including those whose families had no reason to suspect it. The question is therefore no longer simply whether early-stage type 1 diabetes can be found, but how screening can be organised so that early detection, monitoring and emerging treatments reach the children who can benefit.
