In children at genetic risk for type 1 diabetes, the development of multiple circulating islet autoantibodies predicts progression to the disease, usually within a few years, according to a pooled analysisreported in the June 19 issue of JAMA.
This means that at-risk children enter a preclinical stage of type 1 diabetes when they seroconvert, said Dr. Anette G. Ziegler of the Institute of Diabetes Research and Technische Universität Munchen, Neuherberg (Germany), and her associates.
The interval between seroconversion and progression to full-blown type 1 diabetes varies widely, from a few weeks to many years, depending on a variety of factors.
"Our findings highlight the need for research into finding interventions to stop the development of multiple islet autoantibodies and to stop or delay progression to type 1 diabetes. Children with islet autoantibodies who do not develop diabetes for more than 15 years and the factors associated with slower progression ... should also be studied, because it may be helpful for understanding natural protective mechanisms," the investigators wrote.
Dr. Ziegler and her colleagues noted that islet autoantibody seroconversion is relatively common during the first years of life in at-risk children, but information on diabetes progression is limited. They pooled the data from three large, long-term studies to examine the issue.
The Colorado Diabetes Autoimmunity Study in the Young (DAISY), the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study, and the German combined BABYDIAB and BABYDIET studies all investigated the natural history of autoimmunity in children at risk for diabetes, following their study subjects from birth to as old as 18 years.
All three studies frequently tested the subjects’ blood samples for autoantibodies against insulin, glutamic acid decarboxylase (GAD65), and insulinoma antigen 2 (IA2) to track the age at which seroconversion took place. There were 13,377 children in the pooled analysis: 1,962 in Colorado, 8,597 in Finland, and 2,818 in Germany.
A total of 1,059 children, 8% of the entire study population, seroconverted to islet-autoantibody positivity, while 12,318 (92%) did not seroconvert. Of those who did seroconvert, slightly more than half developed positivity to multiple autoantibodies. The median age at seroconversion to multiple islet autoantibodies was 2 years.
A total of 482 study subjects developed type 1 diabetes during follow-up. Only 25 of these progressed to diabetes before showing seroconversion.
The risk of developing diabetes by the age of 15 years was 79% in children who carried all three islet autoantibodies, 62% in those who carried two islet autoantibodies, and 13% in those who carried a single islet autoantibody. In contrast, the risk was only 0.4% in children who had no islet autoantibodies.
Children who seroconverted with multiple islet autoantibodies developed diabetes a median of 3.5 years later, at a median age of 6 years.
Progression to diabetes after seroconversion was 44% at 5-year follow-up, 69% at 10-year follow-up, and 84% at 15-year follow-up, Dr. Ziegler and her associates said (JAMA 2013;309:2473-9).
The interval between seroconversion and progression to diabetes varied from a few weeks to 18 years. Faster progression to diabetes after seroconversion was associated with younger age (less than 3 years) at seroconversion, the human leukocyte antigen (HLA) DR3/DR4-DQ8 genotype, and female sex.
This study was supported by the Juvenile Diabetes Research Foundation, the National Institutes of Health, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft. Dr. Ziegler reported no relevant financial conflicts of interest; one of her associates reported ties to Novo Nordisk Diabetes and Medtronic Nordic.