Insights from TEDDY study provide clues to islet autoimmunity in children

ORLANDO, Fla. — Data from the ongoing TEDDY study show that there are two diabetes-related endotypes defined by insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first appearing autoantibody in children, and ongoing research suggests several maternal, childhood and familial factors play a role in islet autoimmunity risk.

TEDDY, which was designed to identify environmental factors and gene-environment interactions causing islet autoimmunity and type 1 diabetes, is beginning to reveal some of the first clues to the immunogenesis and natural history of type 1 diabetes in a cohort of young children from four countries, Jeffrey Krischer, PhD, distinguished university health professor and director of the Health Informatics Institute at Morsani College of Medicine, University of South Florida, said during an opening presentation on findings from the TEDDY study at the American Diabetes Association Scientific Sessions.

Krischer said there are two different forms of autoimmunity observed in the TEDDY cohort, defined by which antibodies appear first. Genetic background, environmental risk factors and type 1 diabetes risk differ when comparing these endotypes, he said.

“Unfortunately, at this stage, the ability to predict which individuals will actually develop autoimmunity or diabetes is still very limited in TEDDY,” Krischer said. “We still have to work harder. But, TEDDY has a wealth of new data — metabolomics, genomics, proteomics and microbiome data are coming online that may improve prediction.”

Several speakers presented novel findings on the associations between maternal and offspring characteristics and the risk for future islet autoimmunity development in the young TEDDY participants.

Maternal dietary supplement use

Maternal use of vitamin D and omega-3 fatty acid supplementation during pregnancy is not associated with the role of persistent islet autoimmunity overall, nor is it associated with IAA or GADA as the first appearing autoantibodies in TEDDY offspring, Jill M. Norris, MPH, PhD, chair and professor in the department of epidemiology at Colorado School of Public Health, said during a presentation.

In an analysis of maternal supplement use — both dose and duration — collected through self-administered questionnaires, Norris and colleagues calculated cumulative maternal intake of vitamin D and omega-3 fatty acids over the entire pregnancy and in each trimester. Researchers then examined associations between maternal vitamin supplementation in pregnancy and the development of persistent islet autoimmunity in TEDDY offspring, and the secondary outcomes of IAA or GADA as the first appearing autoantibody in children (747 children with persistent, confirmed autoantibodies).

Within the cohort, 63% of mothers reported taking vitamin D supplements and 16% of mothers reported taking omega-3 fatty acid supplements.

A similar null association was observed when researchers examined supplementation by trimester.

“The findings from this large TEDDY cohort of over 8,000 children ... extend our knowledge with regard to this issue by showing that maternal vitamin D and omega-3 fatty acid supplementation is not associated with the risk of islet autoimmunity overall, nor a particular autoantibody appearing first in these high-risk kids,” Norris said.

Gestational infections

In TEDDY children, maternal infections during pregnancy were not associated with first appearing islet autoantibodies overall, Kristian F. Lynch, PhD, assistant professor in the Health Informatics Institute at Morsani College of Medicine, University of South Florida, said here.

However, women who developed respiratory infections during pregnancy showed a protective influence on IAA or GADA as the first appearing islet autoantibody in TEDDY children that depended on their specific genotypes, Lynch said, suggesting the role of gestational respiratory infections may depend on specific alleles.

“These findings suggest that gestational events, such as respiratory infections, interact with CTLA-4, a well-known T-cell regulatory protein, to influence how DR4-DQ8 or DR3-DQ2 react to a hypothetical trigger occurring during the first years of life,” Lynch said.

Lynch said the evidence creates stronger support for the role of the intrauterine environment and prenatal exposures on the risk for islet autoimmunity and type 1 diabetes in offspring.

Gastrointestinal infections

Gastrointestinal viral infections in TEDDY children aged 4 years or younger appear to modulate the risk for islet autoimmunity in genetically predisposed children, Maria Lönnrot, MD, PhD, from Tampere University Hospital in Tampere, Finland, said during a presentation.

Lönnrot said the relationship between GI infections and the later risk for islet autoimmunity depends on the first appearing autoantibody: GI infection in any 6-month period is a predictor of GADA as the first appearing autoantibody. However, there are fewer reports of GI infections prior to IAA as the first appearing autoantibody, she said. There were no associations observed by season, islet autoimmunity-associated genes or by respiratory infections prior to seroconversion with respect to the association between GI infections and GADA autoantibodies, Lönnrot said, but there was an interaction with early-life respiratory infections.

“Our data do not allow identification of the different gastrointestinal viruses, therefore, we need stool virome analyses to identify them,” Lönnrot said. “These analyses are currently underway.”

Family diabetes history

A family history of type 1 diabetes is associated with the development of islet autoimmunity in TEDDY children, whereas a family history of type 2 diabetes is associated with progression from islet autoimmunity to clinical diagnosis in the cohort, Riitta Veijola, MD, PhD, professor of pediatrics at University of Oulu, Finland, said during a presentation.

In an analysis of 7,479 TEDDY children as of Jan. 31, 2016, Veijola and colleagues observed that children with a father or sibling with type 1 diabetes were more likely to develop islet autoimmunity vs. those without a father or sibling with diabetes. However, having a mother with type 1 diabetes was not a significant risk factor for islet autoimmunity.

Additionally, TEDDY children with a second-degree relative with type 2 diabetes showed significantly delayed progression from islet autoimmunity to clinical type 1 diabetes vs. children without such relatives — a finding that was consistently observed in TEDDY children across Finland, Germany, Sweden and the United States, Veijola said.

“We believe this is a true phenomenon that needs to be studied further,” Veijola said here.

The finding, Veijola said, creates two new hypotheses: that type 2 diabetes-susceptibility genes may affect the progression phase of type 1 diabetes, and that families with second-degree relatives with type 2 diabetes may modify their lifestyle to prevent type 1 diabetes. – by Regina Schaffer

Reference:

Krischer J, et al. Lessons learned from the Environmental Determinants of Diabetes in the Young (TEDDY) study — Insights into early autoimmune type 1 diabetes. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.

Disclosures: Krischer, Lönnrot, Lynch, Norris and Veijola report no relevant financial disclosures.