TEDDY: More Small Clues to the Pathogenesis of Type 1 Diabetes

ORLANDO — More small clues to the development of islet autoimmunity prior to the onset of type 1 diabetes are emerging from The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Researchers pinpointed a robust role for childhood infections, in particular gastrointestinal (GI) infections, here at the American Diabetes Association (ADA) 2018 Scientific Sessions although they were keen to stress this flag was only for islet autoimmunity and not for ultimate progression to type 1 diabetes.

They also showed that dietary supplement use during pregnancy doesn't seem to affect the risk of islet autoimmunity developing in the child.

Chair Marian Rewers, MD, PhD, University of Colorado, Aurora, and co-chair of the TEDDY steering committee, spoke to Medscape Medical News in an interview.

"This session gave us very strong evidence that there are subtypes of type 1 diabetes with some cases starting [with] autoimmunity from insulin autoantibodies while others start from GAD autoantibodies," he said, adding that "these autoantibodies target autoantigens present in insulin-making cells but are associated with very different metabolic pathways."

Around 90% of those with type 1 diabetes develop one autoantibody first. Many end up with both autoantibodies days or even years later.

"The evidence presented by the first speaker in the session, Jeffrey Krischer, PhD, sheds new light on subtypes of type 1 diabetes that is pivotal for future preventive trials," said Rewers while explaining the concept. Krischer is from the University of South Florida, Tampa.

Clues to How Infection Drives One Type of Autoimmunity

The TEDDY study aims to help scientists unravel environmental triggers of type 1 diabetes. Researchers across six centers in the United States and Europe have screened over 424,000 newborns and are following 8676 of those with the highest risk genes. The children are now aged 8 to 13 years.

Information has been gathered about exposure to viruses, dietary factors, immunizations, and stressors in the lives of children and pregnant mothers to try to determine which factors, if any, could be altered to try to prevent type 1 diabetes.

Identifying these small pieces in a jigsaw that will one day hopefully fit together is a huge undertaking, and although the pathogenesis of type 1 diabetes remains a mystery, each new finding from TEDDY represents a baby step along the way.

At the meeting, Maria Lönnrot, MD, PhD, from the University of Tampere, Finland, presented the latest findings on GI infections during the first 4 years of life and development of islet autoimmunity, the precursor to type 1 diabetes.

"It appears that GI infections advance the child towards GAD autoantibody-based autoimmunity rather than [autoimmunity to] insulin autoantibodies in genetically predisposed children," she explained to Medscape Medical News.

"But GI infections only appear to influence the development of GAD autoantibodies during autoimmunity onset."

They do not appear to have any further deleterious effect during the later development of type 1 diabetes, she stressed.

Her team found that in children who developed GAD autoantibodies first, there was a 50% greater chance of doing so if they had had a GI infection in the prior year (OR, 1.5; P = .02 compared with children who did not have a prior GI infection).

Conversely, if a child developed insulin autoantibodies first, they were less likely to do so if they'd had a GI infection in the prior year (OR, 0.6; P = .008 compared with those with no prior GI infection).

These findings were consistent across all TEDDY participant countries (Sweden, Germany, Finland, United States).

Reiterating that although these findings may not seem groundbreaking, "understanding the factors triggering autoimmunity is crucial to understanding type 1 diabetes," Lönnrot emphasized.

The Finnish researcher added that there was also a stronger association between GI infections and GAD autoantibody appearance if a child had had respiratory infections before 6 months of age — and the more respiratory infections, the greater this risk.

Looking ahead to future work, she said they are now analyzing stool and nasal samples in a subgroup of children using virome and microbiome analysis to try to identify the specific viruses involved. They also intend to extend the research to older children.

Impact of Dietary Supplements and Family History

Another TEDDY researcher, Jill M. Norris, PhD, from the University of Colorado, Aurora, discussed maternal use of dietary vitamin D and omega-3 fatty acid supplements during pregnancy.

"The take-home message with this study is that supplements [vitamin D and omega-3 fatty acids] that mothers take during pregnancy do not seem to be related to the risk of type 1 diabetes or autoimmunity" in the child, said Rewers, commenting on the work.

However, he added that "intake of vitamin D in children does matter as seen in an earlier publication" (Diabetes. 2018;67:146-154).

Finally, Riitta Veijola, MD, PhD, at the University of Oulu, Finland, presented results on the influence of family history on type 1 diabetes development in TEDDY children.

Of interest, she noted that a family history of type 2 diabetes is associated with slower progression from islet autoimmunity to clinical diagnosis of type 1 diabetes, even after adjusting for potential confounders, including a first-degree relative with type 1 diabetes, a finding she said was intriguing.

Lönnrot and Rewers have reported no relevant financial relationships.

American Diabetes Association 2018 Scientific Sessions. Lessons Learned from the Environmental Determinants of Diabetes in the Young (TEDDY) Study ― Insights into Early Autoimmune Type 1 Diabetes. June 23, 2018; Orlando, Florida.

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