TEDDY data: Early type 1 diabetes signals, environmental triggers and diet associations

Analyses from the ongoing TEDDY study suggest that islet autoimmunity develops by age 2 years for many children who go on to develop type 1 diabetes, and certain illnesses, gut microbiota and even diet may affect disease progression.

Data from The Environmental Determinants of Diabetes in the Young (TEDDY), an international trial designed to identify environmental factors and gene-environment interactions causing islet autoimmunity and type 1 diabetes, show that there are at least two distinct endotypes defined by insulin autoantibodies, and several environmental factors — such as respiratory infections, enteroviruses, and even a diet high in vitamins D or C — could be associated with disease progression, Marian Rewers, MD, PhD, a professor of pediatrics and medicine and executive director of the Barbara Davis Center for Diabetes at the University of Colorado School of Medicine and a co-chair of the TEDDY study, said during a presentation at the virtual American Diabetes Association Scientific Sessions.

TEDDY has two primary endpoints, Rewers said: confirmed, persistent islet autoimmunity, defined as positivity for at least one islet autoantibody (glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A] or insulin antibodies [IAA]), and development of clinical type 1 diabetes. Additional endpoints in TEDDY include celiac disease autoimmunity, thyroid autoimmunity and the clinical diseases that follow those autoimmune conditions, Rewers said.

“By now, we observed more than 840 children develop confirmed persistent islet autoimmunity,” Rewers said. “Most of them have multiple islet autoantibodies. In addition, we have seen almost 400 of these children already progress to type 1 diabetes.”

Early type 1 signals

TEDDY study data has shown that islet autoimmunity develops “quite early” for many children who go on to develop the disease — for many, within the first 2 years of life, Rewers said. In assessing which antibodies are detected first, the researchers observed an interesting phenomenon. Children who are positive for IAA autoantibodies first, or “IAA-first” children, tend to have a different disease course compared with “GADA-first” children who develop GADA autoantibodies first, he said. Optimal primary prevention for these children may differ based on their distinct phenotype.

“Obviously, we wonder if these phenotypes point us to two endotypes of type 1 diabetes, and also how those phenotypes are related to risk of progression to type 1 diabetes,” Rewers said.

The findings suggest that autoantibody screening for at-risk children should start in the first 2 years of life, Rewers said, adding that a risk score that incorporates autoantibodies and genetic markers can enable individualized type 1 diabetes prediction over horizons up to 8 years.

“There appear to be two subtypes of type 1 diabetes that differ by genetic factors and immune phenotypes,” Rewers said. “Metabolomic biomarkers may offer clues to the subtypes and whether a child develops type 1 diabetes. Interestingly, HbA1c has very different predictive characteristics for progression to clinical diabetes in children with islet autoantibodies, compared to adults with risk factors for type 1 diabetes.”

Environmental triggers

In a large epidemiological cohort analysis of TEDDY data that included 8,676 children, researchers found that reported respiratory infections within any 9-month period predicted islet autoimmunity during the following 3 months, Rewers said.

In a nested case-control study assessing thousands of stool samples collected monthly from TEDDY participants when aged 3 to 48 months, researchers found that enteroviruses, particularly enterovirus B, similarly predicted the appearance of islet autoimmunity. The association was stronger among children with the IAA-first phenotype compared with children with the GADA-first phenotype, Rewers said.

In gut bacterial metagenomics, the researchers also observed “subtle” associations between microbial taxonomy and the development of islet autoimmunity in type 1 diabetes.

“We saw some difference between cases and controls in the abundance of bacteria that can produce short-chain fatty acids, such as Lactobacillus, which fits quite well with another finding in TEDDY related to early childhood use of probiotics,” Rewers said, adding studies suggest that probiotic use within the 4 weeks of life may protect children with the HLA-DR3/DR4 genotype from developing islet autoimmunity.

Rewers said randomized controlled trials are needed to determine the clinical implications of TEDDY observations related to enteroviruses, with an assessment of an early enteroviral vaccine starting in the second month of life, and a trial assessing probiotic use “as early as possible” among high-risk children.

Diet findings

TEDDY has also found potentially beneficial effects of vitamin D, vitamin C or a diet rich in polyunsaturated fatty acids, although these observations must be confirmed in randomized clinical trials, Rewers said.

High levels of vitamin D were found to be protective among TEDDY children with the vitamin D receptor (VDR) genotype, whereas higher vitamin C levels were associated with a lower risk for islet autoimmunity, although there was no gene/vitamin D interaction observed, Rewers said.

“It is a little bit too early to recommend that families with children at risk for type 1 diabetes take more vitamin D, C or fatty acids,” Rewers said. “We need randomized clinical trials to show that there is efficacy and a magnitude of effect before it becomes a widespread recommendation,” Rewers said.

Celiac disease, another autoimmune condition, shares many genetic factors with type 1 diabetes, Rewers said. Recently reported TEDDY research showed an association between gluten consumption in the early years of childhood and an increased risk for celiac disease among genetically predisposed children.

“While type 1 diabetes and celiac disease share a lot of genetic characteristics, there are intriguing differences in the ways these diseases develop and progress,” Rewers said. “TEDDY is contributing exciting clues for design of future trials to prevent both type 1 diabetes and celiac disease.”