Development of autoimmunity at an early age associated with more aggressive form of the disease in genetically susceptible children, a USF Health-led study suggests

TAMPA, Fla. (Oct. 21, 2021) — New findings from the international The Environmental Determinants of Diabetes in the Young (TEDDY) study add to the growing body of evidence indicating that type 1 diabetes is not a single disease. The presentation and, perhaps, cause of autoimmune diabetes differs among genetically high-risk children, the research suggests.

In a cohort study published July 22 in Diabetologia, lead author Jeffrey Krischer, PhD, director of the Health Informatics Institute at the USF Health Morsani College of Medicine, and TEDDY colleagues compared the characteristics of type 1 diabetes diagnosed in children before vs. after age 6.  The paper’s senior author was Beena Akolkar, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

“Our results underscore the importance of taking into account the age at development of multiple autoantibodies when evaluating risk factors for progression to a diabetes diagnosis,” said lead author Dr. Krischer, a Distinguished University Health Professor and co-chair for the National Institutes of Health-funded TEDDY consortium. “When the changing picture of autoantibody presentation is considered, it appears type 1 diabetes at an early age is a more aggressive form of the disease.”

In type 1 diabetes, a misdirected immune response attacks and destroys insulin-producing beta cells in the healthy person’s pancreas – a process occurring over months or many years. Four autoantibodies directed against the pancreatic β-cells — glutamic acid decarboxylase autoantibody (GADA), insulin autoantibody (IA), insulinoma-associated-protein-2 autoantibody (IA2-2A), and zinc transporter 8 autoantibody (ZnT8A) – are thus far the most reliable biological indicators of early type 1 diabetes, before symptoms appear. Not all children who test positive for one or more autoantibodies progress to a diagnosis of type 1 diabetes, which requires lifelong administration of insulin to control blood sugar levels and reduce health complications.

Over the last decade, TEDDY researchers have learned more about how the order, timing and type of autoantibodies can help predict which genetically susceptible children are most likely to get type 1 diabetes as they age.

For this multisite study in the U.S. and Europe, the researchers analyzed data from 8,502 children, all at genetically high risk for developing autoimmunity and type 1 diabetes. The children were followed from birth to a median of 9 years. Over this period, 328 study participants (3.9%) progressed from a presymptomatic stage in which autoantibodies first appeared in their circulating blood (signaling initial autoimmunity) to the onset of symptomatic type 1 diabetes.

Study lead author Jeffrey Krischer, PhD, directs the USF Health Informatics Institute and is co-chair for the National Institutes of Health-funded TEDDY consortium.

Half of the 328 participants (2.0%) were diagnosed before age 6, while the other half (1.9%) developed diabetes between ages 6 and 12. The aim was to determine whether the younger group diagnosed with type 1 diabetes differed from the older group, which would suggest that a different form of type 1 diabetes emerges in children as they grow older.

Among the findings:

• As expected, TEDDY participants who progressed to diabetes between ages 6 and 12 were more likely to have first-appearing autoantibodies to the pancreatic enzyme glutamic acid decarboxylase (GAD autoantibodies), while first-appearing insulin autoantibodies (IA antibodies) were much more common in younger children developing the disease.
• The rate of progression to type 1 diabetes was slower if multiple (two or more) autoantibodies appeared after age 6 than if they were present before age 6.
• The significant association of country of origin with diabetes risk found in the younger group declined in the older group. Conversely, the link between certain genotypes and a higher likelihood of developing diabetes significantly increased in the older children.
• Among children 6 and older with multiple autoantibodies, family history did not appear to play a role in whether the child progressed to type 1 diabetes.

“Much of the observed differences in the relationship between genes and environmental exposures can be explained by the age at appearance of autoantibodies,” Dr. Krischer said. “That is important, because it means factors linked with diabetes risk need to be conditioned on age to be properly understood. There may be different environmental exposures occurring at different ages that trigger autoimmunity, or the same environmental trigger may act differently at different ages.”

The research was funded by grants from the NIDDK and several other NIH institutes, JDRF, and the Centers for Disease Control and Prevention (CDC); and supported in part by NIH/NCATS Clinical and Translational Science Awards.

A TEDDY progress report, led by USF’s Jeffrey Krischer, shows for the first time that combining genetic and environmental factors substantially increases prediction of future diabetes

TAMPA, Fla. (July 15, 2019) — With the help of children and their families worldwide, scientists continue to identify how genetic and environmental risk factors converge to trigger autoimmunity and progression to type 1 diabetes in some genetically-susceptible youngsters, but not others.

Since The Environmental Determinants of Diabetes in the Young (TEDDY) study began in 2004, this ongoing National Institutes of Health-sponsored consortium has published research examining type 1 diabetes risk factors, including genotypes, sex, family history, genetic variations, diet (including probiotics and types of infant formula), growth in early life, the microbiome, proteomics, metabolomics, age at autoantibody seroconversion, and first-appearing autoantibody. The 8,600 TEDDY-enrolled children across six centers in the U.S. and Europe are monitored for up to 15 years; those who began being followed as infants are currently ages nine to 14.

Now, in a progress report published June 2019 in Diabetes Care, lead author Jeffrey Krischer, PhD, at the USF Health Morsani College of Medicine, University of South Florida, and colleagues evaluate the ability of TEDDY-identified risk factors to predict islet autoimmunity and progression to type 1 diabetes. The researchers found that individually these statistically significant TEDDY risk factors contribute little in discriminating between children who will get the disease and those who will not. However, when combined in a well-designed, time-dependent statistical model, the factors substantially increased the power of predicting both islet autoimmunity and type 1 diabetes.

Dr. Krischer, an epidemiologist and professor in Morsani College of Medicine’s Department of Internal Medicine, leads coordination and analysis of the massive TEDDY data generated globally — from collection of samples (including blood, saliva, urine, toenails,  stool and even discarded primary teeth) and careful review of parent diaries on everything from doctor visits to over-the counter medications their children take.

“Earlier studies have identified independent risk factors for type 1 diabetes. But this paper, for the first time, describes a way to combine risk factors that shows their combined power to discriminate between those who will or will not develop autoimmunity and diabetes,” Dr. Krischer said. “It demonstrates how much each risk factor contributed to prediction. This has moved the field from having only a genetic-based risk assessment to one that includes gene-environment interactions.”

Jeffrey Krischer, PhD

Type 1 diabetes is an autoimmune disease in which the immune system destroys insulin-producing pancreatic cells – a process that occurs over months or many years.  The presence of autoantibodies (immune proteins) in circulating blood indicates that the body has started to target its own tissues or organs.

TEDDY previously published evidence of two subtypes of type 1 diabetes, each associated with distinct risk factors, which may prove pivotal for future preventive trials. Insulin autoantibodies (IAA) directly attack insulin and appear at an earlier age than glutamic acid decarboxylase antibodies (GADA), the autoantibodies that destroy the enzyme glutamic acid decarboxylase regulating insulin-making cells in pancreatic islets. Most with type 1 diabetes develop one of these autoantibodies first, and many eventually end up with both.

The recently published TEDDY study includes 7,777 children of the original TEDDY cohort, from birth to a median age of approximately 9, for development of islet autoantibodies and progression to type 1 diabetes. A graph plotting time-dependent true positive rates (sensitivity) against false positive rates (specificity) was used to estimate the individual and collective predictive ability of risk factors. Among the findings:

• Human leukocyte antigen (HLA) genotype contributed the most to prediction of IAA appearing first, after family history of type 1 diabetes.
• A child’s weight at age 1 was the best predictor of GADA as the first appearing autoantibodies.
• Age at onset of multiple autoantibodies was the strongest predictor of a child’s progression to type 1 diabetes.

TEDDY’s ultimate aim is to uncover the causes of type 1 diabetes and determine what risk factors might be altered to prevent or delay the condition, which requires life-long dependence on insulin therapy.

“TEDDY is uniquely poised to make this contribution as it adds environmental exposures, pathogens, and extensive genomics to the risk factors identified so far,” Dr. Krischer and his fellow authors conclude. “Going forward, this evaluation framework will serve as a summary tool to evaluate new risk factors as they are identified.”