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.

The Environmental Determinants of Diabetes in the Young study is led by USF Health’s Jeffrey Krischer, who has built a worldwide epidemiological hub for T1D research at USF

TAMPA, Fla (July 11, 2021) — The National Institutes of Health (NIH) has awarded the University of South Florida total expected funds of $69.9 million over the next four years to continue the follow-up of study participants in The Environmental Determinants of Diabetes in The Young (TEDDY) consortium. TEDDY is the largest multicenter prospective study of young children with genetic susceptibility to type 1 diabetes (T1D).

The new grant from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases will also support a second case control study, building upon earlier TEDDY analyses examining how genetic factors and environmental exposures such as infectious agents, diet, and psychosocial stress affect T1D development in high-risk children. The extended project will incorporate viral biomarkers to help explain how viruses may trigger or contribute to the disease process.

Jeffrey Krischer, PhD, is principal investigator of the TEDDY study

Distinguished University Health Professor Jeffrey Krischer, PhD, director of the Health Informatics Institute at the USF Health Morsani College of Medicine, is the principal investigator for TEDDY. He has overseen the NIH-supported data coordinating center for this consortium since its inception in 2004. The Health Informatics Institute employs advanced technologies such as proteomics, epigenetics, gene expression analyses, and metabolomics for TEDDY and other NIH initiatives. Under Dr. Krischer’s leadership, USF has built an internationally recognized hub for epidemiological research in T1D.

A 2019 Nature Medicine paper by Kendra Vehik, PhD, and colleagues at the USF Health Informatics Institute, reporting on unexpected connections between viruses and autoimmune-related diabetes, was recently highlighted by Nature as one of 24 milestones in diabetes research over the last 100 years (milestone No. 23).

Type 1 diabetes is an autoimmune disease in which the body’s immune system attacks the pancreatic β-cells making insulin – a process that occurs over months or many years. The presence of autoantibodies (immune proteins) in circulating blood indicates that the body has begun targeting its own tissues or organs.

TEDDY researchers at six clinical centers in the U.S. and Europe have been following 8,500 children from birth up to age 15, with the aim of identifying environmental factors that influence autoimmune destruction of β-cells. Beta cell autoimmunity ultimately leads to the onset of T1D, which requires life-long insulin injections to treat symptoms.

A 2019 published discovery stemming from TEDDY research showed unexpected connections between viruses, like the enteroviruses illustrated here, and autoimmune-related diabetes. The paper by USF Health’s Kendra Vehik and colleagues was recently highlighted as one of 24 Nature Milestones in Diabetes. | Credit: Kateryn Kon

“Our TEDDY study group has made great strides in understanding the different biological pathways by which a child may develop diabetes-related autoimmunity,” Dr. Krischer said. “We are grateful to the many patients and families who collaborate in our studies. Their resolve inspires us to accelerate our efforts to pinpoint the mechanisms of type 1 diabetes, with the goal of preventing, delaying or reversing this life-altering condition.”

The exact causes of TD1 are unknown. But TEDDY has more clearly defined combined risk factors that can help predict β-cell autoimmunity and T1D onset, including the rates of disease progression, and the distinct stages of type 1 diabetes development.

“Dr. Krischer and his team have provided valuable insights into the interplay between genetic and environmental factors underlying the complex disease process of autoimmune diabetes,” said Charles J. Lockwood, MD, senior vice president of USF Health and dean of the Morsani College of Medicine. “Their work, powered by a research platform supporting high-performance computing and big data, is rigorous and critically important for finding new treatments and preventive approaches.”

Children and adults with type 1 diabetes must monitor their dietary intake and exercise and take insulin injections, or use an insulin pump, daily to help control their blood sugar levels.

Key discoveries from TEDDY investigations over the last several years include:

• Maternal stress during pregnancy and child’s T1D genetic risk: Certain psychological stress during pregnancy (interpersonal and job-related life events) are differentially related to first-appearing autoantibodies –insulin autoantibodies (IAA) vs. glutamic acid decarboxylase autoantibodies (GADA). Excess T1D risk often depends upon specific interactions between the mother’s environmental stress and the child’s genes.

• Distinct autoantibody spreading and progression to disease: Detailed information about the order, timing and type of autoantibodies appearing after the first autoantibody can significantly improve prediction of which children are most likely to advance from initial autoimmunity to symptomatic T1D more rapidly.

• A possible infectious cause of diabetes: In young children at increased genetic risk for T1D, prolonged enterovirus infection plays a role in the development of autoimmunity that precedes T1D diagnosis.

• Human gut microbiome in early-onset T1D: For the first time, TEDDY extensively  characterized the developing gut microbiome (collection of bacteria, viruses and other microorganisms inhabiting the gastrointestinal tract) in relation to T1D. The work laid the foundation to identify gut microbes that may predict, protect against. or cause T1D risk or disease progression.

• Gene-environment interactions modify risk of diabetes-related autoimmunity: In TEDDY children up to age 6, T1D-related immunological changes were clearly dependent upon the interactions of genetic factors and environmental exposures that give rise to IAA or GADA as the first-appearing autoantibodies.

• Linking early supplemental probiotics with T1D autoimmunity: Early intake of probiotics, potentially helpful in maintaining the balance of gut microbes, may decrease the risk of autoimmunity in children at highest genetic risk for T1D. Further studies are needed before probiotic supplementation could be recommended.

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The new grant is funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Award Number U01DK128847.

An international research team, including the USF Health Informatics Institute, created and validated a model with potential for early monitoring of infants at risk for T1D diabetes

Children (and adults) diagnosed with type 1 diabetes must have their blood glucose levels monitored, and take insulin shots or use an insulin pump every day to stay well.

TAMPA, Fla. (June 4, 2021) — Type 1 diabetes mellitis (T1D) is an autoimmune disease in which a misdirected immune system gradually destroys healthy pancreatic islet β cells, resulting in a deficiency of insulin. The exact cause of T1D remains unknown. However, β cell-reactive autoantibodies can be detected in circulating blood months to years before diagnosis, raising the possibility of intervening to stop or delay T1D before children develop the disease.

Monitoring the number, type, and concentration of autoantibodies appearing in the blood can help predict the long-term risk of progression to symptomatic T1D.

Now new findings suggest that measuring how patterns of gene expression in white blood cells change in children starting in infancy – before autoantibodies indicate an autoimmune reaction against the β cells – can predict earlier and more robustly which genetically-susceptible individuals will progress to T1D. The comprehensive international study included co-investigators from the University of South Florida Health Informatics Institute.

The research was published on March 31 in Science Translational Medicine.

Health Informatics Institute Director Jeffrey Krischer, PhD, a professor in the USF Health Morsani College of Medicine’s Department of Internal Medicine, and Hemang M. Parikh, PhD, an assistant professor of bioinformatics in the USF Health Morsani College of Medicine’s Department of Pediatrics, were co-investigators of the study led by the UK researchers at the University of Cambridge.

“Our identification of specific changes in the blood related to natural killer cells provides evidence for the potential involvement of these immune cells in the onset or progression of type 1 diabetes in asymptomatic children,” Dr. Parikh said. “This creates a possible new target for early therapeutic intervention using immune modulation.”

Distinguished University Health Professor Jeffrey Krischer, PhD, director of the USF Health Informatics Institute, leads The Environmental Determinants of Diabetes in the Young (TEDDY) consortium funded by NIH.

Hemang M. Parikh, PhD, assistant professor of bioinformatics at the USF Health Informatics Institute, was a co-investigator for the large-scale, longitudinal study, along with Dr. Krischer.

This study was based on blood samples longitudinally collected from 400 children in The Environmental Determinants of Diabetes in the Young (TEDDY) consortium as they grew older, from birth to age 6. (TEDDY follows children at risk of developing T1D, collecting blood and other samples long before disease symptoms emerge.)

Using genomic approaches and bioinformatics analytical methods, the blood samples were processed to measure the expression of thousands of genes simultaneously. This allowed researchers to identify which genes were switched on and off in each child at varying points in time.

Among the study’s key findings:

• Discovered dynamic, early changes in white blood cell gene expression: Whether or not they progressed to autoimmunity or T1D as they matured, all children in the study showed marked changes in patterns of gene expression in their blood within the first few years of life. This observation highlights the dynamic context in which healthy infants develop early autoimmune disease. When the researchers adjusted for the large changes in gene expression patterns with age, very specific patterns correlating with the rate of progression toward T1D diagnosis became apparent. They identified changes in blood gene expression not seen in healthy children, and these changes began before any other evidence of autoimmunity. Furthermore, the faster the changes occurred, the quicker the children progressed toward T1D onset.

• Linked NK cell signature with T1D progression: By comparing a specific pattern of gene expression associated with T1D progression to groups of genes expressed by many different cell types, the researchers found that this pattern came from a distinct immune cell population known as natural killer (NK) cells. Although NK cells have been observed in the pancreas of children with recent-onset T1D, the role of these immune cells does not figure prominently in current theories explaining how the immunopathology of T1D develops. A more detailed study is needed to determine whether NK cells actively contribute to the T1D-related autoimmune process destroying β-cells in the pancreas, reflecting a pathophysiological response.

• Created a robust predictive model, independently confirmed: The researchers used their new knowledge about longitudinal changes in gene expression patterns to build a model to predict which infants would get T1D and when disease onset was likely to happen. The predictive model incorporates the latest evidence about how the seroconversion of autoantibodies influences progression to T1D. Its accuracy was validated using a second, independent group of prediabetic children from the Type 1 Diabetes Prediction and Prevention Study.

“This type of large-scale research is only possible through the collaboration of many people, including healthy children at risk for T1D, patients with T1D, their families, and countless others,” Dr. Parikh added. “USF is fortunate to play a part in such huge international efforts to tackle this complex autoimmune disease.”

The work was supported by multiple grants from the National Institutes of Health. USF Health’s Dr. Krischer leads the coordinating center for the NIH-funded TEDDY consortium.

USF Health-led TEDDY analysis focuses on development of multiple distinct autoantibodies targeting insulin-producing cells, from initial autoimmunity to symptomatic disease

TAMPA, Fla. — Children with multiple islet autoantibodies – biological markers of autoimmunity – are more likely to progress to symptomatic type 1 diabetes (T1D) than those who remain positive for a single autoantibody.

Now, new findings from The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S. and Europe show that detailed information about the order, timing and type of autoantibodies appearing after the first autoantibody can significantly improve prediction of which children are most likely to progress to type 1 diabetes more rapidly.

The TEDDY analysis was published in the September 2020 issue of Diabetes Care.

“A better understanding of distinct autoantibody spreading is important, because it will allow us to identify at-risk children earlier in the disease process,” said the study’s lead author Kendra Vehik, PhD, a professor of epidemiology at the University of South Florida Health (USF Health) Morsani College of Medicine’s Health Informatics Institute. “That means while children are still asymptomatic, we can start to look at interventions and strategies that may reduce, delay or stop the progression of type 1 diabetes.”

While antibodies are molecules produced by the body’s immune system to detect and destroy specific viruses, bacteria and other harmful substances, autoantibodies are antibodies that target a person’s own healthy tissue. In the case of T1D, a misdirected autoimmune response attacks the pancreas and gradually destroys the organ’s insulin-producing beta cells.

Without the hormone insulin the body cannot regulate its blood sugar levels, which can cause serious, long-term medical complications such as cardiovascular disease, nerve and kidney damage, and vision loss. Children (and adults) with T1D must monitor their dietary intake and exercise and take insulin injections, or use an insulin pump, daily to help control their blood sugar levels.

“Physically and psychologically, it’s a very burdensome disease that needs to be managed every day over a lifetime,” Dr. Vehik said.

Kendra Vehik, PhD, an epidemiologist at the USF Health Informatics Institute, led the TEDDY analysis.

For this TEDDY analysis, eligible children with increased genetic risk for T1D, were followed every three months, from the age of 3 months up to 15 years, for the development of a first-appearing autoantibody directed against pancreatic insulin-producing cells: glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA), or insulinoma-associated-protein-2 autoantibody (IA2-2A). The researchers also looked for the subsequent appearance of a second autoantibody and further progression to T1D. Zinc transporter 8 autoantibody(ZnT8A) was only measured in children who developed an IAA, GADA, or IA-2A. These four different autoantibodies are so far the most reliable biological indicators of early T1D, before symptoms become apparent.

Of the 608 study participants – all testing positive for either a first-appearing IAA or GADA — more than half (336) developed a second autoantibody. Furthermore, 53% of these 336 children with a second antibody progressed to T1D within about 3.5 years.  Only about 10% of the 272 children testing positive for a single autoantibody at the end of the follow-up for this study (Dec. 31, 2019) had transitioned to T1D.

Among the key study findings:

• All study participants had high-risk genotypes for T1D. However, those increased-risk children who also had a parent or sibling with T1D were more likely to develop a second-appearing autoantibody than those without a family history.
• The younger the child at the time they tested positive for a first autoantibody, the greater their risk for developing a second autoantibody. Conversely, the risk for T1D decreased if the first autoantibody appeared when the child was older.
• Children testing positive for a second autoantibody, regardless of the type, had at least a five-fold increased risk of progressing to T1D, compared to children who stayed single autoantibody positive. IA-2A, as a second autoantibody, conferred the highest risk, compared with GADA, IAA, or ZnT8A.
• Risk of progression to T1D was influenced by how quickly the second autoantibody appeared. Emergence of a second autoantibody within a year of the first doubled the risk of progression to T1D. Children’s likelihood of developing T1D declined as the months between the first and second-appearing autoantibodies increased.

Better stratifying the risk of progression from the start of autoimmunity to symptomatic disease could help diagnose T1D earlier and offers the opportunity to prevent diabetic ketoacidosis (DKA) and its serious complications by educating parents to watch for early signs, Dr. Vehik said.

“For instance, if a clinician knows that a young child testing positive for IA-2A as their second-appearing autoantibody will be at a higher risk to more rapidly progress to type 1 diabetes, they can reduce the risk of symptomatic onset of disease. Clinicians can also educate the parents about the early signs of disease, such as, weight loss, extreme thirst, more frequent urination, or other DKA symptoms,” she said. “If that happens, the parents will know they should get their child to a doctor or hospital as soon as possible.”

Specific antibody risk profiling can also help identify those at-risk children most likely to benefit from recruitment for T1D prevention trials, Dr. Vehik added.

Dr. Vehik next plans to build upon a previous TEDDY study linking viral behavior with T1D diabetes to test whether prolonged viral infections may environmentally trigger the transition from first- to second-appearing islet autoantibodies in children genetically susceptible to diabetes.

The recently published autoantibody analysis by Dr. Vehik and TEDDY colleagues was funded by National Institute of Diabetes and Digestive and Kidney Diseases grants. USF Health’s Dr. Jeffrey Krischer is the study chair and director of the data coordinating center for the NIH-sponsored TEDDY international multicenter study.

ABOUT TEDDY
The Environmental Determinants of Diabetes in the Young (TEDDY) study is a longitudinal, multinational study examining genetic-environmental causes of type 1 diabetes (T1D). The study follows children at high genetic risk for T1D from birth to 15 years of age at 6 clinical centers in the U.S. and Europe. TEDDY is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. More information can be found on the TEDDY study website.