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.

Illustration of enteroviruses | Credit: Kateryn Kon

A 2019 Nature Medicine paper by Kendra Vehik, PhD, MPH, and colleagues at the USF Health Informatics Institute has been recognized as one of 24 key advances in diabetes research since insulin was discovered 100 years ago.

Highlighted this month as part of a Nature Milestones in Diabetes special issue, the 2019 research by Vehik et. al. provided intriguing evidence showing that, in young children with increased genetic risk for type 1 diabetes (T1D), prolonged enterovirus infection plays a role in the autoimmune destruction of insulin-producing beta cells. Beta cell autoimmunity ultimately leads to the onset of T1D, a serious chronic disease that requires life-long insulin injections to treat.

The USF Health-led work represented a major advance in understanding the links between the virome (all the viruses in the body) and T1D. Dr. Vehik (lead author) and USF Health coauthors Kristian Lynch, PhD, and Health Informatics Institute Director Jeffrey Krischer, PhD, were members of the research team that used sophisticated genomic sequencing technologies to delve deeper into a possible infectious cause for T1D.

Kendra Vehik, PhD, is a professor of epidemiology at the USF Health Informatics Institute.

The pivotal study was one of many that continue to be generated from The Environmental Determinants of Diabetes in the Young (TEDDY) consortium, the largest multicenter prospective study of young children with a genetic susceptibility to T1D. Dr. Krischer is the principal investigator overseeing the National Institutes of Health-supported TEDDY project, which aims to identify environmental factors, including diet, infections and psychological stress, that may trigger or protect against autoimmunity and T1D onset.

“Our next step includes pinpointing biological responses — changes in inflammatory markers, metabolites and proteins — that may explain how viral infections can influence or contribute to beta cell autoimmunity and the progression of T1D,” Dr. Vehik said. “We are honored to be counted among the researchers whose many years of cumulative work has greatly improved our understanding of the complexity of diabetes.”

To read more about the scientific achievement (Milestone in Diabetes No. 23), go to: https://www.nature.com/articles/d42859-021-00026-x

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.

A TEDDY study, led by USF Health’s Kendra Vehik, has discovered unexpected connections between viruses and T1D

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Tampa, FL (Dec. 2, 2019) — New results from The Environmental Determinants of Diabetes in the Young (TEDDY) study show an association between prolonged enterovirus infection and the development of autoimmunity to the insulin-producing pancreatic beta-cells that precedes type 1 diabetes (T1D). Notably, researchers also found that early adenovirus C infection seemed to confer protection from autoimmunity. The findings were published Dec. 2 in Nature Medicine.

Viruses have long been suspected to be involved in the development of T1D, an autoimmune condition, although past evidence has not been consistent enough to prove a connection. Investigators from the University of South Florida Health (USF Health) Morsani College of Medicine, Baylor College of Medicine, and other institutions studied samples available through the TEDDY study, the largest prospective observational cohort study of newborns with increased genetic risk for T1D, to address this knowledge gap. TEDDY studies young children in the U.S. (Colorado, Georgia/Florida, and Washington State) and in Europe (Finland, Germany, and Sweden).

“Years of research have shown that T1D is complex and heterogeneous, meaning that more than one pathway can lead to its onset,” said lead author Kendra Vehik, PhD, MPH, an epidemiologist and professor with the USF Health Informatics Institute. “T1D is usually diagnosed in children, teens and young adults, but the autoimmunity that precedes it often begins very early in life.”

“T1D occurs when the immune system destroys its own insulin-producing beta cells in the pancreas. Insulin is a hormone that regulates blood sugar in the body. Without it, the body cannot keep normal blood sugar levels causing serious medical complications,” said coauthor Richard Lloyd, PhD, professor of molecular virology and microbiology at Baylor College of Medicine.

Kendra Vehik, PhD, MPH, of the USF Health Informatics Institute, led the TEDDY study linking viruses and type 1 diabetes in high-risk children.

In the current study, Vehik and her colleagues studied the virome, that is, all the viruses in the body. They analyzed thousands of stool samples collected from hundreds of children followed from birth in the TEDDY study, looking to identify a connection between the viruses and the development of autoimmunity against insulin-producing beta cells. Coxsackievirus has been implicated in T1D before, but the current results provide a completely new way to make the connection, by identifying specific viruses shed in the stool. The investigators were surprised to find that a prolonged infection of more than 30 days, rather than a short infection, was associated with autoimmunity.

“This is important because enteroviruses are a very common type of virus, sometimes causing fever, sore throat, rash or nausea. A lot of children get them, but not everybody that gets the virus will get T1D,” Vehik said. “Only a small subset of children who get enterovirus will go on to develop beta cell autoimmunity. Those whose infection lasts a month or longer will be at higher risk.”

A prolonged enterovirus infection might be an indicator that autoimmunity could develop.

Beta cells of the pancreas express a cell surface protein that helps them talk to neighboring cells. This protein has been adopted by the virus as a receptor molecule to allow the virus to attach to the cell surface. The investigators discovered that children who carry a particular genetic variant in this virus receptor have a higher risk of developing beta cell autoimmunity.

“This is the first time it has been shown that a variant in this virus receptor is tied to an increased risk for beta cell autoimmunity,” Vehik said. Ultimately, this process leads to the onset of T1D, a life-threatening disease that requires life-long insulin injections to treat.

Electron microscopy image of the enterovirus Coxsackievirus B3 | Courtesy of the Varpu Marjomäki laboratory at the University of Jyväskylä and Minna Hankaniemi, Tampere University, Finland.

Another discovery was that the presence in early life of adenovirus C, a virus that can cause respiratory infections, was associated with a lower risk of developing autoimmunity. It remains to be investigated whether having adenovirus C in early life would protect from developing beta cell autoimmunity. Adenoviruses use the same beta cell surface receptor as Coxsackievirus B, which may offer one clue to explain this connection, although further research is needed to fully understand the details.

Other factors that affect autoimmunity and the development of T1D are still unknown, but the TEDDY study is working to identify them. The researchers seek to gain insights into the exposures that trigger T1D by studying samples that were taken before autoimmunity developed, starting when the TEDDY participants were 3 months old. Such findings could identify approaches to potentially prevent or delay the disease.

“Taking it all together, our study provides a new understanding of the roles different viruses can play in the development of beta cell autoimmunity linked to T1D, and suggests new avenues for intervention that could potentially prevent T1D in some children,” Lloyd said.

This study was funded by grants from the National Institutes of Health, Centers for Disease Control and Prevention and JDRF.  Information on all the authors, their affiliations and study financial support, is available at this link.

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.

Two USF Health Morsani College of Medicine research-focused institutes rank among the Top 10 Institutes and Centers within Florida’s State University System (SUS).  The ranking was derived from the SUS 2018 survey of its 536 university institutes and centers engaged in scientific research, education, community service and other scholarly activity supported by public and private funds.

The USF Health Informatics Institute (HII) was the No 1 institute with $69.6 million in total expenditures. HII is led by Distinguished University Professor Jeffrey Krischer, PhD, who ranks in the top 1 percent of all National Institutes of Health-funded principal investigators worldwide (Blue Ridge Institute for Medical Research, 2018). He has made USF an international hub for NIH epidemiological research initiatives in both type 1 diabetes and rare diseases.

The USF Health Heart Institute, directed by Samuel Wickline, MD, professor of cardiovascular sciences, attained the No. 7 spot, with $13.4 million in total expenditures. The Heart Institute, created with the support of state and county funding, brings together NIH-funded laboratory researchers and physician-scientists to pioneer new discoveries for heart attacks, stroke and other cardiovascular diseases.

Jeffrey Krischer, PhD, leads the USF Health Informatics Institute

Virtually every major university conducting type 1 diabetes research is linked to Dr. Krischer’s institute at USF Health. The HII team coordinates, analyzes and maintains data from several international NIH-sponsored clinical networks investigating the causes and outcomes of type 1 diabetes, including The Environmental Determinants of Diabetes in the Young (TEDDY), TrialNet, the Rare and Atypical Diabetes Network (RADIANT), and the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Members of the Institute also have funding from industry, the Patient-Centered Outcomes Research Institute (PCORI) and the NIH for studies in oncology, type 2 diabetes, molecular biology and “big data” (‘omics).

“The Health Informatics Institute has been able to design and implement an infrastructure to support high performance computing and big data and create a platform for scientific advances yet to come,” Dr. Krischer said.

Samuel Wickline, MD, is founding director of the USF Health Heart Institute.

The USF Health Heart Institute will be housed within the new Morsani College of Medicine building now in the final stages of construction in downtown Tampa. By bridging basic science and clinical translational research to create new therapies for heart disease, generating biomedical inventions leading to patents and licenses, and attracting biotech and pharmaceutical companies with its innovative work, the Heart Institute is expected to be a major driver of economic activity in the Tampa Bay region.

“USF has put forward a significant investment to pursue solutions to cardiovascular disease, the number one cause of death and health care expenditures worldwide,” said Dr. Wickline, a pioneer in harnessing nanotechnology to combat all types of inflammatory diseases. “It’s vital to the public good for universities to undertake applied translational research that achieves useful bench-to-bedside successes.”

USF Health clinical and molecular geneticist Rebecca Sutphen, MD, has survived breast cancer and melanoma.

Genetic testing has been available since the mid-1990s to determine if a woman is likely to face one of her gender’s greatest fears: inherited breast and ovarian cancer. Yet, questions remain about whether common tests for the genes BRCA1 and BRCA2, which identify mutations that significantly increase a woman’s risk of breast and ovarian cancers, are reaching those who can most benefit and how the information learned from the testing is put to use.

USF Health medical and molecular geneticist Rebecca Sutphen, MD, a breast cancer and melanoma survivor, has broad expertise in genetic conditions affecting both adults and children. She has devoted much of her recent career working with Facing Our Risk of Cancer Empowered (FORCE), the leading national nonprofit advocacy organization for hereditary breast and ovarian cancer, to seek answers that will improve health outcomes of women at high risk for these cancers.

Dr. Sutphen’s research is guided in part by her own experiences as a patient, as well as Big Data’s emerging power to integrate electronic medical information and help build evidence about the effectiveness of clinical care. She emphasizes the need to ensure that patients help shape the investigative process.  In addition to her academic work, she is the chief medical officer of InformedDNA, a national genetic services organization.

The National Cancer Institute estimates only 3 percent of adults with cancer participate in clinical trials, with members of racial and ethnic minorities and low-income individuals particularly underrepresented.

“If research started with the questions that patients want answered, it seems likely there would be more participation in clinical studies, and it would be more obvious to patients how the research is relevant to them,” said Dr. Sutphen, professor of genetics at the USF Health Morsani College of Medicine’s Health Informatics Institute.

Cancer studies still largely focus on determining what treatments contribute to longer life, she said.

“Obviously survival is very important, but patients with cancer often have several options for treatment. What we learn from patients is that they also care about maintaining quality of life – things like the ability to get in their cars and continue to go to the grocery store, or to sleep at night… So, how can we better tailor the treatment options available to match each individual’s preferences?”

 Dr. Sutphen discusses the powerful potential of Big Data.

Dr. Sutphen works out of the Morsani College of Medicine’s Health Informatics Institute led by Jeffrey Krischer, PhD. She is pictured here with clinical research associate Beth Ann Clark, right.

USF helps lead way in BRCA testing and counseling

Dr. Sutphen, proficient in sign language, has a brother and sister who were both born deaf. She says her interest in genetics was sparked as a medical student when she accompanied her sister and her sister’s husband to Johns Hopkins medical genetics clinic for an evaluation of her 2-month-old nephew, also born deaf.

What the family learned about genetics and the probabilities of inheriting certain conditions was informative and fascinating, Dr. Sutphen said. “I saw genetics emerging as a new, growing area of science with the opportunity to impact the lives of people who really need information and can use it in a proactive way to make better decisions for themselves and their families.”

After earning an MD degree from Temple University School of Medicine, she completed a pediatrics residency at All Children’s Hospital in St. Petersburg and a fellowship in human genetics at USF. She is certified by the American Board of Medical Genetics in both clinical and molecular genetics.

In 1995 Dr. Sutphen joined the USF College of Medicine as a faculty member and shortly thereafter became the director of clinical genetics at All Children’s Hospital and at Moffitt Cancer Center.   As BRCA testing became commercially available, she helped USF establish one of the first programs in the state to offer clinical genetic testing and counseling for cancer.

For the first time, a test could identify if a person had inherited a defect in BRCA1 or BRCA2, and therefore tell who was at greater susceptibility for developing breast and ovarian cancer. Also, even if a woman with the inherited mutation never developed cancer herself, she would know she had a 50 percent chance of passing down the mutation, and increased risk, to any offspring.

But many more questions could not be answered. Was the risk the same for everyone who inherited a mutation? Was there a certain age the cancer would be likely to emerge? Could anything modify the risk? Will intensive screening (mammograms, MRIs, ultrasounds) catch a cancer early enough? Should a woman have her breasts or ovaries removed?

“While there was great excitement about the clinical availability of this new testing, there was a huge gap in what we could tell people about their own particular situation and what to do about it,” Dr. Sutphen said.

 Dr. Sutphen comments on engaging patients in the research process.

In the 1990s, Dr. Sutphen helped USF establish one of the first programs in the state to offer clinical genetic testing and counseling for hereditary breast and ovarian cancer.

Meeting begins enduring research collaboration, friendship

Dr. Sutphen began working with Distinguished University Health Professor Jeffrey Krischer, PhD, now director of the Health Informatics Institute, to develop NIH project proposals that would meaningfully address some of these unanswered questions. And in 2004, Dr. Sutphen invited Dr. Sue Friedman, founder and executive director of FORCE, to meet with the USF team to discuss how to best integrate “the patient voice and community” into the group’s hereditary cancer research.

After that initial meeting and learning about USF’s advanced health informatics capabilities, Dr. Friedman said, she quickly drafted a proposal to move her fledging nonprofit organization and family from South Florida to Tampa to work more closely with the USF team.

“When we first started looking at what a collaboration for hereditary breast and ovarian cancer research would look like, we included things like a yearly conference, a patient registry, research grants, writing a book. And, while there have been challenges along the way, in the last 12 years we’ve accomplished a lot of what we dreamed about and continue to build upon it,” Dr. Friedman said. “Aligning with USF has enhanced our organization’s ability to deliver meaningful research to the community, not just in terms of recruiting patients and reporting study results, but to actually help drive the research at every level.”

Along the way, Dr. Friedman, also a breast cancer survivor, and Dr. Sutphen became best friends as well research partners. “Rebecca has been visionary in recognizing the value of including health plan data in the research, and extraordinarily open to bringing in patients as equal stakeholders.”

Sue Friedman (left), founder and executive director of Facing Our Risk of Cancer Empowered, or FORCE, and USF’s Dr. Sutphen have worked together for the last 12 years. They have become friends who share a commitment to making patients equal stakeholders in driving hereditary cancer research.

 Inherited breast and ovarian cancer community’s influence on personalized medicine.

Research and advocacy join forces

Combining their complementary expertise in research and advocacy, USF Health and FORCE have attracted several highly competitive grants. Currently, Dr. Sutphen is the lead investigator for two national research awards focused on hereditary breast and ovarian cancer research.

• Impact of BRCA Testing on Newly Diagnosed U.S. Breast Cancer Patients. This landmark study, supported by a $2.8-million NIH RO1 award, is conducted in collaboration with the commercial health insurance plan Aetna. Researchers previously examined de-identified data on thousands of Aetna members across the country who received BRCA testing and surveyed them about factors associated with the use of this testing including genetic counseling services. Now, analyzing de-identified health claims information, Dr. Sutphen and colleagues will track the outcomes of consenting patients with increased risk for breast and ovarian cancer syndrome — including what types of health care professionals the women saw and how the positive genetic test results affected their decisions about managing cancer risk (including preventive treatment options), which patients subsequently were diagnosed with cancer and their medical treatment choices.

“To date,” Dr. Sutphen said, “there has been no similar study evaluating the health outcomes of a national sample of women undergoing BRCA testing in community settings.”

• Patient-Powered Research Networks, American BRCA Outcomes and Utilization of Testing Network (ABOUT Network). The project, totaling $2.4-million in support from the Patient Centered Outcomes Research Institute (PCORI) for Phases I and II, continues the work led by USF and FORCE to advance a national patient-centered research network of individuals with hereditary breast and ovarian cancer. The ABOUT Network was created to identify this patient community’s unmet needs, promote their governance in research and focus on the questions and outcomes that matter most to patients and their caregivers. USF’s ABOUT patient-powered research network is one of 20 nationwide participating in PCORI’s initiative to help individuals access their electronic health records data through existing patient portals and share it for research that could improve care for their conditions.

“We are establishing mechanisms to allow any patient in the U.S. who has hereditary breast and ovarian cancer to participate in studies relevant to them,” Dr. Sutphen said. “Harnessing the power of Big Data with guidance from patients enables a scale of research never before possible.”

Some early findings have begun to be disseminated. In a study published last year in JAMA Oncology, which attracted national media attention, Dr. Sutphen and co-authors found that most women who underwent BRCA testing did not receive genetic counseling by trained genetics professionals — and lack of physician recommendation was the most commonly reported reason. Yet, those who did get this clinical service before testing were more knowledgeable about BRCA and reported more understanding and satisfaction than women who did not.

This demonstrates gaps in services to be addressed, Dr. Sutphen said, because consultation with a trained genetics clinician is widely available (by phone or in person) and now covered as a preventive health service by most insurers with no out-of-pocket costs to patients.

 Dr. Sutphen talks about her breast cancer diagnosis.

Researcher confronts breast cancer as patient

Dr. Sutphen was diagnosed with breast cancer in 2008, following a routine mammogram. She was premenopausal and had no family history of cancer.   The radiologist who read her mammogram, a colleague, pulled her out of clinic at the Moffitt Lifetime Cancer Screening Center to alert her to the abnormality on her X-ray. The biopsy confirmed early-stage breast cancer.

“I was shocked,” she said. “I remember the part of the conversation ‘you have cancer,” seeing the doctor’s mouth moving and then not hearing any words after that.”

She called her best friend Sue Friedman, herself a breast cancer survivor, for support and after careful consideration of her treatment options decided to undergo a bilateral mastectomy with reconstruction.   The choice worked well for her, Dr. Sutphen said, but another friend with the same type of breast cancer chose lumpectomy instead.

“The first thing to look at is whether the likelihood for a recurrence of the cancer is the same if you have a lumpectomy or a mastectomy – and if the answer is yes, then beyond that it’s a matter of personal preference,” Dr. Sutphen said. “So, two people can make very different choices, but the right choice for each of them.”

In 2013, after having a “mole that looked different” on her arm checked out, Dr. Sutphen was diagnosed and treated for melanoma.

Her own experiences as a two-time cancer survivor have added perspective to her research, Dr. Sutphen said. “It really emphasized to me just what it’s like to be a patient, how difficult the decisions are to make, and how challenging your emotional state becomes.”

To make the often confusing and complex journey a little easier for patients and their families, Dr. Friedman and Dr. Sutphen collaborated with freelance writer Kathy Steligo on a book titled Confronting Hereditary Breast and Ovarian Cancer: Identify Your Risk, Understand Your Options, Change Your Destiny. They wanted to integrate into one book the latest evidence-based information to help women with cancer-susceptibility genes maximize their long-term survival and quality of life.

“The book was published in 2012, but it’s still 95 percent relevant today,” she said.

Dr. Sutphen with her daughter Serenity, 11.

Something you may not know about Dr. Sutphen

Dr. Sutphen was named one of the top 10 cancer medical geneticists in the United States in Newsweek’s “Top Cancer Doctors 2015” list. In 2012, she was selected by TEDMED to be the advocate leading its “Shaping the Future of Personalized Medicine” program, part of the Top 20 Great Challenges annual conference.

For many years she enjoyed the scenic adventure of flying paraplanes, or powered parachutes, ultralight aircraft with a motor, wheels and a parachute. But these days Dr. Sutphen prefers remaining on the ground to cheer on daughter Serenity, 11, a horseback rider who competes in barrel racing.

Photos by Eric Younghans, and audioclips by Sandra C. Roa, USF Health Communications

The University of South Florida played a coordinating role in the international TEDDY study

//www.youtube.com/watch?v=kbJOwVra3ds

Tampa, FL (Nov. 9, 2015) — Probiotic exposure during the first 27 days of an infant’s life may be associated with reduced risk of islet autoimmunity among children at increased genetic risk for type 1 diabetes, although further studies are needed before any recommendations for probiotics can be made, according to a University of South Florida-led study published online by JAMA Pediatrics.

Probiotics are live organisms that may confer health benefits. Animal studies have looked at manipulation of gut microbiota by probiotics and the risk of developing type 1 diabetes (T1DM) related to autoimmunity.

Ulla Uusitalo, PhD, of the University of South Florida, and coauthors examined the association between supplemental probiotic use during the first year of life and islet autoimmunity. Islet autoimmunity occurs when antibodies attacks islet cells in the pancreas that produce insulin. The condition, which precedes the symptoms of type 1 diabetes, can be detected by measuring these islet autoantibodies in the blood.

“We have taken a baby step forward, and there is the possibility that in the future we may find preventive measures for Type 1 diabetes using probiotics, among children at high risk,” said Dr. Uusitalo, associate professor of pediatrics at the USF Health Morsani College of Medicine.

Ulla Uusitalo, PhD, associate professor of pediatrics based at the USF Health Informatics Institute, was lead author of the international study on probiotics and islet autoimmunity.

Dr. Uusitalo and colleagues report the results of The Environmental Determinants of Diabetes in the Young (TEDDY) study, which started in 2004 with children from six clinical centers, three in the United States (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden).

The children were followed-up for T1DM-related autoantibodies with blood samples drawn every three months between 3 and 48 months of age and every six months thereafter to determine persistent islet autoimmunity. Questionnaires and diaries were used to detail infant feeding, including probiotic supplementation and infant formula use.

A final study sample consisted of 7,473 children who ranged in age from 4 to 10 years old. Probiotic supplementation from dietary supplements or infant formula varied by country and was most pervasive in Finland and Germany during the first year of a child’s life.

Receiving probiotics through a dietary supplement or fortified infant formula, or both, by 27 days of age may be associated with a reduced risk of islet autoimmunity compared with those children who first received probiotics after 27 days of age or not at all. Early probiotic exposure appeared to be associated with a 60-percent decrease in the risk of islet autoimmunity among children with the highest-risk HLA genotype DR3/4 but not among other genotypes.

An association does not imply causality and further research needs to be done, the authors note.

“Early exposure to supplemental probiotics may decrease the risk of IA [islet autoimmunity] among children at elevated risk of T1DM. … These results have to be confirmed before making recommendations on the use of probiotic supplementation,” the study concludes.

Infants in the study received probiotics through a dietary supplement of oral drops or fortified infant formula,

The probiotics and islet autoimmunity study is one of many overseen by the Data Coordinating Center of the University of South Florida’s Health Informatics Institute led by Dr. Jeffrey Krischer, Distinguished University Health Professor. The center coordinates, analyzes and maintains research data from several large clinical networks investigating the causes and outcomes of type 1 diabetes, including TEDDY, TrialNet, TRIGR and DPT-1.

This NIH-supported hub also maintains a communication network to enhance collaboration and pooling of data among researchers across the world. Professionals in data management, software developing, biostatistics, epidemiology, psychology, nutrition, and other life sciences work seamlessly as a team, seeking to understand the triggers of type 1 diabetes and related autoimmune diseases and to develop strategies for prevention or improved treatment.

Article citation:

Ulla Uusitalo, PhD; Xiang Liu, PhD; Jimin Yang, PhD, RD: Carin Andren Aronsson, MS; Sandra Hummel, PhD; Martha Butterworth, MS; Ake Lernmark, PhD: William Hogopian, MD, PhD; Jin-Xiong She, PhD;  Olli Simell, MD, PhD; Jorma Toppari, MD, PhD; Anette G. Ziegler, PhD; Beena Akolkar, PhD; Jeffrey Krischer, PhD; Jill M. Norris, PhD; Suvi M. Virtanen, MD, PhD; for the TEDDY Study Group. “Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study,”  JAMA Pediatrics. Published online November 9, 2015. doi:10.1001/jamapediatrics.2015.2757.

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Video and photos by Sandra C. Roa, USF Health Marketing & Communications