Address for correspondence: Marian Rewers, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Mail Stop A140, PO Box 6511, Aurora, CO 80045-6511. Voice: +303-724-6757; fax: +303-724-6787. ude.dcu@srewer.nairam
The publisher's final edited version of this article is available at Ann N Y Acad SciThe etiology of type 1 diabetes (T1D) remains unknown, but a growing body of evidence points to infectious agents and/or components of early childhood diet. The National Institutes of Health has established the TEDDY Study consortium of six clinical centers in the United States and Europe and a data coordinating center to identify environmental factors predisposing to, or protective against, islet autoimmunity and T1D. From 2004–2009, TEDDY will screen more than 360,000 newborns from both the general population and families already affected by T1D to identify an estimated 17,804 children with high-risk HLA-DR, DQ genotypes. Of those, 7,801 (788 first-degree relatives and 7,013 newborns with no family history of T1D) will be enrolled in prospective follow-up beginning before the age of 4.5 months. As of May 2008, TEDDY has screened more than 250,000 newborns and enrolled nearly 5,000 infants—approximately 70% of the final cohort. Participants are seen every 3 months up to 4 years of age, with subsequent visits every 6 months until the subject is 15 years of age. Blood samples are collected at each visit for detection of candidate infectious agents and nutritional biomarkers; monthly stool samples are collected for infectious agents. These samples are saved in a central repository. Primary endpoints include (1) appearance of one or more islet autoantibodies (to insulin, GAD65 or IA-2) confirmed at two consecutive visits; (2) development of T1D. By age 15, an estimated 800 children will develop islet autoimmunity and 400 will progress to T1D; 67 and 27 children have already reached these endpoints.
Keywords: type 1 diabetes, islet autoimmunity, environmental triggers, epidemiologic study, HLA, infectious agents, dietary factors, psychosocial factors
Over the past 60 years, the incidence of type 1 diabetes (T1D) worldwide has been increasing by 3–5% per year, 1 – 3 ( Fig. 1 ) doubling approximately every 20 years. 4 While several T1D susceptibility genes are known, such a rapid increase can only be explained by a powerful influence in the environment interacting with a relatively common genetic background. In some populations, the incidence has increased most markedly in the very youngest children, 3 suggesting a role for very early exposures. The disease also appears to spread to children who carry lower-risk HLA-DR, DQ genotypes, 5 , 6 consistent with an increase in the penetrance of the environmental exposure(s). Population-based cohort studies that preceded TEDDY 7 – 9 as well as rapid advances in immunology and genetics have provided new insights into the pathogenesis of T1D. On the other hand, none of the candidate environmental exposures has been shown beyond reasonable doubt to cause a significant number of the cases. The role of the TEDDY study is to accelerate progress towards preventing T1D prevention through a large-scale sustained international effort to clearly define the causes of T1D.
T1D incidence has doubled every 20 years. Data for Finland are from the Finnish National Public Health Institute (V. Harjutsalo and J. Tuomilehto); data for Sweden are from the Swedish Childhood Diabetes Registry; 66 data for Germany are a compilation of two reports; 67 , 68 data for Colorado are from the Colorado IDDM Registry, the Barbara Davis Center for Childhood Diabetes, and SEARCH for Diabetes in Youth. 4
Islet autoimmunity, marked by the presence of autoantibodies to pancreatic β cell antigens such as GAD65, insulin, or IA-2, precedes clinical T1D in most cases by a few years ( Fig. 2 ). This preclinical period provides a theoretical opportunity for prevention. However, two large randomized trials in relatives of T1D patients—the European Nicotinamide Diabetes Intervention Trial 10 and the Diabetes Prevention Trial-1 (using parenteral 11 and oral insulin 12 )—failed to prevent or delay progression from autoimmunity to diabetes. Significant β cell damage present at trial entry could also play a role. In contrast, TRIGR (the Trial to Reduce IDDM in the Genetically at Risk) 13 is attempting T1D prevention by eliminating cow’s milk in infant nutrition before the onset of islet autoimmunity. Pilot studies using omega-3 fatty acids (NIP) or human oral insulin (Pre-Point) are under way in genetically susceptible young children to prevent islet autoimmunity and T1D. While these approaches may be effective, we lack convincing evidence concerning the initiators of islet autoimmunity to design optimal primary prevention trials. Of importance, our current understanding of T1D etiology originates predominantly from studies of first-degree relatives (FDRs) of T1D patients. These data may not be directly applicable to the causes and prevention of T1D in the general population, in which 90% of the cases occur. TEDDY is filling important gaps in our understanding of the natural history of T1D by studying from birth high-risk general population children and relatives followed systematically for environmental determinants of T1D.
Natural history of T1D and prevention opportunities.
A number of environmental exposures have been proposed to contribute to T1D risk. These include exposures taking place during pregnancy, infancy, childhood, and beyond. Not all islet autoantibody–positive subjects progress to diabetes, 11 and hence the importance of distinguishing whether an environmental agent triggers development of islet autoimmunity or promotes disease progression. This can only be determined by prospective follow-up of large numbers of genetically at-risk children from a very young age.
Exposure to rubella during pregnancy has resulted in diabetes in about 20% of children. 14 Similarly, the risk for T1D in childhood is reported to be increased in children born to mothers with enterovirus infections during pregnancy. 15 , 16 Other potential risk factors include ABO incompatibility and hyperbiliru-binemia, 17 , 18 preeclampsia, 19 mother’s age, 20 and high birth weight for gestational age. 20 , 21 Further evidence of fetal programming of T1D risk comes from the still unexplained decreased T1D risk in children of mothers with T1D as compared to children of fathers with T1D. 22 , 23 Finally, the HLA type of the child appears to affect fetal growth, suggesting potential genetic programming that goes beyond the immune repertoire. 24 , 25 There is a gap in understanding to what extent gestational factors, including genetic interactions, may trigger islet autoimmunity or merely increase T1D susceptibility in the offspring. It cannot be excluded that gestational infection may induce immunologic tolerance to the virus. 26 , 27 An ability of the offspring immune system to regard a virus as self may have consequences for latency and reinfection.
Seroconversion to positivity for islet autoantibodies, the earliest measure of islet autoimmunity which may lead to clinical T1D, may occur already 3–6 months after birth. 20 , 28 Candidate autoimmunity and T1D risk factors operating in infancy include those related to exposure to infectious agents, improved hygiene, 29 mucosal exposure to dietary constituents, 30 , 31 and requirement for increased beta cell functioning. 32 , 33
Previous virus studies have sought to provide a direct evidence for virus-induced T1D. However, in some of these patients developing T1D, it was found that either the insulitis was chronic or that the patients already had islet cell autoantibodies. It could therefore not be excluded that the virus infection accelerated an already ongoing process of islet autoimmunity. 34 Further studies of these phenomena as well as of other microbial agents are therefore warranted to take into account that subjects with an increased T1D risk may show responses that lead to islet autoimmunity or affect ongoing islet autoimmunity.
Enteroviruses, and in particular coxsackie B viruses, remain the prime candidate by nature of their tropism for beta cells, 34 , 35 possible molecular mimicry, 36 and early and more recent reports of their presence in beta cells of patients with T1D. 37 , 38 Data from Finland showing a relationship between enterovirus infection and the appearance of islet autoantibodies as well as a seasonal fluctuation in the appearance of islet autoantibodies supports a role early in the disease. 39 However, substantially more evidence is required to establish a causal role for enterovirus in T1D, especially as a trigger of the islet autoimmunity, because the association could not be demonstrated in children outside Scandinavia, including those in Colorado 40 and Germany. 41 Rotavirus has also been shown to infect beta cells and to have a link to islet autoimmunity by way of molecular mimicry, 42 , 43 but evidence for a causal role is lacking. 44
Seemingly in contrast to the infectious hypotheses is the notion that improved hygiene is responsible for upward trends in T1D incidence as well as incidences of other hyperimmune response diseases such as allergy. 29 There are epidemiologic studies indicating that crowding and exposure to others in day care are associated with reduced T1D risk, supporting the hygiene hypothesis. Few studies have examined the relationship of hygiene to the development of islet autoimmunity. Related to hygiene is a potential role of vaccinations in the development of islet autoantibodies or progression to T1D. Some have suggested that vaccination increases T1D risk, but well-designed studies have found no evidence for this. 45 , 46 The temporal relationship of vaccinations to the development of islet autoantibodies or T1D has never been examined. Prospective analyses of children from 3 months of age through the entire period of mandatory or voluntary vaccination are needed to establish effects of vaccinations on islet autoimmunity and progression to T1D.
Substantial data have been generated on the role of breast-feeding and early exposure to cow’s milk 47 or cereals. 30 , 31 In addition to these there are reports of associations of T1D development with low intakes of vitamin D, 48 tocopherols, 49 ascorbic acid, 50 vitamin E, 51 and omega-3 fatty acids. 52 Other suspected exposures include drinking water, with an increased risk if water is from a local well compared to water-plant drinking water, possibly related to the amount of zinc. 53 Moreover, N-nitroso compounds 54 and mycotoxins 55 have been associated with an increased risk of T1D.
The TEDDY study is uniquely positioned to elucidate the association between T1D and celiac disease because the study eligibility HLA genotypes confer susceptibility to both diseases. 56 – 58 TEDDY is measuring autoantibodies against tissue transglutaminase (tTG), which is a very sensitive and specific marker of celiac disease.
Psychosocial factors may also contribute to appearance of T1D. Stress has long been considered a potential trigger for TID. 59 Screening for high-risk genes associated with T1D could induce anxiety and distress in family members. 60 Prospective studies utilizing detailed psychosocial evaluation of participating parents as well as children as they grow older will be necessary to effectively determine whether life events or stress may increase the risk for islet autoimmunity. Experiences in studies of children at genetic risk for T1D who have gone on to develop T1D have identified benefits such as absence of severe ketoacidosis and a reduction in hospitalization. 61
While there are preliminary data and intriguing hypotheses as to the etiology of T1D, the data are often confounded by imprecise assessment of exposure, recall bias, failure to account for genetic susceptibility, failure to assess exposures at very early ages, or the inability to follow a sufficient sample of children long-term with high intensity. Most of the few studies that have attempted to look at exposure from an early age and in relation to the development of islet autoantibodies were underpowered. TEDDY will fill important gaps in our understanding of the events leading to T1D. In addition, samples collected by TEDDY will create a valuable resource for investigators proposing innovative hypotheses concerning candidate environmental and genetic factors.
The Environmental Determinants of Diabetes in the Young (TEDDY), a multicenter prospective cohort study, was initiated in 2003 to identify environmental factors that trigger or protect against the development of islet autoimmunity and T1D. The details of the TEDDY study’s organization and protocol have been previously published. 62 In brief: the consortium comprises 6 clinical centers located in Denver (Colorado), Augusta (Georgia)/Gainesville (Florida), and Seattle (Washington) in the United States, and in Finland (Turku), Sweden (Malmo), and Germany (Munich). The Data Coordinating Center is in Tampa, Florida. Autoantibody Reference Laboratories are located in Denver (serving the U.S. Clinical Centers) and Bristol (serving the European Clinical Centers). The Central Genetics Reference Laboratory is in Oakland, California, and the Central mRNA Laboratory is in Augusta, Georgia. The NIDDK Bio-sample and Genetics Repositories store samples. For more details, see the Appendix.
The primary objectives of this study are:
To identify environmental factors that trigger or protect against the development of islet autoantibodies or T1D.
Infectious agents: Dietary factors: Psychosocial factors:Genes both within and outside the HLA region are typed to identify gene–environment interactions. It is expected that the joint analyses of genetic and environmental data will improve the identification of both genetic and environmental factors influencing development of islet autoimmunity and T1D, and may explain mechanisms of these interactive effects.
The prospectively collected specimens from TEDDY subjects (DNA, RNA, serum and plasma, cells and other samples) provide a unique opportunity for scientists within and outside the TEDDY consortium to test novel hypotheses.
Consent for genetic screening is obtained from parents of babies born in area hospitals or identified after birth. This blood sample is analyzed at approved and monitored laboratories for the HLA haplotypes that qualify a child for TEDDY. Those results are returned to the DCC and local clinical centers, who notify all subjects of the genetic screening outcome. Among those who are HLA-eligible, trained local staff (e.g., study nurses) contact the subject’s parent to explain genetic risk and introduce in some detail the follow-up phase of TEDDY for which their child is now eligible to join. Enrollment, informed consent, and completion of the first visit must occur before the child reaches the age of 4.5 months. Once this visit has been completed the subject is then on the follow-up visit schedule for data collection described below. A portion of the 9-month blood sample is used to confirm HLA eligibility at a central reference laboratory, where additional high-resolution typing is done to confirm eligibility. Table 1 summarizes current TEDDY accruals by center and cohort (FDRs versus infants without a history of T1D in a FDR). Table 2 compares current accruals with the overall study goals for the number of infants to complete screening, found eligible, and enrolled into follow-up. As of May 2008, TEDDY has screened more than 250,000 newborns and enrolled nearly 5,000 infants—approximately 70% of the study goals. As shown in Figure 3 , TEDDY is ahead of the enrollment goals by several months and on track to complete the screening and enrollment by the end of 2009.
Cumulative number of enrolled subjects (data as of 3/31/08).
