Over the past 60 years, the incidence of type 1 diabetes (T1D) worldwide has been increasing by 3–5% per year,1–3
() 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 TEDDY7–9
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.
Figure 1 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 (more ...)
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 (). This preclinical period provides a theoretical opportunity for prevention. However, two large randomized trials in relatives of T1D patients—the European Nicotinamide Diabetes Intervention Trial10
and the Diabetes Prevention Trial-1 (using parenteral11
and oral insulin12
)—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
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 Colorado40
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 milk47
In addition to these there are reports of associations of T1D development with low intakes of vitamin D,48
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
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.