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Cowie CC, Casagrande SS, Menke A, et al., editors. Diabetes in America. 3rd edition. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018 Aug.
Summary
The incidence of type 1 diabetes is increasing at an annual rate of 3%–5%, which suggests a major environmental exposure has changed, by either the gradual introduction of a susceptibility factor or the removal of a protective factor, during the past 60 or more years. Outbreaks and seasonality of type 1 diabetes may suggest an infectious cause, perhaps related to increasing sanitation and loss of herd immunity. Early childhood diet and environmental toxins are also of interest.
Prospective studies following high-risk children from birth to development of the subclinical phase of the disease (islet autoimmunity) and diabetes have been the most reliable source of information regarding risk factors for type 1 diabetes. Prenatal and early post-natal exposures appear to be critical, as the incidence of islet autoimmunity peaks in the second year of life. Among the infectious agents, enteroviral infections (particularly if they are persistent and acquired in early childhood) have gained most interest. Early leads suggesting the role of cow’s milk exposure in the initiation of islet autoimmunity have not been confirmed by large prospective studies and a large randomized clinical trial. While numerous studies have reported 1.5–2-fold increases in the risk of islet autoimmunity or type 1 diabetes with various components of early childhood diet and infectious exposures, none of the associations appears particularly strong or universal across different populations.
In the United States, 1 in 300 children and adolescents develop type 1 diabetes by age 20 years, but 1 in 40 offspring of mothers with type 1 diabetes and 1 in 15 offspring of fathers with type 1 diabetes develop type 1 diabetes. The disease is likely caused by the interplay of genetic and environmental factors. Systematic investigation of gene-environment interactions in large, prospectively followed cohorts of young children may help to identify and fully characterize modifiable risk factors and design trials to fully evaluate the strongest candidate triggers of autoimmunity.
Introduction
The incidence of type 1 diabetes is increasing worldwide, by 3%–5% annually (1), with rates doubling every 20 years (2,3). The rising incidence, outbreaks (4), and a seasonal pattern (5) may suggest that infectious agents play a role in the pathogenesis. However, the incidence has been increasing since at least the 1950s (Figure 11.1) (2,3,6,7,8,9,10,11). Such a secular trend is unlikely to result from a new infectious agent; however, similar to the polio model (12), an “old” microbe could express its diabetogenic effect due to increasing hygiene and decreasing herd immunity. Changes in early childhood diet have also been implicated, as type 1 diabetes has increased the most in the youngest children. Prospective studies (13,14,15) following high-risk children from birth have made important inroads into the understanding of the role of infectious and dietary factors in type 1 diabetes. Prospective studies have defined two major steps in the pathogenesis of type 1 diabetes (Figure 11.2). Seroconversion to positivity for one or more islet autoantibodies (to insulin, glutamic acid decarboxylase [GAD], insulinoma antigen 2 [IA-2], or zinc transporter 8 [ZnT8]) marks the development of islet autoimmunity. Approximately 70% of children positive for two or more of these autoantibodies develop diabetes in 10 years following the appearance of the first auto-antibody (16). In contrast, most children persistently positive for only one islet auto-antibody do not progress to diabetes (16). Data suggest that a variety of exposures may trigger islet autoimmunity, promote progression to clinical diabetes, or affect both of these steps.
Most of the existing data concerning risk factors for islet autoimmunity and type 1 diabetes have come from a handful of prospective studies that have sometimes generated inconsistent results. While the large international prospective cohort study (The Environmental Determinants of Diabetes in the Young [TEDDY]) will likely reconcile some of the inconsistencies, randomized clinical trials of risk factor modifications will provide the ultimate test.
Type 1 diabetes is caused by the interplay of genetic and environmental factors. The genetics of type 1 diabetes is reviewed in depth in Chapter 12 Genetics of Type 1 Diabetes and only briefly summarized in the following section. In this chapter, infectious, dietary, and other environmental factors are reviewed in detail, as well as potential gene-environment interactions in type 1 diabetes etiology.
Genetic Factors
Family History of Type 1 Diabetes
In the United States, approximately 1 in 300 children and adolescents develop type 1 diabetes by age 20 years (Table 11.1) (2,17). The risk is increased to about 1 in 40 in offspring of mothers with type 1 diabetes and 1 in 15 in offspring of fathers affected by type 1 diabetes; the reason for this difference may have an epigenetic origin. The risk to siblings of type 1 diabetes individuals ranges from 1 in 12 to 1 in 35 (18,19). The risk is significantly higher in siblings of individuals diagnosed at age <7 years than in those diagnosed later (20). It is as high as 1 in 3 among monozygotic twins (21). In parents of individuals with type 1 diabetes, the risk by age 40 years is 2.6% and twofold higher in fathers (3.6%) than in mothers (1.7%) (20). By age 60 years, an estimated 10% of first degree relatives will develop type 1 diabetes (22). However, the “familial” cases account for less than 10% of type 1 diabetes in the general population; they do not differ from “sporadic” cases in terms of the human leukocyte antigen (HLA)-DR,DQ gene frequencies or the prevalence of islet autoantibodies (23).
Similar to type 1 diabetes, the risk of developing islet autoimmunity varies depending on which relative has type 1 diabetes (Table 11.1). Siblings of type 1 diabetes patients develop islet autoimmunity more frequently than offspring or parents of type 1 diabetes patients (24). The risk of islet autoimmunity is markedly increased if both parents or a parent and a sibling have type 1 diabetes compared with a single affected family member (25).
Candidate Genes
The increased risk seen in family members can be attributed to both shared genes and shared environment. The strongest genetic association for type 1 diabetes is with certain alleles of the HLA class II genes (odds ratio [OR] >6). An estimated 30%–50% of the genetic risk for type 1 diabetes is attributable to the HLA region (26). More than 50 confirmed non-HLA loci, found via candidate gene and genome-wide association studies (GWAS), confer the remaining genetic risk, each with modest to small effects (27,28,29,30,31,32). Non-HLA loci most strongly associated with type 1 diabetes include INS (33) and PTPN22 (34), both with an odds ratio of approximately 2. One reason why these genes seem to have relatively small effects is that they may need to work in concert with another factor, such as an environmental exposure (gene-environment interaction), which is covered later in this chapter. The non-HLA gene variants studied more thoroughly so far appear important to both the triggering of islet autoimmunity and to the progression to clinical disease; however, most studies are underpowered to tease out this distinction. (See Chapter 12 for more details on type 1 diabetes genetics.)
Increasing Penetrance of the Moderate-Risk HLA Genotypes
Seven studies (35,36,37,38,39,40,41) have explored temporal changes in the frequency and/or distribution of HLA genotypes associated with type 1 diabetes susceptibility. All but one have suggested a decreasing frequency of the highest-risk HLA-DR,DQ genotype over time in individuals diagnosed with type 1 diabetes (Table 11.2) (35,36,37,38,39,40,41). A study conducted in Finland reported a significant decrease in the frequency of the HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 genotype from 25.3% to 18.2% over a 62-year time period (35). A similar decrease in the frequency of the highest-risk HLA genotypes (from 47% to 35% over a 50-year time period) was noted in the United Kingdom (41). A study combining the Type 1 Diabetes Genetics Consortium participants and a Colorado clinic population cohort (39) showed a similar linear decrease. Additional evidence for decreasing frequency of the highest-risk genotype was published from Colorado (40), Sweden (37), and Australia (36). The decrease in the frequency of cases with the highest-risk HLA genotype with the corresponding increase in moderate and lower risk genotypes suggests an increasing penetrance of moderate and lower risk HLA genotypes that could be explained by increasing environmental pressure, e.g., higher levels of exposure to the critical factor.
Infectious Agents
Prospective studies of high-risk children have shown that the incidence of islet autoimmunity peaks in the second year of life (42,43,44), suggesting that the putative environmental trigger(s) must occur very early in life in many cases. Therefore, in utero, perinatal, or early childhood infections and infant diet are likely candidate exposures.
Seasonality of Type 1 Diabetes Diagnosis, Islet Autoantibodies, and Birth
Type 1 diabetes incidence in children is higher in autumn-winter and lower in spring-summer in both hemispheres, resembling seasonality of viral infections (7,45,46). However, children age 11–15 years show more obvious seasonal variation compared to children diagnosed before age 5 years (47), which may suggest that additional factors may play a role, e.g., easier detection of the onset of diabetic signs/symptoms in children attending school. Development of islet autoimmunity could also depend on an environmental exposure during pregnancy as suggested by seasonality of islet autoantibodies in cord blood (48) and seasonal distribution of birth dates of type 1 diabetes patients in some populations (49,50).
Viral Infections
Viral infections have long been implicated in the etiology of type 1 diabetes, but a definitive proof has been elusive. Footprints of infectious triggers of islet autoimmunity may be hard to detect due to a long incubation period of type 1 diabetes in most cases. A number of agents have been suggested to trigger autoimmune diabetes; the strongest leads are reviewed in this section.
Enteroviruses have shown associations with type 1 diabetes in both animal and human studies (51,52). These viruses have a tropism to human pancreatic islets in vivo and in vitro (53,54,55), and they have been detected in the pancreata of type 1 diabetes patients (56). Animal studies suggest that the timing of an infection may be critical. The outcome of infection may differ in individuals with islet autoimmunity compared to those with unaffected islets. The outcome is also modulated by complex interactions between the microbe and the host, e.g., variants of the innate immune system receptor interferon-induced helicase C domain-containing protein 1 (IFIH1) may determine viral load (57). Despite a number of studies using different approaches, the nature of the relationship between enteroviruses and type 1 diabetes remains controversial. In most cases, diagnosis of type 1 diabetes follows a long period of preclinical islet autoimmunity. Viruses present at diagnosis may have infected the host late in the disease process rather than trigger the process. Alternatively, the triggering infection has likely been cleared by the time of diagnosis, unless the virus is able to persist. Enterovirus infections may potentially initiate islet autoimmunity, modulate progression to clinical type 1 diabetes (58,59,60,61,62), or both (Figure 11.2).
Case-Control Studies of Enteroviral Infections at the Diagnosis of Type 1 Diabetes
Enterovirus Serology
The initial observation of an association between enteroviral infections and type 1 diabetes made by Gamble et al. in 1969 (63) was based on apparently higher prevalence of antibodies against Coxsackie virus in patients with recently diagnosed type 1 diabetes than in controls. Controls were poorly selected, older than the cases, thus less likely to have had a recent infection. That study did not adjust for likely differences in the HLA genotypes among cases and controls. The HLA genotypes associated with type 1 diabetes are a powerful confounder, as they are also associated with a more vigorous antibody response to infection than the other genotypes (64,65). However, none of the 13 studies published up to 2002 (66) determined HLA type in cases and controls. This has helped to reinforce the possibly false-positive initial finding by Gamble. The review by Green et al. (66) concluded that heterogeneity in assays, study design, and results did not allow a conclusion or calculation of a pooled estimate. Smaller studies included in that review had larger estimated odds ratios, suggestive of a publication bias (66). Separate analyses performed for antibodies specific for Coxsackie viruses B3, 4, and 5 (based on 11, 17, and 11 studies, respectively) revealed little or no association overall. Most of the limitations plaguing the early seroepidemiologic studies apply also to more recent studies using reverse transcription-polymerase chain reaction (RT-PCR) for enterovirus detection, covered in the next section.
Enterovirus RNA in Blood Samples
Yeung et al. reviewed studies using modern methods of enterovirus detection (67). This meta-analysis unfortunately pooled estimates across all studies despite the presence of significant heterogeneity in the study designs and results (68). For instance, methods of detection included in situ hybridization or immunohistochemistry on pancreatic tissue, as well as RT-PCR on blood samples.
A less heterogeneous re-analysis of RT-PCR studies utilizing serum, plasma, or whole blood among newly diagnosed type 1 diabetes patients and matched controls is presented in Figure 11.3 (52). The overall results were consistent with an odds ratio of approximately 10 (Figure 11.3A) (69,70,71,72,73,74,75,76) and low heterogeneity among the studies (the I-square estimate was 0%). While the studies varied little in the frequency of enterovirus RNA in healthy controls (Figure 11.3B) (69,70,71,72,73,74,75,76), there was wide variation in the frequency of enterovirus RNA in newly diagnosed type 1 diabetes patients (Figure 11.3C) (62,69,70,71,72,73,74,75,76,77,78). The earliest studies showed a higher frequency of infection among patients than did the more recent ones. It is notable (Figure 11.3C) that one laboratory found no enterovirus RNA in any sample from type 1 diabetes patients at diagnosis in three independent data sets (62,77,78). This was the Finnish laboratory that has reported many positive samples from prediabetic individuals in longitudinal studies (62,78). Thus, lack of assay sensitivity would be unlikely. A large study reported a three times higher proportion of enterovirus RNA in serum from type 1 diabetes patients compared to controls, but interestingly, the majority of patients had longstanding diabetes (79).
Prospective Cohort Studies of Enteroviruses and Islet Autoimmunity
Prospective studies can exclude the possibility that the virus detected in patients infected them after disease onset. They can also demonstrate causation if a virus triggers autoimmunity through a “hit and run” mechanism. Challenges include sampling frequency to capture infectious agents while they are present in biological specimens and statistical power if the infection is rare or very common.
Does Enterovirus Trigger Islet Autoimmunity?
The longitudinal studies investigating enteroviral infections as potential triggers of islet autoimmunity are presented in Table 11.3 (15,62,64,77,78,80,81,82,83,84,85,86,87, reviewed in 52). The largest studies include three Finnish projects: DIPP (Diabetes Prediction and Prevention Study), DiMe (Childhood Diabetes in Finland), and TRIGR (Trial to Reduce IDDM in the Genetically at Risk); the Colorado DAISY study (Diabetes Autoimmunity Study in the Young); the Norwegian MIDIA (Environmental Triggers of Type 1 Diabetes); and the German BABYDIAB and BABYDIET studies. Preliminary data from a study in Australia called VIGR (Viral etiology of type 1 diabetes) have only been presented in abstract form, but the results were included in the meta-analysis by Yeung et al. (67) (Table 11.3). These studies followed children with increased risk of type 1 diabetes, defined by a first degree family history, HLA susceptibility genes, or both, with serial tests of serum or stools for evidence of enterovirus infections. These seven studies have published data from a total of 176 cases of islet autoimmunity; DiMe followed only children with islet autoimmunity for type 1 diabetes as the endpoint. Sample frequency and method of virus detection varied. Results of the prospective studies were reviewed by Stene and Rewers (52) and are summarized in Table 11.4 (64,67,80,83,84,85,86,87).
Presence of Enteroviral RNA in Stool. Three studies (DIPP, MIDIA, and BABYDIET) reported separate data from stool samples; none showed any significant association with islet autoimmunity (85,86,87). In MIDIA, the lack of association remained also when restricting to periods just prior to seroconversion, and there was also no difference when counting samples after seroconversion for islet autoantibodies (87). In DIPP, there was a tendency towards an association, but the result was only significant when combined with enterovirus serology (85). In the BABYDIET study, some infections may have been missed because of sampling every 3 months rather than monthly and only up to age 12 months, while most cases seroconverted to islet autoimmunity at a later age (mean 2.6 years, up to 7.9 years) (86).
Presence of Enteroviral RNA or Antibodies in Serum. DIPP and TRIGR reported significant associations with islet autoimmunity when combining enterovirus RNA in serum with infections defined serologically based on serial increase in at least one of several assays. The fact that the large majority of infections were detected with serology suggests that serology was driving this association (82,84). Another DIPP report (88) found no significant association between serologically defined infections in serial samples from age 3–24 months and later risk of islet autoimmunity in 107 children with islet autoimmunity and 446 matched controls. BABYDIAB analyzed enterovirus serology (80), but infrequent sampling and, in many instances, only one or no sample available from before islet autoimmunity limited the power to detect any relationship. Graves et al. (64) in DAISY found no significant serologic association between enterovirus and islet autoimmunity (M. Rewers, unpublished observation). Notably, these longitudinal studies rarely, if ever, detected enterovirus RNA continuously in the same individual for more than about 3 months, thus providing no evidence for detectable persistent infection.
Does Enterovirus Influence Progression From Islet Autoimmunity to Type 1 Diabetes?
DiMe and DIPP have found that positive enterovirus RNA and serology preceded development of type 1 diabetes (77,78,81). The hypothesis that enterovirus infections can promote progression from islet autoimmunity to type 1 diabetes is consistent with animal model data (58,89). Among children with islet autoimmunity, DAISY was the first to report a higher rate of progression to type 1 diabetes in sample intervals after detection of enterovirus RNA in serum (62). Remarkably, none of the samples available from the day of type 1 diabetes diagnosis was positive for enterovirus RNA. This suggests that the observed association was not due to reverse causality.
Prenatal Enterovirus Infection and Development of Type 1 Diabetes
Some studies have suggested a relationship between prenatal infections and risk of type 1 diabetes in childhood (81,90,91,92), while a number of others have not found any significant relationship (80,83,84,93). There are many methodologic differences between these studies, including timing of exposure assessment (the first trimester, third trimester, or birth).
The Polio Model of Type 1 Diabetes
The analogy between the epidemiology of poliomyelitis and that of type 1 diabetes was pointed out a long time ago (94). Poliovirus and enteroviruses belong to the same family of Picornaviridae. Prior to 1880, most infants were infected with poliovirus during the first year of life (12). These infections were generally mild due to the presence of maternal anti-poliovirus antibodies transmitted transplacentally or in breast milk (95). Viremia was limited, and infection of the central nervous system and paralysis were rare. Importantly, infants acquired active immunity under the cover of passive protection. Improved hygiene led to a delay of the initial infections past the passive protection period. The median age at poliovirus infection increased gradually with associated morbidity until widespread vaccination became available.
It has been hypothesized that in countries with the highest incidence of type 1 diabetes, increased hygiene and sanitation resulted in a decline in herd immunity to enteroviruses among pregnant women, exposing fetuses and newborns to prenatal or infant enteroviral infections (96). While direct evidence for this in humans is lacking, virus-induced diabetes can be prevented in animal models of offspring by infecting mothers with the same virus prior to pregnancy (97). There are, however, important differences between the epidemiology of poliomyelitis and type 1 diabetes. In contrast to polio, the age at diagnosis of type 1 diabetes has been declining with the increase in incidence. It could potentially be explained by an increase in the proportion of type 1 diabetes caused by prenatal enteroviral infections resulting in viral persistence in the pancreas (56,98).
The Hygiene Hypothesis and Potential Protective Effect of Natural Infections
The hygiene hypothesis suggests that autoimmune diseases may be on the rise due to a decreasing frequency of childhood infections from improved hygiene (99,100,101). Children living with siblings and sharing a bedroom have lower risk of type 1 diabetes (102). Infections in early life, routinely recorded by family doctors, have not been associated with subsequent childhood type 1 diabetes in a U.K. population-based study of 367 cases and 4,579 matched controls (103). There was no evidence of any reduction in the subsequent risk of diabetes in children with at least one infection in the first year of life (OR 1.03, 95% confidence interval [CI] 0.79–1.34) or in children prescribed antibiotics in the first year of life (OR 1.03, 95% CI 0.82–1.29). Analyses of infections in the first 2 years of life reached similar conclusions. However, prospective studies have reported a significant association between early childhood infections and islet autoimmunity. The BABYDIET study found respiratory infections during the first 6 months of life predictive of islet autoimmunity (hazard ratio [HR] 2.27, 95% CI 1.32–3.91); the association was weaker for infections between ages 6 and 12 months (HR 1.32, 95% CI 1.08–1.61) and absent beyond 1 year of age (104). Similar results were reported from Norway (105), while the DAISY study in Colorado found an association between islet autoimmunity and early childhood gastrointestinal infections, but not respiratory infections. In summary, prospective studies generally do not support the hygiene hypothesis for type 1 diabetes.
Other Viruses
Congenital rubella syndrome results in persistent viral infection followed by diabetes in about 20% of children (106,107). The onset of type 1 diabetes in these cases was delayed into the second or third decade of life, and >20% of those diagnosed did not require insulin (108). Most of those patients who developed diabetes did not have islet autoantibodies using early, poorly standardized assays (109,110). The mechanisms by which the rubella virus may cause these diseases are not well characterized; however, molecular mimicry has been invoked (111,112). A review has highlighted gaps in the evidence linking congenital rubella infections with type 1 diabetes (113).
Rotavirus also infects beta cells (114) and may have a link to islet autoimmunity by way of molecular mimicry (115); however, evidence for a causal role is lacking (116). A longitudinal Australian study reported an increased incidence of islet autoantibodies shortly after detection of rotavirus infection (117). The limitation of this study was diagnosis of infection based on measurement of serum rotavirus antibodies rather than detection of viral presence in stool by PCR. A Finnish study that measured rotavirus antibodies in serum samples collected at 3–6-month intervals up to age 2 years did not confirm the association (118).
A causal link between mumps and type 1 diabetes has long been suggested. Mumps epidemics were sometimes followed by sudden, sharp increases in type 1 diabetes onset a few years later (119), and the presence of islet-specific antibodies correlated with mumps infections (120). However, despite near-eradication of mumps through routine childhood vaccination, type 1 diabetes incidence is still rising, suggesting that mumps is not a trigger of type 1 diabetes.
Cytomegalovirus (CMV) has also been implicated in the etiology of type 1 diabetes, primarily using serological evidence (121,122,123). In contrast, several epidemiologic studies have failed to demonstrate a link between CMV and the development of islet autoantibodies or type 1 diabetes (124,125,126). A more recent study analyzed specifically a possible association between perinatal CMV infection and islet autoantibodies in young children with type 1 diabetes risk-associated HLA genotypes and found none (127).
The Kilham rat virus (KRV), a member of the parvovirus family, is sufficient to induce type 1 diabetes in diabetes-resistant BioBreeding (BB) rats that do not spontaneously develop diabetes (128). The incidence of human parvovirus infections peaks in childhood, the virus is endemic with irregular intervals of outbreaks, and it promotes a T cell-mediated lympho-proliferative response that could generate autoimmunity. Parvovirus has been related to type 1 diabetes, rheumatoid arthritis, and Grave’s disease in small clinical case-control studies (129,130). A homology between the parvovirus B19 and the extracellular domain of IA-2 islet autoantigen suggests a potential mimicry (131). However, case-control studies have, so far, been negative (132).
Several additional viruses (133,134,135,136) have been associated with onset of type 1 diabetes, but confirmation is lacking. In summary, it has not been established beyond reasonable doubt that any of the candidate infections triggers islet autoimmunity or accelerates islet autoimmunity toward diabetes in a large number of patients. Further prospective studies of these candidate triggers, as well as of other microbial agents, are therefore warranted in subjects at increased type 1 diabetes risk.
High-throughput (“next generation”) sequencing technologies are being applied to human studies of viruses in causation of type 1 diabetes (137). With larger and higher quality data sets in the future, such as those expected from the TEDDY study (11), more sophisticated statistical analyses are being applied to separate information from noise. Progress in sequencing technologies has offered attractive new possibilities to detect microbes in biological samples and carry out metagenomic studies where the whole microbiome and virome can be explored in the context of islet autoimmunity and type 1 diabetes. This concerns not only all known microorganisms represented in GenBank (www.ncbi.nlm.nih.gov/genbank/), but also novel ones.
Intestinal Microbiota
In addition to viruses, bacterial infections and commensal microbiota may modulate the risk of type 1 diabetes (138). The mucosal immune system has specialized regulatory mechanisms to tolerate commensal microorganisms. Some of the candidate environmental factors that appear to affect the risk of type 1 diabetes (e.g., cesarean section delivery, early childhood diet, use of antibiotics) are intertwined with the development and function of the human microbiome. Intestinal bacteria have also been related to type 2 diabetes, inflammatory bowel diseases (139), rheumatoid arthritis (140), atherosclerosis, allergy, colon cancer, and a host of other diseases, but the effect appears to be nonspecific. There is growing evidence that the “Western” diet has altered the genetic composition and metabolic activity of the gut microbiota. Emerging data support the hypothesis that altered gut bacterial composition may play a role in development of type 1 diabetes (141,142,143,144,145,146,147). Gut microbes influence lipid and glucose metabolism, as well as immunity and systemic inflammation outside of the intestine (141,148,149,150); therefore, they could be considered as a target in prevention of metabolic and proinflammatory diseases. In general, however, microbiome studies in the context of type 1 diabetes have, thus far, been underpowered and focused on taxa diversity. Some have reported lower microbial diversity in children with islet autoimmunity before progression to diabetes compared to healthy controls (138,142,147). The picture remains unclear at this time and will require large studies that employ whole genome sequencing of microbiome at multiple time points prior to diagnosis.
Vaccines
As childhood immunization programs have expanded, there has been speculation that vaccines may play a role in the development of childhood diseases that have risen in incidence, such as type 1 diabetes (151). Fortunately, no association between immunizations and islet autoimmunity or type 1 diabetes has been found thus far (14,152,153,154). A meta-analysis reviewed 23 studies investigating 16 vaccinations and analyzed 11 studies that met the inclusion criteria (155). Overall, there was no evidence to suggest an association between any of the childhood vaccinations investigated and type 1 diabetes. The pooled odds ratios ranged from 0.58 (95% CI 0.24–1.40) for the measles, mumps, and rubella (MMR) vaccination in five studies up to 1.04 (95% CI 0.94–1.14) for the haemophilus influenza B (HiB) vaccination in 11 studies. Significant heterogeneity was present in most of the pooled analyses but was markedly reduced when analyses were restricted to study reports with high methodology quality scores.
The Bacillus Calmette-Guérin (BCG) vaccine has attracted some interest as a potential immunomodulator that could theoretically reduce the incidence of autoimmune diabetes. However, human data for any association between BCG vaccination and type 1 diabetes or islet autoimmunity are universally negative. Until recently, BCG has been routinely administered to all neonates in Finland, the country with the highest incidence of type 1 diabetes worldwide. Case-control studies from Canada (156) and Sweden (157) have shown no association of BCG vaccination with the risk of diabetes. Likewise, the German BABYDIAB study (158) reported no association with development of islet autoimmunity. A 20-year follow-up of the 1974 Canadian birth cohort, of which 45% were given BCG in the first year of life, also showed no association (159). In addition, vaccination with BCG at diagnosis of type 1 diabetes does not increase the remission rate or preserve beta cell function (160,161).
Dietary Factors
Dietary factors associated with the appearance of islet autoimmunity and progression from islet autoimmunity to type 1 diabetes are reviewed in this section.
Breastfeeding
An ecologic study suggested an association between the decrease in breastfeeding and increase in type 1 diabetes incidence between 1940 and 1980 (162). Subsequent case-control studies have been inconsistent regarding whether breastfeeding was associated with a decreased risk of type 1 diabetes, as reviewed by Knip et al. (163), and two meta-analyses reached opposite conclusions (164,165). In 2012, a pooled analysis was conducted of 43 retrospective studies, showing a small reduction in the risk of type 1 diabetes associated with exclusive breastfeeding for >3 months (OR 0.87, 95% CI 0.75–1.00) and any (i.e., nonexclusive) breastfeeding for >3 months (OR 0.88, 95% CI 0.78–1.00) (166). The authors concluded that the findings were difficult to interpret because of the possible biases (particularly recall bias) inherent in the included studies.
All but one of the prospective cohort studies failed to find an association between breastfeeding duration and islet autoimmunity (14,167,168,169,170,171,172,173). In Sweden, breastfeeding <4 months was associated with the presence of islet autoantibodies at age 5 years (OR 2.09, 95% CI 1.45–3.02) compared to breastfeeding for ≥4 months (174). DAISY found evidence that a child who is still breastfeeding at the time of introduction to cereals has a reduced risk of islet autoimmunity (168), and a subsequent analysis in DAISY showed that breastfeeding at the time of introduction to gluten-containing grains, specifically, conferred protection for the development of type 1 diabetes (HR 0.47, 95% CI 0.26–0.86) (169). A similar protective relationship between breastfeeding and the introduction of gluten has been observed in celiac disease (175). These findings suggest that while not strongly protective independently, breastfeeding may be a protective factor in the relationship between other dietary factors, including but not limited to cereals and gluten, and type 1 diabetes (as further described in the following sections).
Maternal Diet
Reports attempting to examine the association between maternal diet and islet autoimmunity have not produced supporting evidence. Investigators from Sweden found that a low consumption of vegetables (<1 time/week) in the maternal diet was associated with a higher risk of islet autoimmunity in the child (OR 2.89, 95% CI 1.18–7.05) (176). In the United States, a lower consumption of potatoes by mothers during pregnancy was associated with a higher risk of islet autoimmunity in the child (177).
Cow’s Milk
Breastfeeding may be viewed as a surrogate for the delay in the introduction of diabetogenic substances, such as cow’s milk, that are present in formula. Cow’s milk introduced at weaning has been shown to trigger insulitis and diabetes in animal models (178,179). Numerous studies have been conducted examining the association between age at introduction of cow’s milk and type 1 diabetes or islet autoimmunity, as reviewed in Knip et al. (163), and they have been inconsistent. One meta-analysis of case-control studies (165) and a nested case-control study of a cohort study (180) suggest an increased risk; a second meta-analysis (164) and all of the prospective cohort studies failed to show any association between age at introduction of cow’s milk and either islet autoimmunity (168,170,171,172,173,181) or type 1 diabetes (169).
In a double-blind, randomized trial in Finland (TRIGR Pilot), 230 infants at genetically increased risk for type 1 diabetes were assigned to receive either a casein hydrolysate formula or a conventional, cow’s milk-based formula (control) whenever breast milk was not available during the first 6–8 months of life (182). The incidence of islet antibodies was significantly lower in children fed the casein hydrolysate formula in comparison to the group with conventional cow’s milk-based formula (HR 0.54, 95% CI 0.29–0.95) (182). A larger, multinational randomized intervention study of this same hypothesis, TRIGR, has found no effect on development of islet autoimmunity (183); follow-up of the study participants for type 1 diabetes is underway.
Studies exploring the role of current, i.e., childhood, cow’s milk consumption in the risk for islet autoimmunity and type 1 diabetes have also produced contradictory results. Cow’s milk intake in childhood has been associated with both an increased risk of islet autoimmunity (184,185,186) and type 1 diabetes (187,188), as well as a decreased risk of type 1 diabetes (189). A Finnish study found that cow’s milk consumption during childhood was more closely linked to islet autoimmunity and type 1 diabetes risk than was infant (early) exposure to cow’s milk (188). A nested case-control study within the Finnish DIPP cohort found that increased cow’s milk intake during childhood was weakly associated with increased islet autoimmunity risk (184). While a similar analysis in the DAISY cohort found no association between cow’s milk intake and islet autoimmunity risk, increased cow’s milk intake was associated with progression to type 1 diabetes in children with islet autoimmunity (HR 1.59, 95% CI 1.13–2.25) (190). In DIPP (191), investigators evaluated whether serum fatty acids differed between children developing islet autoimmunity and those remaining autoantibody negative. Myristic acid, pentadecanoic acid, monounsaturated palmitoleic acid isomers 16:1 n-7 and 16:1 n-9, and conjugated linoleic acid were positively associated with the risk of islet autoimmunity at or before the time of seroconversion. Because these serum fatty acids are biomarkers of milk and ruminant meat fat (192,193), this suggests that higher current consumption of milk and meat may be associated with risk of islet autoimmunity. The inconsistencies across these studies may be due to the modifying effects of the underlying genetic profile. This is further described in the Gene X Environment Interactions section.
The reports that newly diagnosed diabetic children compared with age-matched controls have higher levels of serum antibodies against cow’s milk proteins (194,195) have been difficult to reproduce (196). Prospective studies have also been contradictory: the Finnish TRIGR Pilot study showed higher levels of cow’s milk antibodies in infancy prior to the development of type 1 diabetes (197), whereas DAISY did not observe elevations of the cow’s milk IgG4 antibody, beta-lactoglobulin, prior to islet autoimmunity or type 1 diabetes (198).
Solid Foods and Cereals
In addition to breast milk substitutes, such as infant formulas, the infant is exposed to other dietary antigens in the first year of life that may impact oral tolerance or the immune system. Prospective studies of children at increased risk for type 1 diabetes from both Germany (BABYDIAB) and Colorado (DAISY) have shown an increased risk for islet autoimmunity associated with first exposure to cereals prior to the third month of life when compared with introduction in the fourth to sixth months of life. In DAISY, the timing of introduction of any type of cereal (gluten and non-gluten-containing) was associated with an increased islet autoimmunity risk, and the study also found that there appears to be a U-shaped relationship between risk and age at introduction, the nadir of the curve occurring with introduction in the fourth to sixth months of life (168). In contrast, BABYDIAB showed the association with gluten specifically and found that a further protective effect was conferred if foods containing gluten were introduced after the sixth month (171). Given the difference in the defined dietary variables (the non-gluten-containing food variable in BABYDIAB contained non-cereal foods), it is difficult to determine whether the two studies actually contradict each other regarding whether the driving antigen was gluten. The Finnish prospective study (DIPP) suggested that introducing gluten-containing cereals between ages 5 and 5.5 months (the middle tertile of exposure) was associated with an increased risk of islet autoimmunity compared with introducing gluten after age 5.5 months (the third tertile of exposure), but only during the first 3 years of life (173). There was no increased risk of islet autoimmunity associated with introducing gluten earlier than age 5 months (the first tertile of exposure) compared with after age 5.5 months.
Because gluten is the environmental trigger for celiac disease, another childhood autoimmune disease with many similarities to type 1 diabetes, and because gluten is a component of many cereals, gluten has been extensively studied in the context of type 1 diabetes as a potentially important environmental exposure. In the BB diabetes-prone rat, gluten precipitates the onset of islet autoimmunity (199), and MacFarlane et al. identified a wheat storage protein called Glb1 that may be associated with islet damage, by observing that antibodies to this protein were detectable in patients with diabetes, but not in nondiabetic individuals (200). Intervention studies in islet autoantibody-positive children indicate that while a gluten-free diet may not decrease autoantibody titers (201,202), it may improve beta cell function (202). However, an intervention study, in which 150 high-risk infants were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group), found that delaying gluten exposure until age 12 months did not substantially reduce the risk for islet autoimmunity in genetically at-risk children, nor did it increase the risk (104,203).
Other solid foods in the infant diet, besides gluten and cereals, have been implicated in the etiology of islet autoimmunity. In Finland, DIPP found that introduction of root vegetables by age 4 months was associated with an almost twofold increased risk for islet autoimmunity compared with introducing root vegetables after age 4 months (173). They also found that first exposure to egg before age 8 months (the first tertile of exposure) was associated with an increased risk of islet autoimmunity compared with introducing egg after age 11 months (the third tertile of exposure), but only during the first 3 years of life (173). These cross-study differences may be related to country differences in the first solid food that is typically introduced to infants. In the United States, cereals, particularly rice cereal, are often the first solid foods to be introduced to the infant (168), whereas in other countries, root vegetables and fruits are more common first solid foods, suggesting that the focus on cereals may not be relevant across countries and may explain these inconsistent results.
More recently, DAISY and BABYDIAB have prospectively examined the relation of some of these dietary exposures to clinical diabetes in a cohort of children at increased risk for type 1 diabetes. In DAISY (169), both early (age <4 months) and late (age ≥6 months) first exposure to any solid food (compared with exposure at age 4–5 months) predicted development of type 1 diabetes (HR 1.91, 95% CI 1.04–3.51, and HR 3.02, 95% CI 1.26–7.24, respectively). Specifically, early exposure to fruit and late exposure to rice/oat predicted type 1 diabetes (HR 2.23, 95% CI 1.14–4.39, and HR 2.88, 95% CI 1.36–6.11, respectively). BABYDIAB (204) reported that exposure to gluten-containing foods before age 3 months, which occurred rarely, increased the risk of developing islet autoantibodies and type 1 diabetes (n=3) compared to exclusive breastfeeding (HR 3.45, 95% CI 1.04–11.48) or compared to first exposure to gluten between 3.1 and 6.0 months of age. In contrast to DAISY, children who received gluten-containing foods after age 6 months did not have an increased risk of islet autoantibodies, multiple islet autoantibodies, or type 1 diabetes.
These data suggest that there are specific times in infancy wherein exposure is associated with an increased risk of developing islet autoimmunity and type 1 diabetes. In aggregate, these studies lend support to the idea that general antigenic stimulation is more important than the actual antigen in this disease process. The risk associated with early exposure may suggest a mechanism involving an aberrant immune response to dietary antigens in an immature gut immune system among susceptible individuals. The increased risk predicted by late exposure to solid foods may be related to the larger amounts given at initial exposure to older children (168,175), nutrient deficiencies (205), and/or the cessation of breastfeeding before solid foods are introduced, resulting in a loss of the protective effect of breast milk at the introduction of foreign food antigens (168,169,175), described earlier in this chapter.
Vitamin D
Vitamin D has been examined as a potentially protective factor, because it plays an active role in the regulation of the immune system, as well as metabolic pathways relevant to diabetes. Mechanistically, vitamin D has been shown to shift the balance of the body’s T cell response toward down-regulation of the Th1 immune response (206). Both in vitro studies and animal studies have found that vitamin D stimulates a Th2 response (207,208,209). The Th1 response plays a key role in response to intracellular pathogens, primarily viruses and malignancies; its overactivation against autoantigens is thought to cause autoimmunity leading to type 1 diabetes. The Th2 response upregulates antibody production to fight extracellular organisms and promotes tolerance of the fetus during pregnancy; Th2 overactivation may lead to atopic dermatitis or asthma.
Vitamin D status during the intrauterine period may be of special importance for the development of the fetus (210). The seasonality of birth in children with type 1 diabetes and/or the presence of a seasonal pattern at diagnosis of type 1 diabetes could be explained by seasonal variation in endogenous vitamin D production via exposure to the sun (211,212). The monthly averages of maximal daily temperature and daily hours of sunshine were inversely related to the number of new patients per month in Belgium (213). Ecologic studies suggest that ultraviolet radiation exposure, which increases the body’s ability to make vitamin D, is inversely associated with incidence of type 1 diabetes (214,215). However, epidemiologic studies of in utero vitamin D exposures have been inconsistent. In Finland, DIPP (216) examined the maternal diet during pregnancy and found that vitamin D intake was not associated with risk of islet autoimmunity nor type 1 diabetes in the child, which contradicts previous studies from the United States and Sweden that found that maternal vitamin D intake during pregnancy was associated with a decreased risk of islet autoimmunity in the child (217,218). In a meta-analysis, the pooled odds ratio with maternal intake of vitamin D during pregnancy was 0.95 (95% CI 0.66–1.36), suggesting no effect of vitamin D intake (219). A Norwegian study found an association between higher serum 25-hydroxyvitamin D (25(OH)D) in samples collected in late pregnancy and lower risk of type 1 diabetes in the offspring (220), whereas a Finnish study found no such association with samples collected in the first trimester of pregnancy (221).
Multiple studies have examined the role of vitamin D exposure in infancy in the pathogenesis of type 1 diabetes. The EURODIAB multicenter case-control study found that diabetic children were less likely to have been given vitamin D supplements in infancy than control children (222). This finding is similar to that found in the previously described case-control study from Norway, where diabetic children were less likely to have been given cod liver oil supplements during infancy compared to controls (223). However, as fish oils contain both omega-3 fatty acids and vitamin D, it is not possible to attribute this association to one specific component. In a large, historical prospective study from Finland, infants who received no vitamin D supplementation had higher risk of type 1 diabetes than those who did receive supplements (224). Two meta-analyses of retrospective studies showed that the risk of type 1 diabetes was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented (pooled OR 0.71) (219,225). However, in a Swedish prospective study, no association was found between an intermediate dose of vitamin D supplementation during infancy and development of diabetes-related autoantibodies (218).
Determinants of circulating 25(OH)D, the inactive circulating form of vitamin D and an established marker of vitamin D status, include sun exposure, dietary intake (supplements, fatty fish, and vitamin D fortified dairy foods), and genetic predisposition. The aforementioned studies were limited in that they were only able to examine vitamin D from supplements and were not able to examine vitamin D exposure either from foods or via sun exposure. DAISY examined the putative protective factor, vitamin D, and was the first large prospective study to show plasma 25(OH)D levels in infancy or throughout childhood were not associated with islet autoimmunity or progression from islet autoimmunity to type 1 diabetes in children at increased risk for type 1 diabetes (226). Dietary intake of vitamin D (from food and supplements) was also not associated with islet autoimmunity or progression to type 1 diabetes in the DAISY population (226). Interestingly, in a nested case-control study among non-Hispanic white U.S. active duty military personnel, those with 25(OH)D levels ≥100 nmol/L in blood samples measured prior to diagnosis had a 44% lower risk of developing type 1 diabetes than those with 25(OH)D levels <75 nmol/L (rate ratio 0.56, 95% CI 0.35–0.90) (227), suggesting a protective effect of vitamin D levels in adult-onset type 1 diabetes cases. While misclassification of type 1 and type 2 diabetes is common in young adults, results were similar in all study participants and those confirmed to have islet autoantibodies. Two clinical trials reported no effect of 1,25-dihydroxyvitamin D3 (calcitriol) supplementation on sustained insulin production among persons with new-onset type 1 diabetes (228,229). These inconsistent findings suggest that the mechanism by which vitamin D exerts its effect on type 1 diabetes is complex.
One missing component to the aforementioned analyses is the underlying genetic risk. Two GWAS identified variants located within or near genes involved in vitamin D transport (DBP), cholesterol synthesis (DHCR7), and hydroxylation (CYP2R1 and CYP24A1) associated with 25(OH)D levels or vitamin D insufficiency (230,231). Genetic variants influencing 25(OH)D metabolism have been examined in association with both circulating 25(OH)D levels and type 1 diabetes (230,231,232).
The associations found in the aforementioned GWAS were replicated (231) for four vitamin D metabolism genes (DBP, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. CYP27B1, DHCR7, and CYP2R1 were also associated with type 1 diabetes. CYP27B1 had previously been associated with type 1 diabetes in 2007 (233). DAISY found that variants in DHCR7 and CYP27B1 were associated with development of islet autoimmunity, but not progression to type 1 diabetes, in children with islet autoimmunity (234). The DHCR7 variant was also found to be associated with 25(OH)D levels in DAISY children; however, since 25(OH)D levels were not associated with islet autoimmunity or type 1 diabetes risk (226), the effect of this variant is not likely mediated through 25(OH)D levels, suggesting that this enzyme may influence diabetes risk via other mechanisms.
Polyunsaturated Fatty Acids
Several studies have demonstrated a strong effect of long-chain polyunsaturated fatty acids, specifically omega-3 fatty acids, on inflammatory responses in animals and humans (235,236). A relative deficiency of omega-3 fatty acids, a characteristic of many Western diets, may predispose to heightened inflammatory reactions and, thus, increase the risk for autoimmune diseases, such as type 1 diabetes. Alpha-linolenic acid (ALA) is the principal omega-3 fatty acid in Western diets and is found in the green leaves of plants and in flax, canola, walnuts, and soy. The next most common omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are found in fatty fish. Fatty acid levels in plasma or serum and fatty acid content of erythrocyte membranes are short-term and long-term markers of fatty acid status, respectively.
In Norway, a prospective study of DHA and EPA and other fatty acids in the phospholipid fraction of maternal serum collected in late pregnancy found no association with risk of type 1 diabetes before age 15 years (237). However, as mentioned previously, children with type 1 diabetes were less likely to have received cod liver oil (which contains DHA and EPA, along with vitamin D) in infancy (223) and had a decreased percentage of DHA in erythrocyte membranes (238) compared with controls. DAISY reported that higher omega-3 fatty acid intake during childhood was associated with a lower risk of islet autoimmunity and, likewise, that higher omega-3 fatty acid levels in the erythrocyte membrane were associated with a lower risk of islet autoimmunity (Figure 11.4) (13). In DIPP, while investigators did not find an association between serum EPA or DHA and risk of islet autoimmunity, they showed that lower serum linoleic acid, an omega-6 fatty acid, was associated with increased risk of islet autoimmunity (191).
Vitamin E
Animal models suggest that vitamin E, or α-tocopherol, may protect against diabetes (239,240). High maternal intake of vitamin E and other nutrients, such as retinol, beta-carotene, vitamin C, selenium, or manganese, was not associated with development of islet autoimmunity in children (241). Serum α-tocopherol, but not retinol or selenium, was inversely associated with type 1 diabetes in a small case-control study nested within a 21-year follow-up of adult Finnish men (242). In a cohort of initially nondiabetic siblings of children with type 1 diabetes, an inverse association with borderline significance between serum α-tocopherol concentrations and the risk of diabetes was observed (243). However, in DIPP, serum α-tocopherol concentrations were not significantly associated with the risk of islet autoimmunity (244).
Zinc
Studies have shown that serum, plasma, or intracellular zinc levels are significantly lower in type 1 diabetes patients than in controls (245,246). The role of zinc deficiency in triggering onset or progression of islet autoimmunity is unclear, but it could be related to the synthesis, storage, and secretion of insulin that require zinc for conformational integrity of insulin as a hexamer. Autoantibodies to ZnT8 are present in 60%–80% of newly diagnosed patients with type 1 diabetes (247). Ecologic studies suggest that the incidence rate of childhood diabetes is significantly higher in areas with lower levels of zinc in the drinking water (248,249). In Sweden, water samples from families with children with diabetes had lower concentrations of zinc (OR 0.72, 95% CI 0.57–0.90) than water samples from control families (250). A study from Finland suggests no association between maternal consumption of zinc during pregnancy and risk of islet autoimmunity (241).
Weight Gain, Insulin Resistance, and Beta Cell Stress
A number of studies have investigated the hypothesized association between obesity, insulin resistance, beta cell stress, and the development of type 1 diabetes (251,252) and have been reviewed by Rewers (253).
Birth Weight and Infant Growth
A study from Norway found an almost linear correlation between the incidence of type 1 diabetes and birth weight (254). The risk of type 1 diabetes was higher by more than twofold in children with birth weight >4,500 g in comparison to newborns with the lowest birth weight (<2,000 g) (254). Two meta-analyses suggest that children who are heavier at birth have a significant and consistent, but relatively small, increase in risk of type 1 diabetes (255,256). In addition, studies indicate that rapid weight gain during the first year of life is a risk factor for type 1 diabetes (257,258,259). These findings were confirmed in a meta-analysis (255). Another study showed that children developing diabetes had increased height gain at age 0–18 months and were significantly taller from ages 6 to 18 months compared with controls (260). However, DAISY showed that weight growth was not associated with risk of type 1 diabetes neither in the first 9 months nor in the first 15 months of life (height growth not measured before the age of 24 months) (169).
Height, Weight, and Body Mass Index
The “Accelerator Hypothesis” proposes that excess weight gain leading to increases in insulin resistance in early childhood initiates the autoimmunity leading to beta cell destruction and type 1 diabetes development (251). The rising blood glucose (glucotoxicity) may accelerate beta cell apoptosis directly or by inducing beta cell immunogens in genetically predisposed subjects. Ecologic studies have suggested a correlation between increasing body mass index (BMI), weight, and height, and incidence of type 1 diabetes in the population (261,262). Several studies have shown an association between higher BMI Z-scores and earlier age at diagnosis of type 1 diabetes (263,264,265,266), although others have not (267,268,269). In case-control studies, children with type 1 diabetes showed increased weight, height, or BMI Z-scores in early childhood compared with nondiabetic children (260,270,271,272,273,274,275). Analysis of the 1970 British Birth Cohort suggested that increased BMI in childhood increased risk of self-reported type 1 diabetes (276). Similarly, in the Australian BabyDiab cohort, higher weight and BMI Z-scores were associated with development of islet autoimmunity (277). However, analyses of the prepubertal DAISY cohort showed that BMI was not associated with development of islet autoimmunity nor progression to type 1 diabetes and that height and weight were weakly inversely associated with risk of islet autoimmunity (278), which is contrary to the Accelerator Hypothesis. However, greater height growth velocity was associated with islet autoimmunity development and type 1 diabetes development, suggesting that velocity of growth and its related stressors may be involved in the progression from genetic susceptibility to islet autoimmunity and then to type 1 diabetes in prepubertal children. BABYDIAB participants positive for islet autoantibodies did not have an increased homeostasis model assessment of insulin resistance (HOMA-IR) compared with age-matched islet autoantibody-negative children at ages 8 or 11 years (279). Contrary to the accelerator hypothesis, islet autoimmunity status was associated with decreased HOMA-IR values, controlling for age and sex (p=0.01). BMI was similar between islet autoantibody-positive and autoantibody-negative children at ages 2, 5, 8, and 11 years and similar to that of national reference values (279).
In summary, small and inconsistent effects of height or weight have been reported by some studies, mostly from Scandinavia. These are likely not causally related to the autoimmune disease process in a vast majority of the cases.
Glycemic Index
In addition to growth, obesity, and insulin resistance, dietary factors, such as glycemic index and glycemic load, may also stress the beta cells. While development of islet autoimmunity was not associated with either, progression to type 1 diabetes in children with islet autoimmunity was associated with higher glycemic index and load at the first islet autoimmunity-positive visit (280), perhaps due to increased demand on the beta cells to release insulin.
Toxins and Chemical Compounds
Toxins found in foods or water may activate autoimmune mechanisms in genetically susceptible individuals, and exposure to toxins may result in pancreatic islet cell death. Streptozotocin (281,282) or dietary nitrates and nitrosamines (283) induce islet autoimmunity in animal models. Circumstantial and ecologic evidence suggests a connection between type 1 diabetes and water containing nitrates, nitrites, or nitrosamines, although other studies have shown either no or contradictory associations (248,284,285). In a case-control study in Sweden, type 1 diabetes was associated with consuming higher amounts of foods containing nitrosamines (OR 1.7 and OR 2.6) and nitrates or nitrites (OR 0.8 and OR 2.4 for medium and high, respectively, compared with low amounts) (286). In Sweden, water samples from families with children with diabetes had higher concentrations of nitrate (OR 1.32, 95% CI 1.06–1.64) than water samples from control families (250). In Canada, only a nonsignificant trend between increasing consumption of nitrates in food and type 1 diabetes was observed (287). In Germany, water concentrations of nitrate and nitrite were not associated with risk of either islet autoimmunity or progression to type 1 diabetes progression (288).
Animal studies show that ingestion of subtoxic levels of bafilomycin, a natural toxin found in skins of Streptomyces-infected root vegetables, such as potatoes, by pregnant nonobese diabetic mice results in higher incidence and earlier onset of diabetes in their offspring (289,290,291). Thus, exposure to small quantities of bafilomycin in the maternal diet during pregnancy may contribute to risk of type 1 diabetes in the child.
Metabolomic Studies
The serum/plasma metabolite profile detected by combining gas and liquid chromatography followed by mass spectrometry has established metabolomics as a readout of phenotypes that has enabled the discovery of previously undetected associations between metabolic pathways and diseases. Metabolomics is central to the analysis of samples obtained prior to development of islet autoimmunity. These analyses can be used to test the hypothesis that a trigger(s) of islet autoimmunity induces or acts upon metabolic disturbances that predict the appearance of islet autoantibodies. Similarly, children with islet autoimmunity may express specific serum metabolite profiles heralding clinical onset of diabetes.
High genetic risk Finnish children followed since birth until diagnosis of type 1 diabetes had reduced serum levels of succinic acid and phosphatidylcholine already at birth. Furthermore, levels of lysophosphatidylcholine increased months before seroconversion to islet autoantibodies but normalized after seroconversion (292). An independent population of offspring of type 1 diabetes parents has suggested that higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids may predict islet autoimmunity (293). In addition, children developing islet autoimmunity before age 2 years had lower levels of methionine than those developing islet autoimmunity at older ages (293).
A Swedish cohort study used umbilical cord blood lipidomic analysis to identify possible risk markers for the early development of type 1 diabetes while controlling for HLA genotype, sex, and date of birth, as well as mother’s age and gestational age (294). A total of 106 lipid metabolites from cord blood samples were identified and, using principal component analysis, were analyzed for their predictive ability. In the children developing type 1 diabetes before age 4 years, lower levels of cord blood phospholipids (phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins) all predicted development of type 1 diabetes, while in the children developing type 1 diabetes before age 2 years, triglycerides predicted type 1 diabetes. These results were replicated in a study of cord blood from children in the DIPP study, which also showed higher risk of progression to type 1 diabetes associated with lower levels of choline-containing phospholipids, including sphingomyelins and phosphatidylcholines (295).
The metabolomic studies to date present several leads for a search for the environmental factors that trigger islet autoimmunity and are involved in the increasing incidence of type 1 diabetes. The alterations in cord blood lipoprotein profiles noted in both the DIPP and Diabetes Prediction in Skåne (DiPiS) studies suggest that the intrauterine environment may affect type 1 diabetes risk. Further, the other early metabolomic changes may reflect specific alterations in the infant’s microbiome. Other lipidomic and metabolomic changes noted above that precede the development of autoimmunity may reflect the activation of proinflammatory and anti-inflammatory mechanisms in early islet autoimmunity. While fascinating, these findings have to be interpreted with caution as the studies to date have been very small and remain to be replicated (for a comprehensive review see Frohnert and Rewers [296]).
Psychosocial and Socioeconomic Factors
Psychological Stress
A role of psychological stress in the etiology of type 1 diabetes has been suggested by case reports and small case-control studies (297). A cross-sectional study of 4,400 general-population children in Sweden found an association between presence of GAD autoantibodies at age 1 year and the history of high parenting stress (OR 1.8, 95% CI 1.2–2.9, p<0.01), serious life events (OR 2.3, 95% CI 1.3–4.0), foreign origin of the mother (OR 2.1, 95% CI 1.3–3.3), and low paternal education (OR 1.6, 95% CI 1.1–2.3), independent of family history of diabetes (298). The same group of investigators reported that mothers’ experiences of divorce (OR 3.6, 95% CI 1.4–9.6) or violence (OR 2.9, 95% CI 1.0–7.8) were associated with islet autoimmunity in the children age 2.5 years (299). Finally, in a Danish cohort of 1,548,746 children, 39,857 children were exposed to bereavement during their prenatal life. Children (primarily females) who were exposed to maternal bereavement due to traumatic father or sibling deaths had an increased risk of type 1 diabetes (relative risk [RR] 2.03, 95% CI 1.22–3.38) (300). While suggestive, these data need to be confirmed in a prospective study with exposures and outcomes ascertained at frequent intervals.
Socioeconomic Factors
The wide variation in childhood type 1 diabetes incidence rates within different populations could be partially explained by indicators of national and individual prosperity. An Italian study suggested that the association between early-life socioeconomic indicators and the risk of type 1 diabetes varied by age at onset of diabetes (301). These indicators could reflect differences in environmental risk factors, such as nutrition or lifestyle, that are important in determining the risk of type 1 diabetes. The EURODIAB study has shown a positive association of incidence rates with increasing value of gross domestic product (302).
Other Factors
Initiation of persistent islet autoimmunity may be related to factors operating during pregnancy, such as infections, preeclampsia, blood incompatibility, or during the perinatal period.
Prenatal and Perinatal Factors
In utero and perinatal exposures may trigger islet autoimmunity. Viral infection of a fetus or newborn often evades clearance and may induce lifelong immunologic tolerance to the virus (303). The ability of the offspring’s immune system to regard a virus as self may have consequences for latency, re-infection, and autoimmunity. Such a mechanism has been proposed for the role of enteroviruses and rubella virus in the etiology of type 1 diabetes.
Other potential risk factors include ABO incompatibility, hyperbilirubinemia, preeclampsia (304), complicated delivery (169,305), mother’s age (306), and high birth weight for gestational age (305,306,307). In contrast, smoking in pregnant mothers was found to reduce type 1 diabetes risk (307). A systematic review and meta-analysis of 18 studies suggested that preterm birth was significantly associated with increased risk of type 1 diabetes (OR 1.18, 95% CI 1.11–1.25) (308). Subgroup analyses suggested the association was present both in case-control studies (OR 1.16, 95% CI 1.06–1.26) and cohort studies (RR 1.20, 95% CI 1.11–1.29). A large Swedish cohort study found an inverted U-shaped relation between gestational age and type 1 diabetes (309). Children born before the 33rd week or after the 40th week were at the lowest risk, while those born between 33 and 36 weeks were at the highest risk (RR 1.18, 95% CI 1.09–1.28), compared to those born at term. While these factors are unlikely to directly trigger islet autoimmunity, they may direct future research toward causal exposures.
Further evidence of fetal programming of type 1 diabetes risk comes from the still unexplained decreased type 1 diabetes risk in children of mothers with type 1 diabetes compared to children of fathers with type 1 diabetes (310,311).
Gene x Environment Interactions
The inconsistencies in the associations between dietary factors and islet autoimmunity or type 1 diabetes across studies may be explained, in part, by methodologic differences in population selection and data collection. However, another explanation is gene-environment interaction, where the differences in the observed exposure associations may be due to differences in gene allele frequency across populations. There are a number of ways to explore gene x environment interaction in epidemiologic data, each dependent on the underlying hypothesis.
One hypothesis is that the effect of environmental risk factors may be stronger among individuals possessing increased genetic risk variants; whereby the odds ratio (or relative risk) is significantly different than 1 (i.e., associated) in those possessing the genetic risk variants, such as the HLA-DR risk genotypes, and null (i.e., not associated) in those without the variants, perhaps because it is easier to see the effect of the exposure in a genetically susceptible population. Alternatively, the aforementioned rise in type 1 diabetes incidence, coupled with data suggesting an increasing penetrance of moderate-risk HLA-DR genotypes, suggests that the pressures of an increasingly permissive environment may be more easily observed in children with moderate- or low-risk HLA-DR genotypes compared with high-risk genotypes.
In addition, one can examine a potential gene x environment interaction in more detail by dividing analyses into exposure*HLA combinations, with one risk group being those who have the exposure but not the HLA genotype, another risk group contains those who have the HLA genotype and not the exposure, and the putative highest risk group (i.e., representing the interaction) would be those with both the HLA genotype and the exposure. Each of these risk groups would be compared to the referent group, who are those with neither the HLA genotype nor the exposure. If the odds ratio in those with both the genetic variant and the exposure is greater than the product of the odds ratio for the exposure and odds ratio for the genotype, then the interaction is considered more than multiplicative.
Several studies have examined potential interactions between the HLA variants and dietary exposures. Stene et al. tested whether the effect of different dietary factors (use of cod liver oil and multivitamins by the mother during pregnancy, use of cod liver oil or vitamin D supplements in the first year of life, and exclusive breastfeeding for <3 months) differed across HLA risk groups and found no evidence of interaction, although power was limited (312). In DAISY, the hazard ratios for islet autoimmunity for early and late exposure to cereals in children with HLA-DR3/4 genotype were greater than in children with the moderate and low HLA-DR genotypes, although the interaction term was only marginally significant (168). Studies from Colorado and Chile have indicated a more than multiplicative joint effect of HLA-DR risk and either short duration of exclusive breastfeeding (313) or early introduction of cow’s milk and solid foods (314). As an example, in the Colorado study, the odds ratio for type 1 diabetes for being HLA-DR3/4 in the absence of early exposure to solid foods was 3.1 (95% CI 1.4–7.2), the odds ratio for early exposure to solid foods in the absence of HLA-DR3/4 was 1.7 (95% CI 0.5–5.8), and the odds ratio for having both HLA-DR3/4 and early exposure to solid foods was 6.3 (95% CI 2.5–16.1) (314).
The inconsistent findings with childhood cow’s milk consumption and risk of islet autoimmunity or type 1 diabetes may be due to the modifying effects of the underlying genetic profile. In DAISY, greater childhood cow’s milk protein intake (as a surrogate of total milk consumption) was associated with increased islet autoimmunity risk in children with low/moderate-risk HLA-DR genotypes (HR 1.41, 95% CI 1.08–1.84), but not in children with high-risk HLA-DR genotypes (315).
In addition to HLA, other type 1 diabetes candidate genes, such as INS, PTPN22, CTLA4, and IFIH1, have been explored for interactions with dietary exposures. DIPP (316) detected an interaction between early cow’s milk exposure, PTPN22, and appearance of islet autoimmunity, where the PTPN22 polymorphism was associated with the development of islet autoimmunity only in children exposed to cow’s milk formula prior to age 6 months.
Investigators have explored interactions with genes that are not candidate genes for type 1 diabetes but may be related to dietary exposures either with regard to metabolism or action. For example, omega-3 fatty acids may act as ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARG) to promote anti-inflammatory actions. However, no evidence of interaction was found between the PPARG gene variant and cod liver oil intake on risk of type 1 diabetes in a Norwegian case-control study (317). Delta-6-desaturase, encoded by FADS2, and delta-5-desaturase, encoded by FADS1 (318), work in series to convert the omega-3 fatty acid ALA to the more anti-inflammatory fatty acid EPA. DAISY observed a strong interaction between dietary intake of ALA and FADS1 and FADS2 on risk of islet autoimmunity, where ALA intake was significantly more protective for islet autoimmunity in the presence of the increasing number of minor alleles at FADS1 rs174556 (pinteraction=0.017), at FADS2 rs174570 (pinteraction=0.016), and at FADS2 rs174583 (pinteraction=0.045) (Figure 11.5) (319). Thus, the putative protective effect of n-3 fatty acids on islet autoimmunity may result from a complex interaction between intake and genetically controlled fatty acid desaturation.
In BABYDIAB, cesarean section appeared to interact with immune response genes, such as the IFIH1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes-susceptible IFIH1 genotypes (12-year risk, 9.1% vs. <3% for all other combinations, p<0.0001) (320). In Norway, mode of delivery was also found to interact with PTPN22, using a case-only approach, where the relative risks for type 1 diabetes conferred by PTPN22 were 2.11 (95% CI 1.64–2.72) for those born vaginally and 0.99 (95% CI 0.50–1.99) for those born by cesarean section (pinteraction=0.028) (321).
Environment x Environment Interactions
Environmental exposures may also interact, or act in concert, with other environmental exposures; however, examples of these observations are not prevalent in the scientific literature. DAISY (322) observed that a greater number of gastrointestinal illnesses was associated with an increased risk of islet autoimmunity, but only among children who were exposed to gluten-containing grains (wheat or barley) either age <4 months (HR 1.37, 95% CI 1.22–1.55) or age ≥7 months (HR 1.12, 95% CI 1.05–1.19). Power to detect gene-environment or environment-environment interactions has been limited in studies reported so far. Table 11.5 provides a summary of the significant associations with diet described above, including gene-diet and infection-diet interactions.
Prospective cohort studies have contributed enormously to the understanding of the natural history and risk factors for type 1 diabetes. A variety of exposures appear to trigger islet autoimmunity and to promote progression to clinical diabetes in some children; none of the current candidate risk factors seems to explain most of the risk. Future trials may need to take into account the genetic and environmental heterogeneity of this disease in developing personalized interventions.
List of Abbreviations
- 25(OH)D
25-hydroxyvitamin D
- ALA
alpha-linolenic acid
- BB
BioBreeding
- BCG
Bacillus Calmette-Guérin
- BMI
body mass index
- CI
confidence interval
- CMV
cytomegalovirus
- DAISY
Diabetes Autoimmunity Study in the Young
- DHA
docosahexaenoic acid
- DiMe
Childhood Diabetes in Finland Study
- DIPP
Diabetes Prediction and Prevention Study
- EPA
eicosapentaenoic acid
- GAD
glutamic acid decarboxylase
- GWAS
genome-wide association studies
- HLA
human leukocyte antigen
- HOMA-IR
homeostasis model assessment of insulin resistance
- HR
hazard ratio
- IA-2
insulinoma antigen 2
- IFIH1
interferon-induced helicase C domain-containing protein 1
- MIDIA
Environmental Triggers of Type 1 Diabetes Study
- OR
odds ratio
- PPARG
peroxisome proliferator-activated receptor-gamma
- RR
relative risk
- RT-PCR
reverse transcription-polymerase chain reaction
- TEDDY
The Environmental Determinants of Diabetes in the Young
- TRIGR
Trial to Reduce IDDM in the Genetically at Risk
- ZnT8
zinc transporter 8
References
- 1.
- Secular trends in incidence of childhood IDDM in 10 countries. Diabetes Epidemiology Research International Group. Diabetes 39:858–864, 1990 [PubMed: 2354748]
- 2.
- Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith G, Bloch C, Rewers M, Dabelea D: Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes Care 30:503–509, 2007 [PubMed: 17327312]
- 3.
- Harjutsalo V, Sjoberg L, Tuomilehto J: Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 371:1777–1782, 2008 [PubMed: 18502302]
- 4.
- Rewers M, LaPorte RE, Walczak M, Dmochowski K, Bogaczynska E: Apparent epidemic of insulin-dependent diabetes mellitus in Midwestern Poland. Diabetes 36:106–113, 1987 [PubMed: 3792661]
- 5.
- Fleegler FM, Rogers KD, Drash A, Rosenbloom AL, Travis LB, Court JM: Age, sex, and season of onset of juvenile diabetes in different geographic areas. Pediatrics 63:374–379, 1979 [PubMed: 440839]
- 6.
- National Board of Health and Welfare: Health Care and Medical Services—Status Report 2006. Stockholm, Sweden: The National Board of Health and Welfare, 2007
- 7.
- Kostraba JN, Gay EC, Cai Y, Cruickshanks KJ, Rewers MJ, Klingensmith GJ, Chase HP, Hamman RF: Incidence of insulin-dependent diabetes mellitus in Colorado. Epidemiology 3:232–238, 1992 [PubMed: 1591322]
- 8.
- Neu A, Kehrer M, Hub R, Ranke MB: Incidence of IDDM in German children aged 0–14 years. A 6-year population-based study (1987–1993). Diabetes Care 20:530–533, 1997 [PubMed: 9096975]
- 9.
- Rosenbauer J, Icks A, Giani G: Incidence and prevalence of childhood type 1 diabetes mellitus in Germany—model-based national estimates. J Pediatr Endocrinol Metab 15:1497–1504, 2002 [PubMed: 12503857]
- 10.
- Jarosz-Chobot P, Polanska J, Szadkowska A, Kretowski A, Bandurska-Stankiewicz E, Ciechanowska M, Deja G, Mysliwiec M, Peczynska J, Rutkowska J, Sobel-Maruniak A, Fichna P, Chobot A, Rewers M: Rapid increase in the incidence of type 1 diabetes in Polish children from 1989 to 2004, and predictions for 2010 to 2025. Diabetologia 54:508–515, 2011 [PMC free article: PMC3034048] [PubMed: 21165594]
- 11.
- TEDDY Study Group: The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Ann N Y Acad Sci 1150:1–13, 2008 [PMC free article: PMC2886800] [PubMed: 19120261]
- 12.
- Nathanson N, Kew OM: From emergence to eradication: the epidemiology of poliomyelitis deconstructed. Am J Epidemiol 172:1213–1229, 2010 [PMC free article: PMC2991634] [PubMed: 20978089]
- 13.
- Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, Orton HD, Baron AE, Clare-Salzler M, Chase HP, Szabo NJ, Erlich H, Eisenbarth GS, Rewers M: Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 298:1420–1428, 2007 [PubMed: 17895458]
- 14.
- Hummel M, Fuchtenbusch M, Schenker M, Ziegler AG: No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care 23:969–974, 2000 [PubMed: 10895848]
- 15.
- Lonnrot M, Korpela K, Knip M, Ilonen J, Simell O, Korhonen S, Savola K, Muona P, Simell T, Koskela P, Hyoty H: Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. Diabetes 49:1314–1318, 2000 [PubMed: 10923631]
- 16.
- Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS: Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309:2473–2479, 2013 [PMC free article: PMC4878912] [PubMed: 23780460]
- 17.
- Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, Bell R, Badaru A, Talton JW, Crume T, Liese AD, Merchant AT, Lawrence JM, Reynolds K, Dolan L, Liu LL, Hamman RF; SEARCH for Diabetes in Youth Study: Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 311:1778–1786, 2014 [PMC free article: PMC4368900] [PubMed: 24794371]
- 18.
- Wagener DK, Sacks JM, LaPorte RE, MacGregor JM: The Pittsburgh study of insulin-dependent diabetes mellitus. Risk for diabetes among relatives of IDDM. Diabetes 31:136–144, 1982 [PubMed: 6759229]
- 19.
- Allen C, Palta M, D’Alessio DJ: Risk of diabetes in siblings and other relatives of IDDM subjects. Diabetes 40:831–836, 1991 [PubMed: 2060720]
- 20.
- Steck AK, Barriga KJ, Emery LM, Fiallo-Scharer RV, Gottlieb PA, Rewers MJ: Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care 28:296–300, 2005 [PubMed: 15677782]
- 21.
- Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC, Elliott RB, Eisenbarth GS: Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 318:698–702, 1999 [PMC free article: PMC27778] [PubMed: 10074012]
- 22.
- Lorenzen T, Pociot F, Hougaard P, Nerup J: Long-term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 37:321–327, 1994 [PubMed: 8174848]
- 23.
- O’Leary LA, Dorman JS, LaPorte RE, Orchard TJ, Becker DJ, Kuller LH, Eberhardt MS, Cavender DE, Rabin BS, Drash AL: Familial and sporadic insulin-dependent diabetes: evidence for heterogeneous etiologies? Diabetes Res Clin Pract 14:183–190, 1991 [PubMed: 1778111]
- 24.
- Yu L, Cuthbertson DD, Eisenbarth GS, Krischer JP: Diabetes Prevention Trial 1: prevalence of GAD and ICA512 (IA-2) autoantibodies by relationship to proband. Ann NY Acad Sci 958:254–258, 2002 [PubMed: 12021118]
- 25.
- Bonifacio E, Hummel M, Walter M, Schmid S, Ziegler AG: IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes. Diabetes Care 27:2695–2700, 2004 [PubMed: 15505007]
- 26.
- Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA: The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet 59:1134–1148, 1996 [PMC free article: PMC1914851] [PubMed: 8900244]
- 27.
- Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F, Todd JA, Rich SS; Type 1 Diabetes Genetics Consortium: Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes 54:2995–3001, 2005 [PubMed: 16186404]
- 28.
- Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678, 2007 [PMC free article: PMC2719288] [PubMed: 17554300]
- 29.
- Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE, Downes K, Barrett JC, Healy BC, Mychaleckyj JC, Warram JH, Todd JA: Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40:1399–1401, 2008 [PMC free article: PMC2635556] [PubMed: 18978792]
- 30.
- Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, Howson JM, Stevens H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, Todd JA: Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359:2767–2777, 2008 [PMC free article: PMC2840835] [PubMed: 19073967]
- 31.
- Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS; Type 1 Diabetes Genetics Consortium: Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707, 2009 [PMC free article: PMC2889014] [PubMed: 19430480]
- 32.
- Concannon P, Chen WM, Julier C, Morahan G, Akolkar B, Erlich HA, Hilner JE, Nerup J, Nierras C, Pociot F, Todd JA, Rich SS; Type 1 Diabetes Genetics Consortium: Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 58:1018–1022, 2009 [PMC free article: PMC2661598] [PubMed: 19136655]
- 33.
- Bell GI, Horita S, Karam JH: A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183, 1984 [PubMed: 6363172]
- 34.
- Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338, 2004 [PubMed: 15004560]
- 35.
- Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK, Groop PH, Forsblom C, Pettersson-Fernholm K, Ilonen J; FinnDiane Study Group: Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes—indication of an increased environmental pressure? Diabetologia 46:420–425, 2003 [PubMed: 12687342]
- 36.
- Fourlanos S, Varney MD, Tait BD, Morahan G, Honeyman MC, Colman PG, Harrison LC: The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31:1546–1549, 2008 [PMC free article: PMC2494654] [PubMed: 18487476]
- 37.
- Resic-Lindehammer S, Larsson K, Ortqvist E, Carlsson A, Cederwall E, Cilio CM, Ivarsson SA, Jonsson BA, Larsson HE, Lynch K, Neiderud J, Nilsson A, Sjoblad S, Lernmark A; Swedish Childhood Diabetes Study Group, Aili M, Baath LE, Carlsson E, Edenwall H, Forsander G, Granstro BW, Gustavsson I, Hanas R, Hellenberg L, Hellgren H, Holmberg E, Hornell H, Ivarsson SA, Johansson C, Jonsell G, Kockum K, Lindblad B, Lindh A, Ludvigsson J, Myrdal U, Neiderud J, Segnestam K, Sjoblad S, Skogsberg L, Stromberg L, Stahle U, Thalme B, Tullus K, Tuvemo T, Wallensteen M, Westphal O, Aman J: Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk. Acta Diabetol 45:231–235, 2008 [PubMed: 18769865]
- 38.
- Spoletini M, Zampetti S, Campagna G, Marandola L, Capizzi M, Buzzetti R; IMDIAB Study Group: Temporal trends of HLA, CTLA-4 and PTPN22 genotype frequencies among type 1 diabetes in Continental Italy. PLoS One 8:e61331, 2013 [PMC free article: PMC3629148] [PubMed: 23613833]
- 39.
- Steck AK, Armstrong TK, Babu SR, Eisenbarth GS; Type 1 Diabetes Genetics Consortium: Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 60:1045–1049, 2011 [PMC free article: PMC3046823] [PubMed: 21307077]
- 40.
- Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith GJ, Rewers M, Dabelea D: Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care 31:1392–1396, 2008 [PMC free article: PMC2453682] [PubMed: 18356404]
- 41.
- Gillespie KM, Bain SC, Barnett AH, Bingley PJ, Christie MR, Gill GV, Gale EA: The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364:1699–1700, 2004 [PubMed: 15530631]
- 42.
- Ziegler AG, Bonifacio E; BABYDIAB-BABYDIET Study Group: Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia 55:1937–1943, 2012 [PubMed: 22289814]
- 43.
- Ilonen J, Hammais A, Laine AP, Lempainen J, Vaarala O, Veijola R, Simell O, Knip M: Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62:3636–3640, 2013 [PMC free article: PMC3781470] [PubMed: 23835325]
- 44.
- Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark A, Hagopian WA, Rewers MJ, She JX, Simell OG, Toppari J, Ziegler AG, Akolkar B, Bonifacio E; TEDDY Study Group: The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY Study. Diabetologia 58:980–987, [PMC free article: PMC4393776] [PubMed: 25660258]
- 45.
- Christau B, Kromann H, Andersen OO, Christy M, Buschard K, Arnung K, Kristensen IH, Peitersen B, Steinrud J, Nerup J: Incidence, seasonal and geographical patterns of juvenile-onset insulin-dependent diabetes mellitus in Denmark. Diabetologia 13:281–284, 1977 [PubMed: 913920]
- 46.
- Durruty P, Ruiz F, Garcia de los Rios M: [Seasonal distribution of the diagnosis of insulin-dependent diabetes mellitus]. [Article in Spanish] Rev Chil Pediatr 50:7–11, 1979 [PubMed: 552654]
- 47.
- Samuelsson U, Carstensen J, Lofman O, Nordfeldt S: Seasonal variation in the diagnosis of type 1 diabetes in south-east Sweden. Diabetes Res Clin Pract 76:75–81, 2007 [PubMed: 16963147]
- 48.
- Lynch KF, Lernmark B, Merlo J, Cilio CM, Ivarsson SA, Lernmark A; Diabetes Prediction in Skane (DiPiS) Study Group: Cord blood islet autoantibodies and seasonal association with the type 1 diabetes high-risk genotype. J Perinatol 28:211–217, 2008 [PubMed: 18273032]
- 49.
- Vaiserman AM, Carstensen B, Voitenko VP, Tronko MD, Kravchenko VI, Khalangot MD, Mechova LV: Seasonality of birth in children and young adults (0–29 years) with type 1 diabetes in Ukraine. Diabetologia 50:32–35, 2007 [PubMed: 17093948]
- 50.
- Kahn HS, Morgan TM, Case LD, Dabelea D, Mayer-Davis EJ, Lawrence JM, Marcovina SM, Imperatore G; SEARCH for Diabetes in Youth Study Group: Association of type 1 diabetes with month of birth among U.S. youth: the SEARCH for Diabetes in Youth Study. Diabetes Care 32:2010–2015, 2009 [PMC free article: PMC2768213] [PubMed: 19675199]
- 51.
- Tauriainen S, Oikarinen S, Oikarinen M, Hyoty H: Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol 33:45–55, 2011 [PubMed: 20424841]
- 52.
- Stene LC, Rewers M: Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies. Clin Exp Immunol 168:12–23, 2012 [PMC free article: PMC3390488] [PubMed: 22385232]
- 53.
- Hyoty H, Taylor KW: The role of viruses in human diabetes. Diabetologia 45:1353–1361, 2002 [PubMed: 12378375]
- 54.
- Yoon JW, Austin M, Onodera T, Notkins AL: Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300:1173–1179, 1979 [PubMed: 219345]
- 55.
- Tracy S, Drescher KM, Chapman NM: Enteroviruses and type 1 diabetes. Diabetes Metab Res Rev 27:820–823, 2011 [PubMed: 22069266]
- 56.
- Morgan NG, Richardson SJ: Enteroviruses as causative agents in type 1 diabetes: loose ends or lost cause? Trends Endocrinol Metab 25:611–619, 2014 [PubMed: 25175301]
- 57.
- Witso E, Tapia G, Cinek O, Pociot FM, Stene LC, Ronningen KS: Polymorphisms in the innate immune IFIH1 gene, frequency of enterovirus in monthly fecal samples during infancy, and islet autoimmunity. PLoS One 6:e27781, 2011 [PMC free article: PMC3215739] [PubMed: 22110759]
- 58.
- Serreze DV, Ottendorfer EW, Ellis TM, Gauntt CJ, Atkinson MA: Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. Diabetes 49:708–711, 2000 [PubMed: 10905477]
- 59.
- Horwitz MS, Fine C, Ilic A, Sarvetnick N: Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration. J Autoimmun 16:211–217, 2001 [PubMed: 11334485]
- 60.
- Christen U, Edelmann KH, McGavern DB, Wolfe T, Coon B, Teague MK, Miller SD, Oldstone MB, von Herrath MG: A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J Clin Invest 114:1290–1298, 2004 [PMC free article: PMC524231] [PubMed: 15520861]
- 61.
- Drescher KM, Kono K, Bopegamage S, Carson SD, Tracy S: Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection. Virology 329:381–394, 2004 [PubMed: 15518817]
- 62.
- Stene LC, Oikarinen S, Hyoty H, Barriga KJ, Norris JM, Klingensmith G, Hutton JC, Erlich HA, Eisenbarth GS, Rewers M: Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). Diabetes 59:3174–3180, 2010 [PMC free article: PMC2992780] [PubMed: 20858685]
- 63.
- Gamble DR, Kinsley ML, FitzGerald MG, Bolton R, Taylor KW: Viral antibodies in diabetes mellitus. Br Med J 3:627–630, 1969 [PMC free article: PMC1984442] [PubMed: 5811681]
- 64.
- Graves PM, Rotbart HA, Nix WA, Pallansch MA, Erlich HA, Norris JM, Hoffman M, Eisenbarth GS, Rewers M: Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Res Clin Pract 59:51–61, 2003 [PubMed: 12482642]
- 65.
- Sadeharju K, Knip M, Hiltunen M, Akerblom HK, Hyoty H: The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens. Diabetologia 46:1100–1105, 2003 [PubMed: 12845430]
- 66.
- Green J, Casabonne D, Newton R: Coxsackie B virus serology and type 1 diabetes mellitus: a systematic review of published case-control studies. Diabet Med 21:507–514, 2004 [PubMed: 15154932]
- 67.
- Yeung WC, Rawlinson WD, Craig ME: Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35, 2011 [PMC free article: PMC3033438] [PubMed: 21292721]
- 68.
- Systematic Reviews in Health Care: Meta-analysis in Context. Egger M, Davey Smith G, Altman DG, Eds. London, BMJ Publishing Group, 2001
- 69.
- Clements GB, Galbraith DN, Taylor KW: Coxsackie B virus infection and onset of childhood diabetes. Lancet 346:221–223, 1995 [PubMed: 7616803]
- 70.
- Andreoletti L, Hober D, Hober-Vandenberghe C, Fajardy I, Belaich S, Lambert V, Vantyghem MC, Lefebvre J, Wattre P: Coxsackie B virus infection and beta cell autoantibodies in newly diagnosed IDDM adult patients. Clin Diagn Virol 9:125–133, 1998 [PubMed: 9645994]
- 71.
- Nairn C, Galbraith DN, Taylor KW, Clements GB: Enterovirus variants in the serum of children at the onset of type 1 diabetes mellitus. Diabet Med 16:509–513, 1999 [PubMed: 10391400]
- 72.
- Chehadeh W, Weill J, Vantyghem MC, Alm G, Lefebvre J, Wattre P, Hober D: Increased level of interferon-alpha in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J Infect Dis 181:1929–1939, 2000 [PubMed: 10837172]
- 73.
- Coutant R, Carel JC, Lebon P, Bougneres PF, Palmer P, Cantero-Aguilar L: Detection of enterovirus RNA sequences in serum samples from autoantibody-positive subjects at risk for diabetes. Diabet Med 19:968–969, 2002 [PubMed: 12421438]
- 74.
- Moya-Suri V, Schlosser M, Zimmermann K, Rjasanowski I, Gurtler L, Mentel R: Enterovirus RNA sequences in sera of schoolchildren in the general population and their association with type 1-diabetes-associated autoantibodies. J Med Microbiol 54:879–883, 2005 [PubMed: 16091441]
- 75.
- Sarmiento L, Cabrera-Rode E, Lekuleni L, Cuba I, Molina G, Fonseca M, Heng-Hung L, Borroto AD, Gonzalez P, Mas-Lago P, Diaz-Horta O: Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes. Autoimmunity 40:540–545, 2007 [PubMed: 17966045]
- 76.
- Schulte BM, Bakkers J, Lanke KH, Melchers WJ, Westerlaken C, Allebes W, Aanstoot HJ, Bruining GJ, Adema GJ, van Kuppeveld FJ, Galama JM: Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol 23:99–104, 2010 [PubMed: 20121407]
- 77.
- Lonnrot M, Salminen K, Knip M, Savola K, Kulmala P, Leinikki P, Hyypia T, Akerblom HK, Hyoty H: Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group. J Med Virol 61:214–220, 2000 [PubMed: 10797377]
- 78.
- Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R, Simell O, Knip M, Hyoty H: Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 60:276–279, 2011 [PMC free article: PMC3012181] [PubMed: 20943747]
- 79.
- Chistiakov DA, Voronova NV, Savost’Anov KV, Turakulov RI: Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients. Hum Immunol 71:1128–1134, 2010 [PubMed: 20736039]
- 80.
- Fuchtenbusch M, Irnstetter A, Jager G, Ziegler AG: No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes. J Autoimmun 17:333–340, 2001 [PubMed: 11771958]
- 81.
- Hyoty H, Hiltunen M, Knip M, Laakkonen M, Vahasalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, Akerblom HK: A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 44:652–657, 1995 [PubMed: 7789630]
- 82.
- Sadeharju K, Lonnrot M, Kimpimaki T, Savola K, Erkkila S, Kalliokoski T, Savolainen P, Koskela P, Ilonen J, Simell O, Knip M, Hyoty H: Enterovirus antibody levels during the first two years of life in prediabetic autoantibody-positive children. Diabetologia 44:818–823, 2001 [PubMed: 11508265]
- 83.
- Sadeharju K, Hamalainen AM, Knip M, Lonnrot M, Koskela P, Virtanen SM, Ilonen J, Akerblom HK, Hyoty H; Finnish TRIGR Study Group: Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial. Clin Exp Immunol 132:271–277, 2003 [PMC free article: PMC1808709] [PubMed: 12699416]
- 84.
- Salminen K, Sadeharju K, Lonnrot M, Vahasalo P, Kupila A, Korhonen S, Ilonen J, Simell O, Knip M, Hyoty H: Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J Med Virol 69:91–98, 2003 [PubMed: 12436483]
- 85.
- Salminen KK, Vuorinen T, Oikarinen S, Helminen M, Simell S, Knip M, Ilonen J, Simell O, Hyoty H: Isolation of enterovirus strains from children with preclinical type 1 diabetes. Diabet Med 21:156–164, 2004 [PubMed: 14984451]
- 86.
- Simonen-Tikka ML, Pflueger M, Klemola P, Savolainen-Kopra C, Smura T, Hummel S, Kaijalainen S, Nuutila K, Natri O, Roivainen M, Ziegler AG: Human enterovirus infections in children at increased risk for type 1 diabetes: the Babydiet study. Diabetologia 54:2995–3002, 2011 [PubMed: 21932150]
- 87.
- Tapia G, Cinek O, Rasmussen T, Witso E, Grinde B, Stene LC, Ronningen KS: Human enterovirus RNA in monthly fecal samples and islet autoimmunity in Norwegian children with high genetic risk for type 1 diabetes: the MIDIA study. Diabetes Care 34:151–155, 2011 [PMC free article: PMC3005474] [PubMed: 20929993]
- 88.
- Lempainen J, Tauriainen S, Vaarala O, Makela M, Honkanen H, Marttila J, Veijola R, Simell O, Hyoty H, Knip M, Ilonen J: Interaction of enterovirus infection and cow’s milk-based formula nutrition in type 1 diabetes-associated autoimmunity. Diabetes Metab Res Rev 28:177–185, 2012 [PubMed: 21922634]
- 89.
- Tracy S, Drescher KM, Jackson JD, Kim K, Kono K: Enteroviruses, type 1 diabetes and hygiene: a complex relationship. Rev Med Virol 20:106–116, 2010 [PMC free article: PMC7169204] [PubMed: 20049905]
- 90.
- Dahlquist GG, Ivarsson S, Lindberg B, Forsgren M: Maternal enteroviral infection during pregnancy as a risk factor for childhood IDDM. A population-based case-control study. Diabetes 44:408–413, 1995 [PubMed: 7698508]
- 91.
- Dahlquist GG, Boman JE, Juto P: Enteroviral RNA and IgM antibodies in early pregnancy and risk for childhood-onset IDDM in offspring. Diabetes Care 22:364–365, 1999 [PubMed: 10333962]
- 92.
- Dahlquist GG, Forsberg J, Hagenfeldt L, Boman J, Juto P: Increased prevalence of enteroviral RNA in blood spots from newborn children who later developed type 1 diabetes: a population-based case-control study. Diabetes Care 27:285–286, 2004 [PubMed: 14694014]
- 93.
- Viskari HR, Roivainen M, Reunanen A, Pitkaniemi J, Sadeharju K, Koskela P, Hovi T, Leinikki P, Vilja P, Tuomilehto J, Hyoty H: Maternal first-trimester enterovirus infection and future risk of type 1 diabetes in the exposed fetus. Diabetes 51:2568–2571, 2002 [PubMed: 12145172]
- 94.
- Gamble DR: The epidemiology of insulin dependent diabetes with particular reference to the relationship of virus infection to its etiology. Epidemiol Rev 2:49–70, 1980 [PubMed: 7000538]
- 95.
- Athreya BH, Coriell LL, Charney J: Poliomyelitis antibodies in human colostrum and milk. J Pediatr 64:79–82, 1964 [PubMed: 14100104]
- 96.
- Viskari H, Ludvigsson J, Uibo R, Salur L, Marciulionyte D, Hermann R, Soltesz G, Fuchtenbusch M, Ziegler AG, Kondrashova A, Romanov A, Kaplan B, Laron Z, Koskela P, Vesikari T, Huhtala H, Knip M, Hyoty H: Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation. Diabetologia 48:1280–1287, 2005 [PubMed: 15902401]
- 97.
- Larsson PG, Lakshmikanth T, Svedin E, King C, Flodstrom-Tullberg M: Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice. Diabetologia 56:867–874, 2013 [PubMed: 23344730]
- 98.
- Tracy S, Smithee S, Alhazmi A, Chapman N: Coxsackievirus can persist in murine pancreas by deletion of 5’ terminal genomic sequences. J Med Virol 87:240–247, 2015 [PubMed: 25111164]
- 99.
- Bach JF: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920, 2002 [PubMed: 12239261]
- 100.
- Gale EA: A missing link in the hygiene hypothesis? Diabetologia 45:588–594, 2002 [PubMed: 12032638]
- 101.
- Kolb H, Elliott RB: Increasing incidence of IDDM a consequence of improved hygiene? Diabetologia 37:729, 1994 [PubMed: 7958547]
- 102.
- Cardwell CR, Carson DJ, Yarnell J, Shields MD, Patterson CC: Atopy, home environment and the risk of childhood-onset type 1 diabetes: a population-based case-control study. Pediatr Diabetes 9:191–196, 2008 [PubMed: 18547232]
- 103.
- Cardwell CR, Carson DJ, Patterson CC: No association between routinely recorded infections in early life and subsequent risk of childhood-onset type 1 diabetes: a matched case-control study using the UK General Practice Research Database. Diabet Med 25:261–267, 2008 [PubMed: 18201209]
- 104.
- Beyerlein A, Chmiel R, Hummel S, Winkler C, Bonifacio E, Ziegler AG: Timing of gluten introduction and islet autoimmunity in young children: updated results from the BABYDIET study. Diabetes Care 37:e194–e195, 2014 [PubMed: 25147260]
- 105.
- Rasmussen T, Witso E, Tapia G, Stene LC, Ronningen KS: Self-reported lower respiratory tract infections and development of islet autoimmunity in children with the type 1 diabetes high-risk HLA genotype: the MIDIA study. Diabetes Metab Res Rev 27:834–837, 2011 [PubMed: 22069269]
- 106.
- Ginsberg-Fellner F, Witt ME, Fedun B, Taub F, Dobersen MJ, McEvoy RC, Cooper LZ, Notkins AL, Rubinstein P: Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Rev Infect Dis 7(Suppl 1):S170–S176, 1985 [PubMed: 3890104]
- 107.
- Menser MA, Forrest JM, Bransby RD: Rubella infection and diabetes mellitus. Lancet 1:57–60, 1978 [PubMed: 74564]
- 108.
- Burgess MA, Forrest JM: Congenital rubella and diabetes mellitus. Diabetologia 52:369–370, 2009 [PubMed: 19034414]
- 109.
- Patterson K, Chandra RS, Jenson AB: Congenital rubella, insulitis, and diabetes mellitus in an infant. Lancet 1:1048–1049, 1981 [PubMed: 6112424]
- 110.
- Viskari H, Paronen J, Keskinen P, Simell S, Zawilinska B, Zgorniak-Nowosielska I, Korhonen S, Ilonen J, Simell O, Haapala AM, Knip M, Hyoty H: Humoral beta-cell autoimmunity is rare in patients with the congenital rubella syndrome. Clin Exp Immunol 133:378–383, 2003 [PMC free article: PMC1808787] [PubMed: 12930364]
- 111.
- Ou D, Mitchell LA, Metzger DL, Gillam S, Tingle AJ: Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with type I diabetes mellitus. Diabetologia 43:750–762, 2000 [PubMed: 10907121]
- 112.
- Karounos DG, Wolinsky JS, Thomas JW: Monoclonal antibody to rubella virus capsid protein recognizes a beta-cell antigen. J Immunol 150:3080–3085, 1993 [PubMed: 8454875]
- 113.
- Gale EA: Congenital rubella: citation virus or viral cause of type 1 diabetes? Diabetologia 51:1559–1566, 2008 [PubMed: 18641967]
- 114.
- Onodera T, Jenson AB, Yoon JW, Notkins AL: Virus-induced diabetes mellitus: reovirus infection of pancreatic beta cells in mice. Science 201:529–531, 1978 [PubMed: 208156]
- 115.
- Honeyman M: How robust is the evidence for viruses in the induction of type 1 diabetes? Curr Opin Immunol 17:616–623, 2005 [PubMed: 16216484]
- 116.
- Makela M, Oling V, Marttila J, Waris M, Knip M, Simell O, Ilonen J: Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes. Clin Exp Immunol 145:261–270, 2006 [PMC free article: PMC1809689] [PubMed: 16879245]
- 117.
- Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD, Colman PG, Harrison LC: Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49:1319–1324, 2000 [PubMed: 10923632]
- 118.
- Blomqvist M, Juhela S, Erkkila S, Korhonen S, Simell T, Kupila A, Vaarala O, Simell O, Knip M, Ilonen J: Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. Clin Exp Immunol 128:511–515, 2002 [PMC free article: PMC1906266] [PubMed: 12067306]
- 119.
- Hyoty H, Leinikki P, Reunanen A, Ilonen J, Surcel HM, Rilva A, Kaar ML, Huupponen T, Hakulinen A, Makela AL: Mumps infections in the etiology of type 1 (insulin-dependent) diabetes. Diabetes Res 9:111–116, 1988 [PubMed: 3243043]
- 120.
- Helmke K, Otten A, Willems W: Islet cell antibodies in children with mumps infection. Lancet 2:211–212, 1980 [PubMed: 6105384]
- 121.
- Pak CY, Eun HM, McArthur RG, Yoon JW: Association of cytomegalovirus infection with autoimmune type 1 diabetes. Lancet 2:1–4, 1988 [PubMed: 2898620]
- 122.
- Ward KP, Galloway WH, Auchterlonie IA: Congenital cytomegalovirus infection and diabetes. Lancet 1:497, 1979 [PubMed: 85085]
- 123.
- Nicoletti F, Scalia G, Lunetta M, Condorelli F, Di Mauro M, Barcellini W, Stracuzzi S, Pagano M, Meroni PL: Correlation between islet cell antibodies and anti-cytomegalovirus IgM and IgG antibodies in healthy first-degree relatives of type 1 (insulin-dependent) diabetic patients. Clin Immunol Immunopathol 55:139–147, 1990 [PubMed: 2155076]
- 124.
- Banatvala JE, Bryant J, Schernthaner G, Borkenstein M, Schober E, Brown D, De Silva LM, Menser MA, Silink M: Coxsackie B, mumps, rubella, and cytomegalovirus specific IgM responses in patients with juvenile-onset insulin-dependent diabetes mellitus in Britain, Austria, and Australia. Lancet 1:1409–1412, 1985 [PubMed: 2861361]
- 125.
- Hiltunen M, Hyoty H, Karjalainen J, Leinikki P, Knip M, Lounamaa R, Akerblom HK: Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: a prospective study. The Childhood Diabetes in Finland Study Group. Diabetologia 38:705–710, 1995 [PubMed: 7672493]
- 126.
- Ivarsson SA, Lindberg B, Nilsson KO, Ahlfors K, Svanberg L: The prevalence of type 1 diabetes mellitus at follow-up of Swedish infants congenitally infected with cytomegalovirus. Diabet Med 10:521–523, 1993 [PubMed: 8395988]
- 127.
- Aarnisalo J, Veijola R, Vainionpaa R, Simell O, Knip M, Ilonen J: Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia 51:769–772, 2008 [PubMed: 18278478]
- 128.
- Guberski DL, Thomas VA, Shek WR, Like AA, Handler ES, Rossini AA, Wallace JE, Welsh RM: Induction of type I diabetes by Kilham’s rat virus in diabetes-resistant BB/Wor rats. Science 254:1010–1013, 1991 [PubMed: 1658938]
- 129.
- Kerr JR: Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 59:672–683, 2000 [PMC free article: PMC1753262] [PubMed: 10976079]
- 130.
- Munakata Y, Kodera T, Saito T, Sasaki T: Rheumatoid arthritis, type 1 diabetes, and Graves’ disease after acute parvovirus B19 infection. Lancet 366:780, 2005 [PubMed: 16125597]
- 131.
- Kasuga A, Harada R, Saruta T: Insulin-dependent diabetes mellitus associated with parvovirus B19 infection. Ann Intern Med 125:700–701, 1996 [PubMed: 8849170]
- 132.
- O’Brayan TA, Beck MJ, Demers LM, Naides SJ: Human parvovirus B19 infection in children with new onset type 1 diabetes mellitus. Diabet Med 22:1778–1779, 2005 [PubMed: 16401330]
- 133.
- Hyoty H, Rasanen L, Hiltunen M, Lehtinen M, Huupponen T, Leinikki P: Decreased antibody reactivity to Epstein-Barr virus capsid antigen in type 1 (insulin-dependent) diabetes mellitus. APMIS 99:359–363, 1991 [PubMed: 1645169]
- 134.
- Makeen AM: The association of infective hepatitis type A (HAV) and diabetes mellitus. Trop Geogr Med 44:362–364, 1992 [PubMed: 1295148]
- 135.
- Masuda H, Atsumi T, Fujisaku A, Shimizu C, Yoshioka N, Koike T: Acute onset of type 1 diabetes accompanied by acute hepatitis C: the potential role of proinflammatory cytokine in the pathogenesis of autoimmune diabetes. Diabetes Res Clin Pract 75:357–361, 2007 [PubMed: 16968656]
- 136.
- Sano H, Terasaki J, Tsutsumi C, Imagawa A, Hanafusa T: A case of fulminant type 1 diabetes mellitus after influenza B infection. Diabetes Res Clin Pract 79:e8–e9, 2008 [PubMed: 18177974]
- 137.
- Lee HS, Briese T, Winkler C, Rewers M, Bonifacio E, Hyoty H, Pflueger M, Simell O, She JX, Hagopian W, Lernmark A, Akolkar B, Krischer JP, Ziegler AG; TEDDY Study Group: Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes. Diabetologia 56:1705–1711, 2013 [PMC free article: PMC4019381] [PubMed: 23657799]
- 138.
- Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW: Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 6:e25792, 2011 [PMC free article: PMC3197175] [PubMed: 22043294]
- 139.
- Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, Lodinova-Zadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D, Funda DP, Borovska D, Rehakova Z, Sinkora J, Hofman J, Drastich P, Kokesova A: Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 93:97–108, 2004 [PubMed: 15158604]
- 140.
- Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, Toivanen P: Fecal microbiota in early rheumatoid arthritis. J Rheumatol 35:1500–1505, 2008 [PubMed: 18528968]
- 141.
- Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV: Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455:1109–1113, 2008 [PMC free article: PMC2574766] [PubMed: 18806780]
- 142.
- de Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O: Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 62:1238–1244, 2013 [PMC free article: PMC3609581] [PubMed: 23274889]
- 143.
- Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, Queipo-Ortuno MI: Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med 11:46, 2013 [PMC free article: PMC3621820] [PubMed: 23433344]
- 144.
- Endesfelder D, zu Castell W, Ardissone A, Davis-Richardson AG, Achenbach P, Hagen M, Pflueger M, Gano KA, Fagen JR, Drew JC, Brown CT, Kolaczkowski B, Atkinson M, Schatz D, Bonifacio E, Triplett EW, Ziegler AG: Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes 63:2006–2014, 2014 [PubMed: 24608442]
- 145.
- Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW: Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 5:82–91, 2011 [PMC free article: PMC3105672] [PubMed: 20613793]
- 146.
- Gulden E, Wong FS, Wen L: The gut microbiota and type 1 diabetes. Clin Immunol 159:143–153, 2015 [PMC free article: PMC4761565] [PubMed: 26051037]
- 147.
- Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen T, Hamalainen AM, Peet A, Tillmann V, Poho P, Mattila I, Lahdesmaki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen H, Ilonen J, Virtanen SM, Clish CB, Oresic M, Huttenhower C, Knip M; DIABIMMUNE Study Group, Xavier RJ: The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17:260–273, 2015 [PMC free article: PMC4689191] [PubMed: 25662751]
- 148.
- Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY: Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–455, 2013 [PMC free article: PMC3869884] [PubMed: 24226773]
- 149.
- Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ: Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20:159–166, 2014 [PubMed: 24390308]
- 150.
- Maslowski KM, Mackay CR: Diet, gut microbiota and immune responses. Nat Immunol 12:5–9, 2011 [PubMed: 21169997]
- 151.
- Jefferson T: Vaccination and its adverse effects: real or perceived. Society should think about means of linking exposure to potential long term effect. BMJ 317:159–160, 1998 [PMC free article: PMC1113535] [PubMed: 9665892]
- 152.
- Jefferson T, Demicheli V: No evidence that vaccines cause insulin dependent diabetes mellitus. J Epidemiol Community Health 52:674–675, 1998 [PMC free article: PMC1756616] [PubMed: 10023469]
- 153.
- Graves PM, Barriga KJ, Norris JM, Hoffman MR, Yu L, Eisenbarth GS, Rewers M: Lack of association between early childhood immunizations and beta-cell autoimmunity. Diabetes Care 22:1694–1697, 1999 [PubMed: 10526737]
- 154.
- Offit PA, Hackett CJ: Addressing parents’ concerns: do vaccines cause allergic or autoimmune diseases? Pediatrics 111:653–659, 2003 [PubMed: 12612250]
- 155.
- Morgan E, Halliday SR, Campbell GR, Cardwell CR, Patterson CC: Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 59:237–243, 2016 [PMC free article: PMC4705121] [PubMed: 26564178]
- 156.
- Parent ME, Siemiatycki J, Menzies R, Fritschi L, Colle E: Bacille Calmette-Guerin vaccination and incidence of IDDM in Montreal, Canada. Diabetes Care 20:767–772, 1997 [PubMed: 9135940]
- 157.
- Dahlquist G, Gothefors L: The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination. Diabetologia 38:873–874, 1995 [PubMed: 7556994]
- 158.
- Huppmann M, Baumgarten A, Ziegler AG, Bonifacio E: Neonatal Bacille Calmette-Guerin vaccination and type 1 diabetes. Diabetes Care 28:1204–1206, 2005 [PubMed: 15855590]
- 159.
- Rousseau MC, El-Zein M, Conus F, Legault L, Parent ME: Bacillus Calmette-Guerin (BCG) vaccination in infancy and risk of childhood diabetes. Paediatr Perinat Epidemiol 30:141–148, 2016 [PubMed: 26584963]
- 160.
- Elliott JF, Marlin KL, Couch RM: Effect of Bacille Calmette-Guerin vaccination on c-peptide secretion in children newly diagnosed with IDDM. Diabetes Care 21:1691–1693, 1998 [PubMed: 9773732]
- 161.
- Allen HF, Klingensmith GJ, Jensen P, Simoes E, Hayward A, Chase HP: Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study. Diabetes Care 22:1703–1707, 1999 [PubMed: 10526739]
- 162.
- Borch-Johnsen K, Joner G, Mandrup-Poulsen T, Christy M, Zachau-Christiansen B, Kastrup K, Nerup J: Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis. Lancet 2:1083–1086, 1984 [PubMed: 6150150]
- 163.
- Knip M, Virtanen SM, Akerblom H: Infant feeding and risk of type 1 diabetes. Am J Clin Nutr 91:1506S–1513S, 2010 [PMC free article: PMC6443298] [PubMed: 20335552]
- 164.
- Norris JM, Scott FW: A meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role? Epidemiology 7:87–92, 1996 [PubMed: 8664407]
- 165.
- Gerstein HC: Cow’s milk exposure and type I diabetes mellitus. A critical overview of the clinical literature. Diabetes Care 17:13–19, 1994 [PubMed: 8112184]
- 166.
- Cardwell CR, Stene LC, Ludvigsson J, Rosenbauer J, Cinek O, Svensson J, Perez-Bravo F, Memon A, Gimeno SG, Wadsworth EJ, Strotmeyer ES, Goldacre MJ, Radon K, Chuang LM, Parslow RC, Chetwynd A, Karavanaki K, Brigis G, Pozzilli P, Urbonaite B, Schober E, Devoti G, Sipetic S, Joner G, Ionescu-Tirgoviste C, de Beaufort CE, Harrild K, Benson V, Savilahti E, Ponsonby AL, Salem M, Rabiei S, Patterson CC: Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies. Diabetes Care 35:2215–2225, 2012 [PMC free article: PMC3476923] [PubMed: 22837371]
- 167.
- Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M: Lack of association between early exposure to cow’s milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). JAMA 276:609–614, 1996 [PubMed: 8773632]
- 168.
- Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, Rewers M: Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 290:1713–1720, 2003 [PubMed: 14519705]
- 169.
- Frederiksen B, Kroehl M, Lamb MM, Seifert J, Barriga K, Eisenbarth GS, Rewers M, Norris JM: Infant exposures and development of type 1 diabetes mellitus: the Diabetes Autoimmunity Study in the Young (DAISY). JAMA Pediatr 167:808–815, 2013 [PMC free article: PMC4038357] [PubMed: 23836309]
- 170.
- Couper JJ, Steele C, Beresford S, Powell T, McCaul K, Pollard A, Gellert S, Tait B, Harrison LC, Colman PG: Lack of association between duration of breast-feeding or introduction of cow’s milk and development of islet autoimmunity. Diabetes 48:2145–2149, 1999 [PubMed: 10535447]
- 171.
- Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E: Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 290:1721–1728, 2003 [PubMed: 14519706]
- 172.
- Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippila C, Hakulinen T, Ahonen S, Uusitalo L, Niinisto S, Veijola R, Simell O, Ilonen J, Knip M: Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia 49:1512–1521, 2006 [PubMed: 16596359]
- 173.
- Virtanen SM, Takkinen HM, Nevalainen J, Kronberg-Kippila C, Salmenhaara M, Uusitalo L, Kenward MG, Erkkola M, Veijola R, Simell O, Ilonen J, Knip M: Early introduction of root vegetables in infancy associated with advanced β-cell autoimmunity in young children with human leukocyte antigen-conferred susceptibility to type 1 diabetes. Diabet Med 28:965–971, 2011 [PubMed: 21418094]
- 174.
- Holmberg H, Wahlberg J, Vaarala O, Ludvigsson J; ABIS Study Group: Short duration of breast-feeding as a risk-factor for beta-cell autoantibodies in 5-year-old children from the general population. Br J Nutr 97:111–116, 2007 [PubMed: 17217566]
- 175.
- Ivarsson A, Hernell O, Stenlund H, Persson LA: Breast-feeding protects against celiac disease. Am J Clin Nutr 75:914–921, 2002 [PubMed: 11976167]
- 176.
- Brekke HK, Ludvigsson J: Daily vegetable intake during pregnancy negatively associated to islet autoimmunity in the offspring—the ABIS study. Pediatr Diabetes 11:244–250, 2010 [PubMed: 19761530]
- 177.
- Lamb MM, Myers MA, Barriga K, Zimmet PZ, Rewers M, Norris JM: Maternal diet during pregnancy and islet autoimmunity in offspring. Pediatr Diabetes 9:135–141, 2008 [PubMed: 18221424]
- 178.
- Elliott RB, Martin JM: Dietary protein: a trigger of insulin-dependent diabetes in the BB rat? Diabetologia 26:297–299, 1984 [PubMed: 6376238]
- 179.
- Martin JM, Trink B, Daneman D, Dosch HM, Robinson B: Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). Ann Med 23:447–452, 1991 [PubMed: 1718325]
- 180.
- Kimpimaki T, Erkkola M, Korhonen S, Kupila A, Virtanen SM, Ilonen J, Simell O, Knip M: Short-term exclusive breast-feeding predisposes young children with increased genetic risk of type I diabetes to progressive beta-cell autoimmunity. Diabetologia 44:63–69, 2001 [PubMed: 11206413]
- 181.
- Savilahti E, Saarinen KM: Early infant feeding and type 1 diabetes. Eur J Nutr 48:243–249, 2009 [PubMed: 19263185]
- 182.
- Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, Dosch HM, Hakulinen T, Akerblom HK; Finnish TRIGR Study Group: Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 363:1900–1908, 2010 [PMC free article: PMC4242902] [PubMed: 21067382]
- 183.
- Knip M, Akerblom HK, Becker D, Dosch HM, Dupre J, Fraser W, Howard N, Ilonen J, Krischer JP, Kordonouri O, Lawson ML, Palmer JP, Savilahti E, Vaarala O, Virtanen SM; TRIGR Study Group: Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA 311:2279–2287, 2014 [PMC free article: PMC4225544] [PubMed: 24915259]
- 184.
- Virtanen SM, Nevalainen J, Kronberg-Kippila C, Ahonen S, Tapanainen H, Uusitalo L, Takkinen HM, Niinisto S, Ovaskainen ML, Kenward MG, Veijola R, Ilonen J, Simell O, Knip M: Food consumption and advanced β cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case-control design. Am J Clin Nutr 95:471–478, 2012 [PubMed: 22237062]
- 185.
- Virtanen SM, Hypponen E, Laara E, Vahasalo P, Kulmala P, Savola K, Rasanen L, Aro A, Knip M, Akerblom HK: Cow’s milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children. Childhood Diabetes in Finland Study Group. Diabet Med 15:730–738, 1998 [PubMed: 9737801]
- 186.
- Wahlberg J, Vaarala O, Ludvigsson J; ABIS-Study Group: Dietary risk factors for the emergence of type 1 diabetes-related autoantibodies in 21/2 year-old Swedish children. Br J Nutr 95:603–608, 2006 [PubMed: 16578935]
- 187.
- Verge CF, Howard NJ, Irwig L, Simpson JM, Mackerras D, Silink M: Environmental factors in childhood IDDM. A population-based, case-control study. Diabetes Care 17:1381–1389, 1994 [PubMed: 7882806]
- 188.
- Virtanen SM, Laara E, Hypponen E, Reijonen H, Rasanen L, Aro A, Knip M, Ilonen J, Akerblom HK: Cow’s milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood Diabetes in Finland Study Group. Diabetes 49:912–917, 2000 [PubMed: 10866042]
- 189.
- Rosenbauer J, Herzig P, Giani G: Early infant feeding and risk of type 1 diabetes mellitus—a nationwide population-based case-control study in pre-school children. Diabetes Metab Res Rev 24:211–222, 2008 [PubMed: 17968982]
- 190.
- Lamb MM, Miller M, Seifert JA, Frederiksen B, Kroehl M, Rewers M, Norris JM: The effect of childhood cow’s milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes 16:31–38, 2015 [PMC free article: PMC4104257] [PubMed: 24444005]
- 191.
- Virtanen SM, Niinisto S, Nevalainen J, Salminen I, Takkinen HM, Kaaria S, Uusitalo L, Alfthan G, Kenward MG, Veijola R, Simell O, Ilonen J, Knip M: Serum fatty acids and risk of advanced beta-cell autoimmunity: a nested case-control study among children with HLA-conferred susceptibility to type I diabetes. Eur J Clin Nutr 64:792–799, 2010 [PubMed: 20502469]
- 192.
- Crowe FL, Skeaff CM, Green TJ, Gray AR: Serum fatty acids as biomarkers of fat intake predict serum cholesterol concentrations in a population-based survey of New Zealand adolescents and adults. Am J Clin Nutr 83:887–894, 2006 [PubMed: 16600943]
- 193.
- Wolk A, Furuheim M, Vessby B: Fatty acid composition of adipose tissue and serum lipids are valid biological markers of dairy fat intake in men. J Nutr 131:828–833, 2001 [PubMed: 11238766]
- 194.
- Karjalainen J, Martin JM, Knip M, Ilonen J, Robinson BH, Savilahti E, Akerblom HK, Dosch HM: A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 327:302–307, 1992 [PubMed: 1377788]
- 195.
- Savilahti E, Akerblom HK, Tainio VM, Koskimies S: Children with newly diagnosed insulin dependent diabetes mellitus have increased levels of cow’s milk antibodies. Diabetes Res 7:137–140, 1988 [PubMed: 3416556]
- 196.
- Atkinson MA, Bowman MA, Kao KJ, Campbell L, Dush PJ, Shah SC, Simell O, Maclaren NK: Lack of immune responsiveness to bovine serum albumin in insulin-dependent diabetes. N Engl J Med 329:1853–1858, 1993 [PubMed: 8247037]
- 197.
- Luopajarvi K, Savilahti E, Virtanen SM, Ilonen J, Knip M, Akerblom HK, Vaarala O: Enhanced levels of cow’s milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr Diabetes 9:434–441, 2008 [PMC free article: PMC4225539] [PubMed: 18503496]
- 198.
- Lamb MM, Simpson MD, Seifert J, Scott FW, Rewers M, Norris JM: The association between IgG4 antibodies to dietary factors, islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young. PLoS One 8:e57936, 2013 [PMC free article: PMC3585253] [PubMed: 23469110]
- 199.
- Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohe S: Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes 51:73–78, 2002 [PubMed: 11756325]
- 200.
- MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW: A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem 278:54–63, 2003 [PubMed: 12409286]
- 201.
- Hummel M, Bonifacio E, Naserke HE, Ziegler AG: Elimination of dietary gluten does not reduce titers of type 1 diabetes-associated autoantibodies in high-risk subjects. Diabetes Care 25:1111–1116, 2002 [PubMed: 12087006]
- 202.
- Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E, Bosi E: Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clin Endocrinol Metab 88:162–165, 2003 [PubMed: 12519846]
- 203.
- Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG: Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34:1301–1305, 2011 [PMC free article: PMC3114350] [PubMed: 21515839]
- 204.
- Chmiel R, Beyerlein A, Knopff A, Hummel S, Ziegler AG, Winkler C: Early infant feeding and risk of developing islet autoimmunity and type 1 diabetes. Acta Diabetol 52:621–624, 2015 [PubMed: 25038720]
- 205.
- Brown KH: WHO/UNICEF review on complementary feeding and suggestions for future research: WHO/UNICEF guidelines on complementary feeding. Pediatrics 106:1290, 2000 [PubMed: 11061836]
- 206.
- Mathieu C, Badenhoop K: Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab 16:261–266, 2005 [PubMed: 15996876]
- 207.
- Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C: Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract 77:47–57, 2007 [PubMed: 17112620]
- 208.
- Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L: A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 51:1367–1374, 2002 [PubMed: 11978632]
- 209.
- Pedulla M, Desiderio V, Graziano A, d’Aquino R, Puca A, Papaccio G: Effects of a vitamin D3 analog on diabetes in the bio breeding (BB) rat. J Cell Biochem 100:808–814, 2007 [PubMed: 16960873]
- 210.
- Erkkola M, Nwaru BI, Viljakainen HT: Maternal vitamin D during pregnancy and its relation to immune-mediated diseases in the offspring. Vitam Horm 86:239–260, 2011 [PubMed: 21419274]
- 211.
- Laron Z, Lewy H, Wilderman I, Casu A, Willis J, Redondo MJ, Libman I, White N, Craig M: Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in homogenous and heterogeneous populations. Isr Med Assoc J 7:381–384, 2005 [PubMed: 15984382]
- 212.
- Muntoni S, Karvonen M, Muntoni S, Tuomilehto J: Seasonality of birth in patients with type 1 diabetes. Lancet 359:1246, 2002 [PubMed: 11955561]
- 213.
- Weets I, Kaufman L, Van der Auwera B, Crenier L, Rooman RP, De Block C, Casteels K, Weber E, Coeckelberghs M, Laron Z, Pipeleers DG, Gorus FK; Belgian Diabetes Registry: Seasonality in clinical onset of type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence. Diabetologia 47:614–621, 2004 [PubMed: 15298337]
- 214.
- Elliott JC, Lucas RM, Clements MS, Bambrick HJ: Population density determines the direction of the association between ambient ultraviolet radiation and type 1 diabetes incidence. Pediatr Diabetes 11:394–402, 2010 [PubMed: 19968813]
- 215.
- Sloka S, Grant M, Newhook LA: The geospatial relation between UV solar radiation and type 1 diabetes in Newfoundland. Acta Diabetol 47:73–78, 2010 [PubMed: 19238314]
- 216.
- Marjamaki L, Niinisto S, Kenward MG, Uusitalo L, Uusitalo U, Ovaskainen ML, Kronberg-Kippila C, Simell O, Veijola R, Ilonen J, Knip M, Virtanen SM: Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring. Diabetologia 53:1599–1607, 2010 [PubMed: 20369220]
- 217.
- Fronczak CM, Baron AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM: In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 26:3237–3242, 2003 [PubMed: 14633808]
- 218.
- Brekke HK, Ludvigsson J: Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes 8:11–14, 2007 [PubMed: 17341286]
- 219.
- Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ: Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 5:3551–3562, 2013 [PMC free article: PMC3798920] [PubMed: 24036529]
- 220.
- Sorensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC: Maternal serum levels of 25-hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes 61:175–178, 2012 [PMC free article: PMC3237654] [PubMed: 22124461]
- 221.
- Miettinen ME, Reinert L, Kinnunen L, Harjutsalo V, Koskela P, Surcel HM, Lamberg-Allardt C, Tuomilehto J: Serum 25-hydroxyvitamin D level during early pregnancy and type 1 diabetes risk in the offspring. Diabetologia 55:1291–1294, 2012 [PubMed: 22270224]
- 222.
- Vitamin D supplement in early childhood and risk for type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 42:51–54, 1999 [PubMed: 10027578]
- 223.
- Stene LC, Joner G; Norwegian Childhood Diabetes Study Group: Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 78:1128–1134, 2003 [PubMed: 14668274]
- 224.
- Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358:1500–1503, 2001 [PubMed: 11705562]
- 225.
- Zipitis CS, Akobeng AK: Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child 93:512–517, 2008 [PubMed: 18339654]
- 226.
- Simpson M, Brady H, Yin X, Seifert J, Barriga K, Hoffman M, Bugawan T, Baron AE, Sokol RJ, Eisenbarth G, Erlich H, Rewers M, Norris JM: No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 54:2779–2788, 2011 [PMC free article: PMC3478880] [PubMed: 21858504]
- 227.
- Munger KL, Levin LI, Massa J, Horst R, Orban T, Ascherio A: Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel. Am J Epidemiol 177:411–419, 2013 [PMC free article: PMC3626044] [PubMed: 23380046]
- 228.
- Bizzarri C, Pitocco D, Napoli N, Di Stasio E, Maggi D, Manfrini S, Suraci C, Cavallo MG, Cappa M, Ghirlanda G, Pozzilli P; IMDIAB Group: No protective effect of calcitriol on beta-cell function in recent-onset type 1 diabetes: the IMDIAB XIII trial. Diabetes Care 33:1962–1963, 2010 [PMC free article: PMC2928344] [PubMed: 20805274]
- 229.
- Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG: No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 33:1443–1448, 2010 [PMC free article: PMC2890336] [PubMed: 20357369]
- 230.
- Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D: Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745, 2010 [PMC free article: PMC2883344] [PubMed: 20418485]
- 231.
- Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD: Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376:180–188, 2010 [PMC free article: PMC3086761] [PubMed: 20541252]
- 232.
- Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, Greissl C, Ramos-Lopez E, Hypponen E, Dunger DB, Spector TD, Ouwehand WH, Wang TJ, Badenhoop K, Todd JA: Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60:1624–1631, 2011 [PMC free article: PMC3292339] [PubMed: 21441443]
- 233.
- Bailey R, Cooper JD, Zeitels L, Smyth DJ, Yang JH, Walker NM, Hypponen E, Dunger DB, Ramos-Lopez E, Badenhoop K, Nejentsev S, Todd JA: Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes 56:2616–2621, 2007 [PMC free article: PMC2493063] [PubMed: 17606874]
- 234.
- Frederiksen BN, Kroehl M, Fingerlin TE, Wong R, Steck AK, Rewers M, Norris JM: Association between vitamin D metabolism gene polymorphisms and risk of islet autoimmunity and progression to type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab 98:E1845–E1851, 2013 [PMC free article: PMC3816262] [PubMed: 23979957]
- 235.
- Calder PC, Grimble RF: Polyunsaturated fatty acids, inflammation and immunity. Eur J Clin Nutr 56(Suppl 3):S14–S19, 2002 [PubMed: 12142955]
- 236.
- Fritsche K: Fatty acids as modulators of the immune response. Annu Rev Nutr 26:45–73, 2006 [PubMed: 16848700]
- 237.
- Sorensen IM, Joner G, Jenum PA, Eskild A, Stene LC: Serum long chain n-3 fatty acids (EPA and DHA) in the pregnant mother are independent of risk of type 1 diabetes in the offspring. Diabetes Metab Res Rev 28:431–438, 2012 [PubMed: 22396195]
- 238.
- Decsi T, Szabo E, Burus I, Marosvolgyi T, Kozari A, Erhardt E, Soltesz G: Low contribution of n-3 polyunsaturated fatty acids to plasma and erythrocyte membrane lipids in diabetic young adults. Prostaglandins Leukot Essent Fatty Acids 76:159–164, 2007 [PubMed: 17321122]
- 239.
- Beales PE, Williams AJ, Albertini MC, Pozzilli P: Vitamin E delays diabetes onset in the non-obese diabetic mouse. Horm Metab Res 26:450–452, 1994 [PubMed: 7851866]
- 240.
- Murthy VK, Shipp JC, Hanson C, Shipp DM: Delayed onset and decreased incidence of diabetes in BB rats fed free radical scavengers. Diabetes Res Clin Pract 18:11–16, 1992 [PubMed: 1446573]
- 241.
- Uusitalo L, Kenward MG, Virtanen SM, Uusitalo U, Nevalainen J, Niinisto S, Kronberg-Kippila C, Ovaskainen ML, Marjamaki L, Simell O, Ilonen J, Veijola R, Knip M: Intake of antioxidant vitamins and trace elements during pregnancy and risk of advanced beta cell autoimmunity in the child. Am J Clin Nutr 88:458–464, 2008 [PubMed: 18689383]
- 242.
- Knekt P, Reunanen A, Marniemi J, Leino A, Aromaa A: Low vitamin E status is a potential risk factor for insulin-dependent diabetes mellitus. J Intern Med 245:99–102, 1999 [PubMed: 10095823]
- 243.
- Uusitalo L, Knip M, Kenward MG, Alfthan G, Sundvall J, Aro A, Reunanen A, Akerblom HK, Virtanen SM; Childhood Diabetes in Finland Study Group: Serum alpha-tocopherol concentrations and risk of type 1 diabetes mellitus: a cohort study in siblings of affected children. J Pediatr Endocrinol Metab 18:1409–1416, 2005 [PubMed: 16459467]
- 244.
- Uusitalo L, Nevalainen J, Niinisto S, Alfthan G, Sundvall J, Korhonen T, Kenward MG, Oja H, Veijola R, Simell O, Ilonen J, Knip M, Virtanen SM: Serum alpha- and gamma-tocopherol concentrations and risk of advanced beta cell autoimmunity in children with HLA-conferred susceptibility to type 1 diabetes mellitus. Diabetologia 51:773–780, 2008 [PubMed: 18317723]
- 245.
- Hagglof B, Marklund SL, Holmgren G: CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase in lymphocytes and erythrocytes in insulin-dependent diabetic children. Acta Endocrinol (Copenh) 102:235–239, 1983 [PubMed: 6338671]
- 246.
- Walter RM, Jr., Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL: Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care 14:1050–1056, 1991 [PubMed: 1797486]
- 247.
- Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC: The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045, 2007 [PMC free article: PMC2040407] [PubMed: 17942684]
- 248.
- Zhao HX, Mold MD, Stenhouse EA, Bird SC, Wright DE, Demaine AG, Millward BA: Drinking water composition and childhood-onset type 1 diabetes mellitus in Devon and Cornwall, England. Diabet Med 18:709–717, 2001 [PubMed: 11606168]
- 249.
- Valera P, Zavattari P, Sanna A, Pretti S, Marcello A, Mannu C, Targhetta C, Bruno G, Songini M: Zinc and other metals deficiencies and risk of type 1 diabetes: an ecological study in the high risk Sardinia Island. PLoS One 10:e0141262, 2015 [PMC free article: PMC4641716] [PubMed: 26559814]
- 250.
- Samuelsson U, Oikarinen S, Hyoty H, Ludvigsson J: Low zinc in drinking water is associated with the risk of type 1 diabetes in children. Pediatr Diabetes 12:156–164, 2011 [PubMed: 20920146]
- 251.
- Wilkin TJ: The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44:914–922, 2001 [PubMed: 11508279]
- 252.
- Dahlquist G: Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis. Diabetologia 49:20–24, 2006 [PubMed: 16362279]
- 253.
- Rewers M: The fallacy of reduction. Pediatr Diabetes 13:340–343, 2012 [PubMed: 22059463]
- 254.
- Stene LC, Magnus P, Lie RT, Sovik O, Joner G; Norwegian childhood Diabetes Study Group: Birth weight and childhood onset type 1 diabetes: population based cohort study. BMJ 322:889–892, 2001 [PMC free article: PMC30582] [PubMed: 11302899]
- 255.
- Cardwell CR, Stene LC, Joner G, Davis EA, Cinek O, Rosenbauer J, Ludvigsson J, Castell C, Svensson J, Goldacre MJ, Waldhoer T, Polanska J, Gimeno SG, Chuang LM, Parslow RC, Wadsworth EJ, Chetwynd A, Pozzilli P, Brigis G, Urbonaite B, Sipetic S, Schober E, Ionescu-Tirgoviste C, de Beaufort CE, Stoyanov D, Buschard K, Patterson CC: Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data. Diabetologia 53:641–651, 2010 [PubMed: 20063147]
- 256.
- Harder T, Roepke K, Diller N, Stechling Y, Dudenhausen JW, Plagemann A: Birth weight, early weight gain, and subsequent risk of type 1 diabetes: systematic review and meta-analysis. Am J Epidemiol 169:1428–1436, 2009 [PubMed: 19363100]
- 257.
- Hypponen E, Kenward MG, Virtanen SM, Piitulainen A, Virta-Autio P, Tuomilehto J, Knip M, Akerblom HK: Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care 22:1961–1965, 1999 [PubMed: 10587826]
- 258.
- EURODIAB Substudy 2 Study Group: Rapid early growth is associated with increased risk of childhood type 1 diabetes in various European populations. Diabetes Care 25:1755–1760, 2002 [PubMed: 12351473]
- 259.
- Beyerlein A, Thiering E, Pflueger M, Bidlingmaier M, Stock J, Knopff A, Winkler C, Heinrich J, Ziegler AG: Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children. Pediatr Diabetes 15:534–542, 2014 [PubMed: 24785566]
- 260.
- Larsson HE, Hansson G, Carlsson A, Cederwall E, Jonsson B, Jonsson B, Larsson K, Lynch K, Neiderud J, Lernmark A, Ivarsson SA; DiPiS Study Group: Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes. Diabetologia 51:1623–1630, 2008 [PubMed: 18592208]
- 261.
- Knip M, Reunanen A, Virtanen SM, Nuutinen M, Viikari J, Akerblom HK: Does the secular increase in body mass in children contribute to the increasing incidence of type 1 diabetes? Pediatr Diabetes 9:46–49, 2008 [PubMed: 18221438]
- 262.
- Waldhor T, Schober E, Rami B; Austrian Diabetes Incidence Study Group: Regional distribution of risk for childhood diabetes in Austria and possible association with body mass index. Eur J Pediatr 162:380–384, 2003 [PubMed: 12756559]
- 263.
- Betts P, Mulligan J, Ward P, Smith B, Wilkin T: Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood: testing the ‘accelerator hypothesis’ (2). Diabet Med 22:144–151, 2005 [PubMed: 15660730]
- 264.
- Dabelea D, D’Agostino RB, Jr., Mayer-Davis EJ, Pettitt DJ, Imperatore G, Dolan LM, Pihoker C, Hillier TA, Marcovina SM, Linder B, Ruggiero AM, Hamman RF; SEARCH for Diabetes in Youth Study Group: Testing the accelerator hypothesis: body size, beta-cell function, and age at onset of type 1 (autoimmune) diabetes. Diabetes Care 29:290–294, 2006 [PubMed: 16443875]
- 265.
- Kibirige M, Metcalf B, Renuka R, Wilkin TJ: Testing the accelerator hypothesis: the relationship between body mass and age at diagnosis of type 1 diabetes. Diabetes Care 26:2865–2870, 2003 [PubMed: 14514593]
- 266.
- Knerr I, Wolf J, Reinehr T, Stachow R, Grabert M, Schober E, Rascher W, Holl RW; DPV Scientific Initiative of Germany and Austria: The ‘accelerator hypothesis’: relationship between weight, height, body mass index and age at diagnosis in a large cohort of 9,248 German and Austrian children with type 1 diabetes mellitus. Diabetologia 48:2501–2504, 2005 [PubMed: 16283240]
- 267.
- O’Connell MA, Donath S, Cameron FJ: Major increase in type 1 diabetes: no support for the accelerator hypothesis. Diabet Med 24:920–923, 2007 [PubMed: 17535289]
- 268.
- Gimenez M, Aguilera E, Castell C, de Lara N, Nicolau J, Conget I: Relationship between BMI and age at diagnosis of type 1 diabetes in a Mediterranean area in the period of 1990–2004. Diabetes Care 30:1593–1595, 2007 [PubMed: 17372154]
- 269.
- Porter JR, Barrett TG: Braking the accelerator hypothesis? Diabetologia 47:352–353, 2004 [PubMed: 14666370]
- 270.
- Bruining GJ: Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2. Netherlands Kolibrie study group of childhood diabetes. Lancet 356:655–656, 2000 [PubMed: 10968443]
- 271.
- DiLiberti JH, Carver K, Parton E, Totka J, Mick G, McCormick K: Stature at time of diagnosis of type 1 diabetes mellitus. Pediatrics 109:479–483, 2002 [PubMed: 11875144]
- 272.
- Johansson C, Samuelsson U, Ludvigsson J: A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabaetes mellitus. Diabetologia 37:91–94, 1994 [PubMed: 8150235]
- 273.
- Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK; Childhood Diabetes in Finland Study Group: Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23:1755–1760, 2000 [PubMed: 11128347]
- 274.
- Ljungkrantz M, Ludvigsson J, Samuelsson U: Type 1 diabetes: increased height and weight gains in early childhood. Pediatr Diabetes 9:50–56, 2008 [PubMed: 18540867]
- 275.
- Pundziute-Lycka A, Persson LA, Cedermark G, Jansson-Roth A, Nilsson U, Westin V, Dahlquist G: Diet, growth, and the risk for type 1 diabetes in childhood: a matched case-referent study. Diabetes Care 27:2784–2789, 2004 [PubMed: 15562185]
- 276.
- Viner RM, Hindmarsh PC, Taylor B, Cole TJ: Childhood body mass index (BMI), breastfeeding and risk of type 1 diabetes: findings from a longitudinal national birth cohort. Diabet Med 25:1056–1061, 2008 [PubMed: 19183310]
- 277.
- Couper JJ, Beresford S, Hirte C, Baghurst PA, Pollard A, Tait BD, Harrison LC, Colman PG: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care 32:94–99, 2009 [PMC free article: PMC2606838] [PubMed: 18835948]
- 278.
- Lamb MM, Yin X, Zerbe GO, Klingensmith GJ, Dabelea D, Fingerlin TE, Rewers M, Norris JM: Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia 52:2064–2071, 2009 [PMC free article: PMC2813468] [PubMed: 19547949]
- 279.
- Winkler C, Marienfeld S, Zwilling M, Bonifacio E, Ziegler AG: Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes? Diabetologia 52:2072–2078, 2009 [PubMed: 19641897]
- 280.
- Lamb MM, Yin X, Barriga K, Hoffman MR, Baron AE, Eisenbarth GS, Rewers M, Norris JM: Dietary glycemic index, development of islet autoimmunity, and subsequent progression to type 1 diabetes in young children. J Clin Endocrinol Metab 93:3936–3942, 2008 [PMC free article: PMC2579644] [PubMed: 18682514]
- 281.
- Elias D, Prigozin H, Polak N, Rapoport M, Lohse AW, Cohen IR: Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin. Diabetes 43:992–998, 1994 [PubMed: 8039607]
- 282.
- Kantwerk-Funke G, Burkart V, Kolb H: Low dose streptozotocin causes stimulation of the immune system and of anti-islet cytotoxicity in mice. Clin Exp Immunol 86:266–270, 1991 [PMC free article: PMC1554113] [PubMed: 1657463]
- 283.
- Rayfield EJ, Ishimura K: Environmental factors and insulin-dependent diabetes mellitus. Diabetes Metab Rev 3:925–957, 1987 [PubMed: 3315526]
- 284.
- Moltchanova E, Rytkonen M, Kousa A, Taskinen O, Tuomilehto J, Karvonen M; Spat Study Group; Finnish Childhood Diabetes Registry Group: Zinc and nitrate in the ground water and the incidence of type 1 diabetes in Finland. Diabet Med 21:256–261, 2004 [PubMed: 15008836]
- 285.
- Muntoni S, Cocco P, Muntoni S, Aru G: Nitrate in community water supplies and risk of childhood type 1 diabetes in Sardinia, Italy. Eur J Epidemiol 21:245–247, 2006 [PubMed: 16547840]
- 286.
- Dahlquist GG, Blom LG, Persson LA, Sandstrom AI, Wall SG: Dietary factors and the risk of developing insulin dependent diabetes in childhood. BMJ 300:1302–1306, 1990 [PMC free article: PMC1663017] [PubMed: 2369660]
- 287.
- Benson VS, Vanleeuwen JA, Taylor J, Somers GS, McKinney PA, Van Til L: Type 1 diabetes mellitus and components in drinking water and diet: a population-based, case-control study in Prince Edward Island, Canada. J Am Coll Nutr 29:612–624, 2010 [PubMed: 21677125]
- 288.
- Winkler C, Mollenhauer U, Hummel S, Bonifacio E, Ziegler AG: Exposure to environmental factors in drinking water: risk of islet autoimmunity and type 1 diabetes—the BABYDIAB study. Horm Metab Res 40:566–571, 2008 [PubMed: 18500677]
- 289.
- Hettiarachchi KD, Zimmet PZ, Myers MA: Transplacental exposure to bafilomycin disrupts pancreatic islet organogenesis and accelerates diabetes onset in NOD mice. J Autoimmun 22:287–296, 2004 [PubMed: 15120752]
- 290.
- Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR, Zimmet PZ: Dietary microbial toxins and type 1 diabetes. Ann N Y Acad Sci 1005:418–422, 2003 [PubMed: 14679104]
- 291.
- Myers MA, Mackay IR, Zimmet PZ: Toxic type 1 diabetes. Rev Endocr Metab Disord 4:225–231, 2003 [PubMed: 14501173]
- 292.
- Oresic M, Simell S, Sysi-Aho M, Nanto-Salonen K, Seppanen-Laakso T, Parikka V, Katajamaa M, Hekkala A, Mattila I, Keskinen P, Yetukuri L, Reinikainen A, Lahde J, Suortti T, Hakalax J, Simell T, Hyoty H, Veijola R, Ilonen J, Lahesmaa R, Knip M, Simell O: Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med 205:2975–2984, 2008 [PMC free article: PMC2605239] [PubMed: 19075291]
- 293.
- Pflueger M, Seppanen-Laakso T, Suortti T, Hyotylainen T, Achenbach P, Bonifacio E, Oresic M, Ziegler AG: Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. Diabetes 60:2740–2747, 2011 [PMC free article: PMC3198092] [PubMed: 22025777]
- 294.
- La Torre D, Seppanen-Laakso T, Larsson HE, Hyotylainen T, Ivarsson SA, Lernmark A, Oresic M; DiPiS Study Group: Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes. Diabetes 62:3951–3956, 2013 [PMC free article: PMC3806611] [PubMed: 23929934]
- 295.
- Oresic M, Gopalacharyulu P, Mykkanen J, Lietzen N, Makinen M, Nygren H, Simell S, Simell V, Hyoty H, Veijola R, Ilonen J, Sysi-Aho M, Knip M, Hyotylainen T, Simell O: Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 62:3268–3274, 2013 [PMC free article: PMC3749353] [PubMed: 23630305]
- 296.
- Frohnert BI, Rewers MJ: Metabolomics in childhood diabetes. Pediatr Diabetes 17:3–14, 2016 [PMC free article: PMC4703499] [PubMed: 26420304]
- 297.
- Thernlund GM, Dahlquist G, Hansson K, Ivarsson SA, Ludvigsson J, Sjoblad S, Hagglof B: Psychological stress and the onset of IDDM in children. Diabetes Care 18:1323–1329, 1995 [PubMed: 8721932]
- 298.
- Sepa A, Wahlberg J, Vaarala O, Frodi A, Ludvigsson J: Psychological stress may induce diabetes-related autoimmunity in infancy. Diabetes Care 28:290–295, 2005 [PubMed: 15677781]
- 299.
- Sepa A, Frodi A, Ludvigsson J: Mothers’ experiences of serious life events increase the risk of diabetes-related autoimmunity in their children. Diabetes Care 28:2394–2399, 2005 [PubMed: 16186269]
- 300.
- Virk J, Li J, Vestergaard M, Obel C, Lu M, Olsen J: Early life disease programming during the preconception and prenatal period: making the link between stressful life events and type-1 diabetes. PLoS One 5:e11523, 2010 [PMC free article: PMC2901388] [PubMed: 20634978]
- 301.
- Bruno G, Spadea T, Picariello R, Gruden G, Barutta F, Cerutti F, Cavallo-Perin P, Costa G, Gnavi R; Piedmont Study Group for Diabetes Epidemiology: Early life socioeconomic indicators and risk of type 1 diabetes in children and young adults. J Pediatr 162:600–605, 2013 [PubMed: 23084710]
- 302.
- Patterson CC, Dahlquist G, Soltesz G, Green A; EURODIAB ACE Study Group. Europe and Diabetes: Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia 44(Suppl 3):B9–B16, 2001 [PubMed: 11724424]
- 303.
- Zinkernagel RM: Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med 345:1331–1335, 2001 [PubMed: 11794153]
- 304.
- Elfving AM, Lindberg BA, Landin-Olsson M, Hampe CS, Lernmark A, Ivarsson SA: Islet cell autoantibodies in cord blood from children with blood group incompatibility or hyperbilirubinemia. Autoimmunity 36:111–115, 2003 [PubMed: 12820693]
- 305.
- Stene LC, Barriga K, Norris JM, Hoffman M, Erlich HA, Eisenbarth GS, McDuffie RS, Jr., Rewers M: Perinatal factors and development of islet autoimmunity in early childhood: the Diabetes Autoimmunity Study in the Young. Am J Epidemiol 160:3–10, 2004 [PubMed: 15229111]
- 306.
- Blom L, Dahlquist G, Nystrom L, Sandstrom A, Wall S: The Swedish childhood diabetes study—social and perinatal determinants for diabetes in childhood. Diabetologia 32:7–13, 1989 [PubMed: 2707518]
- 307.
- Dahlquist G, Kallen B: Maternal-child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35:671–675, 1992 [PubMed: 1644246]
- 308.
- Li S, Zhang M, Tian H, Liu Z, Yin X, Xi B: Preterm birth and risk of type 1 and type 2 diabetes: systematic review and meta-analysis. Obes Rev 15:804–811, 2014 [PubMed: 25073871]
- 309.
- Khashan AS, Kenny LC, Lundholm C, Kearney PM, Gong T, McNamee R, Almqvist C: Gestational age and birth weight and the risk of childhood type 1 diabetes: a population-based cohort and sibling design study. Diabetes Care 38:2308–2315, 2015 [PubMed: 26519334]
- 310.
- Warram JH, Krolewski AS, Gottlieb MS, Kahn CR: Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 311:149–152, 1984 [PubMed: 6738600]
- 311.
- Harjutsalo V, Reunanen A, Tuomilehto J: Differential transmission of type 1 diabetes from diabetic fathers and mothers to their offspring. Diabetes 55:1517–1524, 2006 [PubMed: 16644714]
- 312.
- Stene LC, Ronningen KS, Magnus P, Joner G: Does HLA genotype influence the relative risk of type 1 diabetes conferred by dietary factors? Diabet Med 19:429–431, 2002 [PubMed: 12027934]
- 313.
- Perez-Bravo F, Carrasco E, Gutierrez-Lopez MD, Martinez MT, Lopez G, de los Rios MG: Genetic predisposition and environmental factors leading to the development of insulin-dependent diabetes mellitus in Chilean children. J Mol Med (Berl) 74:105–109, 1996 [PubMed: 8820406]
- 314.
- Kostraba JN, Cruickshanks KJ, Lawler-Heavner J, Jobim LF, Rewers MJ, Gay EC, Chase HP, Klingensmith G, Hamman RF: Early exposure to cow’s milk and solid foods in infancy, genetic predisposition, and risk of IDDM. Diabetes 42:288–295, 1993 [PubMed: 8425665]
- 315.
- Lamb MM, Miller M, Seifert JA, Frederiksen B, Kroehl M, Rewers M, Norris JM: The effect of childhood cow’s milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes 16:31–38, 2015 [PMC free article: PMC4104257] [PubMed: 24444005]
- 316.
- Lempainen J, Vaarala O, Makela M, Veijola R, Simell O, Knip M, Hermann R, Ilonen J: Interplay between PTPN22 C1858T polymorphism and cow’s milk formula exposure in type 1 diabetes. J Autoimmun 33:155–164, 2009 [PubMed: 19473815]
- 317.
- Stene LC, Thorsby PM, Berg JP, Ronningen KS, Joner G; Norwegian Childhood Diabetes Study Group: Peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism, cod liver oil and risk of type 1 diabetes. Pediatr Diabetes 9:40–45, 2008 [PubMed: 18211635]
- 318.
- Voruganti VS, Higgins PB, Ebbesson SO, Kennish J, Goring HH, Haack K, Laston S, Drigalenko E, Wenger CR, Harris WS, Fabsitz RR, Devereux RB, Maccluer JW, Curran JE, Carless MA, Johnson MP, Moses EK, Blangero J, Umans JG, Howard BV, Cole SA, Comuzzie AG: Variants in CPT1A, FADS1, and FADS2 are associated with higher levels of estimated plasma and erythrocyte delta-5 desaturases in Alaskan Eskimos. Front Genet 3:86, 2012 [PMC free article: PMC3371589] [PubMed: 22701466]
- 319.
- Norris JM, Kroehl M, Fingerlin TE, Frederiksen BN, Seifert J, Wong R, Clare-Salzler M, Rewers M: Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young. Diabetologia 57:295–304, 2014 [PMC free article: PMC3947295] [PubMed: 24240437]
- 320.
- Bonifacio E, Warncke K, Winkler C, Wallner M, Ziegler AG: Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. Diabetes 60:3300–3306, 2011 [PMC free article: PMC3219940] [PubMed: 22110093]
- 321.
- Stene LC, Ronningen KS, Undlien DE, Joner G: Does the relative risk for type 1 diabetes conferred by HLA-DQ, INS, and PTPN22 polymorphisms vary with maternal age, birth weight, or cesarean section? Pediatr Diabetes 12:91–94, 2011 [PubMed: 21352425]
- 322.
- Snell-Bergeon JK, Smith J, Dong F, Baron AE, Barriga K, Norris JM, Rewers M: Early childhood infections and the risk of islet autoimmunity: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Care 35:2553–2558, 2012 [PMC free article: PMC3507568] [PubMed: 23043167]
DUALITY OF INTEREST
Drs. Rewers, Stene, and Norris reported no conflicts of interest.
ACKNOWLEDGMENTS/FUNDING Drs. Rewers and Norris were supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK032493, DK032083, DK049654, and DK104351) and by a grant from the JDRF (17-2013-535). Dr. Stene was supported by a grant from The National Research Council of Norway (221909/F20).
- Review Risk Factors for Type 1 Diabetes.[Diabetes in America. 2023]Review Risk Factors for Type 1 Diabetes.Stene LC, Norris JM, Rewers MJ. Diabetes in America. 2023
- Review Environmental triggers of type 1 diabetes.[J Paediatr Child Health. 2001]Review Environmental triggers of type 1 diabetes.Couper JJ. J Paediatr Child Health. 2001 Jun; 37(3):218-20.
- Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.[Diabetes. 1999]Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.Couper JJ, Steele C, Beresford S, Powell T, McCaul K, Pollard A, Gellert S, Tait B, Harrison LC, Colman PG. Diabetes. 1999 Nov; 48(11):2145-9.
- No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes.[J Autoimmun. 2001]No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes.Füchtenbusch M, Irnstetter A, Jäger G, Ziegler AG. J Autoimmun. 2001 Dec; 17(4):333-40.
- Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.[Diabetes. 1996]Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.Roll U, Christie MR, Füchtenbusch M, Payton MA, Hawkes CJ, Ziegler AG. Diabetes. 1996 Jul; 45(7):967-73.
- Risk Factors for Type 1 Diabetes - Diabetes in AmericaRisk Factors for Type 1 Diabetes - Diabetes in America
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