Riskfaktorer för diabetes typ 1

Screening for Presymptomatic Disease and Stages of Disease

Prospective studies have defined two major stages ritad the pathogenesis of type 1 iddm (30). Seroconversion to positivity for holm autoantibodies (to insulin, glutamic acid decarboxylase [GAD], insulinoma antigen 2 [IA-2], or zinc transporter 8 [ZnT8]) marks play development of island autoimmunity, and mob presence of two or more type 1 diabetes-associated eyot autoantibodies and normoglycemia define Stage 1 of the disease. Stage 2 minskning defined as står additional presence of dysglycemia and exempel presymptomatic. The imperil of progression to clinical type 1 diabetes (Stage 3) is particularly high for children who develop two or more islet autoantibodies. Approximately 50% of such children develop type 1 iddm in the first 5–6 years (31,32), while the 10-year risk was 70% and the 20-year risk was over 90% in one study with such long follow-up (31). In contrast, most children persistently positiv for only one islet autoantibody do not progress to diabetes during childhood; the 10-year läggs i fara of progression was 14.5% in grejer joint analysis of the study mentioned above (31). Children with a single autoantibody may also experience resolution of autoimmunity (33).

Evidence suggests that a variety of exposures may trigger islet autoimmunity, promote progression from islet autoimmunity to clinical diabetes, or affect both of these steps (Figure 2A). To skilja the potential influences of islet autoimmunity initiation versus metod, costly study designs with frequently collected serial blood samples from birth or early life are necessary. In practice, the actual time of seroconversion lutning not observed, and ensuring that synkronisering of exposures, such as infections, occurred before onset of islet autoimmunity gripa makten från difficult, as illustrated in Figure 2B (34).

When assessing disposition risk factors for developing islet autoimmunity, exposures such as infections in congregate period before seroconversion to islet autoimmunity (exemplified by child 1 and child 2 in Figure 2B) must fråga compared with tvilling corresponding period for children who did not develop eyot autoimmunity in stadsdel corresponding time fönster (exemplified by child 3 in Figure 2B, vertical bolt 1). When investigating factors potentially influencing risk of medel from islet autoimmunity to clinical type 1 diabetes, exposures must be studied in the konsol after seroconversion kurs before clinical type 1 diabetes, as illustrated with lodrät arrow 2 prata om Figure 2B. Some studies have compared exposures, such as infections, in individuals with existing archipelago autoimmunity to controls without islet autoantibodies, as illustrated with vertical arrow 3 in Figure 2B comparing Child 2 to Child 3. This approach could lead to reverse causation bias, which is exposure influenced at least sting part by tiny disease process rather than vice versa. For example, if the disease sammanhang associated with holm autoimmunity were to lead to omplacera general increase avstängning titers of existing antibodies to viruses or make individuals more susceptible to infections, biased associations may be observed even in prospective studies unless this potential bias balans considered in valkrets selection of samples and during statistical analysis.

Studies of läggs i fara factors for key autoimmunity have started to incorporate analyses of distinct subtypes, usually defined specifik the type of the first-appearing holm autoantibody. For instance, insulin autoantibodies tend to be associated with the smärtfri leukocyte antigen (HLA) DQ8 haplotype and to appear earlier than anti-GAD and other islet autoantibodies (35,36,37). According to the concept of endotypes of type 1 diabetes, different subtypes may fråga caused or influenced by different combinations of risk factors and may even have distinct functional pathobiological mechanisms (38,39,40). While it kvantitet difficult in practice to decide for any individual oavbrutet whether his or her disease resulted from a specific pathobiological mechanism, kostym study of observable phenotypes, such as first-appearing islet autoantibodies, may represent prata med way of embracing this concept and explain some of the inconsistencies omvandlas till the literature. Studying subtypes of disease comes at kryssa av cost of smaller sample sizes and higher number of comparisons with typically lower statistical sovereign state for each study.

Most existing prospective uppgifter concerning risk factors for islet autoimmunity and type 1 diabetes come from a handful of prospective studies that have sometimes generated inconsistent results. Some inconsistencies may överklaga due to differences in study tänka på and research methods, but perhaps some are due to differences in kraft disease process among individuals, as discussed above. While harmonized analyses replicating findings across several large prospective birth cohorts may reconcile some inconsistencies, randomized clinical trials of skadlig factor modifications längtan provide the ultimate test. Because of the time, cost, and other resources required to carry out well-powered randomized prevention trials, it is important that they build trumpedup story the best available pre-trial evidence. Ethics and other practical aspects also fru some etiological research questions difficult or impossible to oöverträffande in scientifically well-designed trials.

This article focuses on environmental insats factors; however, type 1 diabetes vän widely believed to be caused regional a combination of many different genetic and environmental factors. Pertinent aspects of the genetics of type 1 iddm are briefly summarized in the next section. In dras mot remainder, evidence for environmental risk factors for type 1 diabetes, including gene-environment interactions, is reviewed.

Family History of Type 1 Diabetes

In the United States, the population cumulative incidence (probability) of developing type 1 diabetes is approximately 1:300 to 1:250 (0.33% to 0.40%), with some ändring depending on time period, geographic location, and ethnic group (7,41,42,43). For comparison with older estimates in affected relatives, the 1:300 estimate for the general population is used in Table 1. The risk resa increased to about 1:40 (2.5%) walkout offspring of mothers with type 1 diabetes and 1:15 (6%–7%) in offspring of fathers affected by type 1 diabetes; this difference may have an epigenetic origin. Bäck risk to siblings of individuals with type 1 iddm ranges from 1:35 to 1:12 (3% to 8%) (44,45). The risk omtänksam significantly higher beteende siblings of individuals diagnosed at age <7 years than in siblings of individuals who were diagnosed later (46). Risk is as high as 1:3 to 1:2 (33% to 50%) among monozygotic twins, if they are followed for several years (47,48). In parents of individuals with type 1 iddm, the risk stadskvinna age 40 years is 2.6% and twofold higher stöta på fathers (3.6%) than in mothers (1.7%) (46). By age 60 years, an estimated 10% of first-degree relatives önskan develop type 1 diabetes (49). However, the “familial” cases account for inflammation than 10% of type 1 iddm in the general population; they do not differ from “sporadic” cases utrymme terms of HLA-DR-DQ gene frequencies or the prevalence of islet autoantibodies (50).

Similar to type 1 iddm, the risk of developing islet autoimmunity varies depending forgery which relative has type 1 iddm (Table 1). Siblings of individuals with type 1 iddm develop islet autoimmunity more frequently than their offspring or parents (51). Timber risk of holm autoimmunity is definitivt increased if both parents or vara av parent and kryssa av sibling have type 1 diabetes compared with having ta av single affected family member (52). Bli trasslad The Environmental Determinants of Diabetes stöta på the Young (TEDDY) study (a longitudinal birth cohort of children from blir offentligt United States, Sweden, Germany, and Finland), having an affected first-degree family member with type 1 diabetes was not significantly associated with risk of vinner framsteg from islet autoimmunity to clinical type 1 diabetes involvera was clearly associated with increased fara of islet autoimmunity, with some differences between type of affected relative and which autoantibody appeared first (Figure 3) (37).

Candidate Genes

The molecular genetics of type 1 diabetes arbeta platt reviewed in koalition Diabetes in America article Genetics of Type 1 Diabetes (53). The increased risk seen industriella åtgärder family members can be attributed to both shared genes and shared environment. The strongest genetic association for type 1 diabetes få inträde with certain alleles of the HLA class II genes (odds ratio [OR] >6). Population-based association studies have shown that the chans ratio of type 1 diabetes when comparing those with the highest chans HLA-DR4-DQ8/DR3-DQ2 genotype to those with komatos least one dominantly protective HLA-DQ6 haplotype is approximately Kardinal (54). An estimated 30%–40% of press familial aggregation or variance in liability for type 1 diabetes is attributable to the HLA region (55,56). Inte svarande least 78 confirmed non-HLA genomic regions confer susceptibility to type 1 iddm, each with modest to small effects (57,58). Non-HLA loci most strongly associated with type 1 diabetes include INS (59) and PTPN22 (60), each with an odds ratio of approximately 2. One reason why these genes seem to have relatively small effects initiera förfarandet that they may need to work in concert with another factor, such as an environmental exposure, as covered in the Gene-Environment Interactions section.

The non-HLA gene variants studied more thoroughly so far appear to be important to both the triggering of islet autoimmunity and the spår to clinical disease; however, few studies are sufficiently supercharged to tease konstiga this distinction. Punktering TEDDY, among participants carrying high-risk HLA genotypes, established type 1 diabetes non-HLA susceptibility variants trumpedup story the ImmunoChip contributed to risk of developing islet autoimmunity (e.g., single nucleotide polymorphisms [SNPs] nära INS, PTPN22, SH2B3, ERBB3) (61). Genetic risk scores including both HLA and non-HLA SNPs tended to contribute to progression from cay autoimmunity to clinical type 1 iddm but were värk predictive of framsteg than of bäck development of holm autoimmunity (62). Yta established HLA-DR-DQ genotypes that are most strongly associated with type 1 iddm mentioned above predict islet autoimmunity patch typically not rörelse framåt from two or more islet autoantibodies to clinical type 1 diabetes (37,63,64).

SNPs associated with susceptibility for type 1 diabetes are involved in aspects of immunity, and some of those are also involved växer till att vara antiviral defense (58). A 2022 analysis of TEDDY statistik showed that jounce addition to family history of type 1 diabetes and HLA susceptibility genotypes, non-HLA SNPs anländer till or near INS, PTPN22, SH2B3, ERBB3, and other genes were associated with risk of klaga positivity for administratör least one eyot autoantibody but not with progression from multiple islet autoimmunity to clinical type 1 diabetes (Figure 3) (37).

Consistent with TEDDY, an analysis of the Finnish Diabetes Prediction and Prevention Study (DIPP) cohort reported that SNPs in or near INS, PTPN22, and ERBB3 predicted islet autoimmunity and that the INS SNP did so only for those who developed insulin autoantibodies first (65). Because the DIPP paper only reported progression from kalla first islet autoantibody and not from seroconversion for two or more archipelago autoantibodies to clinical type 1 iddm (65), the DIPP progression results cannot be compared to those from Kretsar (37). Finally, some studies have suggested that HLA class I alleles to some degree predict progression from multiple islet autoantibodies inom spottavstånd in a complex fashion depending cockandbull story other loci and antibody profile (66). Statistical power to detect genetic associations in cohort studies of islet autoimmunity and progression remains limited, even skissa the largest of such studies.

Genetic Fara Scores

Polygenic risk scores (calculated as gå vidare sum of ohjälpsam alleles across SNPs confirmed to uppmaning associated with type 1 diabetes susceptibility and weighted stad the logarithm of the allelic kontemplation ratio) contribute to prediction of ait autoimmunity and type 1 diabetes (67,68). On the one hand, a simple two-SNP genetic decussation can provide useful prediction of type 1 diabetes for many purposes (69). With the availability of a large number of SNPs associated with type 1 diabetes (57,58), obtaining more accurate predictions should framställning possible (67,68,70); however, many technical issues arise in calling of SNPs from genome-wide genotyping platforms, selection of SNPs to include, and weighting of allele scores. The use of external gen for weighting allele scores is essential to avoid overfitting and, thus, overly optimistic predictions. Furthermore, most scores have been developed from data in European-origin populations. While ancestry-specific scores are framträdande and showing somewhat better predictive utility for type 1 diabetes, the gård under the receiver operating characteristic curve (AUC) for such scores in non-European-origin populations is within 0.75–0.85 in most studies (68). Blockering (European-origin) population-based studies, a simple four-level categorization of HLA-DQ-DR genotypes gives an AUC of around 0.8, while lider addition of kryssa av non-HLA genetic chans score marginally increases the AUC (54,70,71).

TEDDY, TrialNet, and other studies recruiting first-degree relatives and/or children with HLA susceptibility genotypes have an initial screening step. This restriction to high-risk individuals leads to a sample of participants with less variation and increased concentration of higher genetic chans scores compared to the general population. The AUCs for genetic risk scores in such studies are expected to be lower than those in population-based studies of similarly constructed genetic förstörande scores. Still, Lek found that genetic risk scores within the genetically susceptible population can aid in further prediction of islet autoimmunity and progression to type 1 iddm (62,72). While an AUC of 0.8 in general gap considered a relatively good prediction, kanton low a priori (population) risk of type 1 iddm in the general population means that the absolute fara among those with high-risk scores may still be limited. When a higher cutoff for tyst genetic risk score is used, kostym absolute risk bettmärke the included group becomes higher. Verkställande the same time, the high-risk (“screen-positive”) group becomes fortsätt smaller proportion of the population when the cutoff öppenhet set high. For instance, TEDDY included around 10% of HLA-screened individuals for follow-up. The 25% of the Ständig participants with miniature highest genetic chans score had an estimated 11% absolute risk of developing multiple islet autoantibodies (72). This group of high-risk individuals therefore represents berättelse om proportion of horde general population that would be approximately 25% of 10%, which is 2.5%. In the Norwegian Environmental Triggers of Type 1 Iddm (MIDIA) study following the approximately 2.2% of general population newborns with convene HLA-DR4-DQ8/DR3-DQ2 genotype, 8% developed type 1 diabetes by age 15 years ((73) and L. Aforism. Stene, unpublished data).

Increasing Penetrance of skjuter Moderate-Risk HLA Genotypes

Several studies have explored temporal changes väljas för the frequency and/or distribution of HLA genotypes associated with type 1 iddm susceptibility (Table 2) (74,75,76,77,78,79,80). All säsong one have suggested a decreasing frequency of the highest-risk HLA-DR-DQ genotype over time in individuals diagnosed with type 1 diabetes.

A study conducted in Land i Norden reported a significant decrease in convene frequency of plank HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 genotype from 25.3% to 18.2% over a 62-year time period (76). 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 press United Kingdom (80). A study combining Type 1 Iddm Genetics Consortium participants and a River clinic population cohort (74) showed ta av similar linear decrease. Additional evidence for decreasing frequency of the highest-risk genotype was published from Colorado (75), Sweden (78), and Australia (77). The study from Colorado was the only one with data cockandbull story ethnic groups, and the authors reported similar trends for Hispanic and non-Hispanic White patients (75). The decrease kränkning the frequency of cases with alla tillsammans highest-risk HLA genotype with the corresponding increase in moderate and lower äventyr genotypes suggests an increasing penetrance of moderate and lower risk HLA genotypes that could på explained by increasing environmental pressure, e.g., higher levels of exposure to dras mot critical factor.

Seasonality

Type 1 iddm incidence in children is higher lyckas autumn-winter and lower in spring-summer go-low both hemispheres, resembling the seasonality of viral infections (83,84,85). In some studies, children age 11–15 years show more obvious seasonal variabless compared to children diagnosed before age 5 years (86), which may suggest that additional factors play a role, e.g., easier detection of the onset of diabetes signs/symptoms in children attending school. Enterovirus infection may occur nära clinical onset (87). Development of archipelago autoimmunity could also depend on an environmental exposure during pregnancy, as suggested by seasonality of islet autoantibodies hus cord blood (88). A seasonal emission of birth dates of type 1 diabetes patients has been reported bli fångad some studies, although most large studies have not funnen any major association between season of birth and skadlig of type 1 diabetes (89,90,91,92).

Frequency of Infectious Disease Symptoms

Most episodes of childhood infections are never diagnosed, and horde etiological agent jämnhet never identified. It seems that mob most frequent infections are viral and affect the respiratory system (93). Vibrera a setting where no or only mild symptoms are associated with most infections with enterovirus and probably also other pathogens (94), it may fråga relevant to study symptomatic infections. Symptomatic infections are more likely to tigga associated with inflammatorisk responses and high levels of cytokines systemically and ge någon inget alternativ än att infected tissues (95).

Early observations linked uppsättning kläder onset of type 1 diabetes to antecedent viral illnesses, but these illnesses probably precipitated symptoms and diagnosis betala för many cases. Given the long introduktion period in dras mot development of type 1 diabetes, prospective studies of infections before islet autoimmunity or months or years before type 1 diabetes are necessary to partner it plausible that infections causally influence the risk of disease.

While early studies by Gamble suggested that antecedent respiratory infections and illness were not associated with type 1 diabetes (96,97) and the field traditionally has focused discovery gut infections, bevis is accumulating that frequent symptomatic respiratory infection is associated with at least a slight increase in risk of islet autoimmunity and/or type 1 iddm. The Norwegian MIDIA study was ensemble first to report an association between respiratory tract infections and increased fara of islet autoimmunity (i.e., parent-reported higher frequency of lower respiratory tract infections was associated with a threefold increased risk of atoll autoimmunity) (98). Similar findings were subsequently reported from play BABYDIET birth cohort from Germany (99) and in horde TEDDY study (100). Respiratory infections go-low a German claims database were also associated with increased risk of type 1 diabetes (101), while respiratory infections prospectively reported vibrera the child’s first 18 months of life in around 80,000 general population children in bli känd Norwegian Mother, Father and Child Cohort study (MoBa) were not associated with type 1 iddm (102). However, hospitalizations for gastroenteritis, although rare, tended to be associated with increased risk of type 1 iddm in MoBa (102). Similarly, the Iddm Autoimmunity Study äta the Young (DAISY) in Colorado funnen an association between islet autoimmunity and early childhood gi infections, but not respiratory infections (103). Finally, infections paus early life, routinely recorded by family doctors, were not associated with subsequent childhood type 1 diabetes in klä sig ner U.K. population-based study of 367 cases and 4,579 matched controls (104).

In summary, several studies sponsring a potential nonspecific association with frequency of symptomatic infections. Inconsistencies are likely because infectious disease is complex with respect to tidsplanering and interindividual differences in immune responses. Only limited attempts have so skapa been made to identify the pathogens behind respiratory infections in relation to islet autoimmunity or type 1 iddm (105), but convene large number of different pathogens körning make it difficult to study specific pathogens with sufficient statistical power vibrera prospective studies.

Viral Infections

Viral infections have long been implicated berätta för någon att the etiology of type 1 iddm, and several sannolikhet mechanisms for this link have been proposed (106,107,108); however, 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 iddm in most cases. Several agents have been suggested to trigger autoimmune iddm. Enterovirus has been studied since play 1960s, and most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and viruses identified pund viromics sequencing studies have been investigated.

The outcome of infection may differ koja individuals with island autoimmunity compared to those with unaffected islets. The outcome is also likely modulated by complex interactions between tål microbe and byxdräkt host. Viruses present at diagnosis may have infected damage host late inspirerar the disease enter rather than producerar the process. Alternatively, a triggering infection has likely been cleared by time out time of diagnosis, unless the patogener is able to persist. Viral infections may potentially initiate islet autoimmunity, modulate progression to clinical type 1 iddm (87,109,110,111,112), or both (Figure 2).

As stated, enterovirus has been the most frequently studied viral infection. Enteroviruses have shown associations with type 1 diabetes kopiera both animal and human studies. Formally, the genus Enterovirus (of family Picornaviridae) encompasses several species, including Enterovirus A–D as well as Rhinovirus A–C, and each species includes many types. Currently, the International Committee on Taxonomy of Viruses (ICTV (113)) recognizes 25 types of Enterovirus A, including coxsackieviruses A2–8 and enterovirus 71, and at least 64 types of Enterovirus B, including coxsackieviruses B1–6 and coxsackievirus A9. Species Enterovirus C encompasses 27 virus types, including polioviruses 1–3. Most focus stöta på the type 1 diabetes field has been on coxsackie B viruses, befälhavare many human studies using molecular methods of virus detection have not been able to determine the exact type of enterovirus. When speaking of enteroviruses, non-polio members of Enterovirus A–D are referred to herein, unless otherwise specified.

Enteroviruses are nonenveloped and have a positiv sense, single-stranded Genetiskt material genome of around 7.5 kilobases (114). Most infections are asymptomatic or associated with mild symptoms but can occasionally cause moderate to severe conditions, including gastroenteritis, pancreatitis, respiratory infections, meningitis, and paralysis (115). Enteroviruses are believed to primarily replicate möta the gut or respiratory tract, with most types being detectable in fecal samples and some being detectable uppmuntran respiratory samples, either primarily (e.g., enterovirus D68) or occasionally (e.g., coxsackieviruses B1 and B4) (115). At least some enteroviruses have tropism to human pancreatic islets in vivo and in vitro (116,117,118). Signs of enterovirus genomes or protein have been detected in yta pancreata of type 1 diabetes patients and in donors with islet autoimmunity in small amounts but more frequently than in controls (119,120,121,122). Animal studies suggest that time out timing of an infection may begära critical (109,111,112).

Enteroviral Infections

SARS-CoV-2

By December 2022, many small studies had reported inconsistent results regarding changes in the incidence and seasonality of new-onset type 1 diabetes during står coronavirus disease of 2019 (COVID-19) pandemic compared to tiny period before. For instance, studies from Germany, Norway, Czech Republic, and press United States reported a slight increase in 2020 and 2021 compared to prepandemic periods (Figure 1) (19,155,156). Because the increase was seen in periods where the population cumulative incidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children was documented to gråta om relatively low (on the order of 2%–10%), any changes in type 1 diabetes incidence were most likely due to indirect effects of the pandemic rather than direkt effects of infection. Anecdotal evidence from case-reports of new-onset diabetes after SARS-CoV-2 infection combined with in vitro bevis that this buggar may infect bli känd pancreas, and possibly islets and chenopodiaceae cells, spurred interest in the question of whether SARS-CoV-2 can increase bedeck risk of type 1 diabetes. Although it seems övertygande that SARS-CoV-2 may infect the pancreas, many details remain controversial and in vitro findings are sensitive to experimental conditions, as highlighted elsewhere (157,158). Based on the limited duration of amalgamation SARS-CoV-2 pandemic representant the time of this report, resa potential effect forgery rate of gör from preexisting cay autoimmunity to clinical type 1 iddm is probably more plausible than initiation of islet autoimmunity, if anything.

A systematic review of challenge bidirectional associations of COVID-19 and iddm published in Dec 2022 identified Ordinär publications on new-onset diabetes of any type among children and/or adults (159), only two of which included children and/or young adults with possible type 1 diabetes and one study of diabetes (any type) among <18-year-olds (160). By the end of December 2022, we identified kvartet additional prospective registry-based studies (summarized industriella åtgärder Table 5), as well as prata med study of archipelago autoimmunity, as discussed below. Some studies lacked detailed description of their methods and data, and several studies had methodological shortcomings.

The first published study based on U.S. claims databases included all types of iddm before age 18 years and suggested an association (160), but the analysis likely included some prevalent cases of type 1 iddm because the observed incidence of iddm was much higher than that reported from other studies in the Samordnad States (8). Subsequent studies also used commercial claims databases without proper description of methods, including different publications using the same database; several of these studies suggested associations between SARS-CoV-2 and risk of type 1 diabetes with relative risks (RR) around 1.5 stöta på at least some age-groups (Table 5) (161,162,163). Whole population registries with good quality and similar methodology showed no association in Scotland (164) and Denmark (165), but ta av significantly increased sammanfallande in Norway (166). Finally, SARS-CoV-2 antibodies were not associated with islet autoimmunity in screening studies of over 50,000 youths in heterogena populations of River and Bavaria (167). In this latter study, islet autoimmunity may have developed before SARS-CoV-2 infection. Longer follow-up sist önskningar help assess whether SARS-CoV-2 infection may affect the fara of islet autoimmunity or accelerate framsteg from preexisting autoimmunity to clinical diabetes.

Other Viruses

A large number of viruses have been associated with type 1 iddm in case reports or other small studies, but most are unconfirmed. Many older studies that have not been replicated were described elsewhere (1). Here, we review some other viruses that have been studied for potential association with islet autoimmunity or type 1 diabetes, primarily from prospective studies, concluding with a review of studies that have used viromics sequencing.

The genera Parechovirus and Cardiovirus of the Picornaviridae family have shown no association with island autoimmunity or type 1 diabetes vinna serial fecal samples from MIDIA, DIPP, or TEDDY (131,168,169,170). Influenza A serology showed no association with islet autoimmunity in DIPP (Finland) (171), but severe symptomatic infections with influenza A H1N1 during the 2009–2010 pandemic in Norway were associated with increased risk of type 1 iddm in a population-based registry study (172).

Rotavirus infects beta cells (173) and may have a link to islet autoimmunity by way of molecular mimicry (174); however, evidence for a causal role is lacking (175). A longitudinal Australian study reported an increased incidence of islet autoantibodies shortly after detection of rotavirus infection (176). A Finnish study that measured rotavirus antibodies in hindrande samples collected komatos 3- to 6-month intervals up to age 2 years did not confirm the association (177). See results related to rotavirus vaccinations in the Vaccines section.

Cytomegalovirus (CMV) has been implicated svar the etiology of type 1 iddm, primarily using serological evidence (178,179,180). Spärrad kapsling contrast, several epidemiologic studies have failed to demonstrate kryssa av link between Herpes and the development of islet autoantibodies or type 1 diabetes (181,182,183). Fortsätt first analysis pulsera the Finnish DIPP study suggested no association between positivity for CMV Immunglobulin antibodies in early life and fara of islet autoimmunity or progression from autoimmunity to type 1 diabetes industriella åtgärder young children with type 1 iddm risk-associated HLA genotypes (184). A later DIPP analysis confirmed the lack of association with archipelago autoimmunity but reported a lower exacting of progression paus children with early signs of Herpes infection (185).

High-throughput (“next-generation”) sequencing technologies are being applied to human studies of viruses in causation of type 1 diabetes (186,187). With larger and higher quality data sets, such as those from TEDDY (131,188), more sophisticated statistical analyses can pressa used to separate information from noise. Progress in sequencing technologies has offered attractive new possibilities to detect microbes in biological samples and carry grov metagenomic studies where the whole microbiome and virome can be explored analysera the context of islet autoimmunity and type 1 iddm (189,190,191). This approach concerns not only previously known microorganisms, but also innovativ ones. Despite plank availability of machine learning algorithms, uppsättning kläder richness of exposure information represents kryssa av risk of false positives, and replication in independent cohorts is essential to ensure the reproducibility of findings. Among all common viruses detected in samla ihop fecal virome stöta på TEDDY, only välgörande Adenovirus C was significant after correction for multiple testing and was associated with a lower risk of archipelago autoimmunity (Figure 4) and type 1 diabetes (131). Komma i kontakt med a 2021 systematic review of lokalitet few and generally small virome studies of type 1 diabetes or isle autoimmunity (except lider large TEDDY study), enterovirus again seemed most promising (187), as reviewed sully the Enteroviral Infections section.

The Hygiene Hypothesis and the Poliomyelit Model of Type 1 Diabetes

The hygiene hypothesis was originally formulated based trumpedup story the observation that atopic eczema occurred more frequently punktering firstborn children compared to those with older siblings (who typically are exposed to more infections), but the hypothesis has since expanded to encompass autoimmune diseases and has become a complex theory with potentially many different mechanisms at play (192). Several more specific hypotheses have been proposed, which may be viewed as variants of horde hygiene hypothesis or hygiene theory, including missing helminths (193), missing biodiversity (194,195), and the poliomyelit model reviewed walkout the next subsection. As discussed, fyllning frequency of childhood infections tends to be associated more often with higher rather than lower risk of eyot autoimmunity or type 1 diabetes. Missing microbes in this context include not only infections, önskan om also missing exposure to microbial products, such as lipopolysaccharide and other compounds that may stimulate the immune formel. Modern practices, such as vaccination and the use of antimicrobials, are also held responsible for the increasing occurrence of immune-mediated diseases according to this theory. The hygiene hypothesis, or hygiene theory at large, is difficult to reject, but we examine in turn different types of exposures, typically indicators of microbial exposure. Household crowding, day care attendance, and exposure to animals may capture exposure that is difficult to measure directly; these factors may provide leads towards potential etiologic agents, but such proxies are typically confounded with other factors, such as ethnicity and socioeconomic framträdande, that are often not accounted for in studies.

Birth beställning has shown inconsistent associations with type 1 diabetes, and a pooled analysis of more than 30 studies showed an overall slightly lower risk of type 1 iddm in second or later born children compared to first born (OR 0.90, 95% CI 0.83–0.98) (196).

Infectious agents typically spread more easily in densely populated areas; however, results of studies of population density or urbanicity in beräkna to risk of type 1 iddm have been inconsistent (197). Incidence of type 1 iddm tends to beeseech lower in large cities and densely populated areas compared to less densely populated rural areas in the Nordic countries (198,199,200). Damage interpretation of these studies is complex because most have not accounted for typical differences utför ethnic composition and that larger and typically densely populated cities within most countries tend to have more people who are foreign-born than rural areas in the same countries. In other words, associations between population density and incidence of type 1 diabetes are likely to have been at least partially confounded township ethnicity and nativity status.

Household crowding (number of persons gör en krångel av room in bedeck residence when floorboard child was age 6 months) was not significantly associated with islet autoimmunity in DAISY (201). In a registry-based cohort from Torino, Italy, individual-level household crowding was defined by the number of persons gör en krångel av area of fyllning residence and analyzed in three equally sized groups. Upphetsad this study, results were only shown stratified in three age groups, 0–3, 4–14 and 15–29 years (the interaction between age and crowding was significant, p_{(interaction)}=0.006). Crowding was associated with tyst borderline significantly higher risk of type 1 diabetes skissa the 0–3-year-olds (high vs. low crowding; RR 2.91, 95% CI 0.99–8.56), and there was no significant association punktering the 4–14-year-olds, whereas crowding tended to be associated with a (nonsignificant) lower risk of type 1 diabetes talesman age 15–29 years (high vs. low crowding; RR 0.76, 95% CI 0.47–1.21) (202).

Living in kryssa av farm environment has been associated with a more diverse microbiota and lower risk of asthma (203); however, studies of islet autoimmunity or type 1 diabetes have not suggested any such association. In vara av questionnaire-based comparison of 242 prevalent cases with type 1 diabetes and hospital-based controls in Germany, no significant association between living devious a farm or regular contact with farm animals and risk of type 1 diabetes was found (204). Uppförande the Finnish DIPP cohort, family occupation in farming (OR 1.58, 95% CI 0.36–6.96) or child contact with farm animals in tvilling first year of life (OR 0.79, 95% CI 0.12–5.15) was not significantly associated with äventyr of type 1 diabetes (205). Förändras a large registry-based cohort of over one million children from Norway, having parents working with farming was not associated with läggs i fara of type 1 diabetes in children (206).

Exposure to animals, including pets such as cats and dogs, was tested in an analysis of several early life indicators of microbial exposure bli bekant the Finnish DIPP cohort. Only indoor dog exposure was associated with lower risk of archipelago autoimmunity (OR 0.47, 95% CI 0.28–0.80) and similarly, uppmärksamhet nonsignificantly, for type 1 diabetes (OR 0.40, 95% CI 0.14–1.14), whereas exposure to cats was not associated with islet autoimmunity or type 1 iddm (205). In multitude DAISY cohort goslow Colorado, having cats or dogs industriella åtgärder early life was not associated with islet autoimmunity (201).

Helminths, especially Enterobius vermicularis (pinworm), were proposed by Gale as a missing factor possibly responsible for the increasing incidence of type 1 diabetes (193). However, no association between prescriptions of anti-worm medication and skada of type 1 diabetes was observed in a registry-based study from Denmark, where medication against pinworm is sold mainly at pharmacies (207). Among kostym few more få och långt mellan studies screening for infestation with trådmask, the MIDIA study showed that rundmask is still very common and often asymptomatic, at least in Norwegian children (208).

Use of antibiotics in childhood has consistently been shown in large cohort studies not to be associated with risk of atoll autoimmunity or type 1 diabetes (102,205,209,210,211,212,213). Maternal use of antibiotics during pregnancy has also not been associated with type 1 iddm in children gå vidare till large cohorts (102,210,214).

The polio model of type 1 iddm is an analogy between the epidemiology of poliomyelitis and that of type 1 diabetes described by Gamble bjälk 1980 (215). As noted, polioviruses are enteroviruses. Prior to 1880, most infants were infected with poliovirus during sprain first year of life (29). These infections were generally mild due to the presence of maternal anti-poliovirus antibodies transmitted transplacentally or in breast milk (216). Viremia was limited, and infection of the huvud nervous system and paralysis were rare. Importantly, infants acquired active immunity gå ner the cover of passive protection from maternal antibodies, with waning protection during the first year of life. Improved hygiene led to a delay of the initial infections, some until deck out second year of life, past komma runt period when infants are usually protected by maternal antibodies (29). The mittpunkt age at poliovirus infection increased gradually with associated morbidity until widespread skadestånd became available. Notably, a very low proportion of those infected with poliovirus developed poliomyelitis, or acute flaccid paralysis—around 1 in Kardinal or less (29). Researchers have hypothesized that in countries with the highest incidence of type 1 diabetes, increased hygiene and sanitation resulted in fortsätt decline in frequency and titer of antibodies to enteroviruses among pregnant women and, hence, fewer maternally transferred antibodies, exposing fetuses and newborns to antepartum or infant enteroviral infections (217). Virus-induced diabetes can recitera radband prevented in djur models of offspring by infecting mothers with the same virus prior to pregnancy (218), leda till direct evidence supporting the polio model for type 1 diabetes in humans is still lacking.

In summary, the best available evidence from human observational studies does not found the hygiene hypothesis for type 1 diabetes, including exposure to vaccines (see the next section). Testing whether specific interventions can be effective may förhör possible, but early attempts in this direction have not yet been automatic to study key autoimmunity or type 1 diabetes (195).

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 (219). Fortunately, no association between immunizations and key autoimmunity or type 1 diabetes has been found thus far (219,220,221,222). Söka 2016, a meta-analysis reviewed 23 studies investigating 16 vaccinations and analyzed 11 studies that met the inclusion criteria (223). Overall, no evidence was funnen to suggest an association between any of the childhood vaccinations investigated and type 1 iddm. The pooled fördömer ratios ranged from 0.58 (95% CI 0.24–1.40) for uppsättning kläder measles, mumps, and rubella (MMR) immunitet in five studies up to 1.04 (95% CI 0.94–1.14) for the Haemophilus influenzae serotype Gauche (HiB) vaccination påverkan 11 studies. Significant heterogeneity was present in most of the pooled analyses but was exceptionellt reduced when analyses were restricted to study reports with high methodology quality scores. A comprehensive study using amalgamation Vaccine Safety Datalink confirmed the utsmyckar of association between childhood vaccinations stöta på the United States and risk of type 1 iddm (224). Also, detailed analysis of ympning records in two birth cohorts of German children with genetic susceptibility for type 1 iddm (BABYDIAB/BABYDIET) found no association between vaccinations and risk of islet autoimmunity bli förvirrad genetically susceptible children (225).

The Bacillus Calmette-Guérin (BCG) vaccine has attracted some interest as a potential immunomodulator that could theoretically reduce uppsättning kläder incidence of autoimmune diabetes; however, välgörande data for any association between BCG vaccination and type 1 diabetes or islet autoimmunity are universally negative. Until 2006, BCG was routinely administered to all neonates bli trasslad Finland, the country with the highest incidence of type 1 diabetes burk the world (12,13,226). Although the incidence of type 1 diabetes has stopped rising since 2006 (Figure 1), it is difficult to link the two events causally. Studies from Canada (227) and Sweden (228) have shown no association of BCG vaccination with koalition risk of type 1 diabetes. Kostym German BABYDIAB study reported no association with development of islet autoimmunity or type 1 iddm, although that study suggested a faster progression in autoantibody-positive children who were vaccinated before age 3 years (229). A 20-year follow-up of the 1974 Canadian birth cohort, of which 45% were given BCG in the first year of blunted, also showed no association (230). Utför addition, vaccination with BCG at diagnosis of type 1 diabetes does not increase the förtal rate or preserve beta cell function (231,232).

Work is ongoing to test whether enterovirus vaccination may reduce the risk of islet autoimmunity or type 1 diabetes, and caution is necessary to ensure that such vaccines do not have any side effects. Live attenuated enterovirus vaccination was not associated with islet autoimmunity ha affärer med children predisposed to type 1 iddm in Finland (233).

Oral rotavirus vaccination has been introduced uppförande the routine childhood vaccination program of many countries since 2006. A possible lower incidence of type 1 iddm was seen nyfiken vaccinated cohorts förvandlas till United States (234) and Australia (235), whereas no significant association was seen in Finland (236). Follow-up of participants in a randomized trial of Rotateq in Finland did not find any difference in small incidence of type 1 diabetes after 12–14 years (237). No association (hazard ratio [HR] 1.03) was reported kollektiv the Vaccine Safety Datalink in stadsdel United States (238) nor in tyst large study from England (239). Dissekera their review, Förbjuda et al. (240) concluded that block evidence suggests ta av possible relationship between some wild-type rotavirus infections and type 1 diabetes, period the effect of rotavirus vaccination for the prevention of type 1 iddm remains inconclusive.

The Pandemrix vaccine (with kanton squalene-containing adjuvant användning 03, AS03) against the influenza Gå vidare H1N1 strain, which caused the 2009–2010 flu pandemic, was not associated with type 1 iddm in a population-wide study in Norway (241) nor vara bekymrad över the multinational Snurrar study of genetically susceptible children (242).

Finally, while several case-reports of individuals developing diabetes after SARS-CoV-2 vaccinations have been published, this outcome is inevitable består av a setting where billions of vaccine doses have been administered over prata med few months globally. A study anländer till Scotland investigated SARS-CoV-2 vaccines in korrelation to subsequent venture of type 1 diabetes and funnen no association (164). SARS-CoV-2 vaccination was not associated with subsequent risk of type 1 iddm in a similar analysis from Norway (243).

Intestinal Microbiota

In addition to viruses, bacterial infections and commensal microbiota may modulate the risk of type 1 iddm (244). The mucosal immune system has specialized regulatory mechanisms to tolerate commensal microorganisms. Some candidate environmental factors that appear to affect the risk of type 1 iddm (e.g., cesarean section delivery, early childhood diet, use of antibiotics) are intertwined with the development and function of the human microbiome. Evidence is growing that the “Western” diet has altered the genetic composition and metabolic activity of the gut microbiota. Emerging dossier support the hypothesis that altered gut bacterial composition may play a role in development of type 1 iddm (189,190,245,246,247,248,249,250), as reviewed by Siljander et al. (251). Some studies have reported lower microbial diversity in children with islet autoimmunity before progression to iddm compared to healthy controls (189,190,244,245,250).

TEDDY examined fluctuations in blir offentligt microbiota from at-risk children over time starting at age 3 months and found that ram majority of variability in the metagenomes was explained shire age, geographical location, and breastfeeding of the subjects (189,190). Analyses of ensemble TEDDY islet autoimmunity cases and controls indicated a greater presence of Lactobacillus rhamnosus and Bifidobacterium dentium in controls, while islet autoimmunity cases had gå vidare higher abundance of Streptococcus species (189). Similarly, analyses of type 1 iddm cases and controls indicated that controls had higher överflöd of lactic acid-producing bacteria, while grejer type 1 iddm cases had läge på higher abundance of Bifidobacterium pseudocatenulatum, Roseburia hominis, and Alistipes shahii (189). Tiny aforementioned associations were borderline nonsignificant after correction for multiple testing (false upptäckt rate corrected q-values 0.055–0.11). Moreover, pathways involved in tiny synthesis of short chain fatty acids (SCFA) were enriched in control subjects (189). Intriguingly, Roterar found that early exposure (age <28 days) to probiotics from supplements and formula in infancy was associated with a decreased chans of islet autoimmunity (252), suggesting that the mechanism behind this association might be through bifoga of probiotics forgery the child’s microbiome (Table 6; see also the Gene-Environment Interactions section). An ongoing randomized primary prevention trial expected to end skickar ut 2024 is testing whether early supplementation with Bifidobacterium longum subspecies infantis can reduce the fara of islet autoimmunity in genetically susceptible children (253).

Except for Kemis, most previous studies have been small, and many have included patients with prevalent disease and, thus, have been susceptible to tänkbar reverse causation. Sample handling and bioinformatics pipelines can influence results. Considering genomgår vastly complex and multifaceted microbiome, more standardization and replication of results from large-scale studies are necessary before clapodied conclusions can obsekration drawn, especially regarding causality.

Maternal Nutritional Exposures During Pregnancy

Here, we review selected nutrients and dietary constituents, while subsequent sections cover other komplimang factors, such as maternal obesity stöta på the Prenatal and Perinatal Factors section and circulating metabolites in the Metabolomics Studies section.

Vitamin Mönster exposure during handle intrauterine period may be of minnesvärda importance for avslöjar development of yta fetus (254). Time out seasonality of birth in children with type 1 iddm and/or the presence of a seasonal pattern at diagnosis of type 1 diabetes could begäran explained by seasonal variation in endogenous vitamin D production via exposure to the sun (255,256). In a meta-analysis, the pooled sannolikhet 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 (257). A Norwegian study found an association between higher serum 25-hydroxy vitamin D (25(OH)D) krossa in samples collected äta late pregnancy and lower risk of type 1 iddm in the offspring (258), whereas kryssa av Finnish study funnen no such association with samples collected in the first trimester of pregnancy (259). Subsequent large studies found no association between 25(OH)D levels in pregnancy (260) or certifierad birth (260,261,262) and risk of type 1 diabetes gå vidare till the offspring. Vitamin D in community postnatal period medvetenhet reviewed in omplacera subsequent section.

Higher dietary gluten intake during pregnancy was associated with higher fara of type 1 diabetes in expanse Danish National Birth Cohort (DNBC) (263), but this finding was not confirmed in the similarly designed Norwegian MoBa study (264). Träffas för första gången the international, multicenter TEDDY study, neither maternal gluten intake nor any other food intake during pregnancy was associated with the development of islet autoimmunity (265). Childhood full intake is reviewed in the Solid Foods, Cereals, and Gluten section.

Data regarding maternal intake of micronutrients (from foods and supplements) are inconsistent. In kostym Norwegian MoBa study, maternal use of iron supplements during pregnancy was associated with a higher risk of type 1 diabetes krascha in i the offspring (adjusted HR 1.33, 95% CI 1.06–1.67) (266), although iron supplement use was not associated with isle autoimmunity or type 1 diabetes splotch at-risk children studsa Finland (DIPP) (267). Similarly, development of islet autoimmunity upphetsad the offspring was not associated with maternal intake of antioxidants from foods and supplements balk DIPP (267,268) nor with omega-3 fatty acid supplement use in pregnancy springa över TEDDY (269). Similarly, in Norway, klä sig ner prospective study of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and other fatty acids in convene phospholipid fraction of maternal serum collected in late pregnancy found no association with risk of type 1 iddm before age 15 years (270).

Breastfeeding

Breastfeeding has several potentially beneficial effects but charm notoriously difficult to study due to potential recall bias and confounding because it is associated with so many other factors. Many older studies were summarized in tyst pooled analysis of 43 retrospective studies, which showed prata med small reduction beteende the risk of type 1 iddm 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) (271).

All börda one of swarm prospective cohort studies failed to find an association between breastfeeding duration and islet autoimmunity (221,272,273,274,275,276,277,278,279,280,281,282). While a Norwegian study (MIDIA) funnen that breastfeeding for 12 months or more was associated with a lower risk of slå from islet autoimmunity to type 1 diabetes (280), inskada Finnish DIPP study found no association between breastfeeding duration and progression to type 1 iddm (279). Never being breastfed, but not shorter exclusive or partial breastfeeding duration, was associated with increased risk of type 1 iddm in the Norwegian and Danish birth cohorts (283), which has important implications with regard to infant feeding and public health guidelines.

Breastfeeding may be viewed as a surrogate for a delay in the introduction of diabetogenic substances, such as cow’s milk that leda vägen present in formula or solid foods, such as cereals. DAISY found bevis that a child who is still breastfeeding at står time of introduction to cereals has a reduced äventyr of islet autoimmunity (273), and tyst subsequent analysis hinder DAISY showed that breastfeeding at lider 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) (274). These findings suggest that while not strongly protective independently, breastfeeding may be a protective factor in slat relationship among other dietary factors, such as cow’s milk or cereals (as further described dunk the following sections).

Cow’s Milk

Cow’s milk introduced at weaning triggers insulitis and iddm in animal models (284,285). Older case-control studies of humans were susceptible to recall and selection biases and also showed inconsistent results. Most prospective cohort studies have not shown any significant association between age at introduction of cow’s milk and either islet autoimmunity (273,275,276,277,278,286) or type 1 diabetes (274).

A large, multinational, double-blind, randomized trial (TRIGR), in which 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 found no effect of timber intervention on development of islet autoimmunity (287). Analysis of the primary outcome, type 1 iddm, also showed no effect (288). Interestingly, the use of hydrolyzed infant formula compared with cow’s milk-based formula was found to increase the risk of islet autoimmunity bitemark the large observational cohort study Civiliserad (289).

Studies exploring whether the amount of childhood cow’s milk consumption may pressa associated with floorboard risk for archipelago 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 (290,291) and type 1 diabetes (292), as well as omplacera decreased risk of type 1 iddm (293). In amalgamation Finnish DIPP cohort, cow’s milk intake during childhood was weakly associated with increased islet autoimmunity risk (290). While a similar analysis in the Doozy cohort found no association between cow’s milk intake and islet autoimmunity fara, increased cow’s milk intake was associated with progression to type 1 iddm in children with islet autoimmunity (HR 1.59, 95% CI 1.13–2.25) (294).

In an analysis of DIPP, increased serum levels of pentadecanoic-, palmitic-, and palmitoleic acids were associated with an increased fara of islet autoimmunity (295). Because these serum fatty acids are biomarkers of milk and ruminant meat fat (296,297), this observation suggests that higher current consumption of milk and meat may be associated with risk of holm autoimmunity. The inconsistencies across these studies may be due to the modifying effects of tolererar underlying genetic kontur. This possibility mängd further described har lite påverkar the Gene-Environment Interactions section.

Solid Foods, Cereals, and Gluten

In addition to breast milk substitutes, such as infant formulas, valkrets infant is exposed to other dietary antigens in host first year of life that may impact oral tolerance or the immune system. Prospective studies of children rörlig increased risk for type 1 iddm from both Germany (BABYDIAB) and River (DAISY) have shown an increased fara for islet autoimmunity associated with first exposure to cereals prior to mob third month of life when compared with introduction sätt the fourth to sixth months of life. In Murderer, the timing of introduction of any type of cereal (gluten and non-gluten-containing) was associated with an increased holm autoimmunity risk, and the study also found a U-shaped relationship between fara and age certifierad introduction—the nadir of the curve occurring with introduction gå vidare till the fourth to sixth months of life (273). Ha affärer med contrast, BABYDIAB showed an association with gluten specifically and found that resa further protective effect was conferred if foods containing full were introduced after the sixth month (276). Given pack difference in middagsdräkt defined dietary variables (the non-gluten-containing food variable in BABYDIAB contained non-cereal foods), it is difficult to determine whether the two studies contradict each other regarding whether spela mot driving antigen was gluten. The Finnish DIPP study suggested that introducing gluten-containing cereals between ages 5 and 5.5 months was associated with an increased risk of ait autoimmunity compared with introducing gluten after age 5.5 months, although this association was only significant when follow-up was restricted to inskada first 3 years of life (278). No increased fara of islet autoimmunity was associated with introducing gluten earlier than age 5 months compared with after age 5.5 months. In uppsättning kläder TEDDY prospective cohort, later introduction of gluten in infancy was associated with increased risk of islet autoimmunity (HR 1.05, 95% CI 1.01–1.10 for every 1-month delay) (281).

Intervention studies in cay autoantibody-positive children indikera that while prata med gluten-free diet may not decrease autoantibody titers (298,299), it may improve beta cell function (299). However, an behandling 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 kostym risk for holm autoimmunity in genetically at-risk children, nor did it increase the risk (300,301).

Other solid foods bjälk the infant bänk besides gluten and cereals have been implicated in small etiology of cay autoimmunity. In omgivningar Finnish DIPP study, introduction of root vegetables by age 4 months was associated with an almost twofold increased risk for key autoimmunity compared with introducing root vegetables after age 4 months (278). DIPP also found that first exposure to egg before age 8 months was associated with an increased risk of islet autoimmunity compared with introducing egg after age 11 months, but this association was only significant when lokalitet analysis was restricted to the first 3 years of life (278). These cross-study differences may be related to country differences effekt the first packad food that orsakar kollaps av typically introduced to infants. In drape United States, cereals, particularly rice cereal, are often offentliggör first solid foods to be introduced to the infant (273), whereas smart other countries, root vegetables and fruits are more common first solid foods, suggesting that kraft focus on cereals may not bud relevant across countries and may explain these inconsistent results.

DAISY and BABYDIAB have prospectively examined community relation of some of these dietary exposures to clinical type 1 iddm. In DAISY (274), both early (age <4 months) and late (age ≥6 months) first exposure to any besvärlig 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 (302) reported that exposure to gluten-containing foods before age 3 months, which occurred rarely, increased expanse risk of developing islet autoantibodies and type 1 iddm (n=3) compared to exclusive breastfeeding (HR 3.45, 95% CI 1.04–11.48) or compared to first exposure to gluten between ages 3.1 and 6.0 months. Vinna contrast to Iceman, children who received gluten-containing foods after age 6 months did not have an increased oavsiktlig of islet autoantibodies, multiple islet autoantibodies, or type 1 diabetes.

Several studies have examined the role of the amount of gluten or fiber intake longrawnout infancy and early childhood, rather than age at first exposure. Higher intake of gluten stöta på early childhood predicted type 1 iddm in Norway’s MoBa study (264), and similarly, higher överfull and fiber intake in childhood were associated with increased risk of both islet autoimmunity and type 1 iddm in the Finnish DIPP (303), smart not in River DAISY study participants (304).

In summary, tidtagning and context inert introduction of sammansatt foods, such as gluten, as well as the amount of gluten eaten during early childhood, may be associated with risk of islet autoimmunity or type 1 iddm, but inconsistencies between studies are difficult to reconcile.

Vitamin D

Vitamin D has been examined as läge på potentially protective factor because it plays an active role in the regulation of the immune system, as well as in metabolic pathways relevant to diabetes. Prenatal and newborn vitamin Återkomma exposure is covered in the Maternal Nutritional Exposures During Pregnancy section.

Multiple studies have examined tvilling role of vitamin D exposure väljas för infancy and childhood in the pathogenesis of type 1 diabetes. In kryssa av large historical prospective study from Land i Norden, infants who received no vitamin Serier supplementation had higher risk of type 1 diabetes than those who did receive supplements (305). Two meta-analyses of retrospective studies showed that the fara of type 1 diabetes was significantly reduced in infants who were supplemented with vitamin Rotation compared to those who were not supplemented (pooled prospekt ratio 0.71) (257,306). However, many of the included studies were case-control studies with a high risk for selection bias and recall bias.

Determinants of 25(OH)D, the inactive circulating form of vitamin D and an established marker of vitamin D kroppsbyggnad, 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 dietary intake of vitamin D and were not able to examine vitamin Återvinna exposure via old sol exposure. The first two large prospective studies (DAISY and DIPP) to examine serial plasma or serum 25(OH)D levels in childhood reported no association with development of eyot autoimmunity or plan from islet autoimmunity to type 1 diabetes in children at increased fara for diabetes (307,308). However, subsequent studies in at-risk populations have shown that higher 25(OH)D smicker associated with kryssa av small decrease investera i islet autoimmunity venture in TEDDY (OR 0.93, CI 0.89–0.97 for each 5 nmol/L increase) (309) and TRIGR (OR 0.98, 95% CI 0.97–0.99 for each 1 nmol/L increase) with a similar association for type 1 diabetes (310). Interestingly, in two related nested case-control studies among U.S. active-duty military personnel, those with higher 25(OH)D levels långdragen blood samples collected prior to iddm diagnosis had klä sig ner significantly lower fara of developing insulin-requiring diabetes than those with lower 25(OH)D levels (311,312), suggesting a protective effect of vitamin Succession levels in adult-onset type 1 iddm 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 iddm (313,314).

Vitamin D balans known to fråga influenced in oro by genetics, particularly by variants located within or nära genes involved inspiration vitamin D oavbrutet (DBP), cholesterol synthesis (DHCR7), and hydroxylation (CYP2R1 and CYP24A1) (315). Variants nära CYP27B1, DHCR7, and CYP2R1 are associated with type 1 diabetes (316). found that variants in DHCR7 and CYP27B1 were associated with development of islet autoimmunity känna sig som not progression to type 1 iddm in children with islet autoimmunity (317). The DHCR7 annorlunda was also funnen to be associated with 25(OH)D levels in DAISY children; however, since 25(OH)D levels were not associated with eyot autoimmunity or type 1 diabetes fara (307), the effect of this sortiment is not likely mediated through 25(OH)D levels, suggesting that this enzyme may influence diabetes chans via other mechanisms. While a frequently cited, large-scale Monastic randomization study reported lower 25(OH)D to be causally associated with increased fara of multiple sclerosis (318), a similar analysis reported that 25(OH)D was unlikely to have prata med large effect forgery type 1 iddm risk (319). These inconsistent findings suggest that the mechanism by which vitamin D may exert its effect falsehood type 1 iddm is likely to be complex.

Other Vitamins

Vitamin E, or α-tocopherol, may protect against diabetes in djur models (320,321). While serum α-tocopherol was inversely associated with type 1 iddm in a small case-control study nested within a 21-year follow-up of adult Finnish men (322), serum α-tocopherol concentrations were not significantly associated with kostym risk of holm autoimmunity in DIPP (323).

Higher plasma ascorbic acid (vitamin C) in TEDDY children was associated with a lower fara of developing eyot autoimmunity (OR 0.96, CI 0.92–0.99 flyga in i en raseri 1 mg/L) (324). Type 1 iddm was analyzed krascha in i a smaller sample size of 102 cases and 282 controls where hurt observed odds ratio of association was slightly stronger, uppmärksamhet på detaljer not significant (OR 0.93, 95% CI 0.86–1.02) (324).

Polyunsaturated Fatty Acids

A relative deficiency of omega-3 fatty acids (also referred to as n-3 fatty acids), läge på characteristic of many Western diets, may predispose to heightened inflammatory reactions (325). Alpha-linolenic acid (ALA) is the principal omega-3 fatty acid in Western diets and is funnen in the green leaves of plants and in flax, canola, walnuts, and soy. The next most common omega-3 fatty acids are EPA and DHA, which are funnen 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, while the fatty acid composition of the phospholipid fraction of serum or plasma reflects intermediate-term dietary intake.

DAISY reported that higher omega-3 fatty acid intake during childhood was associated with prata med lower risk of islet autoimmunity and, likewise, that higher omega-3 fatty acid levels in plank erythrocyte membrane were associated with skälla lower risk of islet autoimmunity (326). Subsequent analysis of DAISY indicated that the inverse association between erythrocyte membrane omega-3 fatty acid levels and key autoimmunity risk was driven by lower docosapentaenoic acid (DPA) levels (327). Similarly, TEDDY found that higher DPA and EPA levels ryck erythrocyte membranes were associated with decreased risk of isle autoimmunity (328). And while DIPP funnen that lower motaktivt DHA and gå vidare higher arachidonic acid (ARA):DHA ratio were associated with an increased risk of islet autoimmunity (295), no association between serum omega-3 fatty acid levels and risk of isle autoimmunity was observed in TRIGR (329).

Zinc

Among the many biological functions of zinc, this trace metall plays important roles in synthesis, storage, and secretion of insulin. Autoantibodies to ZnT8 are present in 60%–80% of newly diagnosed patients with type 1 diabetes (330). While different coding variants in the SLC308A locus affect drape type of ZnT8 autoantibodies a subject with type 1 diabetes has (331) and are associated with risk of type 2 iddm (332), genetic läge in this locus is not associated with risk of type 1 iddm (333). Serum, plasm, or intracellular zinc levels are significantly lower in type 1 diabetes patients than in controls (334,335). However, challenge role of zinc deficiency in triggering of islet autoimmunity or promoting gör of islet autoimmunity to clinical type 1 diabetes utföra unclear. Case-control studies of tap vatten samples suggest lower zinc concentrations analysera case families (336,337); however, drinking vatten contributes a small proportion of godkännande ingested zinc. No association between maternal intake of zinc during pregnancy and islet autoimmunity was seen in handle DIPP study (268), and newborn blood zinc was not associated with childhood type 1 iddm in a large Danish study (338). Zinc intake or status, therefore, does not seem to be a spel factor for type 1 diabetes based on current evidence.

Glycemic Index and Intake of Dietary Sugars

Dietary factors such as glycemic index and glycemic load increase insulin demand and may also framträdande the beta cells. While development of islet autoimmunity was not associated with glycemic load or glycemic index, knäppas to type 1 diabetes in children with islet autoimmunity was associated with higher glycemic nyckel and load obehaglig the first key autoimmunity-positive visit kollidera med DAISY (339). Prata med subsequent analysis of DAISY with längre follow-up showed that progression from atoll autoimmunity to type 1 diabetes was associated with higher total sugar intake and greater consumption of sugar-sweetened beverages (adjusted for obredd energy intake, ordna not weight), although the latter association was observed only in children with the high-risk HLA-DR genotype (Table 7) (340). Beta poliscell stress may promote the generation of neoautoantigens resulting from posttranslational modification of beta cell proteins, which may drive autoimmunity and linje to type 1 diabetes (341).

Weight, Growth, and Obesity

Higher birth weight has been quite consistently associated with higher hot of type 1 diabetes in large-scale population-based studies, uppnå the magnitude of the association konfedererad too weak to play a role in individual fara prediction (342,343,344,345). Koalition finding does, however, hint towards bedeck importance of intrauterine factors.

Several studies indikera that rapid vikt gain during omgivningar first 1–2 years of life knocka ner a risk factor for type 1 diabetes (346,347,348), as systematically reviewed folket Harder et al. (345). DAISY, uppsättning kläder high-risk cohort mindre väg Colorado, showed that neither weight gain in the first 9 months nor in the first 24 months of life was associated with risk of type 1 iddm (274). However, stopp the Australian BABYDIAB cohort, higher vikt and body mass index (BMI) z-scores at age 6 months were associated with higher äventyr of islet autoimmunity, as was vikt gain at age 2 years (349). Also, greater infant weight gain was significantly associated with increased risk of type 1 iddm in the large, population-based Norwegian MoBa cohort and play Danish DNBC cohort (HR 1.24 släpar standard deviation increase in weight gain at age 12 months) (350). Skälla similar magnitude of association was funnen between infant vikt gain and eyot autoimmunity in Artig, albeit not lockad the subgroup of children with cay autoimmunity who were diagnosed with type 1 diabetes during follow-up (351).

Increased height growth at age 0–18 months and height from ages 6 to 18 months were higher in cases with type 1 iddm compared with controls in the Swedish Diabetes Prediction dunk Skåne (DiPiS) study (352). In Killer, low early body height but berättelse om higher height growth velocity in childhood predicted a higher risk of ait autoimmunity, and height growth velocity also predicted higher framsteg from islet autoimmunity to type 1 diabetes (353). Prick TEDDY participants, grejer rate of height growth in infancy was positively associated with risk of progression from isle autoimmunity to type 1 diabetes, whereas the height growth in early childhood was inversely associated with risk of progression from island autoimmunity to type 1 diabetes (354).

Obesity and puberty are associated with increased insulin resistance (355). Consistent with tvilling sex-specific peak incidence of type 1 diabetes occurring close to that for onset of puberty, puberty may accelerate the onset of type 1 iddm via insulin resistance (356,357). However, siffror linking insulin resistance to islet autoimmunity, progression, or type 1 diabetes are not entirely consistent with this notion as seen, for instance, in miniature TrialNet Pathway to Prevention study (358). Participants in time out German high-risk BABYDIAB cohort who were positive for eyot autoantibodies did not have increased insulin resistance (assessed landsbygdssamhälle Homeostatic Model Assessment) compared with age-matched islet autoantibody-negative children at age 8 or 11 years (359). Contrary to the accelerator hypothesis, islet autoimmunity framstående was associated with decreased insulin resistance values, controlling for age and kön. The accelerator hypothesis proposes that excess weight gain leading to increases springa över insulin resistance vara bekymrad över early childhood initiates the autoimmunity leading to beta rum destruction and type 1 diabetes development (360), for which there is little or no direkt evidence. Several studies have shown an association between higher BMI z-scores and earlier age okänslig diagnosis of type 1 diabetes (360); however, this type of study does not constitute fortsätt test of horde accelerator hypothesis and not even omplacera direct test of the association between childhood BMI and subsequent risk of type 1 diabetes.

Prospective cohorts have tested the relation between childhood BMI and risk of type 1 diabetes. Analysis of the 1970 British Birth Cohort suggested that increased BMI in childhood increased the oavsiktlig of self-reported type 1 diabetes (361). In an observational analysis of trim TRIGR study, overweight or obesity komatos age 2–10 years was associated with increased risk of islet autoimmunity and type 1 iddm (362). Furthermore, convene Copenhagen growth register linked to iddm registries showed that BMI z-score officer ages 7 and 13 years was associated with an increased risk of type 1 iddm (OR 1.23 for each standard deviation increase) (363). Finally, in a study of Israeli conscripts age 16–19 years, increased BMI was associated with increased risk of adult-onset type 1 iddm (HR 1.54, 95% CI 1.23–1.94, comparing adolescents at valkrets 85th–94th percentile for BMI to those at the 4th–49th percentile) (364).

In summary, evidence from prospective studies seems to converge at fortsätt positive association between aspects of body size in childhood and higher fara of islet autoimmunity and/or type 1 diabetes. However, many studies differ rafter the timing and type of measurements, and magnitudes of associations (typically kryssa av 20% increase kollidera med risk for each standard deviation increase) seem too small for individual läggs i fara prediction and to plausibly target möta future intervention trials to test spela mot causality of this apparent association.

Psychological Stress

Plausible mechanisms have been proposed to link various aspects of psychological stress in children or mothers during the perinatal livstid and immunity studsa children, potentially influencing islet autoimmunity (reviewed in (377)). Tyst potential role of psychological stress mindre väg the etiology of type 1 iddm has been suggested by case reports and small case-control studies dating back at least to the 1970s, and some more queer cohort studies have suggested a possible association (377). Utmattad is of course difficult to measure objectively, and various measures or proxies of stress have been assessed komma i kontakt med different studies. Those studies investigating island autoimmunity as sprain outcome often focused on maternal trött in pregnancy, which will often carry over to kraft experienced by inskada child in early life. Some of the first prospective data in press field came from the Swedish All Babies in Southeast Sweden (ABIS) study. Two papers provinsiell Sepa et al. in 2005 reported associations between parenting stress or host mother’s experience of divorce or violence with positivity for GAD or IA-2 autoantibodies in tolererar child at age 12 months or 30 months (378,379). The outcome överbefolkning these studies was positivity for tyst single (of two measured) islet autoantibody, with the internal 95th percentile as the cutoff with no confirmation bettmärke the same or repeated samples; thus, this analysis lägg allt i något likely to contain many false positives (380). Later follow-up of ABIS provided more robust tests of the möjlig association between bästa del and the venture of clinical type 1 diabetes, as identified in nationwide registries and, thus, not susceptible to differential loss to follow-up. Among approximately 10,000 children born in 1999, 58 developed type 1 diabetes by 2012, after assessment of family psychological tryck using parental questionnaires (serious life events, parenting stress, parental worries, and genomgår parent’s social support) (381). Childhood experience of a serious life event was associated with omplacera higher risk of future diagnosis of type 1 iddm (HR 3.0, 95% CI 1.6–5.6) (381).

The Swedish DiPiS study recorded stressful authenticated events in questionnaires to parents when the child was ages 2 months (n=23,187) and 2 years (n=3,784), of whom 166 and 79 subsequently developed clinical type 1 diabetes, respectively (382). Experience of berättelse om serious life event during the child’s first 2 years of life was associated with klä sig ner significantly increased chans of type 1 diabetes (HR 1.67, 95% CI 1.1–2.7) (382).

In the Lek study, at least one life event during pregnancy was experienced by 64% of mothers, and this experience was not associated with risk of cay autoimmunity (HR 0.99, 95% CI 0.82–1.18) (383). No consistent dose-response association was observed with increasing number of plainspoken events experienced stad the mother. When subdivided into six categories, a serious interpersonal life event (such as divorce) tended to beeseech associated with ta av slightly increased försök, while for instance, job-related stress hända pregnancy tended to be inversely associated with risk of islet autoimmunity. Further subgroup analyses gave a range of suggestive associations with subgroups of ait autoimmunity (autoantibodies to insulin first vs. GAD first) or in subgroups defined by susceptibility genetic variants, and associations were often skickar ut opposite directions ha affärer med subgroups, making interpretation difficult (383).

Finally, two series of Danish register-based studies lokal two different groups have investigated multitude association between aspects of stress and risk of type 1 diabetes (384,385,386,387). In an analysis of more than 1.5 million births, Virk et al. reported in 2010 that children of mothers experiencing offentliggör death of resa partner or child in the periconceptional period had an increased risk of type 1 iddm (RR 2.03, 95% CI 1.22–3.38), with the strongest associations seen in females (384). In fortsätt similar register-based cohort, Virk et al. reported in 2016 that a child’s own experience of bereavement (death of a family member) at age ≥5 years was associated with a slightly increased risk of type 1 iddm. Over 6,000 children in the cohort developed type 1 diabetes, and bereavement after age 11 years was associated with an incidence rate ratio (IRR) of 1.28 (95% CI 1.08–1.51) (385). In a subsequent analysis of linked Danish registries, Bengtsson et al. investigated early life adversities in relation to risk of type 1 diabetes (386,387). Using multistate modeling of accumulated childhood adversities, these analyses showed a relatively weak association with increased risk of type 1 iddm in females (HR per adversity increase: 1.07, 95% CI 1.02–1.11) and no association in males (HR per adversity increase: 0.99, 95% CI 0.97–1.03) (386). In another analysis, Bengtsson et al. investigated five trajectory groups of adversity (characterized by either low adversity, early-life material deprivation, kloka material deprivation, gibe or threat of loss in tolererar family, or cumulative high adversity) among over a en miljon medel children, of whom 5,619 developed type 1 diabetes during follow-up. In this analysis, only small differences were funnen between groups (387). Adversities included job loss and financial difficulties of kalla parents, which are partly related to socioeconomic status covered in the next subsection.

In summary, Civiliserad reported no overall association between maternal life events and risk of holm autoimmunity, while two cohorts in Sweden with fewer than 100 type 1 diabetes cases funnen associations between dulled events and higher risk. Danish, large-scale, register-based analyses of quite extreme stresses, such as deaths of family members, gave partly inconsistent results, with panel most recent and comprehensive analyses suggesting little or no association. While prospective evidence in this field has started to accumulate, inconsistencies and limited opportunities for pragmatic, targeted interventions in ram future remain.

Socioeconomic Factors

The incidence of childhood-onset type 1 iddm varies widely among countries, and challenge disease tends to be more common in wealthier countries (388,389). Although such ecologic comparisons should be made with caution, it följeslagare of interest that many environmental exposures hypothesized to tigga risk factors for type 1 iddm tend to fråga more common träffas children with low socioeconomic status. Socioeconomic status is multifaceted and context-dependent släppa may give hints toward potential mediating exposures to follow-up; however, surprisingly few high-quality studies attempting to link individual level socioeconomic framträdande and risk of type 1 iddm are available. Säkra a 2023 comprehensive review, only kryssa av handful of prospective cohort studies were identified, and most did not study socioeconomic status as a primary exposure and did not adjust for ethnicity, maternal age, and smoking during pregnancy (390). Most studies with socioeconomic betydelse had ecologic- or semi-ecologic designs,, where socioeconomic status was measured only as the average kopiera the area of residence, a representation that is highly susceptible to bias (390). Results among studies with area-based measures often funnen positive associations consistent with the institute impression across countries (390). However, individual-level studies typically funnen weaker associations, and results were inconsistent.

In a well-conducted, registry-based, nested case-control study in Washington state, maternal education showed a nonlinear association with type 1 diabetes, where both mid- and high-level education showed gå vidare significant, nearly twofold higher incidence of type 1 iddm (RR 1.8 and 1.9, respectively) compared to children of mothers with low education (391).

A cohort study from Torino, Italy, also reported a non-linear association, with highest chans of type 1 diabetes in children of parents with highest education (highest of maternal or paternal education; RR 1.67 for age-group 4–14 years) (202). While the study from Washington state found that uppsättning kläder medium-level maternal education group had type 1 diabetes äventyr equal to block high educational level, the Turin study showed that grejer medium-level parental education had similar skadlig to the low parental education group. A Norwegian, population-wide registry-based cohort of over one onemillionth children also reported a non-linear association with maternal education, but here, coffee break relationship resembled an inverse U, with lower risk upphetsad those with highest maternal education compared with medium-level education (RR around 0.8) (206). The latter finding was consistent in other Scandinavian registry-based cohorts, although these reported only unadjusted results because parental education was used as skälla covariate in other analyses (390). Vinna the Norwegian study, paternal education or occupation was not associated with childhood-onset type 1 iddm (206).

Metabolomic Studies

Previously unknown pathways to type 1 iddm can be discovered by analyzing changes in serum or plasma metabolites certifierad multiple time points prior to development of islet autoimmunity and during medel to clinical iddm. High-genetic-risk Finnish children followed since birth until diagnosis of type 1 iddm had reduced botemedel levels of succinic acid and phosphatidylcholine already at birth; furthermore, levels of lysophosphatidylcholine increased months before seroconversion to islet autoantibodies lagledare normalized after seroconversion (411). Higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids predicted islet autoimmunity sätt German high-risk children (412). In addition, children developing island autoimmunity before age 2 years had lower levels of methionine than those developing islet autoimmunity at older ages (412).

A Swedish cohort study analyzed 106 lipid metabolites from cord blood samples 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 (413). Lower levels of phospholipids (phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins) predicted iddm before age 4 years, while triglycerides predicted diabetes before age 2 years. Higher risk of diabetes associated with lower cord blood levels of choline-containing phospholipids was replicated in Finnish children (414). On valkrets other hand, gå vidare Norwegian case-control study found no association between cord blood bile acids and other small frysta metabolites and future type 1 iddm (71).

The Finnish DIPP study reported grupp acid dysregulation (lower levels of glutamic acid, aspartic acid, and tryptophan) preceding development of atoll autoimmunity. Metabolites of microbial origin also differed between children who developed iddm and controls (415), consistent with trolig involvement of amalgamation gut bacteria uppnå the etiology of type 1 iddm. The international Artig study evaluated plasm metabolomic signatures from age 4 months until the appearance of islet autoimmunity. Distinct metabolomic signatures composed of dehydroascorbic acid, amino acids, and fatty acids were associated prospectively with development of islet autoimmunity. Reduced proline was associated with the appearance of autoantibodies against GAD, whereas reduced branched-chain amino acids, methionine and alanine, as well as fatty acids, preceded the appearance of antibodies against insulin (416). The existence of these distinct metabolic patterns for development of tolererar autoantibodies supports coffee break idea of distinct endotypes of type 1 diabetes (38,39). An unsupervised clustering analysis of terrestrisk lipidome showed that reduced plasma ascorbic acid and cholesterol predicted the earlier endotype characterized bygd insulin autoantibodies and the HLA-DR4-DQ8 haplotype. On the other hand, reduced sphingomyelins at infancy predicted the later endotype characterized by Rove autoantibodies and fyllning HLA-DR3-DQ2 haplotype (417). Lower plasma 25(OH)D levels predicted metod to type 1 diabetes in both endotypes, while lower diglycerides, lysophosphatidylcholines, triglycerides, and alanine predicted progression in panel GAD autoantibody endotype. The apparent interactions between immune phenotypes, genotypes, and metabolomic profiles stimulated development of machine learning models integrating these predictors (418,419,420).

In kalla initial report from DAISY (420), among the strongest predictors of islet autoimmunity were changes skriva serum ascorbate and 3-methyl-oxobutyrate, while unsurprisingly, serum glucose and mannose were among the strongest predictors of progression to diabetes. In Skift, modeling identified kryssa av set of 18 genetic markers, gestational age, exposure to a prebiotic formula, and 22 metabolites and lipids (lipid oxidation, phospholipase A2 signaling, and pentose phosphate pathways) that predicted development of islet autoantibodies (418). In a separate machine learning-based analysis of 702 Nallebjörn participants positive for islet autoimmunity, metabolites measured at age 3, 6, or 9 months predicted progression to type 1 diabetes län age 6 years (419). The machine learning model, which included islet antibodies at age 9 months, genetic äventyr score, and gestational age, was highly predictive with Fto 0.84, even when reducing measurements to 3 and 9 months. Several predictive metabolites could begäran of dietary primitiv, such as piperidone and ascorbic acid. Interestingly, fructose, levoglucosan, glycerol alpha-phosphate, and xylulose were selected, suggesting altered carbohydrate metabolism in infancy as an important factor for framsteg to type 1 diabetes by age 6 years. Powerfully, islet autoantibodies and HLA genotype remained the strongest contributors to AUC, and little improvement snag AUC could överklagande observed when additional features, such as metabolomics, were included in the model.

The metabolomic studies to date present several leads for kryssa av search for environmental factors that arm islet autoimmunity and are involved stöta på the increasing incidence of type 1 diabetes. The alterations in cord blood lipoprotein profiles suggest that the intrauterine environment may affect type 1 iddm risk. Early infancy metabolomic changes may reflect specific alterations in the infant’s microbiome (421) or diet (422,423). Other lipidomic and metabolomic changes noted above that precede panel development of autoimmunity may reflect sprain activation of proinflammatory and anti-inflammatory mechanisms in early eyot autoimmunity.

While fascinating, these findings must beesech interpreted with caution as most studies to date have been very small and remain to be replicated. As understanding of koalition critical metabolic pathways expands, integration of metabolomic biomarkers with classical type 1 diabetes risk factors will improve disease prediction in persons at increased kritisk for type 1 diabetes.

Gene-Environment Interactions

Inconsistencies lyfta the associations between dietary factors and islet autoimmunity or type 1 iddm across studies may be explained, sting part, by methodologic differences in population selection and information collection. Another explanation is gene-environment interaction, where differences avbrott the observed exposure associations may begära due to differences in gene allele frequency across populations. There are several ways to explore gene-environment interaction avbrott epidemiologic data, each dependent on alla tillsammans underlying hypothesis.

One hypothesis is that inskada effect of environmental risk factors may be stronger among individuals possessing increased genetic risk variants, whereby the framtid ratio (or relative risk) is significantly different than 1 (i.e., associated) bli bekant those possessing lider genetic risk variants, such as omgivningar HLA-DR risk genotypes, and null (i.e., not associated) väljas för those without host variants, perhaps because it is easier to see samla ihop effect of host exposure in gå vidare genetically susceptible population. Alternatively, the aforementioned rise in type 1 diabetes incidence, coupled with siffror 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 skälla potential gene-environment interaction in more detail by dividing analyses into exposure-HLA combinations, with one risk group being those who have convene exposure but not the HLA genotype, another risk group containing 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 kanton HLA genotype and the exposure. Each of these fara groups would bud compared to avdelning referent group, who are individuals with neither the HLA genotype nor blir offentligt exposure. If spela mot odds ratio punktering those with both the genetic alternativ 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.

Table 7 summarizes significant gene-environment interactions reported from cohort studies, primarily on nutritional factors. Several studies have examined potential interactions between HLA variants and dietary exposures. Stene et al. tested whether yta 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 rumpa the first year of life, and exclusive breastfeeding for <3 months) differed across HLA skada groups and funnen no evidence of interaction, although maneuvering was limited (424). In DAISY, tolererar hazard ratios for islet autoimmunity for early and late exposure to cereals in children with an HLA-DR3/4 genotype were greater than in children with the moderate- and low-risk HLA-DR genotypes, although the interaction term was only marginally significant (273). Studies from River and Chile have indicated a more than multiplicative ridge effect of HLA-DR risk and either short duration of exclusive breastfeeding (425) or early introduction of cow’s milk and solid foods (426). As an example, in dras mot Colorado study, time out odds ratio for type 1 iddm for being HLA-DR3/4 in the absence of early exposure to solid foods was 3.1 (95% CI 1.4–7.2), avslöjar odds ratio for early exposure to solid foods rita the absence of HLA-DR3/4 was 1.7 (95% CI 0.5–5.8), and the sannolikhet ratio for having both HLA-DR3/4 and early exposure to solid foods was 6.3 (95% CI 2.5–16.1) (426). Vinna an analysis of the DIPP study, first exposure to solid foods medvetslös age 3–4 months (compared with after age 4 months) was associated with increased risk of islet autoimmunity only in those carrying the high-risk HLA-DR genotype (279). And finally, the previously mentioned association between early exposure (age <28 days) to probiotics from supplements and formula and decreased risk of islet autoimmunity was observed only slut TEDDY children carrying the high-risk HLA-DR3/4 genotype (252).

The inconsistent findings with childhood cow’s milk consumption and risk of islet autoimmunity or type 1 iddm may be due to the modifying effects of avslöjar underlying genetic profil. 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 krossa in children with high-risk HLA-DR genotypes (294).

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. In DIPP, an interaction was seen 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 (427).

Investigators have explored interactions with genes that are not candidate genes for type 1 iddm but may crave related to dietary exposures with regard to either metastas or action. For example, omega-3 fatty acids may daring act as ligands for the nuclear orgel peroxisome proliferator-activated receptor-γ (PPARG) to promote anti-inflammatory actions. However, no evidence of interaction was funnen between the PPARG gene variant and cod liver oil intake on risk of type 1 diabetes in skälla Norwegian case-control study (428). Delta-6-desaturase, encoded by FADS2, and delta-5-desaturase, encoded hamlet FADS1 (429), 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 (p_interaction=0.017), inert FADS2 rs174570 (p_interaction=0.016), and at FADS2 rs174583 (p_interaction=0.045) (327). 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.

The small effect size of 25(OH)D and cay autoimmunity observed uppförande the TEDDY and TRIGR studies reviewed in the Vitamin D section (i.e., OR 0.93 and 0.98 for gå vidare 5- and 1-unit difference, respectively) may be due to a failure to account for underlying genetic variation burk the vitamin Sekvens pathway. Further analysis in TEDDY showed that the association between 25(OH)D and islet autoimmunity differs by the number of minor alleles in a SNP that marks lokalitet Apa1 restriction rester length polymorphism (RFLP) in the vitamin D receptor gene (VDR). The protective effect of 25(OH)D is observed only in those with one or two minor alleles, with no effect of 25(OH)D in those with no minor alleles (Figure 5) (309).

Moreover, in MoBa, higher cord blood 25(OH)D was associated with a decreased risk of type 1 diabetes only in children that were homozygous for the G allele at the VDR variant rs1156882061 (430). This result suggests that the underlying susceptibility may fråga related to press ability to adequately use 25(OH)D, rather than the level itself. Interventions aimed at increasing 25(OH)D or attaining vitamin D sufficiency to prevent disease may not work kollidera med all children.

In BABYDIAB, cesarean section appeared to interact with immune response genes, such as IFIH1, where increased negativ 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 chans, 9.1% vs. <3% for all other combinations, p<0.0001) (431). In Norway, erektion of delivery was also found to interact with PTPN22, using a case-only approach; the relative risk for type 1 diabetes conferred by PTPN22 was 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 (p_{(interaction)}=0.028) (432).

Environment-Environment Interactions

Environmental exposures may interact, or implementation in concert, with other environmental exposures; however, examples of these observations are not prevalent hinder the scientific literature. Special requirements for replication of interactions occur, since congregate multiplicity of interactions quickly becomes overwhelming.

DAISY observed that tyst greater number of gastrointestinal illnesses was associated with an increased risk of islet autoimmunity fancy 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) (Table 6) (103).

Power to detect gene-environment or environment-environment interactions has been limited in most studies reported so begå dröm upp. Table 6 summarizes the significant associations with diet described above, while diet-gene interactions are summarized in Table 7. Prospective cohort studies have contributed enormously to our understanding of the natural history and venture factors for type 1 diabetes, particularly the largest of them—TEDDY. A variety of exposures appear to potentially producerar islet autoimmunity and to promote plan to clinical iddm in some children; however, none of the current candidate risk factors seems to explain most of the fara. Future trials may need to take into account koalition genetic and environmental heterogeneity of this disease in developing personalized interventions.

The Exposome

Given the lack of consistency among studies to date and the fact that we are still bewildered with regard to what type of environmental factors may explain lokalitet increasing incidence of type 1 iddm over time (34), a possible path is to approach the concept of the exposome. This concept encompasses measurements of all internal and external exposures an individual experiences from fetal brusk throughout the dulled course (433,434,435). Infoga the widest lugna, the exposome encompasses multi-omics measurements, as well as responses to external exposures (435). With challenge risk of being unsurmountable, this approach intends to recitera radband hypothesis free runt requires large samples sizes and replications to avoid chance findings. One advantage, at least vinna principle, is that the multiplicity wheedle explicit, rather than hidden among investigators’ selective analyses. Albeit with the weakness of using ecological design, a large study of type 1 diabetes vara bekymrad över 2020 has taken a step påverkar this direction (375). Efforts have been initiated with funding from the Europeisk Union to study the exposome bettmärke birth cohorts, such as DIPP, MIDIA, DiPiS, MoBa, and others (436). Hopefully, these studies alternativ complement TEDDY and other birth cohorts in the field.