How To Prevent Juvenile Diabetes – The increase in the incidence of type 1 diabetes (T1D) cannot be attributed to genetics alone, and causative environmental triggers must also contribute. The study proposed by TEDDY has provided the greatest contributions in the modern era, addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date supporting pathways from association to causation across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors that nurture it. Of these, the environmental determinants with the most supporting evidence are enterovirus infection, rapid weight gain early in life, and the microbiome. We provide an infographic showing the main environmental determinants of T1D and their similarity in effect. The next steps are to investigate these environmental triggers, ideally through standard randomized controlled trials and further prospective studies, to help explore public health prevention strategies.
An estimated 1.1 million people under the age of 20 years are affected by type 1 diabetes (T1D) worldwide (1, 2). T1D accounts for 5–10% of the global diabetes burden (3) and is not just a disease of childhood, with almost half being diagnosed in adulthood (4–6). The overall annual increase in T1D is estimated at 3% (2–5%) (1, 7), with increasing trends observed in all age groups over the past three decades (1, 3). Some of the largest increases can be seen in countries with historically low prevalence (4, 8).
T1D is a chronic autoimmune condition characterized by hyperglycemia and long-term insulin dependence (9). The pathophysiology of T1D is defined by three stages of disease progression (10). Step one is seroconversion to one or more antibodies (10), including glutamic acid decarboxylase (GAD), anti-insulin, insulinoma-associated antigen 2 (IA2), and zinc transporter 8 (Zn-T8). The presence of two or more antibodies will cause 70% of children to develop T1D within the next 10 years, while four autoantibodies invariably confer a 100% risk (11). Stage 2 is beta-cell damage causing presymptomatic dysglycemia, and stage 3 is overt T1D due to beta-cell insufficiency with a requirement for exogenous insulin (10). This provides different targets for prevention during primary prevention (preventing seroconversion, in those at genetic risk) and secondary prevention (preventing beta-cell loss and damage in people with autoimmunity/autoantibodies) (12).
The main risk factor for T1D is genetic. It is strongly associated with HLA-DR3-DQ2 and/or HLA-DR4-DQ8 haplotypes (13). The importance of genetics is further highlighted by the increased risk seen when a sibling (8%), father (5%) or mother (3%) has T1D. The major histocompatibility complex (MHC) encoding HLA region confers 50% of the genetic risk for T1D (13). Genome-wide association studies have identified an additional 50 loci that confer susceptibility (13).
However, genetics alone does not equal causation, and a variety of environmental factors are implicated in triggering T1D seroconversion and disease progression (14). The threshold hypothesis describes a model in which genetic and environmental factors represent intersecting and reciprocal trend lines, defined by ranked odds ratios, that confer an increased risk of progression to T1D until a critical threshold is reached ( 15 ).
The evidence supporting the encouraging side of the argument in favor of T1D continues to expand. First, the increasing incidence of T1D in recent decades is too rapid to be explained by genetic changes alone (8). Second, T1D concordance rates between monozygotic twins are <50% (16). Third, the incidence of T1D also shows significant geographic and latitudinal differences, with a higher incidence in Nordic countries (17–20), and migration studies show that the event risk of the new location is assumed (21). Fourth, the number of cases is increasing in all age groups, and the number of cases in younger children is increasing (1), although the highest-risk genotypes have declined over the past 20–40 years (22 , 2. 3). The highest rates are found in countries with previously low incidence and countries with the highest economic growth (8).
It may be more than a coincidence that T1D is therefore a heterogeneous condition driven by a combination of genetic, immunological and metabolic factors, and this complexity reflects the variety of environmental triggers involved in pathogenesis.
A number of other reviews have examined environmental contributions to T1D (8, 12, 14, 24, 25). These have largely emphasized association studies between different environmental determinants and the development of T1D. Some of these reviews also predate the results of the pioneering Environmental Determinants of Diabetes in the Youth (TEDDY) study, various aspects of which have been published over the last 6 years (26).
In this narrative review, we examine putative environmental risk factors for T1D with a focus on evidence of causality. Since the best way to test causality is to create a double-blind randomized controlled trial (RCT), we present the various RCTs in this field. As part of the review, we outline the possible mechanisms underlying the different environmental determinants and the pre-T1D stage at which they may influence.
We conducted this review by searching PubMed and Medline. The following search terms were used “type 1 diabetes average A”; type 1 diabetes (T1D) OR islet autoimmunity (IA) plus the following – enterovirus; rotavirus; Flu; COVID 19; vaccine OR vaccination; birth weight; gain weight; BMI; childhood obesity; gut microbiome OR gut microbiota; diet; breast milk OR breastfeeding; Cow’s milk; formula milk; gluten; an antibiotic; probiotic; vitamin D; and nicotinamide; Omega 3. We included systematic reviews, meta-analyses, RCTs, cohort studies (prospective and retrospective) and case-control studies. We included the largest European retrospective cohort studies and prospective case-control studies, including “Prediction and prevention of type 1 diabetes” (DIPP) (27), “Early childhood diabetes in Finland” (DiMe) (28), ” Danish National Cohort”. Birth. ” (DNBC), “Norwegian Mother and Child Cohort” (MOBA) (29), “Diabetes Autoimmunity Study in the Young” (DAISY) (30), DIABIMMUNE, Environmental Triggers of T1D (MIDIA – Norwegian acronym) (31) , the Finnish Dietary Intervention to Prevent T1D Study (FINDIA) (32), the TEDDY Study (26), and studies including the Trial to Reduce IDDM in the Genetically At Risk (TRIGR) (33), the European Nicotinamide Diabetes Intervention Trial ( ENDIT) (34) and the Deutsche Nicotinamide Intervention Study (DENIS) (35). Reference lists were also checked for relevant articles.
Acute fulminant diabetes, known as type 1b diabetes, is reported following infection with mumps, Coxsackie B3 and B4, rubella, and influenza B (38). Hyperglycemic ketosis is sudden, symptoms appear for a week, isolated antibodies are negative, and C-peptide is very low. In this case, beta-cell damage occurs secondary to the direct lytic effects of viral invasion, causing widespread beta-cell destruction and absolute insulin deficiency, without autoimmunity (37, 38).
Another link, elaborated below, appears to be more chronic, repeated viral exposure. Mechanisms involved here include molecular mimicry, where viral epitope sequences resemble beta-cell antigens and can trigger a cross-reactive autoimmune response (36). Viral infection of beta cells will also lead to MHC class I overexpression, leading to self-antigen presentation and perpetuation of autoimmunity (36, 37, 39). Viruses associated with this more chronic, relapsing infection pattern are listed below.
The strongest evidence for a viral trigger exists for enteroviruses (EVs) (40-42). T1D incidence correlates with enteroviral infection rates, and enteroviral epidemics precede seasonal variation in T1D (41, 43). However, EV is a common childhood infection, and therefore HLA susceptibility to T1D, together with genetically determined susceptibility and the inflammatory response to EV are critical determinants of risk (41, 44–46). EV infection can initiate and accelerate all three stages of T1D pathophysiology (42, 43).
EV spreads and replicates through the upper respiratory and gastrointestinal tracts and invades islet beta cells via the adenocoronavirus receptor (CAR) (36). Inefficient viral clearance of EV (47) and induction of a chemokine response from beta cells triggers islet autoimmunity (IA) through molecular mimicry, inflammation, bystander effects, and T-cell suppression (48). EV chronicity appears essential for maintaining beta-cell autoimmunity; repeated infection with EV strains further increases the risk (36).
Systematic reviews (41, 49) and cohort studies (27, 28, 50, 51) show positive associations between persistent EV infection, autoimmunity, and progression to stage 3. The DiMe study (28) and the DIPP study (27) showed that EV infection during pregnancy or early childhood, respectively, increased the risk of T1D. Interestingly, studies show evidence of seroconversion to islet autoantibodies in the postpartum mother and child after enteroviral infection during pregnancy (52, 53). A meta-analysis showed that maternal infections were also significantly associated with T1D progression, and especially for maternal enterovirus infections, odds ratio (OR) 1.54 (confidence interval (CI) 1.05– 2.27) (54). The putative mechanism is epitope transfer/molecular mimicry that triggers autoimmunity in the offspring, but supporting evidence is limited. Cross-reactivity between EVs with GAD and IA2 epitopes could trigger seroconversion, but similarly, secondary to chronic and cumulative viral infections, primed autoreactive T cells could promote progression to phase 2 in antibody-positive individuals (36).
Most recently, the TEDDY study of a cohort of genetically predisposed children (n=8676) with 15-year follow-up showed that chronicity of Coxsachie B (EVB), persistent stool loss, predicted the development of AI, particularly against – insulin antibodies (51, 55, 56). In contrast, acute EVB infection without prolonged stool loss was not associated with autoimmunity or T1D in this cohort (51). A systematic review and meta-analysis by Yeung et al. (41) further proves that
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