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The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1–3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2–4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.

Type 1 diabetes (T1D)—an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency—often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6–9. Autoantibody surveillance programs effectively prevent most ketoacidosis10–12but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.

Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)1–4. Certain enteroviruses can infect β cells in vitro5, have been detected in the pancreatic islets of patients with T1D6and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADRrs6517774, independently correlated with islet autoimmunity.

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial–immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1–9such as persistent islet autoimmunity and type 1 diabetes10–12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n= 12,005) and metagenomic sequencing (n= 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3–14), a transitional phase (months 15–30), and a stable phase (months 31–46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacteriumspecies (B. breveand B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroidesspecies (particularly B. fragilis) in infants delivered vaginally. Bacteroideswas also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case–control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial–immune crosstalk for long-term health.

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3and the gut microbiome4. Viral infections5and broader gut dysbioses6have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacteriumspecies (B. bifidum, B. breveor B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longumwas present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.

IMPORTANCE: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES: Islet autoimmunity and CD autoimmunity were defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

Objective The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter randomized controlled trial in the knee. This report was undertaken to investigate 5-year structural and clinical outcomes.Design The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. Patients were randomized to receive BST-CarGel® treatment or microfracture alone, and followed standardized 12-week rehabilitation. Co-primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling (%) and T2 relaxation times. Secondary endpoints were clinical benefit measured with WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires and safety. General estimating equations were used for longitudinal statistical analysis of repeated measures.Results Blinded MRI analysis demonstrated that BST-CarGel®-treated patients showed a significantly greater treatment effect for lesion filling (P= 0.017) over 5 years compared with microfracture alone. A significantly greater treatment effect for BST-CarGel® was also found for repair tissue T2 relaxation times (P= 0.026), which were closer to native cartilage compared to the microfracture group. BST-CarGel® and microfracture groups showed highly significant improvement at 5 years from pretreatment baseline for each WOMAC subscale (P< 0.0001), and there were no differences between the treatment groups. Safety was comparable for both groups.Conclusions BST-CarGel® was shown to be an effective mid-term cartilage repair treatment. At 5 years, BST-CarGel® treatment resulted in sustained and significantly superior repair tissue quantity and quality over microfracture alone. Clinical benefit following BST-CarGel® and microfracture treatment were highly significant over baseline levels.

SUMMARY In this review, we will discuss the burdens of Type 1 diabetes (T1D) that are faced by youths in the USA, which impact virtually every aspect of day-to-day life. A multidisciplinary diabetes care team can effectively address the burdens of T1D in order to achieve adequate glycemic control and to minimize the risk of acute and chronic complications. The support of a multidisciplinary diabetes team possessing varying and complementary skills in collaboration with other healthcare providers can assist youth with T1D and their families in overcoming the multitude of potential obstacles. The development of an individualized diabetes care plan that accommodates the patients lifestyle is essential for improving the quality of life, while allowing the patients to maximize their potential and achieve their life goals.