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  • 1
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    Online Resource
    Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. 4 ( 2019-04-01), p. 847-857
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. 4 ( 2019-04-01), p. 847-857
    Abstract: The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02] ) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0882
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 2
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    Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study
    American Diabetes Association ; 2023
    In:  Diabetes Care ( 2023-08-22)
    Details
    In: Diabetes Care, American Diabetes Association, ( 2023-08-22)
    Abstract: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39] ) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at & lt;1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to & lt;2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increas e in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs & lt;6 months prior to autoantibody development in children & lt;4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc23-0518
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 3
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    Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 3 ( 2020-03-01), p. 556-562
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 3 ( 2020-03-01), p. 556-562
    Abstract: This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7–10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children’s individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. RESULTS A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. CONCLUSIONS Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-1670
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 4
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    Early Infant Diet and Islet Autoimmunity in the TEDDY Study
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 3 ( 2018-03-01), p. 522-530
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 3 ( 2018-03-01), p. 522-530
    Abstract: To examine duration of breastfeeding and timing of complementary foods and risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes (T1D) in the U.S., Finland, Germany, and Sweden. This study included 7,563 children with at least 9 months of follow-up. Blood samples were collected every 3 months from birth to evaluate IA, defined as persistent, confirmed positive antibodies to insulin (IAAs), GAD, or insulinoma antigen-2. We examined the associations between diet and the risk of IA using Cox regression models adjusted for country, T1D family history, HLA genotype, sex, and early probiotic exposure. Additionally, we investigated martingale residuals and log-rank statistics to determine cut points for ages of dietary exposures. RESULTS Later introduction of gluten was associated with increased risk of any IA and IAA. The hazard ratios (HRs) for every 1-month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively. Martingale residual analysis suggested that the age at gluten introduction could be grouped as & lt;4, 4–9, and & gt;9 months. The risk of IA associated with introducing gluten before 4 months of age was lower (HR 0.68; 95% CI 0.47, 0.99), and the risk of IA associated with introducing it later than the age of 9 months was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age. CONCLUSIONS The timing of gluten-containing cereals and IA should be studied further.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc17-1983
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 5
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    Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study
    American Diabetes Association ; 2023
    In:  Diabetes Care Vol. 46, No. 7 ( 2023-07-01), p. 1409-1416
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 46, No. 7 ( 2023-07-01), p. 1409-1416
    Abstract: This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5–15 years. RESEARCH DESIGN AND METHODS As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA–positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA–positive children, of whom 148 developed type 1 diabetes. RESULTS No significant association was found in risk group 1 or risk group 2. A significant association was seen in risk group 3 (hazard ratio 0.920 [95% CI 0.856, 0.988] per 10-min increase; P = 0.021), particularly when glutamate decarboxylase autoantibody was the first autoantibody (hazard ratio 0.883 [95% CI 0.783, 0.996] per 10-min increase; P = 0.043). CONCLUSIONS More daily minutes spent in moderate to vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in children aged 5–15 years who had developed multiple IAs.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc23-0036
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 6
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    Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 10 ( 2022-10-01), p. 2342-2349
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 10 ( 2022-10-01), p. 2342-2349
    Abstract: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190). RESULTS A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7–18.6, P & lt; 0.0001) and TrialNet (HR 5.09, 95% CI 3.3–7.9, P & lt; 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82). CONCLUSIONS An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-0828
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 7
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    Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. 3 ( 2020-03-01), p. 465-476
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. 3 ( 2020-03-01), p. 465-476
    Abstract: Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children’s plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-0756
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 8
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    Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 9 ( 2020-09-01), p. 2066-2073
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 9 ( 2020-09-01), p. 2066-2073
    Abstract: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA] , or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody. RESULTS There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88–1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78–10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10–29.29; P & lt; 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61–10.95; P & lt; 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04–4.65; P & lt; 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D. CONCLUSIONS The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-2547
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 9
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    Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 10 ( 2022-10-01), p. 2271-2281
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 10 ( 2022-10-01), p. 2271-2281
    Abstract: To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. RESEARCH DESIGN AND METHODS Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3–12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models. RESULTS Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes. CONCLUSIONS Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-2612
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 10
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    Predicting Islet Cell Autoimmunity and Type 1 Diabetes: An 8-Year TEDDY Study Progress Report
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 6 ( 2019-06-01), p. 1051-1060
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 6 ( 2019-06-01), p. 1051-1060
    Abstract: Assessment of the predictive power of The Environmental Determinants of Diabetes in the Young (TEDDY)-identified risk factors for islet autoimmunity (IA), the type of autoantibody appearing first, and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS A total of 7,777 children were followed from birth to a median of 9.1 years of age for the development of islet autoantibodies and progression to T1D. Time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to provide estimates of their individual and collective ability to predict IA and T1D. RESULTS HLA genotype (DR3/4 vs. others) was the best predictor for IA (Youden’s index J = 0.117) and single nucleotide polymorphism rs2476601, in PTPN22, was the best predictor for insulin autoantibodies (IAA) appearing first (IAA-first) (J = 0.123). For GAD autoantibodies (GADA)-first, weight at 1 year was the best predictor (J = 0.114). In a multivariate model, the area under the ROC curve (AUC) was 0.678 (95% CI 0.655, 0.701), 0.707 (95% CI 0.676, 0.739), and 0.686 (95% CI 0.651, 0.722) for IA, IAA-first, and GADA-first, respectively, at 6 years. The AUC of the prediction model for T1D at 3 years after the appearance of multiple autoantibodies reached 0.706 (95% CI 0.649, 0.762). CONCLUSIONS Prediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-2282
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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