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| 2. |
- Johnson, Randi K., et al.
(författare)
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Metabolite-related dietary patterns and the development of islet autoimmunity
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts. © 2019, The Author(s).
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| 3. |
- Krischer, Jeffrey P, et al.
(författare)
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Predicting Islet Cell Autoimmunity and Type 1 Diabetes : An 8-Year TEDDY Study Progress Report
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 42:6, s. 1051-1060
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: 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.
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| 4. |
- Lind, Alexander, et al.
(författare)
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Immunocyte single cell analysis of vaccine-induced narcolepsy
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:1, s. 247-249
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Increased incidence of narcolepsy type 1 (NT1) was observed following Pandemrix®-vaccination, initiated as a preventive measure against the 2009 Influenza pandemic. Here, single cell analysis was conducted to suggest a lower number of CD8+CD27+ T cells among these patients. These findings provide understanding into the autoimmune pathogenesis of NT1.
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| 5. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 6. |
- Martinez, Maria Månsson, et al.
(författare)
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Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study : TEFA
- 2021
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Ingår i: Endocrinology, Diabetes & Metabolism. - : Wiley. - 2398-9238. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies. Materials and methods: Healthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples. Results: All participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (<42 mmol/mol). Insulin responses to the glucose challenge on OGTT ranged between 13.0 and 143 mIU/L after 120 minutes with C-peptide values between 0.74 and 4.60 nmol/L. In Swedish participants, the first-phase insulin response (FPIR) on IvGTT was lower in those positive for three or more autoantibodies (n = 13; median 83.0 mIU/L; range 20.0-343) compared to those with two autoantibodies (n = 15; median 146 mIU/L; range 19.0-545; P =.0330). Conclusion: Participants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.
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| 7. |
- Martinez, Maria Månsson, et al.
(författare)
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Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA
- 2022
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Ingår i: Clinical diabetes and endocrinology. - : Springer Science and Business Media LLC. - 2055-8260. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046).CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.
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| 8. |
- Salami, Falastin, et al.
(författare)
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Complete blood counts with red blood cell determinants associate with reduced beta-cell function in seroconverted Swedish TEDDY children
- 2021
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Ingår i: Endocrinology, Diabetes and Metabolism. - : Wiley. - 2398-9238. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate whether changes in complete blood count (CBC) in islet autoantibody positive children with increased genetic risk for type 1 diabetes are associated with oral glucose tolerance tests (OGTT) and HbA1c over time. Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study follows children with increased risk for type 1 diabetes in the United States, Germany, Sweden and Finland. In the current study, 89 Swedish TEDDY children (median age 8.8 years) positive for one or multiple islet autoantibodies were followed up to 5 (median 2.3) years for CBC, OGTT and HbA1c. A statistical mixed effect model was used to investigate the association between CBC and OGTT or HbA1c. Results: HbA1c over time increased by the number of autoantibodies (p <.001). Reduction in mean corpuscular haemoglobin (MCH) and mean cell volume (MCV) was both associated with an increase in HbA1c (p <.001). A reduction in red blood cell (RBC) counts (p =.003), haemoglobin (p =.002) and haematocrit (p =.006) levels was associated with increased fasting glucose. Increased red blood cells, haemoglobin, haematocrit and MCH but decreased levels of red blood cell distribution widths (RDW) were all associated with increased fasting insulin. Conclusions: The decrease in RBC indices with increasing HbA1c and the decrease in RBC and its parameters with increasing fasting glucose in seroconverted children may reflect an insidious deterioration in glucose metabolism associated with islet beta-cell autoimmunity.
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| 9. |
- Salami, Falastin, et al.
(författare)
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HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children
- 2022
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 23:8, s. 1586-1593
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/OBJECTIVES: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials. This study aimed to investigate whether HbA1c possibly predicts the progression from first to a subsequent autoantibody or type 1 diabetes in healthy children participating in the Environmental Determinants of Diabetes in the Young (TEDDY) study.METHODS: A joint model was designed to assess the association of longitudinal HbA1c levels with the development of first (insulin or GAD autoantibodies) to a second, second to third, third to fourth autoantibody or type 1 diabetes in healthy children prospectively followed from birth until 15 years of age.RESULTS: It was found that increased levels of HbA1c were associated with a higher risk of type 1 diabetes (HR 1.82, 95% CI [1.57-2.10], p<0.001) regardless of first appearing autoantibody, autoantibody number or type. A decrease in HbA1c levels was associated with the development of IA-2A as a second autoantibody following GADA (HR 0.85, 95% CI [0.75,0.97], p=0.017) and a fourth autoantibody following GADA, IAA and ZnT8A (HR 0.90, 95% CI [0.82,0.99], p=0.036). HbA1c trajectory analyses showed a significant increase of HbA1c over time (p<0.001) and that the increase is more rapid as the number of autoantibodies increased from one to three (p<0.001).CONCLUSION: In conclusion, increased HbA1c is a reliable time predictive marker for type 1 diabetes onset. The increased rate of increase of HbA1c from first to third autoantibody and the decrease in HbA1c predicting the development of IA-2A are novel findings proving the link between HbA1c and the appearance of autoantibodies. This article is protected by copyright. All rights reserved.
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| 10. |
- Salami, Falastin, et al.
(författare)
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Long-Term GAD-alum Treatment Effect on Different T-Cell Subpopulations in Healthy Children Positive for Multiple Beta Cell Autoantibodies
- 2022
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2022
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The objective of this study was to explore whether recombinant GAD65 conjugated hydroxide (GAD-alum) treatment affected peripheral blood T-cell subpopulations in healthy children with multiple beta cell autoantibodies. Method. The Diabetes Prevention–Immune Tolerance 2 (DiAPREV-IT 2) clinical trial enrolled 26 children between 4 and 13 years of age, positive for glutamic acid decarboxylase autoantibody (GADA) and at least one other autoantibody (insulin, insulinoma antigen-2, or zinc transporter 8 autoantibody (IAA, IA-2A, or ZnT8A)) at baseline. The children were randomized to two doses of subcutaneously administered GAD-alum treatment or placebo, 30 days apart. Complete blood count (CBC) and immunophenotyping of T-cell subpopulations by flow cytometry were performed regularly during the 24 months of follow-up posttreatment. Cross-sectional analyses were performed comparing lymphocyte and T-cell subpopulations between GAD-alum and placebo-treated subjects. Results. GAD-alum-treated children had lower levels of lymphocytes (109 cells/L) (), T-cells (103 cells/μL) (), T-helper cells (103 cells/μL) (), and cytotoxic T-cells (103 cells/μL) () compared to the placebo-treated children 18 months from first GAD-alum injection. This difference remained 24 months after the first treatment for lymphocytes (), T-cells (), T-helper cells (), and cytotoxic T-cells (). Conclusion. Our findings suggest that levels of total T-cells and T-cell subpopulations declined 18 and 24 months after GAD-alum treatment in healthy children with multiple beta-cell autoantibodies including GADA.
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