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- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- Salami, Falastin
(författare)
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Peripheral blood biomarkers of cell-specific autoimmunity. Studies in children at increased risk for type 1 diabetes.
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective While the incidence of children suffering from autoimmune type 1 diabetes (T1D) is increasing in Sweden and worldwide, the underlying etiology and cellular mechanisms behind this remain unknown. The predisposition of the high-risk HLA DR-DQ genotype and as yet unknown environmental triggers lead to autoimmunity and the onset of T1D, which is preceded by islet beta-cell autoantibodies acting as markers for ongoing autoimmunity. This study aims to identify peripheral blood biomarkers to predict and explain cellular autoimmune processes leading to beta-cell loss before and after seroconversion. We also investigate whether immune tolerance treatment with GAD-alum affects T-cells in nondiabetic children at increased genetic risk of T1D prospectively followed in longitudinal studies. Methods Children participating in the Swedish TEDDY cohort with or without islet beta-cell autoantibodies were studied. Complete blood count in these children was analyzed and related to autoantibody status, gender, HLA genotype, and glucose metabolism measures. HbA1c, a predictive biomarker for a subsequent autoantibody or T1D, was analyzed in the TEDDY cohort from Finland, Germany, Sweden, and the US. HbA1c trajectories were also studied in the progression from developing a single autoantibody to diagnosing T1D. Children aged 4–17.99 years at enrollment participating in the DiAPREV-IT2 clinical trial were studied and different T-cells were immunophenotyped to investigate the immune tolerance treatment with GAD-alum. Results A reduction in neutrophil counts primarily in boys and children with the HLA-DR3-DQ2/DR4-DQ8 genotype, and a reduction of red blood cell counts, hemoglobin, and hematocrit primarily in girls and in children with HLA-DR3-DQ2/DR4-DQ8 were inversely associated with autoimmunity and the number of beta-cell autoantibodies. A reduction in red blood cell indices (MCH and MCV) was associated with increased HbA1c, by increased number of beta-cell autoantibodies. Reduction in red blood cell count, hemoglobin, and hematocrit levels were associated with increased fasting blood glucose. Increased red blood cell counts and hemoglobin, hematocrit, and MCH were associated with increased fasting insulin. Increased HbA1c was associated with an increased risk of T1D regardless of the number and type of autoantibodies. The development of IA-2A as a second or fourth autoantibody was associated with decreased HbA1c levels. The HbA1c trajectories presented a more rapid increase of HbA1c as the number of autoantibodies increased from one to three. GAD-alum-treated children had lower T-helper cell (CD3+ CD4+ T-cells ) and cytotoxic T-cell (CD3+ CD8+ T-cells) levels 18–24 months after two immunizations with GAD-alum. Conclusion Reductions in neutrophil levels, red blood cells, and red blood cell parameters and increased levels of HbA1c are all associated with multiple autoantibodies, reflecting a prominent islet autoimmune burden. The reduction in different complete blood counts with increasing numbers of beta-cell autoantibodies may suggest an unknown effect of impaired beta-cell function on hematopoiesis. Predicted trajectories of HbA1c could be used to further develop a model to predict the time to T1D diagnosis in children with multiple autoantibodies. The decrease in HbA1c associated with the appearance of IA-2A may be a consequence of aggressive autoimmune destruction of beta-cells leading to insulin leakage into the bloodstream. These results should prove helpful for understanding the pathogenesis of T1D and better predicting the onset of T1D in seroconverted children. Immunization with GAD-alum has a long-term effect on T-cells 18–24 months after treatment.
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