| 1. |
- Brorsson, Caroline, et al.
(author)
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Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes
- 2011
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In: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:2, s. 107-114
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Journal article (peer-reviewed)abstract
- We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.
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| 2. |
- Nilsson, Anna-Lena, et al.
(author)
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Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children
- 2013
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In: Viral immunology. - : Mary Ann Liebert, Inc.. - 0882-8245 .- 1557-8976. ; 26:3, s. 207-215
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Journal article (peer-reviewed)abstract
- Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.
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| 3. |
- Skärstrand, H, et al.
(author)
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Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy
- 2013
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In: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 27:6, s. 609-617
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Journal article (peer-reviewed)abstract
- Aims: The neurotransmitter Neuropeptide Y (NPY) was previously reported as a minor autoantigen in newly diagnosed type 1 diabetes (T1D) patients. The single nucleotide polymorphism at rs16139 (T1128C, L7P) in the NPY gene was associated with an increased risk for the development of type 2 diabetes (T2D). We aimed to develop a radiobinding assay for NPY-L (Leucine) and NPY-P (Proline) autoantibodies (A) to study the levels and the association with other islet autoantibodies and neuropathy. Methods: Autoantibodies against NPY-L, NPY-P, ZnT8, GAD65 and IA-2 were studied in T1D (n = 48) and T2D (n = 26) patients with duration up to 42 and 31 years. A subgroup of T1D (n = 32) patients re-examined, 5-8 years after first visit, was tested for peripheral (Z-score) and autonomic neuropathy (E/I ratio). Results: NPY-LA and NPY-PA were detected in 23% and 19% in T1D (p<0.001), and 12% and 23% in T2D patients (p<0.001) compared to 2.5% controls (n = 398). The levels of NPYA declined during follow-up in the T1D patients (p < 0.001). The neuropathy was not related to the NPYA or the other islet autoantibodies. Conclusions: Regardless of the absence of an association between NPYA and neuropathy, NPY may contribute to the pathogenesis of T1D and T2D as a minor autoantigen.
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| 4. |
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| 5. |
- Andersson Svärd, Agnes, et al.
(author)
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Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes
- 2022
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In: ImmunoHorizons. - : The American Association of Immunologists. - 2573-7732. ; 6:8, s. 614-629
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Journal article (peer-reviewed)abstract
- Recently, a haplotype of three single-nucleotide polymorphisms (tri-SNP) in intron 1 of the HLA-DRA1 gene was found to be strongly associated with type 1 diabetes risk in HLA-DR3/3 individuals. The tri-SNP reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. The aim was to investigate HLA-DRA1 tri-SNPs in relation to extended HLA class II haplotypes and human peripheral blood cell HLA-DQ cell-surface median fluorescence intensity (MFI), the first-appearing islet autoantibody, and autoimmunity burden. A total of 67 healthy subjects (10–15 y) at increased HLA risk for type 1 diabetes and with (n = 54) or without (n = 13) islet autoantibodies were followed longitudinally in the Diabetes Prediction in Skåne study. Among four tri-SNPs, AGG (n = 67), GCA (n = 47), ACG (n = 11), and ACA (n = 9), HLA-DQ cell-surface MFI on CD4+ T cells was lower in AGG than GCA (p = 0.030) subjects. Cumulative autoimmunity burden was associated with reduced HLA-DQ cell-surface MFI in AGG compared with GCA in CD16+ cells (p = 0.0013), CD4+ T cells (p = 0.0018), and CD8+ T cells (p = 0.016). The results suggest that HLA-DRA1 tri-SNPs may be related to HLA-DQ cell-surface expression and autoimmunity burden.
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| 6. |
- Aydemir, Özkan, et al.
(author)
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Polymorphisms in Intron 1 of HLA-DRA Differentially Associate with Type 1 Diabetes and Celiac Disease and Implicate Involvement of Complement System Genes C4A and C4B
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In: eLife. - 2050-084X.
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Journal article (peer-reviewed)abstract
- Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA- DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals isstratified by a haplotype consisting of three single nucleotide polymorphisms (“tri-SNP”) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal “The Environmental Determinants of Diabetes in the Young” (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with celiac disease (CD), and that the particular tri-SNP haplotype (“101”) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes, and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.
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| 7. |
- Baekkeskov, S, et al.
(author)
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Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes
- 1987
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In: Journal of Clinical Investigation. - 0021-9738. ; 79:3, s. 34-926
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Journal article (peer-reviewed)abstract
- Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (Mr) 64,000. Since IDDM seems to develop after a prodromal period of beta-cell autoimmunity, this study has examined whether 64,000 Mr antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered beta-cell function. Sera were screened by immunoprecipitation on total detergent lysates of human islets and positive sera retested on membrane protein preparations. Antibodies to the 64,000 Mr membrane protein were consistently detected in 11/14 IDDM patients, and in all 5 first degree relatives. 10 IDDM patients were already positive in the first samples, obtained 4-91 mo before the clinical onset of IDDM, whereas 1 patient progressed to a high 64,000 Mr immunoreactivity, at a time where a commencement of a decline in beta-cell function was detected. 64,000 Mr antibodies were detected before islet cell cytoplasmic antibodies (ICCA) in two patients. In the control groups of 21 healthy individuals, 36 patients with diseases of the thyroid and 5 SLE patients, the 64,000 Mr antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the Mr 64,000 human islet protein are an early marker of beta-cell autoimmunity and may be useful to predict a later development of IDDM.
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| 8. |
- Bediaga, Naiara G, et al.
(author)
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Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample
- 2021
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 64:11, s. 2432-2444
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw.METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da.RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615.CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.
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| 9. |
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| 10. |
- Burbelo, Peter D., et al.
(author)
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A new luminescence assay for autoantibodies to mammalian cell-prepared insulinoma-associated protein 2
- 2008
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 31:9, s. 1824-1826
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Journal article (peer-reviewed)abstract
- OBJECTIVE - Insulinoma-associated protein 2 (IA-2) is a major autoantigen in type I diabetes, and IA-2 autoantibodies are routinely detected by a liquid-phase radioimmunoprecipitation assay. The present experiments were initiated to develop a new assay that does not require the use of radioisotopes or autoantigens prepared in bacteria or by in vitro transcription/translation. RESEARCH DESIGN AND METHODS - IA-2 luciferase fusion protein was expressed in mammalian cells and assayed for autoantibodies by liquid-phase luciferase immunoprecipitation. RESULTS - Our study showed that there was no significant difference between the luciferase immunoprecipitation and the radioimmunoprecipitation assays in sensitivity and specificity, and comparison of the two assays revealed a high correlation coefficient (R-2 = 0.805). CONCLUSIONS - The luciferase system offers a robust, inexpensive, nonradioactive method for the detection of autoantibodies to mammalian cell-prepared IA-2 and could be of practical value at the clinical level.
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| 11. |
- Dyrberg, Thomas, et al.
(author)
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Humoral immunity in the spontaneously diabetic BB rat
- 1983
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In: Metabolism. - 0026-0495. ; 32:7 SUPPL. 1, s. 87-91
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Journal article (peer-reviewed)abstract
- Litters of BB rats with an expected high and low incidence of insulin-dependent diabetes were followed from weaning until the age of about 140 days. Islet cell surface antibodies (ICSA) and lymphocyte antibodies (LA) were determined in a radioligand assay with fixed rat insulinoma (RIN 5F) cells, an insulin-secreting cell line, or spleen lymphocytes. In the low-incidence litter, 2 out of 14 rats had ICSA and LA; one showed insulitis at the end of the study. In the high-incidence litter, 3 out of 7 developed diabetes; all 3 showed ICSA at weaning. The remaining 4 showed insulitis. All 7 diabetes-susceptible rats had ICSA and LA at some time during the study. It is concluded that there is a high incidence of circulating ICSA and LA in the spontaneously diabetic BB rat. The antibodies can often be detected before the onset of diabetes, and may be implicated in the beta-cell destructive process and in the lymphocytopenia characteristic of the syndrome.
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| 12. |
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| 13. |
- Endesfelder, David, et al.
(author)
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Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children
- 2019
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:1, s. 119-130
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Journal article (peer-reviewed)abstract
- Progression to clinical type 1 diabetes varies among children who develop b-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar profiles associated with various types of progression among 600 children from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study; these children developed persistent insulin autoantibodies (IAA), GAD autoantibodies (GADA), insulinoma-associated antigen 2 autoantibodies (IA-2A), or a combination of these, and they were followed up prospectively at 3- to 6-month intervals (median follow-up 6.5 years). Children who developed multiple autoantibody types (n = 370) were clustered, and progression from seroconversion to clinical diabetes within 5 years ranged between clusters from 6% (95% CI 0, 17.4) to 84% (59.2, 93.6). Children who seroconverted early in life (median age <2 years) and developed IAA and IA-2A that were stable-positive on follow-up had the highest risk of diabetes, and this risk was unaffected by GADA status. Clusters of children who lacked stable-positive GADA responses contained more boys and lower frequencies of the HLA-DR3 allele. Our novel algorithm allows refined grouping of b-cell autoantibody–positive children who distinctly progressed to clinical type 1 diabetes, and it provides new opportunities in searching for etiological factors and elucidating complex disease mechanisms.
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| 14. |
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| 15. |
- Hummel, Sandra, et al.
(author)
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First infant formula type and risk of islet autoimmunity in the environmental determinants of diabetes in the young (TEDDY) study
- 2017
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:3, s. 398-404
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Journal article (peer-reviewed)abstract
- OBJECTIVE Studies on the introduction of infant formulas and its effect on the risk of islet autoimmunity and type 1 diabetes (T1D) have yielded inconsistent results. We investigated whether the introduction of formula based on hydrolyzed cow'smilk as the first formula is associated with reduced islet autoimmunity risk in a large prospective cohort. RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively monitors 8,676 children at increased genetic risk for T1D. Autoantibodies to insulin, GAD65, and IA2 were measured regularly to define islet autoimmunity. Information on formula feeding was collected by questionnaires at 3 months of age. RESULTS In survival analyses, after adjustment for family history with T1D, HLA genotype, sex, country, delivery mode, breast-feeding 3 months, and seasonality of birth, we observed no significant association with islet autoimmunity in infants who received extensively hydrolyzed compared with nonhydrolyzed cow'smilk-based formula as the first formula during the first 3 months (adjusted hazard ratio 1.38 [95% CI 0.95; 2.01]), and a significantly increased risk for extensively hydrolyzed formula introduced during the first 7 days (adjusted hazard ratio 1.57 [1.04; 2.38]). Using a partially hydrolyzed or other formula as the first formula, or no formula, was not associated with islet autoimmunity risk. CONCLUSIONS These results add to the existing evidence that islet autoimmunity risk is not reduced, and may be increased, by using hydrolyzed compared with nonhydrolyzed cow's milk-based infant formula as the first formula in infants at increased genetic risk for T1D .
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| 16. |
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| 17. |
- Jahoor, Farook, et al.
(author)
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Metabolomics Profiling of Patients With A-β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis
- 2021
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:8, s. 1898-1909
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Journal article (peer-reviewed)abstract
- When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.
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| 18. |
- Kanatsuna, Norio, et al.
(author)
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Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets
- 2013
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:40, s. 29013-29023
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Journal article (peer-reviewed)abstract
- Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.
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| 19. |
- Katsarou, Anastasia, et al.
(author)
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Type 1 diabetes mellitus
- 2017
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In: Nature Reviews Disease Primers. - : Springer Science and Business Media LLC. - 2056-676X. ; 3
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Journal article (peer-reviewed)abstract
- Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic beta-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of beta-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in beta-cells -are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent beta-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.
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| 20. |
- Krischer, Jeffrey P., et al.
(author)
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Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age : The teddy study
- 2017
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:9, s. 1194-1202
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Journal article (peer-reviewed)abstract
- OBJECTIVE We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS Infants with HLA-DR high-risk genotypes were prospectively followed for diabetesrelated autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 monthswere associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAAorGADA as the first appearing indication of autoimmunity.
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| 21. |
- Landin-Olsson, Mona, et al.
(author)
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Immunoreactive trypsin(Ogen) in the sera of children with recent-onset insulin-dependent diabetes and matched controls
- 1990
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In: Pancreas. - : Ovid Technologies (Wolters Kluwer Health). - 0885-3177. ; 5:3, s. 241-247
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Journal article (peer-reviewed)abstract
- To evaluate the exocrine pancreatic function at the time of diagnosis of insulin-dependent diabetes mellitus, we determined immunoreactive an-odal and cathodal trypsin(ogen) levels in sera from almost all children (n = 375) 0-14 years of age in Sweden in whom diabetes developed during 1 year, and in sex-, age-, and geographically matched control subjects (n = 312). The median level of anodal trypsin(ogen) was 5 (quartile range, 3-7) µg/L in children with newly diagnosed diabetes, compared with a median level of 7 (quartile range, 4-8) µg/L in control subjects (p < 0.0001). Similarly, the median level of cathodal trypsin(ogen) was 8 (quartile range, 4-10) µg/L in children with diabetes, compared with a median level of 11 (quartile range, 7-15) µg/L in control subjects (p < 0.0001). The median of the individual ratios between cathodal and anodal trypsin(ogen) was 1.4 in the diabetic patients and 1.7 in the control children (p < 0.001). In a multivariate test, however, only the decrease in cathodal trypsin(ogen) concentration was associated with diabetes. The levels of trypsin(ogen)s did not correlate with levels of islet cell antibodies, present in 81% of the diabetic children. Several mechanisms may explain our findings, for example, similar pathogenetic factors may affect both the endocrine and exocrine pancreas simultaneously, a failing local trophic stimulation by insulin on the exocrine cells may decrease the trypsinogen production, and there may be an increased elimination of trypsin(ogen) because of higher filtration through the kidneys in the hyperglycemic state.
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| 22. |
- Lernmark, Ake, et al.
(author)
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Pancreas
- 1989
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In: Endokrinologe, teil A & B : teil B, Krankheitsbilder - teil B, Krankheitsbilder. ; 4, s. 11-802
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Book chapter (peer-reviewed)
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| 23. |
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| 24. |
- Ludvigsson, Johnny, et al.
(author)
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Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents
- 2013
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In: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 100:2, s. 203-209
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: We studied the decline of C-peptide during the first year after diagnosis of Type 1 diabetes (T1D), and its relation to various factors. less thanbrgreater than less thanbrgreater thanMethods: 3824/4017 newly diagnosed patients (95%) were classified as T1D in a national study. In a non-selected subgroup of 1669 T1D patients we determined non-fasting C-peptide both at diagnosis and after 1 year, and analyzed decline in relation to clinical symptoms and signs, initial C-peptide and occurrence of auto-antibodies. less thanbrgreater than less thanbrgreater thanResults: Younger children lost more C-peptide (p andlt; 0.001) and the higher the C-peptide at diagnosis the larger the decline during the first year (p andlt; 0.0000). Patients with higher BMI had higher C-peptide at diagnosis but lost more (p andlt; 0.01), and those with lower HbA1c, without symptoms and signs at diagnosis, and with higher BMI, had higher C-peptide at diagnosis, but lost more during the first year (p andlt; 0.001). Finally, patients diagnosed during autumn had higher C-peptide at diagnosis, but lost more during the coming year (p andlt; 0.001). Occurrence of auto-antibodies did not correlate with C-peptide decline, except possibly for a more rapid loss in IAA-positive patients. less thanbrgreater than less thanbrgreater thanConclusions/interpretation: Even in a restricted geographical area and narrow age range (andlt; 18 years), the natural course of Type 1 diabetes is heterogeneous. This should be considered in clinical trials.
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| 25. |
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| 26. |
- Sacks, David B., et al.
(author)
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Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus
- 2011
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 34:6, s. 61-99
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Research review (peer-reviewed)abstract
- BACKGROUND - Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH - An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A newsystemwas developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral andwritten comments, and a revised draftwas posted in 2010 and againmodified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT - In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A 1c (HbA1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucosemonitoring, genetic testing, andmeasurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY - The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.
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| 27. |
- Sedimbi, S. K., et al.
(author)
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SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients
- 2007
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In: Genes Immun. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:6, s. 518-21
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Journal article (peer-reviewed)abstract
- SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.
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| 28. |
- Sims, Tom J, et al.
(author)
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Serum IgG to heat shock proteins and Porphyromonas gingivalis antigens in diabetic patients with periodontitis.
- 2002
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In: Journal of Clinical Periodontology. - 0303-6979 .- 1600-051X. ; 29:6, s. 551-562
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Journal article (peer-reviewed)abstract
- BACKGROUND: Past studies have reported a correlation between the presence and severity of periodontitis and serum antibody titers to species-specific antigens of Porphyromonas gingivalis or to cross-reactive antigens, such as lipopolysaccharide (LPS) and heat shock proteins (HSP), shared between P. gingivalis and other bacteria. Our recent study of periodontal treatment outcome in insulin-dependent (type 1) diabetes mellitus patients with severe periodontitis (IDDMI/periodontitis) resulted in two key findings: 1. serum glutamic acid decarboxylase autoantibody (GAD65 Ab) levels were significantly associated with periodontal pocket depth change (PDC) and 2. serum IgG titers to P. gingivalis cells were positively associated with GAD65 Ab level in seropositive (GAD65 Ab +) patients. We have therefore hypothesized that profiles of serum autoantibody levels and IgG titers, to P. gingivalis-specific antigens may be useful in assessing risk for refractory periodontitis in such patients.AIM: To determine whether PDC resulting from non-surgical periodontal treatment can be predicted using profiles of baseline IgG titers to P. gingivalis-specific antigens, human HSP, and GAD65.METHODS: PDC was assessed two months after non-surgical periodontal treatment of 7 GAD65 Ab + and 11 GAD65 AbIDDM/periodontitis patients. Pretreatment titers to GAD65, recombinant human heat shock proteins (HSP90, HSP70, and HSP60), and various P. gingivalis antigens were measured using radioligand precipitation or enzyme-linked immunosorbent (ELISA) assays and compared to the same measurements for 154 recent-onset IDDM patients and 46 non-diabetic controls.RESULTS: Median titers (ELISA units) to HSP90 and HSP70 were significantly higher than non-diabetic controls for GAD65 Ab + (p degrees = 0.002) and GAD65 Ab- (p = 0.034) IDDM/periodontitis patients, respectively. Multivariate regression analysis indicated significant partial correlation of PDC with log-transformed titers to HSP90 (r = - 0.62, p = 0.008), HSP70 (r = + 0.62, p = 0.009), GAD65 (r = - 0.60, p = 0.01) and P. gingivalis LPS (r = - 0.5 1, p = 0.04). Furthermore, hierarchical clustering of baseline profiles of log-transformed HSP90, HSP70, and GAD65 Ab titers sorted patients into two distinct clusters with significantly different median PDC (1.45 min, n = 10 vs. 0.65 min, n = 8; p = 0.016, Mann-Whitney).CONCLUSION: Pretreatment profiles of serum antibody titers to HSP90, HSP70, GAD65, and P. gingivalis LPS may be useful for predicting which patients with IDDM/periodontitis will have a poor response to non-surgical periodontal therapy.
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| 29. |
- Stene, Lars C., et al.
(author)
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Epidemiology and Pathogenesis of Type 1 Diabetes
- 2023. - 2
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In: Transplantation of the Pancreas. - 9783031209987 - 9783031209994 ; , s. 13-39
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Book chapter (peer-reviewed)abstract
- Type 1 diabetes is an autoimmune disease that affects 0.1 to nearly 1% of the population, dependent on the country, with its highest incidence around 10–15 years of age. The incidence has increased over time, approximately doubling over the past 2–3 decades. The incidence varies across the world, with the highest among populations of (Northern) European origin and the lowest in Japan. Most diabetic patients do not have affected first-degree relatives, but genetic predispostion encoded in the HLA class II DR- and DQ loci is proabably necessary, albeit not sufficient, for developing disease. Exposure to environmental factors in early life appears to also impact the risk of disease development, but available evidence does not allow for strong conclusions to be drawn. The past decade has brought new data from human pancreatic donors. Hoewever, the timing between etiological triggers and the pathogenesis is poorly defined, and the disease mechanisms need to be elucidated. It is still not possible to prevent or cure type 1 diabetes. The latter can currently only be achieved using invasive beta-cell repacement therapies through transplantation.
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| 30. |
- Stewart, Christopher J., et al.
(author)
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Temporal development of the gut microbiome in early childhood from the TEDDY study
- 2018
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 562:7728, s. 583-588
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Journal article (peer-reviewed)abstract
- 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 diseases1–9 such 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 Bifidobacterium species (B. breve and 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 Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was 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.
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| 31. |
- Vehik, Kendra, et al.
(author)
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Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
- 2020
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:9, s. 2066-2073
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Journal article (peer-reviewed)abstract
- OBJECTIVE: 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 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 IA2 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 < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR = 3.08; 95% CI = 2.04-4.65; P < 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.
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| 32. |
- Vehik, Kendra, et al.
(author)
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Prospective virome analyses in young children at increased genetic risk for type 1 diabetes
- 2019
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 25:12, s. 1865-1872
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Journal article (peer-reviewed)abstract
- 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 T1D6 and 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 viruses7 and 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 CXADR rs6517774, independently correlated with islet autoimmunity.
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| 33. |
- Zhao, Lue Ping, et al.
(author)
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Motifs of Three HLA-DQ Amino Acid Residues (alpha 44, beta 57, beta 135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children
- 2020
-
In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 69:7, s. 1573-1587
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Journal article (peer-reviewed)abstract
- HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients (n= 962) and control subjects (n= 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues alpha 44Q (odds ratio [OR] 3.29,P= 2.38 * 10(-85)) and beta 57A (OR 3.44,P= 3.80 * 10(-84)) to be associated with T1D in the DQ8/9 cluster representing all ten residues (alpha 22, alpha 23, alpha 44, alpha 49, alpha 51, alpha 53, alpha 54, alpha 73, alpha 184, beta 57) due to complete linkage disequilibrium (LD) of alpha 44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found alpha 44C and beta 135D to share the risk for T1D (OR 2.10,P= 1.96 * 10(-20)). The motif "QAD" of alpha 44, beta 57, and beta 135 captured the T1D risk association of DQ8.1 (OR 3.44,P= 3.80 * 10(-84)), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10,P= 1.96 * 10(-20)). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56,P= 6.35 * 10(-8)) but negatively with IA-2A (OR 0.59,P= 6.55 * 10(-11)). QAD was negatively associated with GADA (OR 0.88;P= 3.70 * 10(-3)) but positively with IA-2A (OR 1.64;P= 2.40 * 10(-14)), despite a single difference at alpha 44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (alpha 44, beta 57, beta 135) conferring T1D risk should sharpen functional and translational studies.
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