| 1. |
- Andersson, C, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 2. |
- Kanatsuna, N, et al.
(författare)
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Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
- 2015
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 82:4, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
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| 3. |
- Hampe, C. S., et al.
(författare)
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Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform : relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus
- 2019
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Ingår i: Diabetic Medicine. - : Wiley-Blackwell. - 0742-3071 .- 1464-5491. ; 36:11, s. 1375-1383
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate whether the N‐terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform.Methods: GAD65 antibody‐positive healthy individuals (n=13), people with stiff‐person syndrome (n=15) and children with new‐onset Type 1 diabetes (n=654) were analysed to determine binding to full‐length GAD65 and the N‐terminal truncated GAD65 isoform in each of these settings. GAD65 autoantibody epitope specificity was correlated with binding ratios of full‐length GAD65/N‐terminal truncated GAD65.Results: The N‐terminal truncated GAD65 isoform was significantly less recognized in GAD65Ab‐positive people with stiff‐person syndrome (P=0.002) and in healthy individuals (P=0.0001) than in people with Type 1 diabetes. Moreover, at least two specific conformational GAD65Ab epitopes were not, or were only partially, presented by the N‐terminal truncated GAD65 isoform compared to full‐length GAD65. Finally, an N‐terminal conformational GAD65Ab epitope was significantly less recognized in DQ8/8 positive individuals with Type 1 diabetes (P=0.02).Conclusions: In people with stiff person syndrome preferred binding to the full‐length GAD65 isoform over the N‐terminal truncated molecule was observed. This binding characteristic is probably attributable to reduced presentation of two conformational epitopes by the N‐terminal truncated molecule. These findings support the notion of disease‐specific GAD65Ab epitope specificities and emphasize the need to evaluate the applicability of novel assays for different medical conditions.
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| 4. |
- Ludvigsson, Johnny, et al.
(författare)
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GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 366:5, s. 433-442
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.
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| 5. |
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| 6. |
- Andersson, C, et al.
(författare)
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Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes
- 2013
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Ingår i: Pediatric Diabetes. - : Wiley-Blackwell. - 1399-543X .- 1399-5448. ; 14:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Andersson C, Vaziri-Sani F, Delli AJ, Lindblad B, Carlsson A, Forsander G, Ludvigsson J, Marcus C, Samuelsson U, Ivarsson SA, Lernmark A, Elding Larsson H, the BDD Study group. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatric Diabetes 2013: 14: 97-105. Objective To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA). Methods We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA). Results ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 13 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (pandlt;0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2). Conclusions Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.
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| 7. |
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| 8. |
- ERINGSMARK REGNÉLL, SIMON, et al.
(författare)
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Pancreas volume and fat fraction in children with Type 1 diabetes
- 2016
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 33:10, s. 1374-1379
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: People with Type 1 diabetes have smaller pancreases than healthy individuals. Several diseases causing pancreatic atrophy are associated with pancreatic steatosis, but pancreatic fat in Type 1 diabetes has not been measured. This cross-sectional study aimed to compare pancreas size and fat fraction in children with Type 1 diabetes and controls.METHODS: The volume and fat fraction of the pancreases of 22 children with Type 1 diabetes and 29 controls were determined using magnetic resonance imaging.RESULTS: Pancreas volume was 27% smaller in children with diabetes (median 34.9 cm(3) ) than in controls (47.8 cm(3) ; P < 0.001). Pancreas volume correlated positively with age in controls (P = 0.033), but not in children with diabetes (P = 0.649). Pancreas volume did not correlate with diabetes duration, but it did correlate positively with units of insulin/kg body weight/day (P = 0.048). A linear model of pancreas volume as influenced by age, body surface area and insulin units/kg body weight/day found that insulin dosage correlated with pancreas volume after controlling for both age and body surface area (P = 0.009). Pancreatic fat fraction was not significantly different between the two groups (1.34% vs. 1.57%; P = 0.891).CONCLUSIONS: Our findings do not indicate that pancreatic atrophy in Type 1 diabetes is associated with an increased pancreatic fat fraction, unlike some other diseases featuring reduced pancreatic volume. We speculate that our results may support the hypotheses that much of pancreatic atrophy in Type 1 diabetes occurs before the clinical onset of the disease and that exogenous insulin administration decelerates pancreatic atrophy after diabetes onset. This article is protected by copyright. All rights reserved.
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| 9. |
- Jonsdottir, Berglind, et al.
(författare)
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Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents
- 2013
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Ingår i: Diabetologia. - : Springer Verlag (Germany). - 0012-186X .- 1432-0428. ; 56:8, s. 1735-1742
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. less thanbrgreater than less thanbrgreater thanBlood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). less thanbrgreater than less thanbrgreater thanAt type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p andlt; 0.0001). GADA was positively associated with TPOAb (p andlt; 0.001) and with TGAb (p andlt; 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p (c)) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p (c) = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. less thanbrgreater than less thanbrgreater thanGADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.
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| 10. |
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| 11. |
- Paul, Dirk S., et al.
(författare)
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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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| 12. |
- Persson, M., et al.
(författare)
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The Better Diabetes Diagnosis (BDD) study – A review of a nationwide prospective cohort study in Sweden
- 2018
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227 .- 1872-8227. ; 140, s. 236-244
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Forskningsöversikt (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) in Sweden is one of the highest in the world. However, the possibility of other types of diabetes must also be considered. In addition, individuals with T1D constitute a heterogeneous group. A precise classification of diabetes is a prerequisite for optimal outcome. For precise classification, knowledge on the distribution of genetic factors, biochemical markers and clinical features in individuals with new onset of diabetes is needed. The Better Diabetes Diagnosis (BDD), is a nationwide study in Sweden with the primary aim to facilitate a more precise classification and diagnosis of diabetes in order to enable the most adequate treatment for each patient. Secondary aims include identification of risk factors for diabetes-related co-morbidities. Since 2005, data on almost all children and adolescents with newly diagnosed diabetes in Sweden are prospectively collected and including heredity of diabetes, clinical symptoms, levels of C peptide, genetic analyses and detection of autoantibodies. Since 2011, analyses of HLA profile, autoantibodies and C peptide levels are part of clinical routine in Sweden for all pediatric patients with suspected diagnosis of diabetes. In this review, we present the methods and main results of the BDD study so far and discuss future aspects.
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