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1.
  • Jensen, Richard A., et al. (författare)
  • Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects
  • 2007
  • Ingår i: Journal of Diabetes and its Complications. - Elsevier. - 1873-460X. ; 21:4, s. 205-213
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The aim of this study is to identify risk factors for the loss of measurable plasma C-peptide in newly diagnosed 15- to 35-year-old diabetic subjects. Methods: This Swedish study included 778 subjects. C-peptide levels were obtained each year for 6 years after diagnosis. Loss of measurable C-peptide was defined as a level at or below the lower detection limit of the local assay (0.13 nmol/1). In addition to C-peptide, other baseline covariates included gender, age, body mass index, HLA genotype, and autoantibody levels. Results: Compared with autoantibody-negative subjects, autoantibody-positive subjects had lower median baseline C-peptide (0.27 vs. 0.50, P<.001), their levels declined over the study period, and the risk of losing measurable C-peptide was significantly higher when more than one autoantibody was present [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.13-7.54]. Among autoantibody-positive individuals, the presence of GAD65Ab (OR, 1.8; 95% CI, 1.24-2.51) and islet cell antibodies (OR, 1.6; 95% CI, 1.19-2.18) conferred a higher risk for loss of measurable C-peptide.as did female gender (OR, 1.6; 95% CI, 1.17-2.11) and time after diagnosis (OR, 1.5 for each additional year postdiagnosis; 95% CI, 1.41-1.57). Higher baseline C-peptide levels were protective (OR, 0.5 for each additional log, nanomoles per liter; 95% CI, 0.36-0.58). Conclusions: This study identified autoantibody status, gender, and baseline C-peptide levels as factors that will be useful for predicting the disease course of 15- to 35-year-old diabetic individuals. (C) 2007 Elsevier Inc. All rights reserved.
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2.
  • Jensen, R., et al. (författare)
  • Islet cell autoantibody levels after the diagnosis of young adult diabetic patients
  • 2007
  • Ingår i: Diabetic Medicine. - Wiley-Blackwell. - 1464-5491. ; 24:11, s. 1221-1228
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims The aim was to determine the course of islet cell antibodies [glutamate decarboxylase (GADA), tyrosine phosphatase-like islet antigen 2 (IA-2A) and islet cell (ICA)] after the diagnosis of the diabetic patient. Methods The Diabetes Incidence Study in Sweden (DISS) attempted to prospectively enrol all newly diagnosed diabetic patients aged 15-34 years during 1992 and 1993. C-peptide and autoantibody levels were determined from venous blood samples at diagnosis and again at yearly intervals for 6 years. Results After the first year, the odds of remaining GADA positive decreased by 9% per year [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85-0.96] while the mean GADA index remained unchanged (chi(2)(1) = 0.8, P = 0.37). There was no change in the percentage of subjects testing IA-2A positive after the first year (chi(2)(1) = 0.1, P = 0.75). However, the mean index decreased 0.04 per year (95% CI: 0.03-0.05)-a 7.9% decline (95% CI: 5.4-10.4%). The odds of a subject testing positive for ICA decreased by 24% per year (OR = 0.76, 95% CI = 0.70-0.82). The mean ICA levels decreased 0.75 per year (95% CI: 0.66-0.84)-a 16.4% decline (95% CI: 14.1-18.6%). The rate of change in titres for all three autoantibodies was independent of gender, human leucocyte antigen genotype and C-peptide status. Conclusions GADA levels remained high while ICA levels declined. In contrast to a previous study, we found that the proportion of IA-2A subjects remaining positive did not decrease after the first year, while the average index decreased slightly.
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4.
  • Delli, Ahmed, et al. (författare)
  • Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study.
  • 2012
  • Ingår i: Diabetes. - American Diabetes Association Inc.. - 1939-327X. ; 61:10, s. 2556-2564
  • Tidskriftsartikel (refereegranskat)abstract
    • We examined whether zinc transporter-8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish patients due to different polymorphisms of SLC30A8, HLA-DQ, or both. Newly diagnosed autoimmune (≥1 islet autoantibody) T1D type 1 diabetic patients (n = 2,964, <18 years, 55% male) were ascertained in the Better Diabetes Diagnosis study. Two subgroups were identified: Swedes (n = 2,160, 73%) and immigrants (non-Swedes; n = 212, 7%). Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%). ZnT8-RA (57 and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) than Swedes (46%). We tested whether this inconsistency was due to HLA-DQ as 2/X (2/2; 2/y; y is anything but 2 or 8), which was a major genotype in non-Swedes (40%) compared with Swedes (14%). In the non-Swedes only, 2/X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA. Molecular simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lack of tolerance to ZnT8-R. At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC30A8 CC(RR) genotypes.
5.
  • Vaziri Sani, Fariba, et al. (författare)
  • A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes.
  • 2011
  • Ingår i: Journal of Immunological Methods. - Elsevier. - 1872-7905. ; 371, s. 25-37
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND AIMS: Autoantibodies against the zinc transporter 8 (ZnT8A) are common in type 1 diabetes (T1D). ZnT8A analyses are complicated by the fact that there are three variants of the autoantigen at amino acid position 325 representing ZnT8-R (Arginine), ZnT8-W (Tryptophan) and ZnT8-Q (Glutamin). The aims of the study were: 1) to develop an autoantigen triple mix Radio-Binding Assay (RBA) for ZnT8A; 2) to identify the individual ZnT8-R,-W,-QA reactivity and 3) to validate the triple mix ZnT8A RBA in children with newly diagnosed T1D. METHODS: Serum samples were obtained from 2664 (56% males, n=1436) patients in the Swedish nationwide Better Diabetes Diagnosis (BDD) study representing patients with T1D (97%, n=2582), T2D (1.7%, n=46), MODY (1.0%, n=28) and secondary diabetes (0.3%, n=8). cDNA coding for the C-terminal end of each variant was prepared by site-directed mutagenesis and subcloned into a high efficiency in vitro transcription translation vector. The ZnT8 variants were labeled with 35S-methionine and used in a standard RBA separating free from autoantibody-bound autoantigen with Protein A-Sepharose. RESULTS: ZnT8-TripleA was detected in 1678 (65%) patients with T1D, 4 (9%) T2D, 3 (11%) MODY and in none (0%) of the patients with secondary diabetes. Among the T1D patients ZnT8-RA was detected in 1351 (52%) patients, ZnT8-WA in 1209 (47%) and ZnT8-QA in 790 (31%) demonstrating that 1661 (64%) had one or several ZnT8A. The ZnT8-TripleA assay showed a false positive rate of 1.9% (n=49). Only 1.2% (n=32) of the T1D patients were false negative for ZnT8-TripleA compared to 0/46 (0%) of the T2D patients. The precision (intra assay CV) and reproducibility (inter assay CV) of the ZnT8-TripleA assay did not differ from the RBA of the individual ZnT8 variants. CONCLUSION: We conclude that the ZnT8-TripleA assay had low false positive and false negative rates. The ZnT8-TripleA assay would therefore be highly suitable not only to analyze patient with newly diagnosed diabetes but also for screening the general population since this assay demonstrated high sensitivity and very high specificity.
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6.
  • Agardh, Carl-David, et al. (författare)
  • Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.
  • 2005
  • Ingår i: Journal of Diabetes and its Complications. - Elsevier. - 1873-460X. ; 19:4, s. 238-246
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.
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7.
  • Ahlgren, Kerstin. M, et al. (författare)
  • Diabetes mellitus in dog - : No evidence for a type-1-like phenotype
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p><strong>Aims/hypothesis</strong></p> <p>Diabetes mellitus (DM) is one of the most common endocrine disorders in dogs, and is commonly proposed to be of autoimmune origin. Although the clinical symptoms of human type 1 diabetes (T1D) and canine DM are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.</p> <p><strong>Methods</strong></p> <p> Sera from 121 diabetic dogs representing 38 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs from 40 breeds. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by <em>in vitro</em> transcription and translation (ITT) of human and canine GAD65, followed by immunoprecipitation.</p> <p><strong>Results</strong></p> <p>None of the canine sera analyzed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay.</p> <p><strong>Conclusions/interpretations</strong></p> <p>Based on sera from 121 diabetic dogs from 38 different breeds were tested for humoral autoreactivity using four different assays, contrary to previous observations, we find no support for an autoimmune aetiology  in canine diabetes.</p>
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8.
  • Ahlgren, Kerstin M, et al. (författare)
  • Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus.
  • 2014
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 9:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.
9.
  • Ahlgren, Kerstin M, et al. (författare)
  • Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
  • 2014
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 9:8, s. e105473
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>AIMS/HYPOTHESIS:</strong></p><p>Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.</p><p><strong>METHODS:</strong></p><p>Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.</p><p><strong>RESULTS:</strong></p><p>None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.</p><p><strong>CONCLUSIONS/INTERPRETATIONS:</strong></p><p>Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.</p>
10.
  • Ahlqvist, Emma, et al. (författare)
  • Novel subgroups of adult-onset diabetes and their association with outcomes : A data-driven cluster analysis of six variables
  • 2018
  • Ingår i: The Lancet Diabetes and Endocrinology. - Elsevier. - 2213-8587. ; 6:5, s. 361-369
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods: We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings: We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation: We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. Funding: Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhälsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.
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