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1.
  • Hampe, CS, et al. (författare)
  • Species-specific autoantibodies in type 1 diabetes
  • 1999
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - Oxford University Press. - 0021-972X. ; 84:2, s. 643-648
  • Tidskriftsartikel (refereegranskat)abstract
    • GAD65 autoantibodies (GAD65Ab) are important markers for type 1 (insulin-dependent) diabetes mellitus. Although most patients have GAD65Ab at the time of clinical diagnosis, there are also GAD65Ab-positive individuals in the population at low risk of developing type 1 diabetes. The aim of this study was to test the hypothesis that the GAD65Ab reactivity to GAD65 cloned from human, mouse, and rat in newly diagnosed type 1 diabetic patients differ from antibody-positive healthy individuals. Sera from 254 new-onset 0- to 34- yr-old type 1 diabetic patients and 270 controls were assayed for their reactivity to human, mouse, and rat GAD65. Among the type 1 diabetic patients there was a significant better binding of human GAD65 compared to either mouse (P = 0.03) or rat GAD65 (P = 0.0005). The preference for human GAD65 increased with increasing age at onset (P = 0.0002). This differentiation was not observed in 88 GAD65Ab-positive control subjects. Our data indicate that recognition of epitopes by GAD65Ab in type 1 diabetes is different from that in nontype 1 diabetes, GAD65Ab-positive individuals.
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2.
  • Bieg, S, et al. (författare)
  • The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic biobreeding rats
  • 1997
  • Ingår i: Diabetologia. - Springer. - 0012-186X. ; 40:7, s. 786-792
  • Tidskriftsartikel (refereegranskat)abstract
    • The lymphopenia gene (lyp) on rat chromosome 4 is closely linked to autoimmune diabetes in the BioBreeding (BB) rat. Lyp controls the number of peripheral lymphocytes by reducing T cells of the RT6+ phenotype by almost 90%. Following nine cycles of marker-assisted cross-intercross breeding we have developed congenic lyp/lyp, lyp/+ and +/+ (wildtype) rats on the background of DR rats. Prediabetic and insulitis free lyp/lyp, lyp/+ and +/+ rats were used to determine the effect of lyp on cytokine expression in the thymus. In situ hybridization of thymus cryosections showed that the interferon gamma (IFNγ) mRNA expression was highest in lyp/lyp rats and the hybridization signal was restricted to the medullary compartment. The frequency of IFNγ and interleukin (IL)-10 mRNA expressing cells in isolated thymocytes determined by quantitative image analysis, demonstrated an increased IFNγ:IL-10 ratio in thymocytes from lyp/lyp homozygotes compared to lyp/+ and +/+ rats. This confirmed a lyp gene dose-dependent segregation of the IFNγ(high) phenotype. Recombinant human glutamic acid decarboxylase (GAD65) increased the number of IFNγ and IL-10 mRNA expressing thymocytes after in vitro culture. We conclude that the quantitative ratio of cytokine producing thymocytes is associated with the lyp genotype. These potentially autoreactive thymocytes may explain the establishment of beta-cell directed autoimmunity in the BB rat despite peripheral lymphopenia.
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3.
  • Danielsson, Å, et al. (författare)
  • Effects of pancreozymin and secretin on insulin release and the role of the exocrine pancreas
  • 1974
  • Ingår i: Diabetologia. - Springer. - 0012-186X. ; 10:5, s. 407-409
  • Tidskriftsartikel (refereegranskat)abstract
    • Mouse pancreatic islets microdissected free from, or surrounded by, exocrine cells were used to study the effects of secretin and choleeystokinm-pancreozymin on insulin release. Both secretin and cholecystokinin-pancreozymin potentiated glucose-stimulated insulin release regardless of whether exocrine cells were present. The results fail to support the idea that the presence of the exocrine parenchyma is essential for elicitation of insulin release by these gastrointestinal hormones.
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4.
  • Graham, J, et al. (författare)
  • A comparison of three statistical models for IDDM associations with HLA
  • 1996
  • Ingår i: Tissue Antigens. - Wiley-Blackwell. - 0001-2815. ; 48:1, s. 1-14
  • Tidskriftsartikel (refereegranskat)abstract
    • The association between HLA-DQ haplotypes and insulin-dependent diabetes mellitus (IDDM) was studied in 48 children from 44 families ascertained from the high incidence area around Umea, Sweden. Numerous hypotheses have been proposed to explain associations between HLA and IDDM, but comparisons of statistical models based on these hypotheses have not been attempted. The aim of the present study was to compare the goodness-of-fit and predictive abilities among different statistical models. A likelihood-based analysis rather than a conventional analysis based on contingency tables was therefore adopted. We first used parental haplotype information in a conditional likelihood analysis (1) and then compared this analysis with that of an unaffected control group which used information on geographically matched controls. Under the analysis conditional on parental haplotype, a statistical model motivated by the hypothesis that the entire DQ heterodimer is involved in IDDM pathogenesis fit the data significantly better and had greater predictive ability than either a model motivated by the explanation that an IDDM gene is linked to DQB1 or that the DQB1 chain itself is involved in IDDM pathogenesis, or a model arising from the hypothesis that single amino acids at codon 57 of DQB1 and codon 52 of DQA1, respectively, confer susceptibility. Under the case-control analysis, the identity of the best-fitting or most predictive statistical model was not as clear, although both approaches to analyzing risk suggested that the single-amino-acids model had significantly poorer fit compared to the remaining two models.
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5.
  • Hampe, CS, et al. (författare)
  • Glutamate decarboxylase (GAD) autoantibody epitope shift during the first year of Type 1 diabetes
  • 1999
  • Ingår i: Hormone and Metabolic Research. - Georg Thieme Verlag. - 0018-5043. ; 31:10, s. 553-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Autoantibodies in Type 1 diabetes patients may differentiate between glutamate decarboxylase (GAD65) cloned from human, mouse and rat with a significant better binding to the human antigen. A subgroup of 15% (27/183) patients showed significantly better binding to rodent than to human GAD65. The aim of this study was to determine whether the autoantibody specificity would remain anti-rodent during longitudinal follow-up for one year. We observed 1) that the average slope of the difference between human and mouse GAD65 autoantibodies binding increased between onset and after one year, which demonstrates reduced binding to rodent GAD65 and 2) that, in a group followed every third month, 9/11 (80%) children with rodent specific GAD65 autoantibodies at onset converted within one year to preference against human GAD65. This shift in preference was confirmed by significantly lower EC50 values in the initially anti-rodent GAD65 autoantibodies compared to samples taken one year after clinical diagnosis as determined in displacement studies with unlabeled human GAD65. We speculate that the evolution of GAD65 autoantibodies in Type 1 diabetes includes reactivity to a non-human GAD65 N- terminal end conformation. Progression towards Type 1 diabetes is, however, associated with a maturation of the immune response towards human GAD65 autoreactivity.
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6.
  • Kasuga, A, et al. (författare)
  • HLA class II is associated with the frequency of glutamic acid decarboxylase M(r) 65,000 autoantibodies in Japanese patients with insulin dependent diabetes mellitus
  • 1996
  • Ingår i: Acta Diabetologica. - Springer. - 0940-5429. ; 33:2, s. 108-113
  • Tidskriftsartikel (refereegranskat)abstract
    • Autoantibodies to glutamic acid decarboxylase (GAD65Ab) are common in both caucasian and Japanese patients with insulin-dependent diabetes mellitus (type 1), while the type 1-associated HLA haplotypes differ. In the present study, we analyzed GAD65Ab in relation to HLA-DQ and -DR alleles in Japanese type 1 patients. GAD65Ab were found in 58% short-duration (less than 5 years) type 1, 23% long-duration type 1, 56% slowly progressive type 1, 3% type 2 patients, and 1.7% healthy individuals. In 75 HLA-typed type 1 patients, the GAD65Ab frequency was higher in short-duration patients with DRB1(*)08 allele (100%, Pc < 0.05). GAD65Ab frequencies in DQB1(*)0302, DQB1(*)0303, and DRB1(*)09-positive, long-duration type 1 patients were lower than those in short-duration type 1 patients (14%, 19%, and 20%, Pc < 0.02 compared with short-duration type 1, 90%, 75%, and 71%, respectively), while the frequency varied less in DQB1(*)04 individuals (44% and 30% in short- and long-duration type 1 patients, respectively). These findings were also observed among patients with DRB1(*)04, i.e., the haplotype DRB1(*)0405-DQB1(*)0401 showed less variation in frequency of GAD65Ab (44% and 35% in short- and long-duration type 1 patients, respectively), while DRB1(*)04xx-DQB1(*)0302 showed lower frequency in long-duration type 1 than short-duration (13% and 100%, respectively), Thus, HLA class II is associated with frequency GAD65Ab, and this association might be affected by disease duration in Japanese type 1 patients.
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7.
  • Kockum, I, et al. (författare)
  • Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus
  • 1996
  • Ingår i: Hormone and Metabolic Research. - Georg Thieme Verlag. - 0018-5043. ; 28:7, s. 344-347
  • Tidskriftsartikel (refereegranskat)abstract
    • Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune markers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recombination frequency within the HLA region. The frequency of the DR3-DQA1 * 0501-DQB1 * 0201 haplotype and the DR3-DQA1 * 0501 DQB1 * 0201 (DQ2)/DR4-DQA1 * 0301-DQB1 * 0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30. The negatively associated haplotype, DR15-DQA1 * 0102-DQB1 * 0602 was absent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tandem repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive but not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onset and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest sensitivity (54%) was in 0-10 year old boys, while age did not affect the sensitivity in girls. In contrast, the sensitivity of IAA was highest (46%) before the age of 15 but decreased thereafter as did the sensitivity for ICA. Classification of patients who develop IDDM above 20-25 years of age was inadequate since many patients classified with NIDDM either had GAD65Ab or ICA or developed these antibodies after 1-2 years of NIDDM. We conclude that not only age but also gender affects the risk for IDDM associated with HLA, other IDDM genes as well as commonly used immunological markers for IDDM.
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8.
  • KOCKUM, I, et al. (författare)
  • Population analysis of protection by HLA-DR and DQ genes from insulin-dependent diabetes mellitus in Swedish children with insulin-dependent diabetes and controls
  • 1995
  • Ingår i: European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics. - 0960-7420. ; 22:6, s. 443-465
  • Tidskriftsartikel (refereegranskat)abstract
    • A negative association between insulin‐dependent diabetes mellitus (IDDM) and HLA‐DR, DQA1 or DQB1 was found in a large population‐based investigation of childhood‐onset patients (more than 420 patients) and controls (more than 340 controls) from Sweden. The relative risk was decreased for several haplotypes that were negatively associated with IDDM: DR15‐DQA1*0102‐DQB1*0602, DR7‐DQA1*0201‐DQB1*0303, DR14‐DQA1*0101‐DQB1*0503, DRI1‐DQAI*0501‐DQB1*0301, DR13‐DQA1*0103‐DQB1*0603 and DR4‐DQA1*0301‐DQB1*0301. In a relative predispositional effect (RPE) analysis, however, only the DR15‐DQA1*0102‐DQB1*0602 haplotype was significantly decreased, which suggests that the major protective effect for IDDM is carried by this haplotype. This was supported by the observation that all genotypes which were negatively associated with IDDM, except DR7/13, included at least one allele from the DR15‐DQA1*0102‐DQB1*0602 haplotype. Relative predispositional effect (RPE) analysis of genotypes showed further that the DR15‐DQA1*0102‐DQB1*0602 haplotype was also negatively associated with IDDM when combined with any other haplotype, whether negatively or positively associated with IDDM. This supports previous suggestions that DR15‐DQA1*0102‐DQB1*0602 acts dominantly. However, both the stratification and the predispositional allele test failed to distinguish the negative association between IDDM and DR15 from that of DQBT0602. On the other hand, these tests indicated that DQA1*0102 was not likely to explain the negative association between IDDM and the DR15‐DQA1*0102‐DQB1*0602 haplotype. We conclude that the
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9.
  • Lotfi, K, et al. (författare)
  • The beta cell glucokinase promoter variant is an unlikely risk factor for diabetes mellitus
  • 1997
  • Ingår i: Diabetologia. - Springer. - 0012-186X. ; 40:8, s. 959-962
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucokinase plays an important role in the regulation of insulin secretion and is therefore an attractive candidate gene for both insulin dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. A single G-A nucleotide polymorphism at the -30 position of the beta-cell specific promoter region of the glucokinase gene was previously associated with reduced beta-cell function. In the present study we analysed 268 consecutive newly diagnosed Swedish patients classified with either IDDM (n = 205), NIDDM (n = 31) or unclassifiable (n = 32) diabetes between the ages of 15 and 35 years along with a group of 158 age- and sex-matched control subjects. The beta-cell promoter region was amplified by the polymerase chain reaction and the G-A variant identified by single strand conformational polymorphism. There was no significant difference in allele frequencies of G and A between any of the subject groups and likewise, no significant difference in the frequencies of the G/G, G/A, or A/A genotypes. Eight subjects were homozygous for the less common A allele, five had IDDM and three were control subjects. Our results suggest that the -30 beta-cell glucokinase promoter variant is not associated with IDDM.
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10.
  • Ortqvist, E, et al. (författare)
  • Age governs gender-dependent islet cell autoreactivity and predicts the clinical course in childhood IDDM
  • 1997
  • Ingår i: Acta Paediatrica, International Journal of Paediatrics. - Wiley-Blackwell Publishing Ltd. - 0803-5253. ; 86:11, s. 1166-1171
  • Tidskriftsartikel (refereegranskat)abstract
    • Most IDDM patients temporarily restore some of their beta-cell function following the initiation of insulin therapy. The aim of this study was to analyse the influence of age, gender, metabolic state at diagnosis and presence of autoantibodies (GAD65 antibodies and ICA) on the duration of the clinical partial remission. In total, 149 consecutively diagnosed IDDM children, 0-16 y old (70F, 79M, mean age 9.5 y) were studied. Partial remission was arbitrarily defined as the period when the insulin dose was below 0.5 U/BW 24 h-1 and HbA1c below 7.5%, and occurred in 119/149 patients with a duration between 1 and 38 months. Cox's regression analysis showed that the factors significantly associated with the duration of remission were age, gender, interaction between age and gender, ICA and a high initial HbA1c, whereas GAD65Ab had no influence. Young boys had the shortest remission period, while adolescent boys had the longest, as compared to young and adolescent girls. The ICA-negative patients (n = 42) had a longer remission period (median 9.7 months) than the ICA-positive children (n = 107; 5.0 months;p = 0.0001), regardless of GAD65Ab status. We speculate that the relative insulin resistance, which is more pronounced in pubertal girls than in boys, may be associated with a more rapid increase of exogenous insulin requirement. These findings are important when evaluating the effect of islet cell autoreactivity on the clinical course of IDDM in children.
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