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  • Artikel: DFG Deutsche Nationallizenzen  (8)
  • Type 1 (insulin-dependent) diabetes  (3)
  • HLA risk markers.  (2)
  • HLA-DQ  (2)
  • longitudinal  (2)
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  • Artikel: DFG Deutsche Nationallizenzen  (8)
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  • 1
    ISSN: 1432-0428
    Schlagwort(e): Type 1 (insulin-dependent) diabetes ; restriction fragment length polymorphism ; HLA-DQ ; prediction of Type 1 diabetes ; genetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Finnish Type 1 (insulin-dependent) diabetic families were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type 1 diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type 1 diabetes at the population level.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    ISSN: 1432-0428
    Schlagwort(e): Type 1 (insulin-dependent) diabetes mellitus ; HLA haplotypes ; HLA-DQ ; restriction fragment length polymorphism ; genetics ; disease susceptibility
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In Caucasians the predisposition to Type 1 (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQβ chain. In Finland the haplotype-specific absolute risk for developing Type 1 diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQα and DQβ restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type 1 diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,Cw4,Bw35,DR4 A3,Cw3,Bw62,DR4, A24,Cw7,Bw39,DR4, A2,Cw3,Bw62, DR4, and A2,Cw1,Bw56,DR4 was 35/100,000, 130/100,000, 166/100,000, 196/100,000, and 218/100,000, respectively. The absolute risks for DR3,DQw2 positive haplotypes A1, Cw7,B8,DR3 and A2,Cw7,B8,DR3 were 68/100,000 and 103/100,000, respectively. These results provide further evidence that not only the polymorphism at the DQ locus but also other genes of the haplotypes contribute to susceptibility to Type 1 diabetes.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1432-0428
    Schlagwort(e): Type 1 (insulin-dependent) diabetes ; insulin autoantibodies ; islet cell antibodies ; metabolic control ; C-peptide ; clinical remission
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary To study the possible clinical significance of the appearance of insulin autoantibodies prior to the diagnosis of Type 1 (insulin-dependent) diabetes, and their value in predicting the antibody response to exogenous insulin, we observed 46 newly diagnosed diabetic children and adolescents over the year following diagnosis for the occurrence and duration of clinical remission, daily insulin dose, metabolic control, residual B-cell function, insulin-binding antibodies and conventional as well as complement-fixing islet cell antibodies. Insulin-binding antibodies were determined using both monoiodinated human and porcine insulin. Sixteen children (34.7%) were positive for insulin autoantibodies upon diagnosis of Type 1 diabetes. These subjects were significantly younger (6.2±1.0 versus 10.8±0.8 years; mean±SEM, p〈0.001), and their haemoglobin A1 levels were lower (14.1±0.6 versus 16.0±0.8%, p〈0.05) at diagnosis than in the insulin autoantibody negative group. There were no significant differences in the occurrence and duration of clinical remission between insulin autoantibody-positive and -negative test groups. Daily insulin dose, haemoglobin A1 and serum C-peptide concentrations were of the same magnitude in both groups after the diagnosis, and no association could be found between the presence of insulin autoantibodies at diagnosis and persistently positive islet cell antibodies. In tests conducted 3 months after diagnosis, the group of patients with insulin autoantibodies showed significantly higher levels (p〈0.05) of antibodies binding human insulin than the group negative for insulin autoantibodies, but no significant differences could be found between the insulin binding titres of the two groups in subsequent analyses. Those who were still positive for conventional islet cell antibodies one year after diagnosis had significantly higher levels of antibodies binding human insulin (34.6±6.1 versus 12.9±1.7%, p〈0.05) as well as antibodies binding porcine insulin (33.0±5.9 versus 12.7±2.9%, p〈0.05) than the other subjects. Our observations suggest that insulin autoantibodies developing before the diagnosis of Type 1 diabetes have no influence on the clinical course of the disease over the first year following diagnosis, and they appear to serve as a poor predictor of the antibody response to insulin treatment.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1432-0428
    Schlagwort(e): Keywords IA-2 antibodies ; GAD antibodies ; insulin autoantibodies ; islet cell antibodies ; HLA risk markers.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary To study the relationship of IA-2 antibodies (IA-2A) to other autoantibodies and genetic risk markers in insulin-dependent diabetes mellitus (IDDM), 758 children and adolescents younger than 15 years of age (mean age 8.4 years) with newly diagnosed diabetes were analysed for IA-2A, GAD antibodies (GADA) and insulin autoantibodies (IAA) with radiobinding assays, for islet cell antibodies (ICA) with immunofluorescence and for HLA DR alleles by serology. IA-2A were detected in 85.9 % of cases with no association with gender or age. An overwhelming majority of the patients (71.3 %) tested positive for three or more antibodies, and 90.7 % for at least two. Fifty-four subjects (7.1 %) had one antibody detectable, whereas only 2.1 % of the patients tested negative for all four. A higher proportion of patients was positive for IA-2A and/or GADA than for ICA alone (95.5 vs 84.2 %, p 〈 0.001). The prevalence and level of IA-2A were increased in cases carrying HLA DR4/non-DR3 compared with other DR combinations. The results indicate that almost all patients with newly diagnosed childhood IDDM can be identified by screening with these four autoantibodies. The combination of IA-2A and/or GADA had a higher sensitivity for IDDM than ICA alone. The close association between IA-2A and HLA DR4, the strongest single allele predisposing to IDDM, suggests that IA-2A may be a more specific marker of beta-cell destruction than GADA, which have been shown to associate with the DR3 allele and thyroid autoimmunity. [Diabetologia (1998) 41: 424–429]
    Materialart: Digitale Medien
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  • 5
    ISSN: 1432-0428
    Schlagwort(e): Type 1 (insulin-dependent) diabetes ; insulin autoantibodies ; islet cell antibodies ; viral antibodies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In order to elucidate the possible relationship between insulin autoantibodies (IAA), conventional (ICA-IgG) and complement-fixing (CF-ICA) islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies (IgG, IgM and IgA classes), we studied 194 children and adolescents with newly diagnosed Type 1 (insulin-dependent) diabetes. Sixty-one (31.4%) of the subjects were IAA-positive at diagnosis and 73.8% (45/61) of these also had ICA-IgG compared to 51.1% (68/113, p〈0.01) of IAA-negative children. CF-ICA showed no significant association with IAA. The levels of IAA were significantly higher in the patients with ICA-IgG compared to those without [5.9±1.6% (SEM) vs 2.5±0.3%, p〈0.01]. The patients positive for IAA were younger at diagnosis than the IAA-negative ones; (7.1±0.5 vs 9.3±0.3 years, p〈0.001) and this was also true for ICA-IgG-positive children (8.1±0.4 vs 9.4±0.5 years, p〈0.05) in comparison to ICA-IgG-negative subjects. No significant associations were found between IAA or ICA on the one hand and a positive family history of Type 1 diabetes or metabolic derangements at diagnosis on the other. Subjects negative for ICA were more frequently positive for mumps virus specific IgG antibodies than the ICA-positive patients (50/80 vs 53/111, p〈0.05), and Coxsackie-B4 virus-specific IgA antibodies were more common in the CF-ICA-negative than the CF-ICA-positive children (53/111 vs 29/80, p〈0.05). There was no association between the IAA levels and Coxsackie-B4 or mumps virus specific antibodies. However, patients with serological evidence of a recent mumps infection (n=13) had higher IAA levels than the other children (4.4±7.7% vs 2.8±1.4%, p〈0.02). Our data suggest a positive association between IAA and ICA-IgG, supporting the view that IAA are like ICA serological markers of autoimmune B cell damage. The inverse associations between autoantibodies and age and between ICA and viral antibodies support the hypothesis that autoimmune mechanisms may play a more crucial role in younger patients contracting Type 1 diabetes while environmental factors may be more important in older ones.
    Materialart: Digitale Medien
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  • 6
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; longitudinal ; clustering ; children ; adolescents ; serum lipoproteins ; blood pressure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In adults hyperinsulinaemia is associated with an atherogenic risk profile including obesity, low levels of HDL-cholesterol, high levels of triglycerides and elevated blood pressure. To examine these associations in the young we studied the cross-sectional relationships of insulin with obesity indices (body mass index, subscapular skinfold thickness), serum lipids and blood pressure in 1,865 children, adolescents and young adults aged 6–24 years. We also used longitudinal data to study the value of a single insulin measurement to predict high risk factor levels and clustering of multiple risk factors after a 6-year follow-up. In cross-sectional analyses the levels of triglycerides, HDL-cholesterol, systolic blood pressure and obesity indices were usually significantly different across the quartiles of fasting insulin in both sexes among children, adolescents and young adults. In general, no associations were seen with total cholesterol or LDL-cholesterol. In prospective analysis elevated baseline insulin was related to the incidence of hypertriglyceridaemia (≥95th percentile) at the follow-up. This relationship persisted even after adjustments for baseline obesity or 6-year change in obesity status. Moreover, baseline insulin concentration was higher in subjects who subsequently showed clustering of high triglycerides, low HDL-cholesterol and high systolic blood pressure levels at the follow-up. We conclude that high fasting insulin levels measured in children and adolescents predict the development of hypertriglyceridaemia years later. In addition, high insulin levels seem to precede the development of a potentially atherogenic risk factor profile including low HDL-cholesterol, high triglycerides and high systolic blood pressure.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1432-0428
    Schlagwort(e): Key words Insulin ; longitudinal ; clustering ; children ; adolescents ; serum lipoproteins ; blood pressure.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In adults hyperinsulinaemia is associated with an atherogenic risk profile including obesity, low levels of HDL-cholesterol, high levels of triglycerides and elevated blood pressure. To examine these associations in the young we studied the cross-sectional relationships of insulin with obesity indices (body mass index, subscapular skinfold thickness), serum lipids and blood pressure in 1,865 children, adolescents and young adults aged 6–24 years. We also used longitudinal data to study the value of a single insulin measurement to predict high risk factor levels and clustering of multiple risk factors after a 6-year follow-up. In cross-sectional analyses the levels of triglycerides, HDL-cholesterol, systolic blood pressure and obesity indices were usually significantly different across the quartiles of fasting insulin in both sexes among children, adolescents and young adults. In general, no associations were seen with total cholesterol or LDL-cholesterol. In prospective analysis elevated baseline insulin was related to the incidence of hypertriglyceridaemia (≥ 95th percentile) at the follow-up. This relationship persisted even after adjustments for baseline obesity or 6-year change in obesity status. Moreover, baseline insulin concentration was higher in subjects who subsequently showed clustering of high triglycerides, low HDL-cholesterol and high systolic blood pressure levels at the follow-up. We conclude that high fasting insulin levels measured in children and adolescents predict the development of hypertriglyceridaemia years later. In addition, high insulin levels seem to precede the development of a potentially atherogenic risk factor profile including low HDL-cholesterol, high triglycerides and high systolic blood pressure. [Diabetologia (1995) 38: 1042–1050]
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 8
    ISSN: 1432-0428
    Schlagwort(e): Keywords IA-2 antibodies ; GAD antibodies ; islet cell antibodies ; insulin autoantibodies ; clinical characteristics ; HLA risk markers.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary To study the persistence of Type I (insulin-dependent) diabetes mellitus associated autoantibodies and their relation to genetic risk markers and clinical characteristics of the disease after clinical manifestation, serum samples were obtained from 90 children and adolescents at diagnosis and 2, 5 and 10 years later. The samples were analysed for islet cell antibodies (ICA) by immunofluorescence and for antibodies to glutamic acid decarboxylase (GADA), intracellular portion of the protein tyrosine phosphatase related IA-2 antigen (IA-2A) and insulin autoantibodies by specific radiobinding assays. Of the subjects tested 79 % were positive for IA-2A at diagnosis, 62 % for GADA, 81 % for ICA and 28 % for insulin autoantibodies, but the prevalence of IA-2A, GADA and ICA decreased substantially as a function of increasing duration of the disease (p 〈 0.05 or less), their levels following the same pattern (p 〈 0.001 for all three autoantibodies). Two thirds of the subjects still tested positive for at least one autoantibody specificity after the first 10 years of the disease and 42 % had two or three antibodies detectable. An increase over the initial antibody concentrations after the diagnosis was seen more often for GADA than for ICA (p 〈 0.001) or IA-2A (p 〈 0.05). In conclusion, autoantibodies associated with Type I diabetes appear to persist longer than expected after manifestation of the clinical disease, possibly due to small scale continuous beta-cell regeneration after diagnosis or to structural and/or functional mimicry between exogenous proteins and beta-cell antigens or both. [Diabetologia (1998) 41: 1293–1297]
    Materialart: Digitale Medien
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