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  • 1
    ISSN: 1432-0428
    Keywords: Keywords Type I (insulin-dependent) diabetes ; prediction ; screening approach ; schoolchildren ; normal population ; autoantibodies ; GADA ; IA2A ; IAA ; ICA.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The Karlsburg Type I (insulin-dependent) diabetes risk study on schoolchildren aims to evaluate the predictive diagnostic value of diabetes-associated autoantibodies in the general population. Methods. We took capillary serum from 9419 schoolchildren, aged 6–17 years, for testing of autoantibodies (AAbs) to glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA2A) and insulin (IAA) by 125I-antigen binding. We also tested for autoantibodies to cytoplasmic islet cell antigens (ICA) immunohistochemically. Results. By testing of 9419 sera for the four AAbs at cut-off at or greater than the 98th centile for the radioassayed AAbs and at or greater than 10 Juvenile Diabetes Foundation (JDF) units for ICA, 8.1 % of schoolchildren had at least one AAb. We found that 3.04, 2.97, 2.35, and 0.86 % had IAA, GADA, IA2A or ICA, respectively. 7.3 % had only one AAb and 0.8 % (75) had two or more AAbs, reflecting a risk to develop diabetes. Thus, by primary screening by combined testing of GADA and IA2A, 98.7 % (74/75) would be identified. At high AAb levels, cut-off at or greater than the 99.8th centile and at or greater than 40 JDF units for ICA, 0.23 % (22/9419) of schoolchildren, similar to the disease prevalence of 0.3 %, had two or more AAbs. Ten of 17 children tested had reduced (p 〈 0.001) first-phase insulin secretion by intravenous glucose tolerance test. Six of 22 subjects developed Type I diabetes within a follow-up of 19 ± 10 months. Conclusion/interpretation. For children older than 5 years the combined anti-GAD/IA2 test with cut-off at or greater than the 98th centile should be used for primary screening followed by testing for IAA and ICA. Subjects at risk for diabetes have two or more AAbs at or greater than the 98th centile. Subjects at risk for rapid progression to Type I diabetes have two or more AAbs at or greater than the 99.8th centile. [Diabetologia (1999) 42: 661–670]
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-5233
    Keywords: Key words Murine monoclonal glutamate decarboxylase antibodies ; Autoantibodies ; Type 1 diabetes mellitus ; Stiff-man syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To study the immune response to glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus, monoclonal GAD antibodies after fusion of splenocytes from a nondiabetes-susceptible BALB/c mouse immunized with human recombinant GAD65 were generated. Of the 44 monoclonals, 35 are specific for the GAD65 isoform, whereas 9 also react with GAD67. Some 37 monoclonals, including all GAD65/67 reactive antibodies, react with GAD by Western blot analysis. The remaining 7 GAD65 monoclonals bind GAD only in an immunoprecipitation assay, which implies that they target epitopes dependent on the conformation of the GAD molecule. The 125I-GAD binding of the GAD65 monoclonals reactive on Western blotting was significantly diminished by all 3 sera from Stiff-man syndrome patients but only by 3/30 (10%) sera from type 1 diabetic patients. In contrast, the 7 monoclonal antibodies reactive with a conformation-dependent GAD epitope were competitive with 83% of GAD-autoantibody-positive sera from these diabetic patients. Using chimeric GAD65/67 proteins, the epitope region targeted by these monoclonals was mapped to the middle of GAD65 (amino acids 221–442). This central conformation-dependent GAD region was also targeted by sera from patients with type 1 diabetes. In conclusion, our data show that even after common immunization of a nondiabetes-susceptible mouse strain, monoclonals were obtained which preferentially react with the GAD65 linear amino-terminus (amino acids 4–17) and a conformation-dependent region located in the middle of GAD targeted by autoantibodies, indicating that this GAD region is not restricted to the autoimmune response associated with the Stiff-man syndrome and the beta-cell destruction in type 1 diabetes mellitus.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-5233
    Keywords: Murine monoclonal glutamate decarboxylase antibodies ; Autoantibodies ; Type 1 diabetes mellitus ; Stiff-man syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To study the immune response to glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus, monoclonal GAD antibodies after fusion of splenocytes from a nondiabetes-susceptible BALB/c mouse immunized with human recombinant GAD65 were generated. Of the 44 monoclonals, 35 are specific for the GAD65 isoform, whereas 9 also react with GAD67. Some 37 monoclonals, including all GAD65/67 reactive antibodies, react with GAD by Western blot analysis. The remaining 7 GAD65 monoclonals bind GAD only in an immunoprecipitation assay, which implies that they target epitopes dependent on the conformation of the GAD molecule. The125I-GAD binding of the GAD65 monoclonals reactive on Western blotting was significantly diminished by all 3 sera from Stiff-man syndrome patients but only by 3/30 (10%) sera from type 1 diabetic patients. In contrast, the 7 monoclonal antibodies reactive with a conformation-dependent GAD epitope were competitive with 83% of GAD-autoantibody-positive sera from these diabetic patients. Using chimeric GAD65/67 proteins, the epitope region targeted by these monoclonals was mapped to the middle of GAD65 (amino acids 221–442). This central conformation-dependent GAD region was also targeted by sera from patients with type 1 diabetes. In conclusion, our data show that evne after common immunization of a nondiabetes-susceptible mouse strain, monoclonals were obtained which preferentially react with the GAD65 linear amino-terminus (amino acids 4–17) and a conformation-dependent region located in the middle of GAD targeted by autoantibodies, indicating that this GAD region is not restricted to the autoimmune response associated with the Stiff-man syndrome and the bete-cell destruction in type 1 diabetes mellitus.
    Type of Medium: Electronic Resource
    Library Location Call Number Volume/Issue/Year Availability
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