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  • 1
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; HLA ; seasonal variation ; age at diagnosis ; sex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To clarify the heterogeneity of Type 1 (insulin-dependent) diabetes mellitus, differences between patients with different HLA risk antigens were investigated with regard to sex, age at diagnosis, season of year and calendar year at diagnosis of the disease. The study consisted of 293 HLA-typed patients from the Department of Paediatrics, University of Oulu, Oulu, Finland. HLA-Dw2 was extremely rare among diabetic patients, whereas Dw3 and Dw4 were associated with increased risk in this as in other series. Male patients more often had the HLA-A1 antigen than females. On comparison of the Dw3 positive patients, boys more frequently had the combination A1,B8 than girls. A1,B8-positive patients were more often diagnosed during the warm months, in the late summer and autumn. Patients with both Dw3 and Dw4 were younger at diagnosis when compared with the rest of the patients. The results support the concept of heterogeneity in the pathogenesis of Type 1 diabetes associated with HLA-linked genetic determinants.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; T-lymphocytes ; heterogeneity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Percentages of various T-lymphocyte subpopulations in the blood were studied at the onset of Type 1 (insulin-dependent) diabetes. The number of lymphocytes with OKT8 markers was higher in the diabetic patients than in control subjects (p〈 0.005) and the ratio between helper and suppressor/cytotoxic T-cells (OKT4/OKT8 ratio) was lower in the diabetic patients than in the control group (p〈 0.005). The values in the diabetic patients were, however, essentially within the normal range. When Ia-antigen-positive cells were analysed in T-cell-enriched cell populations, Type 1 diabetic patients had higher percentages of these cells (p〈 0.01), suggesting T-cell activation. When patients with either of the two major HLA risk antigens (Dw3 or Dw4) were compared, there was a significant difference in the OKT4/OKT8 ratio (p〈 0.005), as Dw3-positive patients had higher and Dw4-positive patients lower ratios. This finding supports the concept of heterogeneity of the disease and can also explain the discrepant findings of earlier studies. When patients with complement-fixing islet cell antibodies were compared with patients without islet cell antibodies, there was no significant difference, although the OKT4/OKT8 ratio was slightly lower in the complement-fixing islet cell antibody-positive patients.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; children ; HLA ; DR4 associated ; specificity (‘JA’)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The HLA antigen combination A9, Bw16 has been found to be associated with Type 1 (insulin-dependent) diabetes characterized by some special features in Northern Finland. This antigen combination has now been associated with a ‘new’ DR4-associated D antigen, provisionally called ‘JA’ or ‘SN’. This ‘new’ D specificity was also associated with HLA-B18. Although the combination, Dw3/DJA, was common in Type 1 diabetic patients, the frequency of the combination Dw4/DJA was decreased compared with the expected value. This supports the hypothesis of two different risk factors associated with DR3 and DR4.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Conclusions Considerations of the structure of a candidate initiating antigen have led us to propose a new model for the susceptibility to Type 1 diabetes. It is quite likely there are other antigens of similar structure of viral or bacterial origin that will provoke a similar response directed against islet beta cells. However, we believe that this hypothesis will provide a framework for the further investigation and research into the mechanism of development of Type 1 diabetes and for the design of therapeutic manoeuvres for its prevention.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Islet cell antibodies, glutamic acid decarboxylase antibodies, HLA-DQB1, relatives of Type II diabetic patients, insulin sensitivity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. This study was undertaken to investigate metabolic and genetic characteristics of latent autoimmune diabetes in adults (LADA).¶Methods. We evaluated insulin secretory capacity with oral and intravenous glucose tolerance tests (early insulin response) and hyperglycaemic clamp (insulin secretory capacity) and the rates of whole body glucose uptake with the euglycaemic clamp, HLA-DQB1 genotypes (time-resolved fluorescence) and islet cell antibodies (ICA) (immunofluoresence) and antibodies to glutamic acid decarboxylase (GAD) (radio-immunoprecipitation) in 36 non-diabetic offspring (LADA-offspring) of patients with Type II (non-insulin-dependent) diabetes mellitus who tested positive for ICA and/or GAD antibodies during the 10-year follow-up from the diagnosis and in 19 healthy control subjects without a family history of diabetes.¶Results. The early insulin response during the first 10 min of an intravenous glucose tolerance test was about 40 % lower in the LADA-offspring than in the control group (p = 0.008). Insulin secretory capacity in the hyperglycaemic clamp was also about 30 % lower in the LADA-offspring (p = 0.048). The rates of whole body glucose uptake were similar in both groups. The frequency of low risk HLA-DQB1 genotypes was higher in the LADA-offspring than among Finnish healthy blood donors (p = 0.033). The risk conferring genotypes were associated with the lowest tertile of insulin secretory capacity in the LADA-offspring (p = 0.032). There were no associations between the autoantibodies and early insulin response or insulin secretory capacity within the study groups.¶Conclusion/interpretation. We conclude that LADA is a familial disease involving most likely gene defects leading to a slow progressive beta-cell destruction and insulin deficiency. [Diabetologia (2000) 43: 69–78]
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 41 (1998), S. 79-85 
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; prediction ; prevention ; screening ; genetic risk ; islet cell antibodies ; autoimmunity ; costs.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Programmes aiming at prediction and prevention of insulin-dependent diabetes mellitus (IDDM), a multifactorial autoimmune disease, have been launched or are in the planning phase in several countries. We hypothesized that the costs of finding the correct target subjects for preventive interventions are likely to vary markedly according to the prediction strategy chosen. Average direct costs accruing in the Finnish IDDM Prediction and Prevention Project (DIPP) were analysed from the health care provider's viewpoint. The genetically targeted strategy included costs of assessing genetic IDDM susceptibility followed by measurement of marker(s) of islet autoimmunity in the susceptibility restricted population at 3 to 6-month intervals. In the pure immunological strategy markers of autoimmunity were repeatedly analysed in the entire population. The data were finally exposed to sensitivity analysis. The genetically targeted prediction strategy is cost-saving in the first year if autoimmune markers are analysed as frequently as under the DIPP project, and in all circumstances later. The 10-year direct costs per child are US$ 245 (present value $ 217, 5 % discount rate) if the genetically targeted approach is used and $ 733 (present value $ 619) if the pure immunological strategy is chosen. In sensitivity analysis the 10-year costs (present value) per child of the genetically targeted strategy and of the pure immunological strategy varied from $ 152 to $ 241 and from $ 430 to $ 788, respectively. The genetically targeted IDDM prediction strategy is remarkably cost-saving as compared with the pure immunological strategy mainly because fewer subjects will need retesting during the follow-up. [Diabetologia (1998) 41: 79–85]
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: Keywords Cow's milk protein antibodies ; infant feeding ; dairy products ; human leucocyte antigens ; IDDM ; children.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Dietary factors are suspected to play an aetiological role in the development of insulin-dependent diabetes mellitus (IDDM). We analysed cow's milk formula, betalactoglobulin, and bovine serum albumin antibodies by an enzyme-linked immunoassay in unselected children with newly diagnosed IDDM and in their non-diabetic siblings and enquired about infant feeding practices by questionnaire. Among 410 diabetic sibling pairs matched for age and sex, by logistic regression analysis – including overall duration of breast-feeding, age at introduction of dairy products, recent consumption of cow's milk and HLA-DQB1 genotype (“high/moderate” vs “low/decreased” risk of IDDM) – bovine serum albumin IgG antibody levels (OR 2.12, 95 %CI 1.25–3.57) and genetic risk (OR 3.81, 95 %CI 2.43–5.17) were positively associated with IDDM; cow's milk formula IgM antibodies were inversely associated with the risk of IDDM (OR 0.50, 95 %CI 0.29–0.87). Of the diabetic sibling pairs, 42 were identical for HLA-DQB1 alleles associated with IDDM risk or protection (DQB1*0201, *0301, *0302 and *0602/03). In these 42 pairs, children with IDDM had higher median levels of bovine serum albumin IgG, of betalactoglobulin IgG, and of cow's milk formula IgG and IgA antibodies than the non-diabetic siblings (p 〈 0.05). In conclusion, children with IDDM have higher levels of cow's milk protein antibodies than their HLA-DQB1-matched sibling controls, and these high levels of antibodies are independent risk markers for IDDM. [Diabetologia (1998) 41: 72–78]
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0428
    Keywords: Keywords Autoantibodies, FPIR, HLA, schoolchildren, Type I diabetes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. To study temporal changes in positivity for autoantibodies associated with Type I (insulin-dependent) diabetes mellitus and the relations between these antibodies, HLA-DQB1-risk markers and first-phase insulin response (FPIR) in non-diabetic schoolchildren.¶Methods. The stability of the antibody status over 2 years was assessed in 104 schoolchildren initially positive for islet cell antibodies (ICA) or antibodies to the 65 000 Mr isoform of the glutamic acid decarboxylase (GADA) or both and in 104 antibody-negative control children matched for sex, age and place of residence. All children were also studied for their first-phase insulin response and HLA-DQB1 alleles on the second occasion.¶Results. On the second occasion 3 of the 98 initially ICA-positive children, 3/13 of those positive for antibodies to the IA-2 protein (IA-2A), 1/17 GADA-positive and 2/7 of those positive for insulin autoantibodies (IAA) tested negative for these antibodies. Children with IA-2A, GADA, IAA and multiple ( ≥ 2) antibodies had significantly lower first-phase insulin responses than the control children. In contrast, these responses did not differ between subjects with and without specific HLA-DQB1-risk alleles or genotypes. Of the six subjects with a considerably reduced first-phase insulin response three had multiple antibodies on both occasions but none of them had a DQB1 genotype conferring increased diabetes risk. Two subjects progressed to Type I diabetes within 3.4 years of follow-up, both of them having multiple antibodies and a considerably reduced first-phase insulin response but neither of them having a DQB1-risk genotype.¶Conclusions/interpretation. Positivity for diabetes-associated autoantibodies is a relatively stable phenomenon in unaffected schoolchildren, although conversion to seronegativity can occur occasionally. Our observations also indicate that DQB1 alleles associated with decreased susceptibility to Type I diabetes do not protect from impaired beta-cell function or from progression to overt disease in initially unaffected schoolchildren. [Diabetologia (2000) 43: 457–464]
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 39 (1996), S. 123-123 
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0428
    Keywords: Keywords IA-2 antibodies ; GAD antibodies ; islet cell antibodies ; insulin autoantibodies ; clinical characteristics ; HLA risk markers.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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]
    Type of Medium: Electronic Resource
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