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  • 1
    ISSN: 1432-0428
    Keywords: Children ; Type 1 (insulin-dependent) diabetes ; C-peptide ; islet cell antibodies ; insulin antibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pattern of fall in B-cell function measured as plasma and 24 h urinary C-peptide excretion, as well as levels of islet cell antibodies, insulin antibodies and metabolic parameters, were followed for two years in 39 children aged 1–17 years prospectively from clinical onset of Type 1 (insulin-dependent) diabetes. At onset 32/36 patients had measurable plasma C-peptide (median 0.13 nmol/l). Maximum values of fasting and postprandial plasma C-peptide were reached at a median duration of three months. Thereafter both plasma and urinary C-peptide declined linearly. The median value of the rate of fall in postprandial plasma C-peptide was 0.019 nmol·1−1·month−1. Age at onset was positively correlated to the maximum value of postprandial plasma C-peptide in each patient (rs=0.57, p=0.0001) and throughout the observation time positively correlated to fasting and postprandial C-peptide and to the 24 h urinary C-peptide excretion (rs range 0.35–0.70, p=0.03–0.0001). The rate of fall of postprandial C-peptide was unrelated to age at onset and was strikingly parallel in different age groups. Islet cell antibodies were present in 87% of the patients at onset and decreased to 38% at 24 months. Islet cell antibody litres were not correlated to age at onset or to plasma or urinary C-peptide at any single observation. However, islet cell antibody negative patients had significantly higher (p〈0.05) postprandial plasma C-peptide values at 1, 9, and 12 months of duration, compared to islet cell antibody positive patients. Insulin antibodies and metabolic state at onset did not influence the C-peptide values. It is concluded that age at onset is the most important variable in predicting the duration and magnitude of endogenous insulin secretion during the first two years of Type 1 diabetes in children.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; coxsackie B virus ; immunoglobulin M ; radioimmunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Sera from essentially all Swedish children aged 0–14 years with Type 1 (insulin-dependent) diabetes mellitus with onset during an autumn period (October–December 1985) and a late spring period (May–June 1986) were selected. In all, 98 patients were analysed for IgM antibodies against coxsackie B virus serotypes 1 through 5 by a μ-antibody capture radio immunoassay technique. Sera from 94 referent children matched for age, sex and residential area, collected during the same period, were also analysed. During the autumn period, 10 out of 67 (15%) diabetic children were IgM positive while 14 out of 75 (19%) of the healthy referent children demonstrated positivity. During the late spring period only one out of 31 (3%) children with diabetes and two out of 19 (10%) referent children were IgM positive. In the diabetic patients, five were coxsackie B2 positive while coxsackie B1, 3, 4 and 5 were represented by one to three patients each. Eight referent children were coxsackie B4 positive, six were B3 positive and two B2 positive, while no referent children were positive against coxsackie B1 and 5. During these two periods in late 1985 and early 1986 these data demonstrate no evidence of increased antibody frequency against coxsackie B virus 1 through 5 at the onset of childhood diabetes in Sweden.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Glutamic acid decarboxylase ; receiver-operating characteristic plot ; diagnostic accuracy ; islet cell antibodies ; autoimmunity ; diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin-dependent diabetes mellitus (IDDM) is associated with autoreactivity against GAD but the diagnostic sensitivity (positivity in disease) and specificity (negativity in health) of isoform-specific GAD antibodies have yet to be defined in assay systems suitable for screening large number of samples. One set of IDDM patient (n=10) and control (n=50) standard sera were used to develop quantitative antibody assays with in vitro synthesized recombinant 35S-methionine-labelled GAD65 and GAD67, respectively, and protein A-Sepharose to separate free from antibody-bound ligand. Binding levels were not normally distributed (p〈0.0001) and therefore, the diagnostic accuracy of GAD antibodies was analysed by the ROC plots in population-based, consecutively-diagnosed, recent onset, 0–14 year-old patients (n=105), and matched, healthy control subjects (n=157). The ROC plots showed that the diagnostic sensitivity of GAD65 antibodies was 77% and the specificity 92% compared with 8% and 98%, respectively for GAD67 antibodies. In the IDDM sera, GAD65 and GAD67 antibodies were concordant in 7% (6 of 81) and GAD65 antibodies and ICA in 89% (72 of 81) without a correlation between the autoantibody levels. Autoantibodies to recombinant human islet GAD65 are specific and sensitive markers for childhood IDDM in this immunoassay with in vitro synthesized 35S-methioninelabelled recombinant GAD.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords IDDM ; NIDDM ; glucokinase gene ; polymerase chain reaction ; single strand conformational polymorphism ; islet cell antibodies ; GAD65 antibodies.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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. [Diabetologia (1997) 40: 959–962)
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  • 5
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes ; Type 2 (non-insulin dependent) diabetes ; incidence ; age ; body mass index ; HbA1c
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The differential diagnosis between Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes is complicated since no specific markers are available for either disease. In this study, 244 consecutive patients were diagnosed with diabetes mellitus during two years in Malmö (230000 inhabitants), corresponding to an incidence rate of 53·100000−1·year−1. Age, body mass index, HbA1c, C-peptide, and levels of islet cell antibodies were determined at the clinical onset, and related to the classification at diagnosis and at follow-up (n=233) after a median time of 31 (range 1–49) months. After diagnosis, 42 of 244 (17%) were started on insulin while 202 of 244 (83%) were not. Islet cell antibodies were present in 25 of 42 (60%), and in 18 of 183 (10%), respectively. In the non-insulin treated group, patients with islet cell antibodies had lower body mass index (p〈0.001), higher HbA1c (p〈0.004), and lower C-peptide (p〈0.001) than patients without. At follow-up, 11 of 18 (61%) islet cell positive patients were changed to insulin treatment, as were six other patients. Insulin was discontinued in five initially insulin-treated but islet cell antibody negative patients. The sensitivity, specificity and predictive value for insulin treatment at follow-up were for islet cell antibody positivity; 72%, 96% and 84%, respectively, and for low C-peptide value; 60%, 96%, and 80%, respectively. Islet cell antibodies and low C-peptide at diagnosis of diabetes mellitus are concluded to be useful markers to predict insulin dependence.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; molecular mimicry ; Epstein-Barr virus ; class II MHC molecules ; EBV BOLF1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A role for the Epstein-Barr virus in initiating Type 1 (insulin-dependent) diabetes mellitus has been proposed since Epstein-Barr virus BOLF1(497–513) AVTPL RIFIVPPAAEY has an 11 amino acid identity with HLA-DQw8β (49–60) AVTPL GPPAAEY. Rabbit antisera to the BOLF1 (496–515) peptide crossreacted with the homologous DQw8β (44–63) peptide but not with the related DQw7β(44–63) peptide, which differed from the DQw8 peptide only in an ALA to ASP substitution in position 57. Antisera to DQw8β(49–60) reacted with the DQw8β(44–63) peptide and BOLF1 (496–515), but not with DQw7β (44–63). The antiserum to the BOLF1 peptide bound to denatured class II major histocompatibility complex β chains from Epstein-Barr virus-transformed DQw8-positive lymphocytes in an immunoblotting analysis. Epstein-Barr virus antibodies were detected at equal frequencies and similar titres in sera of 30 patients with Type 1 diabetes (16 of 30;63%) and in sera of 20 non-diabetic control subjects (13 of 20;65%). Sera from diabetic patients did not bind to DQw8β (44–63) or BOLF1(496–515) peptides. From these data we conclude that there is no simple relationship between serological evidence of Epstein-Barr virus infection and crossreactions between homologous Epstein-Barr virus and class II major histocompatibility complex peptides.
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  • 7
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; Friedreich's ataxia ; HLA ; first phase insulin secretion ; islet cell antibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Friedreich's ataxia is known to be associated with diabetes mellitus in up to 20% of the patients. However, type, development and course of diabetes mellitus are not well characterised. We report on 3 patients (2 female and 1 male, age 13–20 years) with the combination of Friedreich's ataxia and diabetes mellitus. Diabetes mellitus was characterised as follows: (1) it was strictly insulin-dependent and ketosis-prone, (2) the average insulin requirement was 1 U/kg body weight, (3) the HLA haplotype was not typical of Type 1 (insulin-dependent) diabetes mellitus, (4) there were no positive immune parameters typical of Type 1 diabetes at the clinical onset of diabetes mellitus and (5) there was no remission. To evaluate a preclinical phase as in common autoimmune Type 1 diabetes, i.v. glucose tolerance tests (0.5 g glucose/kg body weight) were performed in 8 patients with Friedreich's ataxia without diabetes mellitus. Seven patients had normal early phase insulin response. In contrast, the glucose disappearance rate was slow in 4 and normal in 3 patients. One of the 8 patients showed a prediabetic metabolic state: the early-phase insulin response was abolished and the glucose disappearance rate was abnormal. The results suggest that diabetes in Friedreich's ataxia is caused by a loss of islet cells similar to common Type 1 diabetes but without HLA-association and without serologic evidence for autoimmune destruction of the islet cells.
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  • 8
    ISSN: 1432-0428
    Keywords: Keywords Severe retinopathy ; insulin-dependent diabetes mellitus ; HLA-DR ; HLA-DQ ; allele ; haplotype ; genotype.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1*0301, DQA1*0501 and DQB1*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p 〉 0.05) and DQB1*0201/0302 (p 〈 0.01). The findings of the present study suggest that DQB1*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0401 -DQA1*03-DQB1*0302) are at greater risk of developing severe retinopathy. [Diabetologia (1996) 39: 1313–1317]
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  • 9
    ISSN: 1432-0428
    Keywords: Keywords Autoimmunity ; GAD65 antibodies ; ICA- 512 antibodies ; insulin autoantibodies ; islet cell antibodies.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet autoantibodies are early markers for Type I (insulin-dependent) diabetes mellitus. The aim of this study was to establish whether islet autoantibodies were present at birth in children who developed Type I diabetes before 15 years of age. Cord blood sera from 81 children who developed Type I diabetes between 10 months and 14.9 years of age were tested for glutamic acid decarboxylase autoantibodies (GAD65Ab), islet cell antigen 512 autoantibodies (ICA512Ab), insulin autoantibodies (IAA) all by quantitative radioligand binding assays and islet cell autoantibodies (ICA) by indirect immunofluorescence. Cord blood sera from 320 randomly selected matched children were controls. The children who developed Type I diabetes had an increased frequency of cord blood islet autoantibodies compared with control subjects: Glutamic acid decarboxylase autoantibodies were detected in 6 % (5/81) patients and 2 % (5/320) control subjects (p = 0.03); islet cell antigen 512 autoantibodies in 5 % (4/73) patients and 1 % (4/288) control subjects (p = 0.06); insulin autoantibodies (IAA) in 0 % (0/79) patients and 0.3 % (1/320) control subjects (p = 0.36); and islet cell autoantibodies in 10 % (8/81) patients compared with 0.6 % (2/320) control subjects (p = 0.0001). Taken together, 17 % (14/81) patients had one or more islet autoantibody compared with 4 % (12/320) control subjects (p = 0.0001). Whereas none of the control children had more than one antibody, 4 % (3/81) children who later developed Type I diabetes were double positive (p = 0.002). Although glutamic acid decarboxylase autoantibodies' concentrations in cordblood correlated to those in the mothers' blood at the time of delivery, no corresponding correlation was found for the other two types of autoantibodies. The increased frequency of cord blood islet autoantibodies suggests that the Type I diabetes process could already be initiated in utero. [Diabetologia (1999) 42: 181–187]
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  • 10
    ISSN: 1432-0428
    Keywords: Autoimmunity ; disease prediction ; sensitivity ; specificity ; predictive value
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Most studies evaluating immune markers for prediction of Type 1 (insulin-dependent) diabetes mellitus have focused on first degree relatives, although only 10 % of newly-diagnosed patients have an affected first degree relative. The Swedish Childhood Diabetes Register identifies 99 % of all diabetic children at diagnosis. In this population-based study, islet cell antibodies and insulin autoantibodies in 0–14-year-old Swedish consecutively-diagnosed patients and control subjects were analysed to define their sensitivity and specificity. Over 16 months (1986–1987), 515 Swedish children developed diabetes. Plasma samples were obtained from 494 (96 %) patients, and 420 matched control children. Among patients, the frequency of islet cell antibodies was 84 % (415 of 494), insulin autoantibodies 43 % (145 of 334); 40 % (135 of 334) were positive for both and 88 % (294 of 334) were positive for one or both. Among control children, 3 % (14 of 420) had islet cell antibodies, 1 % (4 of 390) insulin autoantibodies, and 4 % (16 of 390) had either autoantibody marker. The predictive value of finding a patient with the disease was only 7% since 4 % of the control children were antibody-positive and the cumulative incidence rate up to 15 years of age is 0.38 %. None of the autoantibody-positive (n = 21) or negative control children developed diabetes during 3 to 5 years of follow-up. Longitudinal investigations of islet cell or insulin-autoantibody-positive healthy children are necessary to accurately determine the conversion rate from marker positivity to disease onset.
    Type of Medium: Electronic Resource
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