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  • 1
    ISSN: 1432-0428
    Keywords: DNA inserts ; insulin gene ; Type 1 diabetes ; HLA antigens ; prevalence ; pedigree studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A polymorphic DNA sequence in the 5′-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p〈0.0005 from χ2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Polyglandular failure syndrome ; hypoglycaemia ; glucose counter-regulation ; diabetes mellitus ; glucagon deficiency ; glucagon and plasma amino acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The case of a female patient with fasting hypoglycaemia before the development of Type 1 (insulin-dependent) diabetes mellitus is reported. She presented with primary hypothyroidism, partial hypopituitarism, adrenal insufficiency and glucagon deficiency. Thyroid microsomal and gastric parietal cell antibodies were detected as well as HLA-B8, whereas islet cell antibodies were not demonstrable, even 2 years after the onset of diabetes. Plasma chromatography revealed true pancreatic glucagon (IRG3500) close to undetectable in basal samples with a questionable increase from 3 to 18 pg/ml during insulin-induced hypoglycaemia. After an overnight fast, moderate hyperaminoacidaemia was found with elevations of alanine, glycine, serine, arginine and ornithine as seen in pancreatectomized patients. It is suggested that the deficient glucagon secretion in this patient might, at least in part, have been the cause of fasting hypoglycaemia and the failure of glucose recovery following insulin-induced hypoglycaemia. Possibly, the A cell deficiency was part of the polyglandular failure syndrome in this patient.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 17 (1979), S. 161-164 
    ISSN: 1432-0428
    Keywords: American Indians ; autoimmunity ; diabetes mellitus ; islet cell antibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pancreatic islet cell antibodies and 12 other autoantibodies were measured at the time of diabetes diagnosis in 46 Pima Indians, aged 17–47 years, and in 46 age-sex matched non-diabetic controls. Islet cell antibodies were found in only two diabetics, aged 20 and 25, compared with none of 46 controls. Neither of the subjects with islet cell antibodies had other autoantibodies. At least one type of autoantibody was found in 14 (30%) of the diabetics and in 14 controls, but none was significantly associated] with diabetes. This study indicates that diabetes in the Pima Indians, even those with an onset below 25 years of age, is almost entirely of type II, in that the disease is not associated with islet cell antibodies, ketoacidosis, or insulin dependence.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Insulin-dependent diabetics ; beta-cell function ; islet-cell antibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Residual insulin secretion and islet-cell antibodies were studied in 399 insulin-dependent diabetics with age at onset of between 10–19.9 years (248 patients) or 30–39.9 years (151 patients). We found the prevalence of islet-cell antibodies to be independent of residual beta-cell function as measured by serum C-peptide and age at onset. The cause and role of the persistence of islet-cell antibodies in insulin-dependent diabetics remain obscure.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Cytoplasmic islet cell antibodies ; islet cell surface reacting antibodies ; Type 1 (insulin-dependent) diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Sixteen pancreases from 11–24 week old human fetuses were cultured for up to 11 days to investigate islet cell surface antibodies. Hormonal content and presence of cytoplasmic autoantigen were assessed by immunofluorescence with specific antihormone sera and high titre cytoplasmic islet cell antibody positive sera. Viable islet cells cultured on coverslips were tested with 21 islet cell antibody positive sera from Type 1 (insulin-dependent) diabetics, one islet cell antibody positive serum from a non-diabetic and four normal control sera. Surface binding immunoglobulins were detected by indirect immunofluorescence in nine out of 11 newly diagnosed Type 1 diabetics and in two out of ten longstanding diabetics with another coexistent autoimmune endocrinopathy. The four-layer double immunofluorescence technique showed that the surface antibody stained insulin secreting cells, but owing to rarity of A and D cells in the fetal cultures it has not yet been possible to exclude the reactivity of islet cell surface antibodies with glucagon or somatostatin cells.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; pre-diabetic state ; genetic susceptibility ; lymphocyte subpopulations ; activated T-cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A prospective study of lymphocyte subsets has been carried out for 18 months in 58 healthy first-degree relatives of Type 1 (insulin-dependent) probands. Subjects selected for presence or absence of islet cell antibodies included 10 with complement-fixing islet cell antibodies, 10 with conventional islet cell antibodies and 38 without islet cell antibodies. Immunoregulatory and effector lymphocyte subsets, and in particular activated T-cells, were investigated using a panel of monoclonal antibodies. The results showed no significant changes in total T, helper, suppressor/cytotoxic cells or K/ NK cells. Activated T-cells were observed at least once in 22 subjects using the 4F2 monoclonal antibody and in 11 using the Tac antibody. Seven subjects had 4F2-positive cells on repeated occasions and one twice showed Tac-positive cells. Fluctuations and/or loss of islet cell antibodies were observed during follow-up. There was no correlation between presence of activated T-cells and either islet cell antibody status or HLA haplotype sharing with the diabetic proband. On the other hand, a significant correlation was observed between HLA-DR3 positivity of subjects and the occurrence of activated T-cells (both 4F2-positive and Tac-positive). We conclude that subjects with HLA-DR3 may be especially prone to T-cell activation. As none of the ‘high risk’ individuals developed diabetes in the course of follow-up, the relevance of these observations in the pathogenesis of Type 1 diabetes needs more prolonged investigation.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: Islet cell antibodies ; Type 1 (insulin-dependent) diabetes mellitus ; polyendocrinopathy ; indirect immunofluorescence ; glutamate decarboxylase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal antiproinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells (‘whole’ islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells (‘selective’ islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a ‘mixed’ islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular ‘selective’ pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p〈0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The ‘whole’ islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.
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  • 8
    ISSN: 1432-0428
    Keywords: Key words Islet cell antibodies ; glutamic acid decarboxylase 65 antibodies ; islet autoantigens ; insulin-dependent diabetes mellitus prediction ; carboxypeptidase-H ; ICA69.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Identification of islet autoantigens offers the possibility that antibody tests other than islet cell antibodies may be used for assessing risk of insulin-dependent diabetes mellitus (IDDM). The aim of this study was to determine the combination of islet autoantibody markers that could identify most future cases of IDDM. Islet cell antibodies, antibodies to glutamic acid decarboxylase (GAD)65, 37,000/40,000 Mr islet tryptic fragments, carboxypeptidase-H, and islet cell autoantigen (ICA)69 were measured in sera from 100 newly-diagnosed IDDM patients, 27 individuals prior to onset of IDDM, and 83 control subjects. Islet cell antibodies were detected in 88 % of IDDM patients and 81 % with pre-IDDM, GAD65 antibodies in 70 % of IDDM patients and 89 % with pre-IDDM, and antibodies to 37,000/40,000 Mr islet tryptic fragments in 54 % of IDDM patients and in 48 % with pre-IDDM. The latter were found only in conjunction with islet cell antibodies and were more frequent in young onset cases. All 20 IDDM patients and the 3 pre-IDDM subjects who had islet cell antibodies without GAD65 antibodies had antibodies to 37,000/40,000 Mr islet tryptic fragments, and all but one had disease onset before age 15 years. No sera strongly immunoprecipitated in vitro translated ICA69 or carboxypeptidase-H; 4 % of patients had anti-ICA69 and 11 % anti-carboxypeptidase-H levels above those of the control subjects. The findings suggest that none of the single antibody specificities are as sensitive as islet cell antibodies, but that a combination of GAD65 antibodies and antibodies to 37,000/40,000 Mr islet tryptic fragments has the potential to identify more than 90 % of future cases of IDDM. Such a strategy could eventually replace islet cell antibodies in population screening for IDDM risk assessment. [Diabetologia (1995) 38: 816–822]
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  • 9
    ISSN: 1432-0428
    Keywords: Lymphocyte subsets ; pre-Type 1 (insulin-dependent) ; diabetes ; lymphocyte activations ; genetic susceptibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Over a period of 5 years, lymphocyte subpopulations and their markers of activation were studied prospectively in 56 first degree relatives of Type 1 (insulin-dependent) diabetic probands. Lymphocytes were phenotyped using a panel of monoclonal antibodies which recognise CD3, CD4, CD8 lymphocytes, K/NK cells, HLA Class II products and IL-2 receptors (IL-2r). Twenty-six subjects were negative for islet cell antibody (ICA), 18 had complement fixing ICA (CF-ICA) and 12 only conventional ICA (ICA-IgG). The total number of observations (blood samples collected) was 386. Overall, changes in T cell data were observed in the three groups of first degree relatives compared to 70 normal subjects without a family history of diabetes. Six individuals developed Type 1 diabetes in the course of the study. They all possessed CF-ICA and five out of six showed a persistent reduction (〈1.5) of the CD4/CD8 lymphocyte ratio before the clinical onset of the disease. Activated lymphocytes were found on two occasions in two of these subjects. We conclude that imbalance of lymphocyte immunoregulatory subsets is present before the onset of Type 1 diabetes in susceptible individuals; the persistence of a reduced CD4/CD8 lymphocyte ratio may reflect the ongoing process leading to B-cell destruction.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0428
    Keywords: Islet cell antibody ; Type 1 (insulin-dependent) diabetes ; standards ; quality control ; Juvenile Diabetes Foundation units
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Forty-one assays were analysed at the 3rd International Workshop on the standardisation of islet cell antibodies. Analysis of precision demonstrated assays consistently detecting blind duplicates within one doubling dilution and capable of discriminating one doubling dilution differences in islet cell antibody concentration. Some assays, however, reported duplicates discrepantly by more than seven doubling dilutions, and consequently could not distinguish even large quantities of islet cell antibodies. Precision was best in assays from laboratories which had participated in all three Standardisation Workshops and was not dependent upon methodology. The use of the Juvenile, Diabetes Foundation reference islet cell antibody standard and standard curves reduced the scatter of results, and was best amongst assays with better precision. Twenty-seven assays reported all ten blood donor sera as negative. However, 14 assays did not, and specificity (negativity in health) was 〈50% in three assays. Low specificity was strongly associated with poor precision. The detection limit of assays ranged from 〈5 to 50 JDF units and was partially dependent upon methodology. Assays incorporating extended incubation had the lowest detection limits without a decrease in the specificity of the ten blood donor sera. Precise quantification is fundamental for the standardisation and comparability of islet cell antibodies. Precise quantitative assays have been identified and reference standards and common units established.
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