Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to test for the presence (alone or in combination) of 4 autoantibodies directed against beta cells in the sera of children at diagnosis of the overt clinical phase of insulin-dependent diabetes mellitus. Children recorded in 1989 in the population-based French Registry of Incidence of Insulin-Dependent Diabetes Mellitus were included in the present study. One hundred and thirty-eight sera were tested for islet cell antibodies (ICA), insulin autoantibodies (IAA) and antibodies against glutamic acid decarboxylase (GAD-Ab) and tyrosine phosphatase (IA2-Ab). IAA showed significantly lower sensitivity (36%) than the other antibodies (ICA: 84%; GAD-Ab: 74%; IA2-Ab: 81%). In the age-range of the registry, the prevalence rates for the 4 antibodies were not significantly affected by age. IAA and GAD-Ab were significantly associated with ICA, whereas GAD-Ab and/or IA2-Ab was(were) associated with 93% sensitivity at diagnosis. Sensitivity was 100% with the 4 antibodies combined. No significant association was found between the antibodies and HLA DR phenotypes. This study shows that a combination of the 4 major autoantibodies allows all children with insulin-dependent diabetes to be identified.
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PMID:Sensitivity at diagnosis of combined beta-cell autoantibodies in insulin-dependent diabetic children. French Registry of IDDM in Children Study Group. 913 5

Women with gestational diabetes mellitus (GDM) have a considerable risk of developing diabetes later in life. To determine the predictive value of autoantibody markers in gestational diabetic pregnancy for the development of type 1 diabetes postpartum, we tested 437 patients with GDM (289 women treated with diet only [GDM-A] and 148 requiring insulin treatment during pregnancy [GDM-B]) for antibodies to islet cells (ICAs), GAD (GADAs), and tyrosine phosphatase ICA512/IA-2 (IA2As). We prospectively followed them with repeated oral glucose tolerance tests and antibody determinations for up to 7 years postpartum (mean, 1.6 years; range, 0-7.2 years). The cumulative risk of diabetes up to 5 years postpartum was 17% (95% CI 12-22%). The risk of type 1 diabetes was 3% (2-5%) by 9 months and 7% (4-9%) 2 years after delivery. At delivery, 8.5% of all patients were ICA+, 9.5% were GADA+, 6.2% were IA2A+, and 18.1% were positive for at least one antibody (12.6% for GDM-A vs. 30.4% for GDM-B, P < 0.0001). During follow-up, GADAs persisted in 75%, ICAs in 35%, and IA2As in 30% of the subjects positive for the respective marker at delivery. By 2 years postpartum, 29% (19-39%) of patients positive for at least one antibody developed type 1 diabetes, compared with 2% (1-4%) of antibody-negative patients (P < 0.0001). Thereby, the risk for type 1 diabetes 2 years postpartum increased with the number of antibodies present at delivery from 17% (6-28%) for one antibody, to 61% (30-91%) for two antibodies, and to 84% (55-100%) for 3 antibodies. Risk of progression to type 1 diabetes postpartum was also associated with the status of parity. Women with one or more pregnancies before the index pregnancy had a higher risk for type 1 diabetes 2 years after delivery (14.7% [4.9.-24.5%]) than women having their first (i.e., index) pregnancy (5% [2.9-7.1%]) (P < 0.006). A comparison of different prediction strategies showed that single antibody screening with GADA yielded the highest sensitivity of 63% (45-75%), compared with ICA (48% [31-65%]) and IA2A (34% [13-47%]). Combined screening with two autoantibodies increased sensitivity to 74% (58-90%) and 75% (60-92%) when using GADA plus ICA or GADA plus IA2A, respectively. Screening with all three markers improved sensitivity further to 82% (67-100%). Beta-cell autoantibodies determined at delivery in women with GDM are highly predictive for the development of type 1 diabetes postpartum. Autoantibody screening in pregnant women with GDM from populations at high risk for type 1 diabetes should therefore be considered to allow early diagnosis and appropriate therapy.
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PMID:Prediction of type 1 diabetes postpartum in patients with gestational diabetes mellitus by combined islet cell autoantibody screening: a prospective multicenter study. 928 47

Antibodies to the 40 kD antigen (identified as tyrosine phosphatase IA-2) and glutamate decarboxylase (GAD65) are strongly associated with insulin dependent diabetes mellitus (IDDM). However, antibodies to GAD (GADA) can appear in the absence of IDDM, particularly in stiff man syndrome (SMS) and in some individuals with autoimmune polyendocrine syndrome type II (APS II) and organ specific autoimmune diseases. The aim of this study was to compare the specificity of IA-2 antibodies (IA-2A) and GADA for IDDM by determining their frequency in different patient groups. IA-2A were present in 64/114 (56%) IDDM patients and 9/19 (47%) APS II patients with IDDM but in only 4/28 (14%) SMS patients. 1/24 (4%) APS II patients without IDDM and 1/113 (0.9%) patients with organ specific autoimmune disease had low level IA-2A. In contrast GADA were present in 77/114 (68%) IDDM patients and 17/19 (89%) APS II patients with IDDM, but also in 25/28 (89%) SMS patients, 5/24 (21%) APS II patients without IDDM and 22/113 (19%) patients with organ specific autoimmune diseases. Furthermore, within the group of new onset IDDM, IA-2A seemed to be associated with ICA and age: 63% of ICA positive IDDM patients had IA-2A (74% had GADA) increasing to 77% in the group below 20 years of age (69% for GADA). Our results demonstrate that IA-2A may be more specific for IDDM than GADA, as the latter are also present in patients with SMS, APS II without IDDM and organ specific autoimmune diseases. IA-2A were less frequent in older patients with IDDM than GADA or ICA. A combination of IA-2A and GADA detected 84% of total and 93% of ICA positive IDDM patients.
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PMID:Antibodies to the tyrosine phosphatase-like protein IA-2 are highly associated with IDDM, but not with autoimmune endocrine diseases or stiff man syndrome. 934 28

T cells recognize peptide epitopes bound to major histocompatibility complex molecules. Human T-cell epitopes have diagnostic and therapeutic applications in autoimmune diseases. However, their accurate definition within an autoantigen by T-cell bioassay, usually proliferation, involves many costly peptides and a large amount of blood. We have therefore developed a strategy to predict T-cell epitopes and applied it to tyrosine phosphatase IA-2, an autoantigen in IDDM, and HLA-DR4(*0401). First, the binding of synthetic overlapping peptides encompassing IA-2 was measured directly to purified DR4. Secondly, a large amount of HLA-DR4 binding data were analysed by alignment using a genetic algorithm and were used to train an artificial neural network to predict the affinity of binding. This bioinformatic prediction method was then validated experimentally and used to predict DR4 binding peptides in IA-2. The binding set encompassed 85% of experimentally determined T-cell epitopes. Both the experimental and bioinformatic methods had high negative predictive values, 92% and 95%, indicating that this strategy of combining experimental results with computer modelling should lead to a significant reduction in the amount of blood and the number of peptides required to define T-cell epitopes in humans.
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PMID:Strategies for identifying and predicting islet autoantigen T-cell epitopes in insulin-dependent diabetes mellitus. 945 87

Autoantibodies to the neuroendocrine protein insulinoma-associated protein 2 (IA-2), a member of the tyrosine phosphatase family, have been observed in individuals with or at increased risk for IDDM. Because this disease is thought to result from a T-cell-mediated autoimmune destruction of the insulin-producing pancreatic beta-cells, we analyzed humoral and cellular immune reactivity to this autoantigen to further define its role in the pathogenesis of IDDM. Peripheral blood mononuclear cells (PBMC) from individuals with newly diagnosed IDDM or at varying levels of risk for the disease were stimulated in vitro with the entire 42-kDa internal domain of IA-2 (amino acids 603-979), a series of control antigens (glutathionine-S-transferase, tetanus toxoid, Candida albicans, mumps, bovine serum albumin), and a mitogen (phytohemagglutinin). The frequency and mean stimulation index of PBMC proliferation against IA-2 was significantly higher in newly diagnosed IDDM subjects (14 of 33 [42%]; 3.8+/-4.5 at 10 microg/ml) and autoantibody-positive relatives at increased risk for IDDM (6 of 9 [66%]; 3.9+/-3.2) compared with autoantibody-negative relatives (1 of 15 [7%]; 1.8+/-1.0) or healthy control subjects (1 of 12 [8%]; 1.5+/-1.0). The frequencies of cellular immune reactivities to all other antigens were remarkably similar between each subject group. Sera from 58% of the newly diagnosed IDDM patients tested were IA-2 autoantibody positive. Despite investigations suggesting an inverse association between humoral and cellular immune reactivities against islet-cell-associated autoantigens, no such relationship was observed (rs=0.18, P=0.39) with respect to IA-2. These studies support the autoantigenic nature of IA-2 in IDDM and suggest the inclusion of cellular immune responses as an adjunct marker for the disease.
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PMID:The relationship between humoral and cellular immunity to IA-2 in IDDM. 956 88

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensitivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibody (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile of 105 nondiabetic control subjects, and results were confirmed by testing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA+/IA2A+, 44 GADA+/IA2A-, and 4 IA2A+/GADA-). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADIA2-combi assay as well as in the single test for GADA or IA2A. Twenty-four relatives progressed to IDDM within a median follow-up time of 5.6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30-73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P=0.0001) and on the presence of IA2A in addition to GADA (5-year risk: GADA+/IA2A+, 47% [25-68]; GADA+/IA2A-, 15% [2-28]; P=0.006). In those with detectable antibodies, risk was not associated with age (<15 vs. >15 years) or relation to proband (offspring, sibling, parent). Relatives with GADIA2-combi antibodies >10 U and the additional presence of IAA had a slightly higher diabetes risk than relatives without IAA (5-year: IAA+, 46% [23-68]; IAA-, 19% [6-32]; P=0.07). Furthermore, low first-phase insulin release after intravenous glucose tolerance test was associated with risk in relatives with GADIA2-combi antibodies (P=0.01). These results indicate that the GADIA2-combi test is a valuable marker for first-line screening and risk assessment of type 1 diabetes in relatives. It can be used for venous as well as capillary blood samples.
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PMID:GADIA2-combi determination as first-line screening for improved prediction of type 1 diabetes in relatives. 956 92

The related tyrosine phosphatase-like proteins, islet cell antigen 512 (ICA512) and phosphatase homologue in granules of insulinoma (phogrin), are major targets of autoantibodies in patients with type 1 diabetes. In the current study, we have examined the overlapping specificities and antigenic epitopes of autoantibodies to ICA512 and phogrin and determined whether intramolecular epitope spreading occurs during the development of diabetic autoimmunity. ICA512 autoantibodies and phogrin autoantibodies were detected in 65-70% (n = 110) of patients with new-onset type 1 diabetes and 60-65% (n = 42) of prediabetic relatives of patients with type 1 diabetes. Of the sera, 10% reacted with ICA512 but not phogrin, whereas only 1% of sera reacted with phogrin but not ICA512. The binding of phogrin autoantibodies in 88 dual (ICA512 and phogrin) autoantibody-positive sera could be completely blocked by excess recombinant ICA512, whereas the blocking of ICA512 autoantibodies with recombinant phogrin was only partial (mean inhibition of 58.9 +/- 3.7%, mean +/- SE). Binding and competition analysis using multiple chimeric ICA512/phogrin constructs demonstrated that a major unique epitope for ICA512 autoantibodies is localized to amino acids 762-887. A conformational epitope associated with the carboxy-terminal 31 amino acids of ICA512 was recognized by one-third of sera, and a minor epitope is located on amino acids 601-762 of ICA512. The major epitopes for phogrin-selective autoantibodies were localized to amino acids 640-922 of phogrin. Sequential serum samples were analyzed in 22 relatives who expressed ICA512/phogrin autoantibodies. Intramolecular epitope spreading was found for 5 of 13 relatives who have progressed to type 1 diabetes. Among nine relatives who have remained nondiabetic, three demonstrated a decrease in the number of epitopes recognized. These studies highlight the complexity of autoantibody recognition of ICA512/phogrin and are consistent with the hypothesis that ICA512/phogrin may be recognized as a consequence of beta-cell destruction.
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PMID:Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes. 958 44

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate beta-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.
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PMID:T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents. 960 76

To evaluate the potential of autoimmune markers in identifying patients with slowly progressive IDDM in the prediabetic state, we screened a population of 151 patients aged 37-70 years with impaired glucose tolerance (IGT) for the presence of islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GADA), and antibodies to tyrosine phosphatase IA-2 (IA-2A). Autoantibodies were found in 5 (3.3%) patients with IGT suggesting the presence of an autoimmune-mediated beta cell destruction. All of them were positive for high level ICA (> 20 JDF-U) and 1 ICA positive subject had additional GADA (100 GADA-U). In contrast, none of the subjects had IA-2A or IAA. We here demonstrate a low prevalence of autoimmune diabetes among middle-aged subjects with IGT. ICA and GADA but not IA-2A or IAA may represent autoimmune markers for slowly progressive IDDM before the manifestation of the disease.
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PMID:Prevalence of diabetes-specific autoantibodies in patients at risk for adult onset diabetes mellitus. 962 41

The Schwabing Insulin Prophylaxis Trial is a randomised, controlled pilot study designed to examine whether insulin therapy can delay or prevent the clinical onset of Type I diabetes in high risk first degree relatives of people with the disease. First degree relatives of patients with Type I diabetes, who were aged 4 years or more, had an islet cell antibody (ICA) value more than 20 Juvenile Diabetes Foundation Units (JDF-U), a reduced first phase insulin response (FPI) to an i.v. glucose tolerance test less than the 5th centile, and a normal oral glucose tolerance test were eligible for the trial. Between January 1989 and October 1995, 1736 relatives of patients with Type I diabetes were screened for ICA. We identified 64 cases (3.7%) with ICA values more than 20 JDF-U. Of ICA positive relatives, 17 (27%) had a low FPI and were eligible for enrolment. Of these 14 agreed to participate, of whom 7 were randomised to the treatment group and 7 to the control group. In the treatment group, human insulin was administered i.v. by continuous infusion for 7 days, followed by daily s. c. injections for 6 months. Intravenous insulin infusions were repeated every 12 months. In the treatment group 3 of the 7 individuals (follow-up from time of eligibility: 2.3 to 7.1 years) and in the control group 6 of the 7 untreated individuals (1.7 to 7.1 years) developed clinical diabetes. Life table analysis showed that clinical onset of Type I diabetes was delayed in insulin-treated subjects compared with control subjects (means+/-SEM diabetes-free survival: 5.0+/-0.9 years vs 2.3+/-0.7 years, p < 0.03). Insulin levels after i.v. glucose increased in the first year of intervention therapy. Titres of ICA, and antibodies to glutamic acid decarboxylase, and tyrosine phosphatase-like protein IA2 remained unchanged. These data suggest that insulin prophylaxis can delay the onset of overt diabetes in high risk relatives. This is encouraging in view of 1) the continuing American Diabetes Prevention Trial, which is currently testing the effect of parenteral insulin in a large nation-wide study and 2) the initiation of pilot trials to determine whether new antigen-specific intervention is more effective in delaying the clinical onset of Type I diabetes.
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PMID:Delay of type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial. 962 70


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