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)

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

Several methods are available for the measurement of antibodies to glutamic acid decarboxylase (anti GAD). These antibodies are valuable tools for the immunodiagnosis of insulin-dependent (type 1) diabetes mellitus (IDDM) and for the assessment of risk for the future development of IDDM. We here describe a new enzyme-linked immunosorbent assay (ELISA) for the detection of anti-GAD which was tested in a multicenter study. The results of the new anti-GAD ELISA correlate well with those obtained by radioimmunoassays (RIA) and they have a higher sensitivity (69%) and specificity (98%) compared to other anti-GAD enzyme immunoassays as determined in the IDW Proficiency Test Program for the detection of GAD antibodies. The new ELISA is simple and easy to perform, with convenient handling of the reagents. Quantitative and reproducible test results are available within approximately four hours. The new anti-GAD ELISA can be used for large scale population screening to indicate a prediabetic state as well as to diagnose autoimmune diabetes in adults (LADA) and the risk for IDDM in pregnant women with gestational diabetes.
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PMID:Comparison of a new anti-glutamic acid decarboxylase (GAD) enzyme-linked immunosorbent assay (ELISA) with radioimmunoassay methods: a multicenter study. 928 79

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

Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolchildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies > or =97.5th centile of the schoolchild population were found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) for antibodies to GAD, in 193 (75%) for antibodies to protein tyrosine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insulin (IAAs). Estimates of risk of progression to IDDM within 10 years, derived by comparing the distribution of antibody markers in the two populations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6.6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoolchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most children with IDDM had multiple antibody markers, and 89% of those diagnosed over age 10 years had > or =2 antibodies above the 97.5th centile, as compared against 0.7% of schoolchildren, in whom this combination gave a 27% 10-year estimated risk of IDDM. Risk increased but sensitivity fell as combined antibody thresholds were raised, or the number of antibodies above the threshold was increased. Strategies based on detection of > or =2 antibodies with primary testing for GAD and IA-2 antibodies and second line testing for ICAs and/or IAAs were evaluated. Detection of at least two markers selected from GAD antibodies > or =97.5th centile and/or IA-2 antibodies > or =99.5th centile and/or ICAs > or =97.5th centile identified 0.25% of schoolchildren and 83% of children with newly diagnosed IDDM, with an estimated risk of 71% (95% CI 57-91). Although confirmation from prospective studies is still needed, this analysis suggests that antibody combinations can predict diabetes in the general population.
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PMID:Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. 935 15

Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic beta-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0-10 years) than in the older (11-16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11-16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb- patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic beta-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12-18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target beta-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.
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PMID:Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children. 935 42

This paper describes a simple, rapid, routine method to detect anti-GAD65 autoantibodies by a solid-phase radioimmunoassay using human recombinant GAD65 coated microwells and 125I-protein A to reveal antibody binding. Both recombinant and radiolabelled proteins are commercially available. This new method was validated by investigating the presence of GAD65 autoantibodies in two different studies (A and B); the first including subjects originating from our own case histories (group A sera), the second made up of recoded subjects and standards sent to our lab by the Second International GAD Antibody Workshop organizers (group B sera). In study A we tested sera from 52 normal subjects, 25 newly diagnosed type 1 diabetics and 3 stiff man syndrome (SMS) subjects detecting GAD65 autoantibodies in 72% of IDDM and 100% of SMS patients. In study B we tested (in blind fashion) 89 recoded sample sera or standards that were part of the larger group used in the Second International GAD Antibody Workshop, finding GAD65 autoantibodies in 3.3% of healthy control subjects (1/30), 60% of IDDM patients (18/30), 100% of ICA + nondiabetic subjects (3/3) but in none of 4 nondiabetic patients with Graves disease. Comparing our solid-phase RIA results with those published for the same sera from the Second International GAD Antibody Workshop we obtained for our method a sensitivity of 85.7%, a specificity of 93.9% and a consistency of 100%. These result indicate that our assay, which is based on commercially available reagents, should be a useful tool for the detection of GAD65 autoantibodies in large scale studies.
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PMID:A new solid-phase radioimmunoassay to detect anti-GAD65 autoantibodies. 936 37

The GM2-1 islet ganglioside has been sequenced, found to be a novel ganglioside structure with a sialic acid moiety in the terminal position and two residues of non-acetylated galactosamine and also shown to be a target of autoantibodies in a subset of ICA+ relatives of type 1 diabetic patients who subsequently progressed to the overt disease. In the present study we determined whether antibodies to GM2-1 or to other pancreatic gangliosides (a) are also expressed at disease onset and (b) are correlated with other diabetes-associated autoantibodies. Pancreatic gangliosides were extracted from human pancreas and purified by thin layer chromatography (TLC). Anti-ganglioside autoantibodies were determined using an indirect immunoperoxidase technique performed directly on TLC plates in the following groups of patients: (a) newly diagnosed type 1 diabetic subjects before insulin therapy (n = 45); all were tested for GAD65 autoantibodies in a fluid-phase RIA using 35S-methionine-labelled recombinant human GAD65. Of these patients, 24 were also tested for insulin autoantibodies (IAA) by a competitive fluid phase radioimmunoassay and 21 were tested for GAD67 reactivity. (b) Forty-two age- and sex-matched normal control subjects. Autoantibodies to GM2-1, but not to other pancreatic gangliosides (GM3, GD3, GD1a), were expressed in 31 of 45 new-onset type 1 diabetic subjects and in one of 42 normal controls (P < 0.01), while anti-GAD65, IAA and anti-GAD67 were found in 31 of 45, 12 of 24 and three of 21 patients respectively, but not in the control group of subjects. Interestingly, occurrence of GM2-1 autoantibodies was significantly correlated (P < 0.005) with positivity for GAD65 autoantibodies, but not for IAA or GAD67 autoantibodies. It is of note that both GAD and gangliosides are mainly expressed in islets and in neuronal tissues and, therefore, type 1 diabetes may be regarded as a neuroendocrine autoimmune disease.
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PMID:Autoantibodies to the GM2-1 islet ganglioside and to GAD-65 at type 1 diabetes onset. 945 98

Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing beta-cells in the Langerhans' islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7 molecules generate a lower proportion of compact alphabeta heterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7 molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7 in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7 or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7 molecules than for I-Ak molecules, implying an intrinsic defect of the I-Ag7 molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7 cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7 cells. The IL-2 response to GAD when presented by DAP.3Ag7 was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7 molecules and not affected by other genes in the NOD background. The DAP.3Ag7 cell line should be a valuable tool with which to dissect the role of the I-Ag7 molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM.
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PMID:Development of an I-Ag7-expressing antigen-presenting cell line: intrinsic molecular defect in compact I-Ag7 dimer generation. 948 Jul 24

The majority (> 80%) of patients with non insulin dependent diabetes mellitus (NIDDM) present in Europe and America are obese. In developing countries like India, most NIDDM (> 60%) are non-obese and many are actually lean with a body mass index (BMI) of < 18.5 and are referred to as 'lean NIDDM'. This paper compares the clinical profile of a cohort of 347 lean NIDDM, with a group of 6274 NIDDM of ideal body weight (IBW) and 3252 obese NIDDM attending a diabetes centre at Madras in South India. The lean NIDDM who constituted 3.5% of all NIDDM patients seen at our centre, had more severe diabetes and an increased prevalence of retinopathy (both background and proliferative), nephropathy and neuropathy. Although a larger percentage of the lean NIDDM patients were treated with insulin, 47% of the males and 53% of the females were still on oral hypoglycaemic agents even after a mean duration of diabetes of 9.2 +/- 8.1 years. Studies of GAD antibodies, islet cell antibodies (ICA) and fasting and stimulated C-peptide estimations done in a small subgroup of the lean NIDDM showed that they were distinct from IDDM patients. More studies are needed on metabolic, hormonal and immunological profile of lean NIDDM seen in developing countries like India.
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PMID:Clinical profile of lean NIDDM in South India. 948 73

Sardinia and Finland have the highest incidence of IDDM in the world. Thus, both regions represent ideal observatories for investigating the environmental, genetic and immunological factors, which have led to this dramatic increase. We have concentrated our efforts in Sardinia. Among several projects, there is the mapping of the Island for hot and cold spots for overt IDDM. In order to map the Island for pre-IDDM, we have collected and bled around 10,000 school children (age 6-14 years) and we are now in the process to enroll around 30,000 newborn. We report here our initial results, which show that progression to IDDM is accompanied in both cohorts by the presence of a combination of ICA with either GAD and IA-2 antibodies or both. This approach should lead to design reliable models of IDDM prediction in the general population, which will benefit an early insulin treatment and, hopefully, an effective prevention of the disease.
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PMID:The "Sardinia-IDDM study": an attempt to unravel the cause of insulin-dependent diabetes mellitus in one of the countries with the highest incidence of the disease in the world. 954 74


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