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)

This study has investigated the genetic basis of the heterogeneous autoimmune response to glutamic acid decarboxylase (GAD) in 179 Australian patients with IDDM. Antibodies to GAD have been correlated with HLA-DQB1 alleles and genotypes, as determined by sequence-specific oligonucleotide hybridizations after polymerase chain reaction was applied to exon 2 of the DQ beta 1 gene. HLA-DQ2 was significantly increased (p < 0.01) in IDDM patients with antibodies to GAD. Antibodies to GAD were detected in 64% of 72 DQ2.8 patients, in 55% of 29 DQ2.2 or DQ8.8 patients and in 41% of 78 patients with other HLA-DQB1 genotypes. HLA-DQ genotype association with autoimmunity to GAD was statistically significant (p = 0.02) and reflected early formation of antibodies to GAD, rather than an HLA association with persistence of antibodies to GAD, since the genotype effect was more evident (p = 0.02) in those with more recent onset (0-5 years) of IDDM. Also, the HLA-DQ genotype effect was more evident in patients with IDDM onset after the age of 14 years (p = 0.003). Multivariate analysis showed that HLA-DQB1 genotypes had a more significant impact on antibodies to GAD than either duration or age of onset of IDDM. In patients with IDDM in childhood, only a minority had low-risk HLA-DQB1 genotypes (37%) when compared with those with onset in adulthood (62%) (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA-DQ genotypes are associated with autoimmunity to glutamic acid decarboxylase in insulin-dependent diabetes mellitus patients. 810 72

The effects of plasmapheresis on islet autoantibody levels, C-peptide (beta-cell function), and hemoglobin-A1c (HbA1c, metabolic control) were tested in a prospective blinded study of 18 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients randomly assigned to receive plasmapheresis (P), carried out as double filtration, or sham (S) treatment at diagnosis and 3 months thereafter. At diagnosis, 6 of 8 patients (75%) in group P and 9 of 10 patients (90%) in group S had islet cell antibodies (ICA), whereas 4 of 8 (50%) and 7 of 10 (70%) patients, respectively, had glutamic acid decarboxylase antibodies (GAD65-Ab), with no significant differences between the groups in ICA and GAD65-Ab levels. After 6 months, P patients showed significantly lower ICA levels than S patients (11 +/- 6 and 128 +/- 47 Juvenile Diabetes Foundation International Units, respectively; P < 0.02) due to an increase in ICA levels in 8 of 9 (88%) of the S patients not seen in P patients (P < 0.002). Concurrently, HbA1c stabilized in P, but not in S, patients and was significantly lower by 24 months (6.58 +/- 0.54% vs. 9.76 +/- 1.21%; P < 0.05). Moreover, fasting C-peptide increased significantly (214 +/- 11 pmol/L; P < 0.05) over the first 6 months in P. After the initial 6 months, ICA levels tended to decrease in all patients and were not detected after 60 months. GAD65-Ab levels were not influenced by plasmapheresis and, also in contrast to ICA, increased significantly (P < 0.05) in the whole study population after 60 months. In fact, 4 initially negative patients became GAD65-Ab positive after diagnosis (in 2 patients > 24 months after diagnosis). We conclude that plasmapheresis of newly diagnosed IDDM patients does not change subsequent GAD65-Ab levels, but ICA are significantly decreased with associated improved C-peptide and HbA1c levels.
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PMID:Islet cell antibodies, but not glutamic acid decarboxylase antibodies, are decreased by plasmapheresis in patients with newly diagnosed insulin-dependent diabetes mellitus. 817 73

Knowing the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic beta-cells. Several beta-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to beta-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.
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PMID:Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. 823 29

Insulin-dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, autoimmune islet damage. Our aim was to identify the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identification of the earliest beta-cell-specific autoantigen is extremely important in allowing advances in prevention and treatment of initial events in the development of inflammatory insulitis that precedes beta-cell destruction and overt diabetes. Therefore, we analyzed the proliferative responses of peripheral T-cells from young, female nonobese diabetic (NOD) mice to extracts of pancreatic beta-cell lines. We were able to demonstrate that T-cells responsive to beta-cell antigens exist in the peripheral lymphoid tissue of these mice in the absence of deliberate priming before the manifestation of histologically detectable insulitis. T-cell lines and clones isolated from the peripheral lymphatic tissues of young, unimmunized, female NOD mice were also shown to react with extracts of beta-cells. Fractionation of the beta-cell extracts showed that these T-cell clones recognized multiple beta-cell-specific autoantigens but none of the previously reported putative autoantigens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, carboxypeptidase-H, and peripherin). Thus, we can conclude that these responses are specific for novel beta-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of human islets suggesting potential shared antigenic determinants between human and mouse beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes. 826 14

Stiff-man syndrome (SMS) is a rare disorder of the central nervous system of probable autoimmune origin. Patients with SMS often have other autoimmune diseases, in particular type I (insulin-dependent) diabetes mellitus (IDDM). Approximately 60% of patients with SMS have high titers of autoantibodies against the enzyme glutamic acid decarboxylase. Similar to SMS, the majority of patients with IDDM have autoantibodies against glutamic acid decarboxylase at or before diabetes onset, although usually at a lower titer and with a different reaction pattern than patients with SMS. To investigate the immunogenetic basis of SMS, we HLA-typed 18 patients with the disease. Seventy-two percent carried the DQB1*0201 allele (13 of 18, P = 0.02 vs. 18 of 48 controls), indicating that SMS is associated with this allele. DQB1*0201 is also a susceptibility allele for IDDM and other autoimmune diseases. Patients with SMS carried the IDDM-protective DQB1*0602 allele and other sequence-related DQB1*06 alleles with the same frequency observed in controls. In contrast, these alleles are rarely found in IDDM. Five of 8 (62.5%) SMS patients lacking a DQB1*06 allele were diabetic in contrast to only 2 of 10 (20%) with a DQB1*06 allele (P = 0.08), suggesting that the presence of DQB1*0602 or other DQB1*06 alleles may be associated with a reduced prevalence of diabetes among patients with SMS.
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PMID:Association of HLA-DQB1*0201 with stiff-man syndrome. 826 40

Target antigens defined by autoantibodies in IDDM include insulin, a putative glycolipid that reacts with islet cell antibodies, and a 64,000-M(r) protein recently identified as glutamic acid decarboxylase. In addition, some IDDM sera that contain antibodies to glutamic acid decarboxylase also coprecipitate a 38,000-M(r) protein from islets. This study used a high titer anti-38,000-M(r) serum to screen bacteriophage lambda cDNA expression libraries and identified human islet and placental clones encoding jun-B, the nuclear transcription protein, of predicted 38,000 M(r). Peripheral blood T-cells exhibited significant proliferation in response to a recombinant fragment of jun-B (amino acids 1-180) in 12 of 17 (71%) recent-onset IDDM subjects, 8 of 16 (50%) ICA-positive first-degree relatives of IDDM subjects who were at risk, 3 of 12 (25%) other autoimmune disease subjects, and 0 of 10 healthy control subjects. Proliferation to tetanus toxoid did not differ significantly between the groups. Responses to jun-B were not related to age, sex, or human leukocyte antigen status. Thus, autoreactive T-cells identify a novel antigen, p38 jun-B, in IDDM and appear to indicate subjects at risk for the development of clinical disease.
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PMID:Transcription factor jun-B is target of autoreactive T-cells in IDDM. 845 14

Our objective was to ascertain the frequency of antibodies to glutamic acid decarboxylase (GAD) in Europids and four Asian ethnic groups with insulin-dependent diabetes mellitus (IDDM) to gain insight into why the prevalence and incidence of IDDM varies so widely among ethnic and/or geographically diverse population groups. The subjects in this study were Europid (n = 49), Japanese (n = 16), Thai (n = 7), Korean (n = 21), and Chinese (n = 13) persons with IDDM with a duration ranging from 5 to 14 years. There were similar numbers of healthy controls matched for each ethnic group. A validated radioimmunoprecipitation assay used GAD from pig brain radiolabeled with 125I using chloramine T. Islet cell cytoplasmic antibodies measured by indirect immunofluorescence were expressed as Juvenile Diabetes Foundation units. The prevalence of antibodies to GAD, compared with Europids (63%), was much lower in all Asian populations with IDDM: Japanese (31%), Thai (29%), Korean (5%), and Chinese (27%). The mean level of antibodies to GAD, however, among diabetics from each population who gave a positive reaction, was similar. For all groups, the prevalence of antibodies to GAD was much higher than that of islet cell cytoplasmic antibodies. Almost all IDDM subjects positive for islet cell antibodies had antibodies to GAD, but the converse did not hold. A radioimmunoprecipitation assay for antibodies to GAD applied to serum from subjects with IDDM in various ethnic groups showed that Europids with IDDM had a much higher prevalence of such antibodies than did Asians. This held for all ethnic groups, and particularly Koreans. Thus, among different populations, there may be etiologic heterogeneity of IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The ethnic distribution of antibodies to glutamic acid decarboxylase: presence and levels of insulin-dependent diabetes mellitus in Europid and Asian subjects. 848 44

Heat shock proteins (HSP) are the most widely conserved group of proteins in phylogeny and play an important role in infection and autoimmunity. HSP65 has been suggested as the primary antigen in insulin dependent diabetes while an alternative antigen glutamic acid decarboxylase (GAD), has similar amino acid sequences. A 'double insult theory' for the development of insulin dependent diabetes is suggested whereby a bacterial infection leads to the production of HSP antibody. If during a 'window of opportunity' this is followed by a viral infection of the islet cells this could, in certain histocompatibility locus antigen (HLA) groups only, lead to the production of HSPs on the cell surface and a destructive autoimmune reaction.
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PMID:Heat shock protein and the double insult theory for the development of insulin dependent diabetes. 850 31

Glutamic acid decarboxylase (GAD) catalyzes formation of gamma-aminobutyric acid from glutamic acid and is a major autoantigen in insulin-dependent diabetes mellitus. Its two isoforms, GAD65 and GAD67, are encoded by two separate genes. We prepared human islet cDNA library and screened it with cDNA probes of rat brain GAD67. We cloned the cDNA for GAD67, the large isoform of glutamic acid decarboxylase, and determined its nucleotide sequence. Sequencing of the resulting clone identified a 1,785 residue open-reading frame encoded a 594 amino acid polypeptide that showed a 99.4% similarity with GAD67 from human brain. The bacterially expressed human islet GAD67 protein was enzymatically active and immunoreactive. The isolation of cDNA for this additional islet GAD isoforms will be important in studying the etiology and pathogenesis of IDDM.
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PMID:Cloning and expression of large isoform of glutamic acid decarboxylase from human pancreatic islet. 850 3

We determined the prevalence of antibodies to glutamic acid decarboxylase (anti-GAD) in Japanese diabetic patients. Anti-GAD were detected by RIP Anti-GAD Hoechst, which is a new sensitive radioimmunoassay (RIA) kit using purified pig brain GAD as the antigen. One thousand nine hundred Japanese patients were collected by the Study Group for Antibodies to GAD. The prevalence of anti-GAD in the subjects of this study was: 35.4% (326/921) in all patients with IDDM, 50.3% (96/191) in patients with IDDM less than 1-year duration, 4.3% (29/680) in NIDDM, 37.9% (39/103) in slowly progressive IDDM, 10.5% (4/38) in gestational diabetes mellitus, 0% (0/27) in impaired glucose tolerance, 4.8% (6/124) in the school children with glycosuria, 2.1% (1/47) in the relatives of IDDM and 5.0% (1/20) in neurological diseases without diabetes. The prevalence in normal subjects was 2.2% (7/323). Anti-GAD are frequently detected by the RIA kit in patients with IDDM of short duration and this assay may be useful for population screening for IDDM and for better understanding of its pathogenesis.
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PMID:Antibodies to GAD in Japanese diabetic patients: a multicenter study. 852 98


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