Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme glutamate decarboxylase (GAD) is considered one of the major Beta cell antigens in Type 1 diabetes mellitus. The GAD autoantibody (GAD-AAb) prevalence in newly diagnosed Type 1 diabetic patients has been described up to 80%, depending on the detection method used. The aim of this study was to evaluate a simple, specific, and sensitive radioimmunoassay (RIA) method for detection of AAb against both isoforms of the enzyme, GAD65 and GAD67, in a cross-sectional study using sera from newly diagnosed Type 1 diabetic patients and in a longitudinal study using sera from prediabetic patients and individuals at risk of developing the disease. The 125I-labelled full-length human recombinant proteins of GAD65 and GAD67 expressed in SF9 cells were used as the antigen source. The prevalence of GAD65-AAb in newly diagnosed Type 1 diabetic patients was found to be 73% (112/153), in contrast to 19% (14/72) of GAD67-AAb. Only one patient produced AAb restricted to GAD67. Furthermore, GAD65-AAb could also be detected in 73% (11/15) of prediabetic patients (up to 122 months before clinical manifestation of the disease), whereas only 27% (4/15) of them were positive for GAD67-AAb. In the group at risk of developing Type 1 diabetes, these prevalences were 77% (10/13) and 46% (6/13), respectively. In all GAD67-AAb-positive patients investigated in the longitudinal study, AAb to GAD65 were detectable. In 47% of patients positive for both GAD65-AAb and ICA, the GAD65-AAb appeared by up to 46 months before the occurrence of ICA was detected. The data illustrated that GAD65 is the main immunogenic isoform of the enzyme in the preclinical and clinical stages. The RIA detecting AAb against this isoform may facilitate the screening for individuals at risk of developing the disease.
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PMID:Autoantibodies against GAD65 rather than GAD67 precede the onset of type 1 diabetes. 777 5

The value of a test for islet cell cytoplasmic antibodies together with a test for GAD65 antibodies to predict the subsequent development of diabetes over a period of 11.5 years was assessed in an open childhood population comprising 2,805 individuals. A single serum sample was obtained from each individual between 1975 and 1977 and screened for islet cell cytoplasmic antibodies for which eight individuals were positive (0.29%). During the average follow-up period of 11.5 years, four of eight islet cell antibody positive and three islet cell antibody negative individuals developed clinical diabetes. Sera from all individuals, who were islet cell antibody positive and/or developed diabetes (total of 11) and from 100 randomly selected control subjects were analysed for GAD65 antibodies. Six of eight islet cell antibody positive individuals were GAD65 antibody positive including all four who subsequently developed IDDM. Furthermore, one of the three islet cell antibody negative individuals who developed IDDM was GAD65 antibody positive both in 1976 and in 1989. Thus, a positive test for GAD65 antibodies alone correctly predicted diabetes in five of seven children, who developed the disease. Only one of the children, who developed diabetes was positive for insulin autoantibodies and this individual was also positive for islet cell cytoplasmic antibodies and GAD65 antibodies. One of the 100 control subjects was positive for GAD65 antibodies (1%). The results suggest that a single GAD65 antibody test may have a higher sensitivity for predicting IDDM than a test for islet cell cytoplasmic antibodies, but that a combined positive test for both antibodies increases the specificity for predicting IDDM over a period of 11.5 years.
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PMID:Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. 780 22

Glutamic acid decarboxylase (GAD) is a candidate target autoantigen involved in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). The functional state of the beta cells has been suggested to play a pathogenic role in IDDM by altering beta-cell autoantigen expression. In this study, we investigated expression of GAD-65 and GAD-67 in isolated Sprague-Dawley rat islets cultured at different glucose concentrations. Using GAD isoform-specific antibodies in an immunoblot assay, we found that expression of both GAD-65 and GAD-67 in cultured islets was glucose dependent and that increased expression of both forms of GAD correlated with increased functional state of the beta cell. Our data indicate that the functional state of the beta cell influences islet cell expression of GAD. Thus, decreasing islet cell expression of GAD by suppressing beta cells activity may have a potential role in blunting the autoimmune destruction of pancreatic islet beta cells.
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PMID:Functional state of the beta cell affects expression of both forms of glutamic acid decarboxylase. 780 9

HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB1*1601-DRB5*0201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB1*1501-DRB5*0101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB1*0502-DQA1*0102 (DQ5)-DRB1*1601-DRB5*0201 (DR16 Dw21) and DQB1*0301-DQA1*0501 (DQ7)-DRB1*1602-DRB5*0202 (DR16 Dw22) was observed resulting in the DQB1*0301-DQA1*0501 (DQ7) DRB1*1601-DRB5*0201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB1*0602-DQA1*0102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB1*1501, DRB5*0101, DQB1*0602-DQA1*0102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
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PMID:Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus. 781 75

The clinical onset of insulin-dependent diabetes is associated with several autoimmune phenomena including islet cell antibodies, glutamic acid decarboxylase (the GAD65 isoform) autoantibodies (GAD65Ab) as well as insulin autoantibodies. The molecular cloning of these autoantigens has permitted the development of precise and reproducible antibody immunoassays to identify marker-positive patients and control subjects. Among patients with new-onset diabetes about 70% were GAD65Ab positive compared to 1.5% among control subjects while 46% of patients had IAA compared to 1% among control subjects. The autoreactive sites or epitopes of GAD65 and insulin remain to be determined. The disease association with HLA on chromosome 6 may help to define the epitope specificity of the autoimmune reaction. Recent data suggest that 95% of new-onset IDDM children (0-15 years of age) are positive for either DQ2, DQ8 or both compared to about 50% of healthy control subjects. HLA-DQ6 is negatively associated with the disease. Both HLA-DQ2 and DQ8 therefore seem to be necessary, but not sufficient for diabetes. Molecular modelling suggests comparable physicochemical properties of DQ2 and DQ8 but are widely different from DQ6. In 1984, the conclusion was that molecular cloning of the genes for the autoantigens, antibodies, T-cell receptors, as well as HLA class I and II molecules associated with diabetes are essential for analysing the components which control the development of pancreatic beta-cell autoimmunity. In 1994, autoantigens and HLA molecules have been cloned and recombinant reagents developed to be used in experiments aimed at testing whether it will be possible to predict IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of IDDM. 782 43

We studied the distribution of the M(r) 65,000 and M(r) 67,000 isoforms of glutamic acid decarboxylase, GAD65 and GAD67, in rat islets and brain by immunocytochemistry. Synthetic peptides representing selected GAD65 or GAD67 sequences were used to produce sequence-specific antibodies, allowing differential immunocytochemical detection of the two isoforms. GAD-specific reactivity of each peptide antiserum was confirmed by ELISA, immunoblotting, and immunoprecipitation. Immunostaining specificity was verified by displacement with either immunizing or irrelevant peptide. Dual immunostaining with GAD isoform-specific antibodies and polyclonal antibodies to glucagon showed that GAD65 was primarily detected in rat pancreatic islet beta-cells, whereas alpha-cells had weak GAD65 staining. In contrast, GAD67 was detected primarily in alpha-cells. In rat brain, GAD65 and GAD67 were present in neuron cell bodies and processes. These data demonstrate that antibodies raised against the N-terminus of GAD allow differential immunocytochemical identification of GAD67 and GAD65. Differential expression of GAD isoforms within islet alpha- and beta-cells supports the role of GAD65 in autoimmune diabetes and stiff-man syndrome.
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PMID:Differential detection of rat islet and brain glutamic acid decarboxylase (GAD) isoforms with sequence-specific peptide antibodies. 782 65

Type 1 diabetes in man and the NOD (H-2g7) mouse is frequently associated with an autoimmune response to two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. GAD-specific autoantibodies produced by B cells and GAD-specific T cells have been observed in both species. In the current study, the response to a GAD65-derived peptide, GAD65 524-543, previously reported to be an epitope recognized by spleen cells obtained from 3-week-old NOD mice, was assessed in NOD MHC and non-MHC congenic strains. Although spontaneous reactivity to GAD65 524-543 was not observed in NOD mice, the peptide was immunogenic in NOD mice as well as in two NOD congenic strains which are both H-2g7, B10.H-2g7 and NOD.B6Il2-Tshb. This was surprising since the B10.H-2g7 strain does not develop diabetes or insulitis and fewer than 3% of NOD.B6Il2-Tshb mice develop diabetes. The response to GAD65 524-543 was shown to be controlled by the MHC since neither the B10 nor the NOD.H-2b strain, both of which are H-2b, responded to the peptide. This study demonstrates that T cell responsiveness to GAD-derived peptides can be elicited in strains of mice that are resistant to the development of spontaneous diabetes, suggesting that peripheral tolerance to GAD is not associated with protection from diabetes.
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PMID:Responses of NOD congenic mice to a glutamic acid decarboxylase-derived peptide. 784 Aug 55

Patients with adult-onset Type 1 (insulin-dependent) diabetes mellitus (IDDM) are more difficult to identify than young patients, as their clinical onset is often less acute with a questionable state of insulin dependency. Classification may be facilitated by the detection of autoantibodies that are associated with IDDM. The prevalence of islet cell autoantibodies (ICA) and insulin autoantibodies (IAA) is, however, markedly lower in adult than in young patients. The present study assesses the usefulness of antibodies against glutamate decarboxylase (GAD), as a complementary marker. Sera from 312 recent-onset IDDM patients under age 40 and 163 age-matched controls were assayed for IAA, ICA, and antibodies against recombinant GAD65 (M(r) 65,000) or GAD67 (M(r) 67,000). IAA or ICA occurred in over 90% of patients diagnosed under age 20 but only in 65% of patients between age 20 and 40. Determination of GAD65-Ab did not increase the percent antibody positive patients under age 10, but did so at older ages: from 92-98% in the 10-19 years age group, and from 65-85% in the 20-39 years age group. The determination of GAD67-Ab did not add to the information provided by the GAD65-Ab assay. Our results indicate that, alone or in combination with ICA, the GAD65-Ab assay identified more patients with an IDDM marker in the age group 20-39 years than in the group under age 20.
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PMID:High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. The Belgian Diabetes Registry. 788 41

The clinical onset of insulin-dependent diabetes (IDD) can be predicted by determination of autoantibodies to several pancreatic-islet cell antigens. Islet-cell autoantibodies (ICA) and insulin autoantibodies (AA) are most commonly used. We have developed a recombinant human glutamic acid decarboxylase (GAD65) radioimmunoassay and measured autoantibodies to GAD65 (GAD65A) in the sera of 73 documented prediabetic individuals, 76 newly-diagnosed patients, 103 relatives of IDD probands at increased risk for the development of IDD because they were positive for ICA and/or IAA, 72 ICA and IAA negative relatives, and 207 healthy controls. Our data demonstrate that GAD65A are strongly associated with the currently established autoantibody markers of IDD. Their presence in prediabetic subjects with only ICA or IAA enhances their risk for progression to IDD, yet does not much enhance the screening sensitivity already available through conventional ICA and IAA for IDD prediction.
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PMID:GAD65 autoantibodies increase the predictability but not the sensitivity of islet cell and insulin autoantibodies for developing insulin dependent diabetes mellitus. 788 42

We have investigated whether glutamic acid decarboxylase (GAD) autoantibodies (GAD65 Ab) were affected by cyclosporin therapy and were related to subsequent non-insulin-requiring remission and loss of glucagon-stimulated C-peptide response in 132 recent-onset insulin-dependent diabetes mellitus (IDDM) patients treated with cyclosporin or placebo for 12 months. GAD65 Ab were detected in a quantitative radioligand assay using as tracer recombinant, in vitro translated, human islet [35S]methionine-labeled GAD65. GAD65 Ab were found at onset in 66% (87 of 132) of IDDM patients and in 1% (1 of 100) of healthy control subjects. The prevalence of GAD65 Ab and median GAD65 Ab levels did not change in serum samples taken 3, 6, 9, and 12 months after study entry in either the cyclosporin- or the placebo-treated groups. The presence or absence of GAD65 Ab at study entry did not predict non-insulin-requiring remission in either cyclosporin- or placebo-treated patients. However, the relative (compared with 0 months) glucagon-stimulated C-peptide response was more than 30% lower in GAD65 Ab+ patients receiving placebo at 9 and 12 months compared with the GAD65 Ab- placebo patients (P < 0.035). Islet cell cytoplasmic antibody (ICA) and GAD65 Ab+ placebo-treated patients showed no significant differences in stimulated C-peptide levels compared with those who were ICA- and GAD65 Ab+, suggesting that ICA was not independently associated with loss of beta-cell function.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Nov
PMID:Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group. 792 2


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