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)

Insulin-dependent diabetes mellitus (IDDM) is associated with serum antibodies that precipitate a 64-kDa pancreatic islet cell protein reported to be glutamic acid decarboxylase (GAD; glutamate decarboxylase, EC 4.1.1.15). Previously, antibodies to GAD were found in the rare neurological disorder stiff man syndrome. To demonstrate directly antibodies to GAD, enzymatically active GAD was first purified from fresh human cerebellum. Brain GAD activity was precipitated by noninhibitory antibodies in the sera of 16/26 (62%) subjects defined as having preclinical IDDM (islet cell antibody-positive first-degree relatives of a person with IDDM), 3/13 (23%) with recent-onset IDDM, and 3/3 with the stiff man syndrome. In addition, sera of 5/26 (19%) preclinical and 2/13 (15%) recent-onset IDDM subjects contained antibodies that precipitated GAD but inhibited its activity. Thus, overall, 21/26 (81%) preclinical and 5/13 (38%) recent-onset IDDM subjects had antibodies that precipitated GAD activity. Antibodies to GAD were not detected in sera from subjects with other autoimmune diseases (n = 29) or healthy controls (n = 14). GAD affinity-purified to homogeneity (specific activity, 58 units/mg) was specifically immunoprecipitated as a single 60-kDa species by the IDDM sera. In an ELISA incorporating whole mouse brain GAD captured by the GAD-6 monoclonal antibody the frequencies of GAD antibodies for all subject groups were indistinguishable from those found by precipitation of human brain enzymatic activity. We conclude that (i) GAD is an (auto)antigen in a majority of subjects operationally defined as having preclinical IDDM, (ii) pancreatic islet and brain GAD are likely to be cross-reactive, and (iii) the majority of GAD antibodies are directed away from the catalytic site of the brain enzyme. The lower frequency of GAD antibodies in recent-onset IDDM subjects indicates either that immunoreactivity is lost with near-total beta-cell destruction or that GAD antibodies denote a low risk of progression to clinical disease.
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PMID:Glutamic acid decarboxylase autoantibodies in preclinical insulin-dependent diabetes. 140 9

Recent data suggest that the enzyme glutamic acid decarboxylase (GAD) may be a primary beta-cell antigen involved in the autoimmune response leading to insulin dependent diabetes mellitus (IDDM). Following three days culture of human islets at different glucose concentrations (5.6, 11 or 28 mM), there was a single 65 kDa/GAD band in the islet extracts, as assessed by immunoprecipitation both with serum from a newly diagnosed IDDM patient and a sheep anti-GAD serum. The synthesis of GAD was strongly stimulated at the higher glucose concentrations. Likewise, Western blot analysis indicated a glucose-induced increase of GAD in the islets. The data suggest that an enhanced function of human islet cells increases expression of GAD65. Possibly, this could exacerbate the autoimmune assault in the early stages of IDDM, and be of practical importance in attempts to ameliorate the autoimmune response towards the beta-cells in IDDM.
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PMID:Glucose regulation of the autoantigen GAD65 in human pancreatic islets. 146 67

Insulin-dependent diabetes mellitus (IDDM) is marked by circulating antibodies to a 64,000-M(r) islet cell antigen identified as glutamic acid decarboxylase (GAD). We describe a radioimmunoprecipitation assay with GAD isolated from pig brain. The sera tested were from 80 patients with IDDM including 26 with disease of recent onset and 54 with disease of longer duration (3-42 yr), 20 with non-insulin-dependent diabetes mellitus (NIDDM), and 55 nondiabetic subjects. Conventional assays for islet cell cytoplasmic antibodies were performed concurrently. The level of antibody in serum was expressed in units based on percentage reactivity of a standard reference serum. The frequency of antibody to GAD in IDDM was 69% in short-duration cases and 59% in long-duration cases. The latter was substantially higher than the frequency of islet cell cytoplasmic antibody. Antibodies to GAD were elevated (means +/- 3 SD) in 5% NIDDM cases and in none of the nondiabetic subjects. A simple laboratory test with a defined autoantigen has substantial implications for population screening and early diagnosis of IDDM and for better understanding of its pathogenesis.
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PMID:Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus. 160 79

Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-M(r) islet cell protein, at least part of which is identified as glutamic acid decarboxylase (GAD). These antibodies are detected as two distinct antibody specificities to 50,000-M(r) and 37,000/40,000-M(r) tryptic fragments of the autoantigen (50K and 37K antibodies, respectively). We determined the frequencies of antibodies to intact GAD, tryptic fragments of islet 64,000-M(r) antigen, islet cell antibodies (ICAs), and insulin autoantibodies (IAAs) in sera from 58 nondiabetic identical twins of patients with IDDM, of whom 12 subsequently developed diabetes. ICA, antibodies to intact GAD, and those to tryptic fragments were detected at similar frequencies in prediabetic twins (67-75%), but only 25% had IAA. Of 46 twins who remain nondiabetic, GAD antibodies, 50K antibodies, and ICA were detected in 6 (13%), 7 (15%), and 5 (11%), respectively, whereas only 1 (2%) possessed 37K antibodies and 2 (4%) had IAA. Eight of 9 twins with 37K antibodies and all 6 twins with ICA greater than 20 Juvenile Diabetes Foundation U have developed diabetes. Antibodies to GAD are sensitive markers for diabetes development but may also be present in genetically susceptible individuals who are unlikely to develop disease. Antibodies to 37,000/40,000-M(r) fragments of the 64,000-M(r) antigen or high-titer ICA were the best markers for diabetes development in these twins.
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PMID:Antibodies to GAD and tryptic fragments of islet 64K antigen as distinct markers for development of IDDM. Studies with identical twins. 161 92

Insulin-dependent diabetes mellitus (IDDM) is viewed as a thymus-dependent autoimmune disease, although the specific beta-cell autoantigen or autoantigens remain unknown. The recent identification of the beta-cell 64K antigen as the enzyme glutamic acid decarboxylase (GAD) permits investigation of GAD as a candidate for the autoantigen associated with beta-cell destruction, mediated by T-lymphocytes, in susceptible individuals. In this study, we describe the isolation of GAD-specific T-lymphocyte lines from BB rats, an animal model of IDDM. GAD (Escherichia coli) was inoculated into the footpads of diabetes-resistant BB rats, and after 10 days, a popliteal lymph node cell culture suspension was prepared. GAD-specific T lymphocytes were obtained by culture with interleukin 2 and repeated stimulation with GAD in the presence of BB rat thymic antigen-presenting cells. Four stable, CD4+, MHC (RT1u)-restricted T-lymphocyte lines were isolated. They proliferate selectively in the presence of GAD and secrete interleukin 2 and interferon-gamma. T-lymphocyte lines such as these could be important in the definition of pathogenetic epitopes associated with GAD.
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PMID:T-lymphocyte lines specific for glutamic acid decarboxylase (GAD) the 64K beta-cell antigen of IDDM. 172 31

The 64-kDa pancreatic beta-cell autoantigen, which is a target of autoantibodies associated with early as well as progressive stages of beta-cell destruction, resulting in insulin-dependent diabetes (IDDM) in humans, has been identified as the gamma-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase. We have identified two autoantigenic forms of this protein in rat pancreatic beta-cells, a Mr 65,000 (GAD65) hydrophilic and soluble form of pI 6.9-7.1 and a Mr 64,000 (GAD64) component of pI 6.7. GAD64 is more abundant than GAD65 and has three distinct forms with regard to cellular compartment and hydrophobicity. A major portion of GAD64 is hydrophobic and firmly membrane-anchored and can only be released from membrane fractions by detergent. A second portion is hydrophobic but soluble or of a low membrane avidity, and a third minor portion is soluble and hydrophilic. All the GAD64 forms have identical pI and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results of pulse-chase labeling with [35S]methionine are consistent with GAD64 being synthesized as a soluble protein that is processed into a firmly membrane-anchored form in a process which involves increases in hydrophobicity but no detectable changes in size or charge. All the GAD64 forms can be resolved into two isoforms, alpha and beta, which differ by approximately 1 kDa in mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis but are identical with regard to all other parameters analyzed in this study. GAD65 has a shorter half-life than the GAD64 forms, remains hydrophilic and soluble, and does not resolve into isomers. Comparative analysis of the brain and beta-cell forms of GAD show that GAD65 and GAD64 in pancreatic beta-cells correspond to the larger and smaller forms of GAD in brain, respectively. The expression of different forms and the flexibility in subcellular localization of the GAD autoantigen in beta-cells may have implications for both its function and autoantigenicity.
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PMID:Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble. 174 45

Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.
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PMID:Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. 328 Oct 11

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) has been implicated in autoimmune diabetes in NOD mice, but the role of the 67-kDa GAD isoform (GAD67) is less clear. We found that immunization of 4-week-old NOD mice with purified recombinant mouse GAD67 prevented or significantly delayed the onset of diabetes. To further explore this phenomenon, we characterized anti-GAD67 immune responses in naive and GAD-immunized NOD mice. Anti-GAD67 antibodies titers were relatively low in naive mice at all ages, but a single immunization with GAD67 at 4 weeks induced high titers of anti-GAD antibodies by 6 weeks of age. In both 4-week-old and diabetic NOD mice, there were significant endogenous T-cell proliferative responses against purified recombinant mouse GAD67. These T-cell proliferative responses were blocked by anti-I-ANOD and anti-CD4 antibodies. To characterize the anti-GAD T-cell responses in the NOD mice, we established T-cell lines and T-cell clones which recognized GAD67, and we used recombinant subfragments of GAD to localize the predominant T-cell epitopes in GAD67. T-cells from naive NOD mice proliferated in response to all GAD subfragments, whereas T-cells from diabetic mice responded primarily to the COOH-terminal 83 amino acids of GAD67. These results suggest that GAD67 is an autoantigen in IDDM and immunization of prediabetic NOD mice with GAD67 can prevent the onset of diabetes.
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PMID:Immunization with the larger isoform of mouse glutamic acid decarboxylase (GAD67) prevents autoimmune diabetes in NOD mice. 752 93

T cells reacting with pancreatic islet beta cell proteins play a pivotal role in the pathogenesis of type 1 diabetes in experimental animal models and man, although the islet cell autoantigens against which these T cells are directed remain to be characterized. We have previously shown the presence of disease-related antigens residing in the transplantable RIN insulinoma membranes which are recognized by T cells from diabetic NOD mice. We now report on the establishment of CD4+, T cell lines reacting with insulinoma membranes from six newly diagnosed type 1 diabetic patients. Detailed examination of T cell lines from two patients revealed that both the lines continued to react with normal islet cell proteins and, interestingly, were also stimulated by antigens present in brain microsomes. The two T cell lines showed reactivity with different molecular weight proteins of the insulinoma membranes and both the lines were histocompatibility-linked antigen (HLA)-DR restricted. Although the insulinoma membrane preparation is known to contain glutamic acid decarboxylase (GAD), none of the six T cell lines proliferates in response to purified GAD. These T cell lines will be valuable in characterizing novel islet beta cell antigens which are likely to be implicated in type 1 diabetes.
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PMID:HLA-DR-restricted T cell lines from newly diagnosed type 1 diabetic patients specific for insulinoma and normal islet beta cell proteins: lack of reactivity to glutamic acid decarboxylase. 755 82

The nonobese diabetic (NOD) mouse spontaneously develops insulin-dependent diabetes (IDDM or type I diabetes), resulting from T-lymphocyte-mediated destruction of pancreatic beta cells. This autoimmune phenomenon includes mononuclear cell infiltration of the islets of Langerhans (insulitis) and the presence of circulating autoantibodies. The specificity of the autoantibodies and of the autoreactive T cells was investigated and several autoantigens were proposed, in particular glutamic acid decarboxylase (GAD). This enzyme exists in two forms (GAD 65 and GAD 67) encoded by two independent genes. To explain the role of GAD in type I diabetes, we prepared recombinant rat GAD 65 as fusion protein, produced in an Escherichia coli expression system, and we treated NOD female mice from 4 to 7 weeks of age by repeated intraperitoneal injections of 5 micrograms fusion protein (3 injections per week); control groups received the fusion partner, maltose binding protein (MBP) or dissolving agent (NaCl 0.9%). We investigated two parameters, the degree of insulitis 5 weeks after the last injection and the overall incidence of the disease. Histological examination of the pancreata from GAD-treated mice revealed a significant reduction in the severity of insulitis compared with the two control groups. Furthermore, we observed that the time of onset and the frequency of diabetes in NOD females injected with GAD fusion protein differed significantly from the control groups receiving MBP or NaCl (P < 0.0001). These results show that a 3-week treatment of NOD female mice starting at 4 weeks of age protects them from diabetes, again emphasizing the crucial role of GAD as autoantigen in type I diabetes.
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PMID:Prevention of autoimmune diabetes in nonobese diabetic female mice by treatment with recombinant glutamic acid decarboxylase (GAD 65). 760 72


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