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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Diabetes 1992 Jan
PMID:T-lymphocyte lines specific for glutamic acid decarboxylase (GAD) the 64K beta-cell antigen of IDDM. 172 31

Type I diabetes occurs as a result of T-cell-mediated beta-cell destruction. Several candidate antigens have been described recently, including glutamic acid decarboxylase, heat shock protein 65 and peripherin. Restricted T-cell receptor V beta gene usage in non-obese diabetic mice has been suggested but not yet proven. In addition to major histocompatibility genes, several non-H-2 predisposing genes have been mapped on chromosomes 1, 3 and 11.
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PMID:Insulin-dependent diabetes mellitus. 179 33

It has recently been proposed that the islet 64,000 Mr protein autoantigen (64K) of insulin-dependent diabetes mellitus (IDDM) is glutamic acid decarboxylase (GAD). We evaluated, by means of a newly developed immunotrapping enzyme activity assay (ITEAA), the prevalence of circulating GAD-autoantibodies (Ab) in a large population of IDDM patients (n = 168), blood donors (n = 87) and non-diabetic autoimmune patients (n = 40). The latter two groups were used as controls. Overall, GAD-Ab were found in 22% of IDDM patients, but in none of the two control groups (P = 0.007). These specificities were invariably associated with islet cell antibodies (ICA) (31.6% in IDDM with ICA vs 0 in IDDM without ICA, P = 0.0001), and this prevalence was higher in sera with high titer ICA (54.5% in IDDM with ICA greater than 80 JDF-units vs 22.6% of IDDM with ICA 5-80 JDF units; P = 0.002). Moreover, GAD-Ab were associated with the female sex (P = 0.002) and the concomitant presence of thyroid and/or gastric antibodies (P = 0.002). No correlation was observed between GAD-Ab and age of the patients, duration of IDDM, or associated non-organ specific antibodies. Our study indicates that GAD-Ab measured by ITEAA are: (1) detected in a proportion of IDDM patients; (2) strongly associated with ICA; (3) preferentially found in IDDM female patients with autoimmune polyendocrine serology; and (4) detected with lower frequency than that reported for 64K-Ab in IDDM.
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PMID:Autoantibodies to glutamic acid decarboxylase (GAD) detected by an immuno-trapping enzyme activity assay: relation to insulin-dependent diabetes mellitus and islet cell antibodies. 181 96

A 64-kDa islet protein is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). Autoantibodies against the 64-kDa protein were recently shown to immunoprecipitate glutamic acid decarboxylase (GAD; L-glutamate 1-carboxy-lyase, EC 4.1.1.15) from brain and from islets. We present evidence that the autoantisera also recognize a hydrophilic islet protein of approximately 67 kDa in addition to the amphiphilic 64-kDa form. We have isolated a full-length rat islet GAD cDNA encoding a hydrophilic 67-kDa protein, which appears to be identical to rat brain 67-kDa GAD. A partial sequence of human insulinoma 67-kDa GAD was identical to human brain 67-kDa GAD. Allelic variations were observed in rat as well as in human 67-kDa GAD sequences. The expressed rat islet 67-kDa GAD protein is functional and is immunoprecipitated by IDDM sera; it comigrates electrophoretically with the 67-kDa islet autoantigen. The hydrophilic 67-kDa form of GAD in islets is an additional autoantigen in IDDM and is recognized by a different subset of autoantibodies than the 64-kDa autoantigen. Thus, mammalian cell lines expressing functionally active, recombinant GAD may become important tools to study the nature and the role of GAD autoreactivity in IDDM.
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PMID:Cloning, characterization, and autoimmune recognition of rat islet glutamic acid decarboxylase in insulin-dependent diabetes mellitus. 192 35

A simple, direct assay for T-lymphocyte reactivity to islet antigen(s) in human insulin-dependent diabetes mellitus (IDDM) should facilitate preclinical diagnosis and the evaluation of intervention therapy to avert autoimmune-mediated beta-cell destruction. In subjects with preclinical or clinical IDDM, we measured the reactivity of peripheral blood mononuclear cells (PBMCs) incubated over 6 days with either adult human islets or fetal pig proislets, or other fetal pig tissues, and with human insulin. With islets, the stimulation index (SI) of [3H]thymidine uptake by PBMCs exceeded the mean + 2SD of control subjects in 6 of 6 preclinical subjects (SI 8.7 +/- 3.7), 7 of 11 clinical subjects (SI 5.2 +/- 3.4), and 1 of 12 control subjects (SI 2.7 +/- 1.7); with insulin, the responses were less in frequency and magnitude, being 4 of 6 (2.7 +/- 1.6), 3 of 11 (2.2 +/- 1.1), and 0 of 12 (1.20 +/- 0.55), respectively. The mean responses to islets of PBMCs from preclinical and clinical subjects differed significantly from control subjects (P less than 0.02 by 2-tailed Kruskal-Wallis test). Secretion of granulocyte macrophage colony-stimulating factor by PBMCs over 6 days was assayed in the preclinical group and generally paralleled the uptake of [3H]thymidine. PBMC reactivity to islets appeared to be at least as sensitive a marker of preclinical IDDM as autoantibodies to a 64,000-Mr protein, presumably the enzyme glutamic acid decarboxylase, in fetal pig proislets. In conclusion, islet-reactive T lymphocytes in subjects with preclinical and clinical IDDM can be identified in bulk culture of PBMCs.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Sep
PMID:Reactivity to human islets and fetal pig proislets by peripheral blood mononuclear cells from subjects with preclinical and clinical insulin-dependent diabetes. 193 20

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

First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a Mr 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n = 6) and low (n = 30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. 195 5

We report partial nucleotide sequences of the human enzyme glutamic acid decarboxylase (GAD) from brain and pancreatic islets which encode the middle 180 amino acids of GAD. The brain and islet GAD sequences display a high degree of sequence homology with the equivalent region of other mammalian brain GAD cDNAs. Alignment of the brain and islet GAD sequences showed that there were 45 nucleotide differences which, at the translational level, would result in seven amino acid substitutions. These results which suggest that different isomeric forms of human GAD exist in brain and pancreas may be relevant to the pathogenesis of stiff man syndrome (SMS) and insulin-dependent diabetes mellitus (IDDM), respectively, two distinct but associated clinical disorders in which GAD is the target of autoantibodies.
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PMID:Cloning and partial nucleotide sequence of human glutamic acid decarboxylase cDNA from brain and pancreatic islets. 203 9

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.
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PMID:Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. 213 82

Phosphate-activated glutaminase (PAG) and glutamic acid decarboxylase (GAD) were assayed in homogenates and synaptosomes obtained from starved (48 hr or 120 hr) and diabetic (streptozotocin) rat brain cortex. Glutamine synthetase (GS) was assayed in homogenates, microsomal and soluble fractions, from brain cortex of similarly treated rats. L-Glutamate uptake and exit rates were determined in cortex slices and synaptosomes under the same conditions. The specific activity (s.a.) of PAG, a glutamate producing enzyme, decreased (50%) in the homogenate after 120-hr starvation. In synaptosomes it decreased (25%) only after 48-hr starvation. The s.a. of GAD and GS, which are glutamate-consuming enzymes, were progressively increased with time of starvation, reaching 39% and 55% respectively after 120 hr. GS in the microsomes or the soluble fraction and GAD in the synaptosomes showed no change in s.a. under these conditions. Diabetes increased (40%) microsomal GS s.a. and decreased GAD s.a. (18%) in the homogenate. The L-glutamate uptake rate was decreased (48%) by diabetes in slices but no in synaptosomes. It is suggested that a) enzymes of the glutamate system respond differently in different subcellular fractions towards diabetes or deprivation of food and b) diabetes may affect the uptake system in glial cells but not in neurons.
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PMID:Effects of fasting and diabetes on some enzymes and transport of glutamate in cortex slices or synaptosomes from rat brain. 289 38


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