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

Serological findings have suggested that antibodies (Ab) to bovine serum albumin (BSA-Ab) are associated with type 1 diabetes mellitus. The aim of our study was to evaluate a competitive fluid-phase radioimmunoassay for detecting BSA-Ab using different incubation times and to study a possible association of these BSA-antibodies with autoantibodies (AAb) frequently detected in type 1 diabetic patients. For the overnight incubation time, there was an enormous overlap in the [125I]BSA binding by serum samples between 52 newly diagnosed type 1 diabetic patients (mean [125I]BSA binding 23.6 +/- 17.4%) and 54 healthy blood donors (mean [125I]BSA binding 10.2 +/- 15.7%). By an incubation time of only 3 min the BSA-antibody prevalence was found to be 15.4% (8/52) for type 1 diabetic patients and 3.7% (2/54) for control subjects. However, there was no association between BSA-Ab and type 1 diabetes-associated antibodies as cytoplasmic islet cell antibodies (ICA), or glutamate decarboxylase autoantibodies. Our results confirm that (i) BSA-Ab occur more frequently in newly diagnosed type 1 diabetic patients compared with a healthy control group and (ii) that the BSA-Ab detected by the fluid-phase radioimmunoassay with an incubation time of 3 min are more disease-associated than the [125I]BSA binding after an overnight incubation. The competitive BSA-Ab fluid-phase radioimmunoassay described is a simple and rapid method to detect antibodies specifically reactive with BSA. It is suggested that the humoral immune reactivity to BSA in type 1 diabetic patients probably reflects an unspecific defect of the immune system and gives no additionally diagnostic value about the type 1 diabetes.
Diabetes Res Clin Pract 1994 Nov
PMID:No association between anti-bovine serum albumin antibodies and islet cell reactive antibodies in newly diagnosed type 1 diabetic patients. 787 48

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

Molecular mimicry between viral antigens and host proteins was often suggested to be involved in induction of autoimmune diseases. In type 1 diabetes where pancreatic beta cells are destroyed by autoimmune phenomena, a linear sequence homology between a major autoantigen, glutamate decarboxylase (GAD), and the 2C protein of coxsackie B4 was identified. In addition, a sequence homology between GAD and the mycobacterial heat shock protein 60 was described and the suggestions were made that molecular mimicry between GAD, coxsackievirus B4-2C protein, and/or heat shock protein 60 (hsp60) may be actively involved in an autoimmune reaction towards the pancreatic beta-cells. Our group was the first to isolate human monoclonal autoantibodies to GAD (MICA 1-6) from a patient with newly diagnosed type 1 diabetes. The MICA allowed a detailed characterization of the diabetes associated self-epitopes in GAD and represent a set of GAD autoantibodies present in sera from patients with type 1 diabetes. Using deletion mutants of GAD we demonstrated that the regions of GAD covering the homology sequences to coxsackievirus B4 and to the hsp60 were absolutely required for binding of the MICA to GAD. We now designed an antibody-based analysis to ask whether molecular mimicry between GAD and coxsackie B4-2C or hsp60 is relevant in type 1 diabetes. Since part of the MICA recognize conformational epitopes, they allow to test for conformational molecular mimicry in viruses that have been incriminated in the development of type 1 diabetes. Our data reveal no crossreactivity between the diabetes associated GAD epitopes defined by the MICA and hsp60, rubellavirus, cytomegalovirus, and coxsackie B1-B6 virus antigens. Neither coxsackie B4-specific antibodies in sera from normal individuals nor GAD-positive sera from patients with type 1 diabetes indicated a crossreactivity between coxsackie B4-2C and GAD. Although the regions in GAD homologous to coxsackie B4-2C and hsp60 represented parts of GAD indispensible for binding of diabetes associated autoantibodies they did not mediate a crossreactivity of autoantibodies between GAD and these two proteins. No evidence for molecular mimicry between GAD and a whole panel of foreign antigens was detected by autoantibodies in type 1 diabetes.
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PMID:Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies. 791 51

Apart from islet cell antibodies (ICAs), antibodies to glutamate decarboxylase (GAD), insulin autoantibodies (IAAs), and a novel islet antigen (37k antigen) are potential markers for insulin-dependent diabetes mellitus (IDDM). GAD is also an antigen in stiff-man syndrome (SMS), and both SMS and IDDM are associated with ICAs and autoimmunity to other endocrine organs. We investigated possible links between antibody responses to islet antigens with autoimmunity to other endocrine organs and determined which specific antibodies can identify individuals who progress to IDDM. Antibodies to GAD were detected in > or = 90% of both diabetic and nondiabetic patients with ICAs and other endocrine autoimmunity, in 59% of ICA-positive IDDM patients without endocrine autoimmunity, in all patients with SMS, but in only 1-3% of healthy (nondiabetic) and autoimmune disease control subjects. GAD antibody levels were increased in ICA-positive IDDM patients with polyendocrine autoimmunity compared with those without. In contrast, antibodies to 37k antigen were only detected in patients who developed acute-onset IDDM. IAAs were also associated with IDDM. Thus, certain factors enhance antibody responses to GAD in polyendocrine autoimmunity, but this does not necessarily lead to development of IDDM or SMS. Antibodies to 37k antigen are strongly associated with acute-onset IDDM and are useful serological markers for disease.
Diabetes 1994 Oct
PMID:Antibodies to islet 37k antigen, but not to glutamate decarboxylase, discriminate rapid progression to IDDM in endocrine autoimmunity. 792 97

Insulin-dependent diabetes (IDD) results from the autoimmune destruction of the insulin-producing pancreatic beta cells. Autoreactive T-lymphocytes are thought to play a pivotal role in the pathogenesis of IDD; however, the target antigens of these cells, as well as the inductive events in the disease, are unclear. PBMC in persons with or at increased risk for IDD show elevated reactivity to the beta cell enzyme glutamate decarboxylase (GAD). To identify the T-lymphocyte-reactive determinants of GAD, an overlapping set of synthetic peptides was used to stimulate the PBMC from these individuals, PBMC responsiveness to GAD peptides was not restricted to those with IDD, and a number of peptides elicited responses in PBMC. However, the major determinant of GAD recognized by persons at increased risk for IDD was amino acids 247-279, a region which has significant sequence similarity to the P2-C protein of Coxsackie B virus (47% of 15 increased risk [islet cell autoantibody-positive relatives]; 25% of 16 newly diagnosed IDD patients; and 0% of 13 healthy control subjects). Responses to tetanus and insulin antigens were not different between the study groups. In addition, PBMC from individuals responding to GAD peptides within 247-279 also responded to a Coxsackie viral peptide (i.e., P2-C amino acids 32-47), an observation supporting potential molecular mimicry in this immune response. Although the role of environmental agents in the pathogenesis of the disease remains unclear, these cellular immunological findings support the epidemiological evidence suggesting an inductive role for enteroviruses like Coxsackie B in the autoimmunity underlying IDD.
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PMID:Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. 796 18

Limited regions of amino acid sequence similarity frequently occur between microbial antigens and host proteins. It has been widely anticipated that during infection such sequence similarities could induce cross-reactive T cell responses, thereby initiating T cell-mediated autoimmune disease. However, the nature of major histocompatibility complex (MHC)-restricted antigen presentation confers a number of constraints that should make this type of T cell cross-reactivity a rare, MHC allele-dependent event. We tested this prediction using two insulin-dependent diabetes mellitus (IDDM)-associated antigens, coxsackievirus P2-C (Cox P2-C) protein and glutamate decarboxylase (GAD65), which share a prototypic sequence similarity of six consecutive amino acids within otherwise unrelated proteins. We surveyed a panel of 10 murine MHC class II alleles that encompass the spectrum of standard alleles for the ability to cross-reactively present Cox P2-C and GAD65. Out of the 10 restriction elements tested, the sequence similarity regions were both dominant determinants and were cross-reactively displayed after the natural processing of whole antigens, only in the context of I-Anod. These data show that cross-reactive T cell recognition of sequence similarity regions in unrelated proteins is confined to certain MHC alleles, which may explain MHC association with autoimmune disease. It is striking that these two diabetes-associated antigens were cross-reactively recognized only in the context of a diabetes susceptibility allele. Since the human and the murine class II alleles associated with IDDM share conserved features, cross-reactive T cell recognition of GAD65 and Cox P2-C may contribute to the pathogenesis of human IDDM and account for the epidemiological association of coxsackievirus with IDDM.
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PMID:T cell cross-reactivity between coxsackievirus and glutamate decarboxylase is associated with a murine diabetes susceptibility allele. 796 74

The contribution of glutamate decarboxylase (Mr 65000) antibodies to the reactivity of islet cell cytoplasmic antibodies with the 'whole' islet staining pattern from patients with newly diagnosed Type I diabetes was investigated. Diluted sera (n = 10) were preincubated with increasing concentrations of purified recombinant human islet glutamate decarboxylase (Mr 65000) and the change in islet cell cytoplasmic antibody binding was evaluated by quantitative immunocytochemistry. Binding to islet cells was partially blocked by glutamate decarboxylase in 9/10 diluted sera; the maximum blocking obtained at high concentrations of glutamate decarboxylase (5 micrograms/ml) was 36% (median, range 24-61%). In contrast, binding to islet cells in three diluted sera (two polyendocrine patients without Type I diabetes and one patient with newly diagnosed Type I diabetes) with the 'selective' islet staining pattern was totally blocked by glutamate decarboxylase. The concentration of glutamate decarboxylase required to achieve maximum blocking was less for the 'whole' islet (0.4-8.0 micrograms/microliters undiluted serum) compared to the 'selective' islet (20-645 micrograms/microliters undiluted serum) positive sera. All sera were positive for glutamate decarboxylase antibodies in an immunoprecipitation assay using 35S-methionine labelled extract of baby hamster kidney cells transfected with glutamate decarboxylase. However, the binding activity of these antibodies was less in the sera positive for the 'whole' islet compared to the 'selective' islet staining pattern. In conclusion, glutamate decarboxylase antibodies contribute partially to the reactivity of islet cell cytoplasmic antibodies of the 'whole' islet staining pattern in the sera of newly diagnosed patients with Type I diabetes, and totally to reactivity of the 'selective' islet staining pattern. The antigens recognized by the other antibodies contributing to the 'whole' islet reactivity remain to be defined.
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PMID:Contribution of glutamate decarboxylase antibodies to the reactivity of islet cell cytoplasmic antibodies. 798 Aug 51

A new and novel form of L-glutamate decarboxylase (GAD; EC 4.1.1.15) was purified from whole porcine brain to apparent homogeneity by a combination of column chromatographies on DE-52, ultragel AcA 34, hydroxylapatite and Sephadex G-200, and native gel electrophoresis. The purified GAD was established as an integral membrane protein based on hydrophobic interaction chromatography and membrane extraction studies. This membrane GAD (MGAD) has a native molecular weight of 120 +/- 5 kDa and is a homodimer of 60 +/- 2 kDa. Immunoprecipitation and immunoblotting tests using the sera from insulin-dependent diabetes mellitus (IDDM) patients revealed the presence of antibodies against this newly identified MGAD in IDDM. The role of MGAD in the pathogenesis of IDDM and related autoimmune disorders is also discussed.
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PMID:An integral membrane protein form of brain L-glutamate decarboxylase: purification, characterization and its relationship to insulin-dependent diabetes mellitus. 803 92

The diabetes syndrome of the BB rat resembles human Type 1 (insulin-dependent) diabetes including the prevalence of autoantibodies to the 64 kDa Beta-cell autoantigen, which has been identified as glutamate decarboxylase. This study aimed at detecting the prevalence and level of glutamate decarboxylase autoantibodies in 120-day-old diabetic and non-diabetic diabetes-prone BB/OK rats compared to those of sex- and age-matched diabetes-resistant LEW.1A rats. The antibodies were detected using semipurified glutamate decarboxylase from rat brain in two immunoassays, a direct and a sandwich enzyme-linked immunosorbent assay. For the last assay autoantibody-containing immunoglobulins of a serum from a patient with the stiff-man syndrome were used to bind specifically the enzyme as autoantigen in plastic wells. The antibody levels measured as optical density at 490 nm (x +/- SD)/prevalence of the diabetic group (120 +/- 29 days of age) of BB/OK rats 0.57 +/- 0.29 (n = 51)/88% as well as those of the nondiabetic group (121 +/- 26 days of age) with 0.51 +/- 0.29 (n = 32)/97% was significantly increased (p < 0.01) compared to those of the diabetes-resistant control group 0.15 +/- 0.06 (n = 29)/0%. Furthermore in a 209 +/- 27-day-old group (n = 21) of non-diabetic but diabetes-prone BB/OK rats the autoantibody levels of 1.21 +/- 0.39 vs 0.51 +/- 0.26 were further significantly enhanced (p < 0.01). These results were confirmed by a sandwich assay.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoantibodies to glutamate decarboxylase detected in diabetes-prone BB/OK rats do not distinguish onset of diabetes. 805 59

The aims of our study were to correlate the specificities of islet cell cytoplasmic autoantibodies (ICA) observed in 14 first-degree relatives of diabetic patients with the development of clinical diabetes. To detect whether ICAs recognized in an homogeneous fashion the two major islet cell components, namely beta and alpha cells, the number of islet cells simultaneously recognized by ICAs and anti-glucagon antibodies was determined using a four layer indirect immunofluorescence technique and confocal laser microscopy. The different types of pattern, either whole islet cell staining (type I) or beta cell predominant staining (type II), was then correlated to the presence of autoantibodies to glutamate decarboxylase (GAD), as well as to metabolic outcome. Eight relatives (57.2%) had the type I pattern and 6 (42.8%) the type II pattern. Type 1 diabetes occurred in all ICA positive relatives with the type I pattern and in only 2 out of the 6 relatives with the type II pattern. Interestingly, this later pattern was significantly associated with the presence of autoantibodies to GAD although 2 relatives with antibodies with the type I pattern were also positive. Although more effective for 5 sera with the type II pattern, preincubation with rat brain homogenate significantly decreased the titres of 3/6 sera with the type I pattern. Altogether, our results suggest that autoimmunity to beta cells may be associated with antibodies directed to separate autoantigens with different cellular distributions. From these observations, additional autoantigens distinct from glutamate decarboxylase are also certainly involved.
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PMID:Heterogeneity of islet cell cytoplasmic antibodies and autoantibodies to glutamate decarboxylase in relatives of patients with type 1 (insulin-dependent) diabetes. 808 16


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