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

Modulation of beta-cell antigens at birth may affect the course of type I diabetes. Since the functional state of beta cells modulates antigen expression, we investigated whether neonatal injections of glucose and arginine (G-A) influence diabetes in non-obese diabetic (NOD) mice. Two groups of 90 mice (45 female, 45 male) were injected for the first 6 days of life with G-A or saline. To determine whether these injections influenced beta cell functional maturation, isolated islets were characterized according to insulin response to glucose or arginine. Modulation of antigens for islet-cell autoantibodies (ICA antigens) was analyzed by indirect immunofluorescence using ICA-positive human sera. Variations of pancreatic glutamic acid decarboxylase 67-kD (GAD 67) mRNA were evaluated by polymerase chain reaction (PCR), hybridization with a 32P-labeled probe, and densitometry of the autoradiographic bands. Female NOD mice treated with G-A displayed diabetes earlier and with a higher incidence (P < .01) than control mice, whereas the diabetes incidence was not statistically modified in G-A-treated male NOD mice. Insulitis was more severe (P < .03) in 2-month-old G-A-treated female NOD mice than in control mice, but was not statistically modified in male NOD mice. In both sexes, ICA antigens and GAD 67 mRNA were higher in G-A-treated mice than in control mice (P < .01). Islets isolated after neonatal G-A injections exhibited improved insulin sensitivity to both stimuli (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diabetes enhancement and increased islet antigen expression following neonatal injections of glucose and arginine in non-obese diabetic mice. 796 96

Antibodies to glutamic acid decarboxylase (anti-GAD) are common in typical insulin-dependent diabetes mellitus, and also identify a sub-group of older persons who are originally misdiagnosed as having non-insulin-dependent disease (NIDDM). The Wanigela people of Papua New Guinea are highly susceptible to diabetes mellitus, with a prevalence of 20.4% in urbanised young adults aged 25-34 years. On the basis of clinical features including the presence of obesity and relatively high insulin concentrations the Wanigelas have NIDDM. To determine whether anti-GAD is present in this high prevalence form of diabetes, and to investigate whether there might be an autoimmune component to the disease, we measured anti-GAD in 93 newly-diagnosed diabetic subjects aged 25-44 years, and in 40 controls with normal glucose tolerance. There was no difference in mean levels of anti-GAD in diabetic subjects and normal controls. Two subjects had borderline elevated anti-GAD levels: one was a normal control, and the other a diabetic. This study shows that anti-GAD is not present in this (and probably other) high prevalence variant of NIDDM. Moreover, the results suggest strongly that diabetes in the Wanigela people is unlikely to have an autoimmune component to its pathogenesis.
Diabetes Res Clin Pract 1994 Jul
PMID:Lack of antibodies to glutamic acid decarboxylase in young adults of the high diabetes prevalence Wanigela people of Papua New Guinea. 798 52

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

Glutamic acid decarboxylase antibodies (GADAbs) are being increasingly used in clinical and research programs for the prediction and classification of insulin-dependent diabetes mellitus (IDDM). A number of different assay formats for the measurement of GADAbs have been reported, but the degree of concordance between assays is unknown. In this study, GADAbs were measured on 16 coded sera in 34 assays to examine concordance between GADAb assays and establish the feasibility of an international GADAb standard of measurement unit. The 16 lyophilized coded samples consisted of sera from healthy control subjects (n = 2), IDDM patients (n = 3), a patient with polyendocrine autoimmunity (n = 1), and duplicate dilutions of plasmapheresis serum from a patient with stiff-man syndrome (SMS). A high level of concordance was found in the ranking of GADAb levels (P = 0.99, Friedman's test) in the samples. Thirteen (38%) assays could reproducibly distinguish dilutions of SMS serum and detect GADAbs in all IDDM and polyendocrine autoimmunity sera tested. Although assessed on only four samples, disease specificity was 100% in 29 assays. The majority of assays that immunoprecipitated radiolabeled GAD gave high results for sensitivity and specificity. Enzyme-linked immunosorbent assays and assays using immunofluorescence were generally less sensitive. Several assays, in particular those measuring GAD enzymatic activity immunoprecipitated in fluid phase from rat brain homogenate, showed a prozone-like phenomenon in the SMS dilution curve. Interpolation of results from a standard curve into workshop units resulted in relatively low scatter in samples with lower levels of GADAbs. Hence, the use of an international reference serum to enable comparison of results between laboratories appears feasible.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Aug
PMID:High level of concordance between assays for glutamic acid decarboxylase antibodies. The First International Glutamic Acid Decarboxylase Antibody Workshop. 803 93

With regard to progression to diabetes, ICA cross-reactive with mouse pancreas, antibodies to the M(r) 64,000 islet antigen (64K), antibodies immunotrapping brain GAD activity, and IAA were analysed in 53 ICA-positive first-degree relatives of IDDM patients and 18 ICA-positive schoolchildren without a family history of diabetes. Sera from 29 (55%) relatives did not bind to mouse pancreas, whereas 24 (45%) displayed cross-species reaction. ICA titres on human and mouse pancreas were weakly correlated in the overall population (p < 0.05) but more strongly (p < 0.01) in only those subjects who displayed antibodies on tissues from both species. GAD and 64K antibodies were detected in 31% and 35% of relatives. In schoolchildren, the frequencies of cross-species reactive ICA (22%), GAD antibodies (6%), 64K antibodies (22%), and IAA (6%), were lower (p < 0.05) than in relatives. A strong correlation (p < 0.0001) was observed between GAD and 64K antibodies. GAD or 64K antibodies were strongly correlated with ICA on human pancreas (p < 0.0001) but poorly with ICA on mouse pancreas (p = 0.05). After pre-incubation of sera with brain homogenate, ICA titres were unaffected on mouse pancreas but reduced on human pancreas. ICA-positive subjects who displayed neither cross-species reactive ICA nor GAD or 64K antibodies were more frequent (p < 0.05) among schoolchildren than relatives, whereas subjects who displayed all antibody specificities were more numerous (p < 0.04) in relatives. All relatives with ICA binding only to human pancreas, as well as all schoolchildren, permanently displayed an AIRG higher than the first control percentile and remained non-diabetic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined analysis of islet cell antibodies which cross-react with mouse pancreas, antibodies to the M(r) 64,000 islet protein, and antibodies to glutamate decarboxylase in subjects at risk for IDDM. 805 87

The 12th International Immunology of Diabetes Workshop was held during April 1993 in Orlando, Florida, to review research progress since the 11th Immunology of Diabetes Workshop meeting in Nagasaki, Japan, one and a half years before. The NOD mouse may have as many as 10 susceptibility genes, including its novel IA major histocompatibility complex antigen and a defective interferon-gamma receptor, whereas human IDDM is so far known to be encoded by cis and trans complementation products of certain DQ genes on chromosome 6q, and a gene in the insulin-like growth factor II region on chromosome 11p. A unique protein regulator of the X box promotor of the highly susceptible DQB1*0302 allele has also been found. Islet cell antibody negative siblings of IDDM patients appear to have lower than expected abilities to secrete insulin in response to intravenous glucose. Sera from patients before and/or after developing IDDM immunoprecipitate two native proteins of 64,000- and 38,000-M(r) glutamic acid decarboxylase (GAD65) reacting to conformational epitopes. However, a multitude of other autoantibodies often reacting to denatured proteins through linear epitopes have also been identified. The first workshop for GAD antibody assays was successfully completed; however, the 38,000-M(r) antigen has not yet been identified. Other autoantibodies reactive to gangliosides and to sulfatides continue to be reported. Insulitis has come to be recognized as a sometimes protective event. Protective insulitis predominates in older lesions. It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Aug
PMID:The 12th International Immunology and Diabetes Workshop. Orlando, Florida. 810 Jul 86

Antibodies to glutamic decarboxylase (GADAb) are present in insulin-dependent diabetes (IDD) but their association with age and sex and their temporal profile in relation to disease onset have not been fully documented. We have examined the association between GADAb and islet cell antibodies (ICA), age and sex, and have cross-sectionally and longitudinally measured the levels of GADAb before and after diagnosis of IDD. GADAb were measured by allowing serum immunoglobulin prebound to protein A Sepharose to precipitate GAD enzymatic activity from a fetal pig brain extract. GADAb levels were above the normal range (mean + 3SD of healthy controls, 460 nU/ml) in 19/44 (43%) at-risk subjects (ICA positive first degree relatives of persons with IDD), 35/108 (32%) recent-onset IDD subjects and 22/46 (47%) established IDD subjects. When analysed according to age and sex, GADAb levels were significantly higher (P < 0.05) in post-pubertal females in at-risk, recent-onset and established IDD groups. There was a significant association between GADAb and ICA > 20 in both first degree relatives (P < 0.001) and recent-onset subjects (P < 0.01) and GADAb were uncommon in the absence of ICA. Levels of GADAb were similar in at-risk, recent-onset and established IDD subjects and GADAb status remained stable in all but 2/41 at-risk subjects followed for 17 (mean, range 3-33) months. In conclusion, GADAb levels are strongly influenced by age, sex and ICA status, and generally remain stable in at-risk subjects and after the onset of clinical IDD.
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PMID:Antibodies to glutamic acid decarboxylase in at-risk and clinical insulin-dependent diabetic subjects: relationship to age, sex and islet cell antibody status, and temporal profile. 819 2

Type I, insulin-dependent diabetes (IDD) results from an autoimmune response against the insulin producing pancreatic beta cells. This autoimmune reaction involves both humoral and cell-mediated factors; nevertheless, the relative role of each remains unresolved. Furthermore, while adoptive transfer experiments have provided evidence for the role of T cells in beta cell destruction, the specific events which initiate leukocyte migration into the islets (insulitis) are unknown. Earlier studies indicated that NOD pancreatic beta cells may bind small amounts of autoantibody. Because of the possible importance of an early humoral response to the initiation of insulitis and subsequent disease, we have investigated a number of aspects of this phenomenon to determine the nature and specificity of the early autoantibodies as well as the time at which autoantibody binds to beta cells. Results of this study demonstrate that NOD/Uf mice are sensitized to islet-cell associated antigens, including GAD, prior to the first appearance of insulitis; that a small percentage of the beta cells of NOD/Uf mice have autoantibody bound to their surface prior to insulitis; that sera collected from preinsulitis NOD/Uf mice contain autoantibodies which will bind to beta cells of both IDD-prone and IDD-resistant mice; and that the autoantibodies which bind pancreatic beta cells are predominantly IgM with lesser amounts of IgG and IgA. These findings suggest that, in the natural course of IDD, insulitis may develop in response to an initial autoantibody-mediated injury of beta cells.
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PMID:Insulin-dependent diabetes in the NOD mouse model. I. Detection and characterization of autoantibody bound to the surface of pancreatic beta cells prior to development of the insulitis lesion in prediabetic NOD mice. 821 37

Sera from 114 first-degree relatives of insulin-dependent diabetes mellitus (type I diabetes) patients and 81 healthy individuals living in Germany were analyzed for antibodies to rat brain glutamic acid decarboxylase (GAD-ab) using an immunoprecipitation assay. The determination of GAD-ab in the 81 islet cell antibody (ICA) and insulin autoantibody (IAA) negative healthy individuals established a normal range (mean +/- 2 SD); 2 healthy individuals (2.5%) possessed GAD-ab levels above this range, but became negative on follow-up. None of 86 ICA-/IAA- first-degree relatives had GAD-ab; whereas, 42.9% of 28 ICA+ and/or IAA+ relatives were positive for GAD-ab. Presence of GAD-ab was negatively correlated with IAA (P = 0.02) and positively with ICA (P = 0.0006). Follow-up samples were obtained from 25 of 28 ICA+ and/or IAA+ relatives with a mean (+/- SD) follow-up period of 20.6 +/- 12.1 months. In these 25 relatives, GAD-ab were positive in 70% ICA+/IAA-, 0% ICA-/IAA+, and 57.1% ICA+/IAA+ relatives in the first sample and in 57.1% ICA+/IAA-, 0% ICA-/IAA+, and 70% ICA+/IAA+ relatives in the last sample. GAD-ab, once detected, persisted in 9 of 11 GAD-ab+ relatives. Of the relatives, 2 converted to GAD-positivity, concomitant with the appearance of ICA, and 2 others lost GAD-ab during follow-up. Of the 28 ICA+ and/or IAA+ relatives, 6 progressed to overt type I diabetes on follow-up, and GAD-ab were detectable in 4 of these relatives.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Jan
PMID:Associations of anti-GAD antibodies with islet cell antibodies and insulin autoantibodies in first-degree relatives of type I diabetic patients. 826 11

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)
Diabetes 1994 Jan
PMID:Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes. 826 14


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