UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The frequency of antibodies to glutamic acid decarboxylase (GAD) and insulin (IAA) in presymptomatic Type 1 diabetes mellitus with a positive test for antibodies to islet cell antigen (ICA) was examined. Thirty-two persons positive for ICA (> 10 JDF units) were tested 2 to 48 months before their ascertained onset of Type 1 diabetes. ICA was quantitated by immunofluorescence as JDF units, anti-GAD by radioimmunoprecipitation and anti-insulin by radioimmunoassay. There was a positive test for anti-GAD in 25 (78%), and for IAA in 23 (72%), of the 32 prediabetic ICA-positive subjects. Stratification according to age at the onset of diabetes showed differing frequencies of anti-GAD and IAA in the prediabetic stage. Thus the positivity rate for anti-GAD for 18 subjects older than 10 years at onset of diabetes was 83%, and for 14 aged 10 or younger at onset was 71%; conversely, the rate for IAA for 18 subjects older than 10 at onset was 56% and for 14 aged 10 or less at time of onset was 93% (p = 0.01). The frequency of anti-GAD was higher in females (88%) than males (71%) whereas the frequency of IAA was higher in males (82%) than in females (60%). Since autoantibodies to GAD and insulin occur in presymptomatic Type 1 diabetes with differences in frequencies by age and gender, the stimuli to autoimmunity may operate differently at different ages, and may also be gender-related.
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PMID:Autoantibodies to glutamic acid decarboxylase and insulin in islet cell antibody positive presymptomatic type 1 diabetes mellitus: frequency and segregation by age and gender. 770 24

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

IDDM is known to be a heterogeneous disease which is frequently complicated with other autoimmune diseases (AID). We previously reported that IDDM patients with AID were characterized by late onset of diabetes, persistent ICA-positivity and increased association with DR9, while those without AID were characterized by rapid decline of ICA with duration of diabetes and increased association with DR4. The present study was performed to investigate the prevalence of autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64KDa islet cell protein (64K antibodies) and islet cell antibodies (ICA) in Japanese IDDM patients with and without AID. In short-duration diabetes (< 1 year), the prevalence of GAD antibodies, 64K antibodies and ICA were 100%, 100%, and 100%, respectively, in IDDM patients with AID, and 82%, 64% and 82%, respectively, in patients without AID. In long-standing diabetes (3-28 years), the prevalence of GAD antibodies were 76%, 48% and 33%, respectively, in IDDM patients with AID, and 48%, 28% and 16%, respectively, in patients without AID. The mean levels of GAD antibodies, 64K antibodies and ICA in IDDM patients with AID was significantly higher than in those without AID. Furthermore, the prevalence of GAD antibodies were detected more frequently than ICA and 64K antibodies in long standing IDDM patients. Our results demonstrate that the prevalence of GAD antibodies in IDDM patients were as high as those reported in Caucasians, and high levels of GAD antibodies were observed in IDDM patients with AID.
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PMID:Autoantibodies to glutamic acid decarboxylase (GAD), 64,000-Mr islet cell protein (64K) antibodies and islet cell antibodies (ICA) in insulin-dependent diabetes mellitus with and without autoimmune diseases in Japan. 785 40

Intrathymic (i.t.) injection of islet cells or whole islets retards development of insulin dependent diabetes mellitus (IDDM) in spontaneous animal models of the disease. Protection of 4-week-old prediabetic NOD/Lt female mice from subsequent IDDM development was specific for the it route of administration since intraperitoneal injection of an equal number of syngeneic islets failed to retard IDDM. The protective effect of i.t. injection of islet cells was compared with the effect of i.t. injection of syngeneic peritoneal exudate cells, NIT-1 cells, bovine serum albumin (BSA), ABBOS peptide, a 52 kDa islet cell membrane protein, various synthetic peptides from human glutamic acid decarboxylase (GAD) and a Coxsackievirus B4-derived peptide with homology to GAD. Interestingly, only a GAD-derived peptide containing sequence homology to Coxsackie-virus B4, and the corresponding Coxsackievirus B4-derived peptide, delayed IDDM onset. To establish the immunological mechanism underlying the reduced IDDM incidence following i.t. injection of islet cells, adoptive transfer of splenic leukocytes into NOD-scid/scid mice was performed. Splenic leukocytes from i.t.-injected non-diabetic females transferred IDDM into NOD-scid/scid recipients, but more slowly than splenocytes from unmanipulated, diabetic (control) donors. Co-transfer of 1:1 mixtures of splenic leukocytes from it islet-injected (and diabetes-free) NOD/Lt females and from untreated NOD/Lt diabetic donors produced IDDM as rapidly as splenocytes from diabetic donors injected alone. Hence, any peripheral suppression generated in i.t.-protected females was not sufficiently strong to prevent IDDM transfer by committed T-effector cells from the diabetic donors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The thymus as a site for evaluating the potency of candidate beta cell autoantigens in NOD mice. 788 41

Insulin-dependent diabetes mellitus (IDDM), in which only the pancreatic beta cells are destroyed by the autoimmune response, is the paradigm of organ-specific autoimmunity. As a result of a combination of factors, the number of immunohistologic/cellular/molecular studies of pancreas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one long standing (case 2). In case 1, we demonstrated the presence of morphologically normal viable beta cells without evidence of viral infection. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in the islet cells whereas expression of hsp60, another putative autoantigen, was normal. Over-expression of HLA class I was detected in 58% of the islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any insular cell type. In case 1, there was "inappropriate" HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpression, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overexpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 had CD8+ lymphocytes as the predominant population. Reverse transcription-PCR demonstrated moderate V beta skewing and the profile of cytokines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perforin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differently from spontaneous animal models of diabetes, in the pancreas of IDDM patients there are no elements of the inductive phase of the autoimmune response.
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PMID:Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. 791 15

A recent report identified two islet cell cytoplasmic antibody subclasses using an immunohistochemical method. The islet cell cytoplasmic antibody subclass which reacts with only Beta-cells was termed 'Beta-cell islet cell cytoplasmic antibodies' and another islet cell cytoplasmic antibody subclass which reacts with Beta and non-Beta cells was called 'whole islet cell cytoplasmic antibodies'. The whole islet cell cytoplasmic antibody reactivity with pancreatic islets has been shown not to be abolished by pre-incubation with rat brain homogenate. In this study, we examined the inhibitory effect of purified glutamic acid decarboxylase to islet cell cytoplasmic antibody reactivity among whole islet cell cytoplasmic antibodies and assessed the heterogeneity of islet cell cytoplasmic antibodies. Auto-antibodies to 64,000 Mr islet cell protein (64 K antibodies) were also determined by conventional method. Sera from 17 Type 1 (insulin-dependent) diabetic patients containing whole islet cell cytoplasmic antibodies with more than 20 Juvenile Diabetes Foundation units were used. In 11 (78.6%) of 14 sera positive for 64 K antibodies, the reactivity of islet cell cytoplasmic antibodies was markedly blocked by pre-incubation with purified glutamic acid decarboxylase. In contrast, none of the 64 K antibody-negative sera were blocked. All of the patients showed similar clinical characteristics regardless of the inhibitory effect of glutamic acid decarboxylase on islet cell cytoplasmic antibodies, except for islet cell cytoplasmic antibody titer and glutamic acid decarboxylase antibody titer. The mean log 2 islet cell cytoplasmic antibody titer was 2.4 +/- 0.6 (mean +/- SD) JDF unit in the 'markedly blocked' group and 1.6 +/- 0.3 (mean +/- SD) in the 'never blocked' group. The islet cell cytoplasmic antibody titer was significantly higher (P < 0.05) in the former, and the mean glutamic acid decarboxylase antibody titer was 624 +/- 127.0 (mean +/- SE) units in the 'markedly blocked' group and 127 +/- 55.5 (mean +/- SE) in the 'never blocked' group. The glutamic acid decarboxylase antibody titer was also significantly higher (P < 0.05) in the former. We demonstrated here that some whole islet cell cytoplasmic antibodies are absorbed by purified glutamic acid decarboxylase, suggesting heterogeneity of islet cell cytoplasmic antibodies among the 64 K glutamic acid decarboxylase antibody positive group.
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PMID:The heterogeneity of whole islet cell cytoplasmic antibodies evidenced by absorption test with glutamic acid decarboxylase. 791 10

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and M(r) 37,000 and M(r) 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs > or = 10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43% risk of IDDM within 10 years for those with ICAs > or = 10 JDF U, rising to 53% for those with ICAs > or = 20 JDF U. The risk for ICAs > or = 10 JDF U was 62% in the family members in the youngest age quartile (< 13.2 years) and fell with increasing age to 4% in those > 40.7 years of age (P = 0.03). ICAs > or = 10 JDF U combined with IAAs gave a risk of 84% (P = 0.03 compared with IAA-), and ICAs > or = 10 JDF U combined with GAD antibodies gave a risk of 61% (P = 0.018). The risk for ICAs > or = 10 JDF U with antibodies to 37-kDa antigen was 76% (P < 0.0001). Risk increased with the number of autoantibodies, from 8% for ICAs alone to 88% with > or = 3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. 792 4

Insulin-dependent diabetes mellitus (IDDM) is associated with the formation of autoantibodies against different antigens in the islets of Langerhans, so-called islet cell antibodies (ICA). The expression of a major autoantigen, the beta-cell specific enzyme glutamic acid decarboxylase (GAD), is glucose-dependent in vitro and correlated to insulin release in vitro. In this study the expression of islet autoantigens was examined in vivo and the relationship between beta-cell function and islet cell surface antibody (ICSA) reactivity was tested. Rats were fed for 10 days with glipizide or diazoxide, in order to stimulate or inhibit insulin release, respectively. Frozen sections of pancreata were incubated with ten ICA-positive IDDM sera and analyzed by indirect immunofluorescence. Two sera with a "beta-cell restricted" staining, five with an "all-islet cell" staining and three with a "mixed" pattern were employed. In all three groups, the highest end-point titres were obtained when pancreata of rats treated with glipizide were used. Intermediate titres were seen in control animals and the lowest titres were observed on pancreata from diazoxide-treated rats, regardless of the serum used. In contrast to these observations, no correlation between ICSA reactivity and islet cell activity could be demonstrated. Conflicting results concerning ICSA in previous reports and our failure to show a glucose regulation of ICSA reactivity, indicate that ICSA is a phenomenon with a low degree of specificity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of beta-cell activity and its influence on islet cell antibody (ICA) and islet cell surface antibody (ICSA) reactivity. 800 13

Type 1 diabetes mellitus in adults may present in a manner similar to that of Type 2 diabetes but with a late development of insulin dependency. We studied 65 patients who presented with 'adult-onset' diabetes after the age of 30 years. Of these patients, 19 required insulin therapy. The insulin-treated patients were significantly younger, their onset of diabetes was at an earlier age, and their postprandial serum C-peptide levels were lower than those of the non-insulin-treated group. Moreover, the insulin-treated subjects had a higher mean concentration of antibodies to glutamic acid decarboxylase (GAD) (66.8 +/- 10.2 units) than the patients who did not require insulin (9.9 +/- 1.9 units) (p < 0.001) and their frequency of anti-GAD positivity was 73.7% versus 4.3% (p < 0.001). Thus, among patients attending a diabetes clinic, the majority (73.7%) of subjects who presented with diabetes after 30 years of age and who subsequently required therapy with insulin, actually have the islet cell lesion of Type 1 diabetes which progresses at a slower tempo than in children. We conclude that testing for anti-GAD in adult-onset non-obese diabetic patients should be a routine procedure in order to detect latent insulin-dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.
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PMID:Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. 803 30

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)
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PMID:The 12th International Immunology and Diabetes Workshop. Orlando, Florida. 810 Jul 86

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