Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Patients with insulin-dependent diabetes mellitus (IDDM) possess antibodies to the cytoplasmic domains of two closely related tyrosine phosphatase-like proteins, IA-2 and phogrin, previously detected as 40 kDa and 37 kDa tryptic fragments, respectively. A higher proportion of IDDM patients possess antibodies to IA-2 than to phogrin, and autoimmunity to phogrin might arise through cross-reactivity with the highly homologous IA-2. In this study, we have investigated the major regions of IA-2 recognized by antibodies in IDDM patients and examined the ability of phogrin to block antibody binding to these regions as a measure of cross-reactivity. Analysis of antibody binding to in vitro transcribed and translated polypeptides representing different regions of the cytoplasmic domain of IA-2 identified five different patterns of reactivity with antibodies in IDDM. Protein footprinting analysis, whereby polypeptide fragments generated on protease treatment of immune complexes are studied, indicated considerable heterogeneity in antibody recognition of IA-2, even between sera with similar reactivity to deletion mutants. Blocking studies with recombinant phogrin indicated that IA-2 antibodies recognize epitopes that are both unique to IA-2 and shared with phogrin. The amino-terminal 150 amino acids of the cytoplasmic domain of IA-2 encompass epitopes that are not represented on phogrin, whereas shared epitopes are localized within the carboxy-terminal 220 amino acids. The results demonstrate considerable heterogeneity between IDDM patients in autoantibody recognition of IA-2 in IDDM, whereas antibody recognition of phogrin is restricted in most patients to epitopes also present on IA-2.
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PMID:Cross reactivity between IA-2 and phogrin/IA-2beta in binding of autoantibodies in IDDM. 938 26

The prodromal period of insulin-dependent diabetes mellitus (IDDM) is characterized by circulating islet cell autoantibodies (ICA) and other beta cell specific autoantibodies. Despite biochemical characterization of the major beta cell autoantigens insulin, glutamic acid decarboxylase and protein tyrosine phosphatase and development of the respective antibody assays, ICA has remained the standard in IDDM prediction. Conventional ICA quantitation using classic fluorochromes is prone to errors since fluorescence intensity is estimated subjectively using the human eye, which is also unable to differentiate specific signals from non-specific signals and autofluorescence. Using Eu(3+)-chelate labelled anti-human polyclonal IgG (decay time 1000 microseconds) as the secondary antibody in time-resolved fluorescence imaging (TRFI), the chelate and autofluorescence signals (typical decay time < 100 ns) are fully separated. The image is recorded using an optically gated cooled digital CCD camera. The specificity of the ICA signal is further improved by interactive analysis of the image. Signal detection is objective, the signal-to-background ratio improves, and ICA quantitation is possible using undiluted serum. Of 57 consecutive new-onset IDDM patients, 55 (96.5%) were ICA positive in the new assay while 51 (89.5%) were positive in the conventional assay suggesting that the sensitivity of TRFI exceeds that of the IAA, GAD65 and IA-2 autoantibody assays combined. For later comparisons, the stained slides may be stored in the light for years without any decrease in specific fluorescence.
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PMID:Time-resolved fluorescence imaging in islet cell autoantibody quantitation. 943 72

An unselected population of 755 siblings of children with insulin-dependent diabetes mellitus (IDDM) was studied to evaluate the predictive characteristics of islet cell antibodies (ICA), antibodies to the IA-2 protein (IA-2A), antibodies to the 65-kD isoform of glutamic acid decarboxylase (GADA), insulin autoantibodies (IAA), and combinations of these markers. We also evaluated whether the histochemical ICA test could be replaced by the combined detection of other markers. 32 siblings progressed to IDDM within 7.7 yr of the initial sample taken at or close to the diagnosis of the index case (median follow-up, 9.1 yr). The positive predictive values of ICA, IA-2A, GADA, and IAA were 43, 55, 42, and 29%, and their sensitivities 81, 69, 69, and 25%, respectively. In contrast to the other three antibody specificities, GADA levels were not related to the risk for IDDM. The risk for IDDM in siblings with four, three, two, one, or no antibodies was 40, 70, 25, 2, and 0.8%, respectively. Combined screening for IA-2A and GADA identified 70% of all ICA-positive siblings, and all of the ICA-positive progressors were also positive for at least one of the three other markers. The sensitivity of the combined analysis of IA-2A and GADA was 81%, and the positive predictive value was 41%. In conclusion, combined screening for IA-2A and GADA may replace the ICA assay, giving comparable sensitivity, specificity, and positive predictive value. Accurate assessment of the risk for IDDM in siblings is complicated, as not even all those with four antibody specificities contract the disease, and some with only one or no antibodies initially will progress to IDDM.
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PMID:Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group. 943 4

Islet cell antibodies (ICA), the classical autoimmunity marker for insulin-dependent diabetes mellitus (IDDM), are detected in approximately 85% of children with recently diagnosed diabetes. Because the ICA assay is semiquantitative and difficult to standardize, alternative assays are needed. When glutamic acid decarboxylase 65 (GAD 65) was discovered as a major islet antigen, the measurement of antibodies to GAD 65 (GADA) was considered a good alternative to ICA. Recently, however, we showed that 1 in 3 ICA-positive diabetic patients do not have GADA. Now, antibodies against the protein tyrosine phosphatase-like protein IA2 (IA2-ab) have been detected in IDDM. To find out whether measurements of IA2-ab combined with those of GADA could detect autoimmunity to the same extent as ICA, we have measured all three kinds of antibodies (using radioligand binding assays for IA2-ab and GADA) in 100 recently diagnosed diabetic and 100 control children: ICA were found in 87, IA2-ab in 69, and GADA in 66 of the 100 diabetic patients, whereas in the 100 control children ICA were found in 2, IA2-ab in 1, and GADA in 3. Among the 87 ICA-positive patients, 45 (52%) had both IA2-ab and GADA, 21 (24%) had only IA2-ab, and 16 (18%) had only GADA, whereas 5 (6%) lacked both IA2-ab and GADA. Among the 13 ICA-negative patients, 1 (8%) had both IA2-ab and GADA, 2 (15%) had only IA2-ab, and 4 (31%) had only GADA. Thus, 6 of the 100 patients had neither ICA, IA2-ab, nor GADA. Combining the IA2-ab and GADA assays gave positive results for autoimmunity in 89 of the 100 patients, compared with 87 by the ICA assay. The combination of the IA2-ab and GADA assays appears to be an effective alternative to the ICA assay.
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PMID:Protein tyrosine phosphatase-like protein IA2-antibodies plus glutamic acid decarboxylase 65 antibodies (GADA) indicates autoimmunity as frequently as islet cell antibodies assay in children with recently diagnosed diabetes mellitus. 943 55

We previously reported that IA-2 autoantibodies (Ab) facilitated the diagnosis of Japanese insulin-dependent diabetes mellitus (IDDM), but the number tested was not large enough to investigate whether IA-2Ab can improve the diagnostic accuracy. In this report, sera from 78 patients with less than 2 year-disease duration (the mean (range) ages were 19.2 (6-52) years old) were tested in order to clarify that the combination of IA-2Ab and glutamic acid decarboxylase 65 (GAD65)Ab would improve the test sensitivity for IDDM. Both of the autoantibodies were frequently detected in Japanese abrupt-onset IDDM but the frequency of GAD65Ab was higher than that of IA-2Ab (69% and 47%, respectively, P = 0.024). The two autoantibodies were discordant in respect to both positivity and titer. The positivity for IA-2Ab decreased with the increasing onset-age of the patients (76, 47, 37, 21% for each quartile of age tested), but the frequency of GAD65Ab was unaffected. Among the youngest quartile (< or = 12 years old), IA-2Ab, in combination with GAD65Ab, significantly improved sensitivity (68% to 92%, P < 0.05), but when we tested patients over 12 years old, IA-2Ab caused little, if any, improvement in sensitivity. We confirmed that IA-2 antibody was detected in IDDM among Japanese, as seen in Caucasians, but the test sensitivity was improved only in young IDDM patients among Japanese.
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PMID:Autoantibody against IA-2 improves the test sensitivity for insulin-dependent diabetes mellitus in Japanese patients of child onset. 944 80

There is evidence that insulin-dependent diabetes mellitus (IDDM) may develop in association with other non-beta-cell-specific autoimmune diseases. We aimed to assess whether autoantibodies to the islet cell antigens glutamic acid decarboxylase (Mr 65,000 isoform) (GAD65) and ICA512(IA-2), present alone or in combination, are limited to IDDM or also occur in other organ- or non-organ-specific autoimmune disorders. We determined the frequency of these autoantibodies by radioimmunoassay in 199 sera from patients with autoimmune thyroid diseases (AITD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC), and compared the results with those from 507 newly diagnosed patients with IDDM and 280 healthy controls. ICA512(IA-2) autoantibodies were detected exclusively in AITD with concurrent IDDM, but not in other autoimmune diseases without IDDM, whereas GAD65 autoantibodies exceeded the limit of normal in 67.7% (21 of 31) of patients with AITD who also had IDDM and in 5.5% (three of 55) of patients with PBC. The frequency of either GAD65 and/or ICA512(IA-2) autoantibodies was significantly higher in patients with AITD who also had IDDM (27 of 31, 87.1%) than in those with AITD alone (one of 53, 1.9%; P<10(-6)), but was not significantly different from those patients with newly diagnosed IDDM (418 of 507, 82.4%). Neither patients with organ- or non-organ-specific autoimmune diseases without IDDM nor healthy controls had autoantibodies against both GAD65 and ICA512(IA-2). Despite the fact that one of the two autoantibodies was occasionally detected in patients with non-beta-cell-specific autoimmune diseases without IDDM, combined determination of GAD65 and ICA512(IA-2) autoantibodies specifically identified IDDM in the majority of patients with AITD. In conclusion, because of the strong association of IDDM with AITD, testing for multiple islet autoanti-bodies could be useful as a predictive marker for risk of progression to IDDM onset amongst patients with autoimmune thyroid disorders.
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PMID:Combined analysis of GAD65 and ICA512(IA-2) autoantibodies in organ and non-organ-specific autoimmune diseases confers high specificity for insulin-dependent diabetes mellitus. 948 Jul 18

HLA-DQA1*0102/DQB1*0602 (DQ0602) is observed at a decreased frequency in insulin-dependent diabetes mellitus in different ethnic groups, suggesting a protective role for DQ0602. Analysis of overlapping peptides from human insulin found that insulin B(1-15) bound well to DQ0602 and exhibited a high degree of allelic specificity. Truncation analysis of insulin B(1-15) identified insulin B(5-15) as the minimal peptide for DQ0602 binding. Insulin B(5-15) bound to DQ0602 with an apparent KD of 0.7 to 1.0 microM and peptide binding reached equilibrium at 96 h. Single arginine substitutions at each position of the insulin B(5-15) peptide identified amino acids 6, 8, 9, 11, and 14 (relative positions P1, P3, P4, P6, and P9) as important for binding. Extensive substitutions for each of these amino acids revealed that amino acids 11 and 14 (P6 and P9) exhibited the highest specificity. Amino acid 11 (P6) preferred large aliphatic amino acids, while amino acid 14 (P9) preferred smaller aliphatic and hydroxyl amino acids. Binding of an overlapping series of peptides from a randomly chosen protein, the herpes simplex virus-2 tegument protein UL49, correlated completely with the presence or absence of the DQ0602 peptide binding motif. Peptides 11 amino acids long were selected from GAD65, IA-2, and proinsulin, that contained the DQ0602 peptide binding motif. Of these, 79% (19 of 24) were able to bind DQ0602. This study identifies a peptide binding motif for DQ0602 and peptides from insulin-dependent diabetes mellitus autoantigens that bind DQ0602 in vitro.
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PMID:A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. 949 78

A 29-year-old man was observed to develop insulin-dependent diabetes mellitus following a 5-month treatment with recombinant alpha-2b-interferon for chronic hepatitis C. After the onset of the disease, serum samples that had, respectively, been collected before therapy commencement, at month 3, and at the onset of insulin-dependent diabetes mellitus were tested for islet-cell (ICA-IgG), glutamic acid decarboxylase (GAD-Abs), IA2 (IA2-Abs) and insulin (IA-Abs) autoantibodies. The following results were obtained: ICA-IgG, 5, >80, and >80 JDF-U, respectively; GAD-Abs: >100 U/ml in all three measurements; IA2-Abs and IA-Abs: negative. During treatment, thyroid microsomal autoantibodies increased markedly (from 1:100 to 25,600 titer); thyroid-stimulating hormone was persistently normal. HLA class II typing revealed a genetic predisposition to insulin-dependent diabetes mellitus as demonstrated by the presence of DRB1* 04/08, DQ A1 52 Arg+/Arg+, and DQB1 57 N-Asp/Asp alleles. One year after the onset of insulin-dependent diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and HCV-RNA is negative. These data support the hypothesis that, in predisposed patients, alpha-interferon therapy can enhance an ongoing autoimmune process against pancreatic beta-cells and induce overt insulin-dependent diabetes mellitus. We therefore suggest that, in patients with a documented predisposition to insulin-dependent diabetes mellitus, alpha-IFN therapy should be administered with caution.
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PMID:Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. 955 92

To study the relationship of IA-2 antibodies (IA-2A) to other autoantibodies and genetic risk markers in insulin-dependent diabetes mellitus (IDDM), 758 children and adolescents younger than 15 years of age (mean age 8.4 years) with newly diagnosed diabetes were analysed for IA-2A, GAD antibodies (GADA) and insulin autoantibodies (IAA) with radiobinding assays, for islet cell antibodies (ICA) with immunofluorescence and for HLA DR alleles by serology. IA-2A were detected in 85.9% of cases with no association with gender or age. An overwhelming majority of the patients (71.3%) tested positive for three or more antibodies, and 90.7% for at least two. Fifty-four subjects (7.1%) had one antibody detectable, whereas only 2.1% of the patients tested negative for all four. A higher proportion of patients was positive for IA-2A and/or GADA than for ICA alone (95.5 vs 84.2%, p < 0.001). The prevalence and level of IA-2A were increased in cases carrying HLA DR4/non-DR3 compared with other DR combinations. The results indicate that almost all patients with newly diagnosed childhood IDDM can be identified by screening with these four autoantibodies. The combination of IA-2A and/or GADA had a higher sensitivity for IDDM than ICA alone. The close association between IA-2A and HLA DR4, the strongest single allele predisposing to IDDM, suggests that IA-2A may be a more specific marker of beta-cell destruction than GADA, which have been shown to associate with the DR3 allele and thyroid autoimmunity.
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PMID:IA-2 antibodies--a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group. 956 46

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensitivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibody (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile of 105 nondiabetic control subjects, and results were confirmed by testing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA+/IA2A+, 44 GADA+/IA2A-, and 4 IA2A+/GADA-). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADIA2-combi assay as well as in the single test for GADA or IA2A. Twenty-four relatives progressed to IDDM within a median follow-up time of 5.6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30-73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P=0.0001) and on the presence of IA2A in addition to GADA (5-year risk: GADA+/IA2A+, 47% [25-68]; GADA+/IA2A-, 15% [2-28]; P=0.006). In those with detectable antibodies, risk was not associated with age (<15 vs. >15 years) or relation to proband (offspring, sibling, parent). Relatives with GADIA2-combi antibodies >10 U and the additional presence of IAA had a slightly higher diabetes risk than relatives without IAA (5-year: IAA+, 46% [23-68]; IAA-, 19% [6-32]; P=0.07). Furthermore, low first-phase insulin release after intravenous glucose tolerance test was associated with risk in relatives with GADIA2-combi antibodies (P=0.01). These results indicate that the GADIA2-combi test is a valuable marker for first-line screening and risk assessment of type 1 diabetes in relatives. It can be used for venous as well as capillary blood samples.
Diabetes 1998 Apr
PMID:GADIA2-combi determination as first-line screening for improved prediction of type 1 diabetes in relatives. 956 92


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