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)

ICA512 was isolated from an islet cDNA expression library and was identified as transmembrane protein closely related to the T-cell tyrosine phosphatase CD45. In order to determine the frequency of antibodies (ab) to ICA512, we tested sera of 124 newly diagnosed type 1 diabetic patients (IDDM) and 30 patients with long standing IDDM, 44 non-diabetic first degree relatives (FDR) with positive ICA or IAA, and 76 healthy control subjects using an ELISA. The mean +/- SD that we obtained in our control population was 4.1 +/- 3.9 U and a cut-off of 16 U was defined as normal range (mean + 3 SD). Of newly diagnosed diabetic patients and patients with long standing IDDM, 32% and 23% respectively had positive ICA512-ab with a mean of 22 +/- 33 U (vs controls p < 0.001) and 14 +/- 14 U (p < 0.01). Of antibody-positive first degree relatives, 36% were found to have elevated ICA512-ab with a mean of 24 +/- 41 U (p < 0.01). In relatives with multiple follow-up samples, ICA512-ab were found to be constantly positive or negative in 86% of cases, whereas fluctuation of ICA512-ab positivity occurred in five relatives in which three developed positive ICA512-ab and two lost ICA512-ab positivity during follow-up. Of ICA512-ab + relatives, 76% progressed to clinical type 1 diabetes within 5 years of follow-up, whereas only 24% developed diabetes in the ICA512-ab negative group (p < 0.01). ICA512-ab were more frequent in newly diagnosed diabetic children below age 15 years (p < 0.02) and in patients with positive ICA (p < 0.001) or positive IAA (p < 0.02). There was, in contrast, no correlation of ICA512-ab with GADA. One patient with newly diagnosed type 1 diabetes exclusively exhibited ICA512-ab. In conclusion, these results suggest that ICA512-ab are related to autoimmune type 1 diabetes and useful as an additional screening marker for the prediction of type 1 diabetes.
Exp Clin Endocrinol Diabetes 1996
PMID:Value of ICA512 antibodies for prediction and diagnosis of type 1 diabetes. 881 40

An insulin granule membrane protein, phogrin (phosphatase homologue of granules from rat insulinoma), with homology to islet cell antigen (ICA) 512/IA-2 has recently been cloned from an insulinoma cDNA expression library with antigranule membrane sera. We have developed a radioimmunoassay for detecting antiphogrin autoantibodies using in vitro transcribed and translated phogrin and have established the sensitivity and specificity of this assay. Thirty-two of 57 (56%) new-onset patients with type I diabetes and 26 of 44 (59%) first-degree relatives followed to diabetes had anti-phogrin antibody levels exceeding the 99th percentile of 108 normal control subjects. Levels of antiphogrin autoantibodies correlated with ICA512/IA-2 autoantibodies (r = 0.82, P < 0.0001), but minimally with insulin autoantibodies (r = 0.20, P = 0.05) and not with GAD65 autoantibodies (r = 0.16, P = 0.12). Ninety-eight percent (57 of 58) of patients positive for anti-phogrin autoantibodies were also positive for autoantibodies against ICA512/IA-2. Nine percent (9 of 101) of new-onset patients and relatives followed to diabetes were ICA512/IA-2 autoantibody-positive but anti-phogrin autoantibody-negative. Preincubation of sera with recombinant ICA512/IA-2 protein completely for the majority and partially for a minority inhibited binding to in vitro translated phogrin. In three relatives in which ICA512/IA-2 autoantibodies converted to positivity with sequential follow-up, anti-phogrin autoantibodies developed at the same time. These results suggest that anti-phogrin and ICA512/IA-2 autoantibodies are related subsets of anti-islet autoantibodies.
Diabetes 1996 Oct
PMID:Autoantibodies to protein tyrosine phosphatase-like proteins in type I diabetes. Overlapping specificities to phogrin and ICA512/IA-2. 882 69

A considerable body of data supports the hypothesis that type I diabetes is a chronic progressive autoimmune disorder. Individuals with very high probability of progressing to diabetes can now be readily identified. Assays for autoantibodies reacting with insulin (IAA), glutamic acid decarboxylase (GAD65AA), and the neuroendocrine tyrosine phosphatase ICA512/IA-2 (ICA512AA) allow for the identification of more than 95% of individuals developing type I diabetes. The expression of a single autoantibody does not indicate high risk for diabetes and in general, prediabetic individuals express a series of biochemically defined autoantibodies. Levels of such autoantibodies are usually stable over years of follow-up. Unusual variants of autoantibody expression (e.g. GAD-ICA with high titers of GAD65 autoantibodies as the sole autoantibody) have low prognostic significance. Given the presence of multiple autoantibodies, low first phase insulin secretion (following intravenous glucose) is the best predictor of time to diabetes onset. Measurement of autoantibodies can now be automated and applied to large populations such that screening and prediction in the general population is now feasible. We favor the hypothesis that insulin may be the primary autoantigen for type I diabetes, and therapies which after the immune response to insulin may lead to safe and effective preventive modalities.
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PMID:Chronic autoimmunity of type I diabetes. 885 79

Insulin, glutamate decarboxylase (GAD) and the protein tyrosine phosphatase-like molecule IA-2 are major targets of humoral autoimmunity in insulin-dependent diabetes mellitus (IDDM). These autoantibodies are heterogeneous with respect to age and patient human leukocyte antigen (HLA) phenotype. We have previously demonstrated that GAD and IA-2 antibodies potentially identify different subsets of IDDM patients. The aim of this study was to determine whether GAD and IA-2 autoantibodies were associated with different HLA DR phenotypes. We studied 160 patients with IDDM onset before age 16 years. At disease onset serum was tested for GAD and IA-2 antibodies by immunoprecipitation by in vitro-translated 35S-methionine labelled recombinant proteins. IA-2 antibodies were significantly associated with HLA DR4: 67 (86%) of 78 patients with HLA DR4 vs 31 (38%) of 82 non-DR4 patients had IA-2 antibodies (Pc < 0.0001) and IA-2 antibody levels were higher in patients with HLA DR4 (Pc < 0.0001). In contrast, GAD antibodies were more prevalent (Pc < 0.05) and antibody levels highest (Pc < 0.01) in patients with HLA DR3 phenotypes. These data provide further evidence that, in IDDM, production and titre of major autoantibody specificities are associated with HLA class II alleles.
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PMID:Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM. 889 11

To determine the value of antibodies to the intracytoplasmic domain of the tyrosine phosphatase IA-2 (anti-IA-2ic) and glutamic acid decarboxylase (GADA) for identification of subjects at risk for insulin-dependent diabetes mellitus (IDDM) we investigated 1238 first degree relatives of patients with IDDM for the presence of anti-IA-2ic and GADA and compared the results with cytoplasmic islet cell antibodies (ICA). Anti-IA-2ic were observed in 54 (4.4%) first degree relatives, in 51 of 86 (59.3%) ICA positive relatives and in 3 of 4 individuals who developed overt IDDM within a follow-up period of 1 to 28 months. GADA were found in 78 of 1238 (6.3%) first degree relatives. They were detected in 22 of 35 (62.9%) sera with ICA alone and in 1 of 3 subjects with anti-IA-2ic in the absence of ICA. Of the 1238 subjects 37 (3.0%) sera were positive for all three antibodies. Both anti-IA-2ic and GADA were positively correlated with high levels of ICA. Anti-IA-2ic and GADA were detected in 39.1 and 47.8% of subjects with ICA of less than 20 Juvenile Diabetes Foundation units (JDF-U) but in 66.7 and 76.2% of individuals with ICA of 20 JDF-U or more, respectively (p < 0.05). The levels of ICA and GADA in first degree relatives with at least one additional marker were significantly higher than in subjects with ICA alone (p < 0.005) or GADA alone (p < 0.03). The combination of anti-IA-2ic and GADA identified 84.9% of all ICA positive subjects and 93.7% of individuals with high level ICA (> or = 20 IDF-U). All 4 individuals who progressed to IDDM had either IA-2ic or GADA. Our data indicate that primary screening for anti-IA-2ic and GADA provides a powerful approach with which to identify subjects at risk for IDDM in large-scale population studies which may represent the basis for the design of new intervention strategies.
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PMID:Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM. The DENIS Study Group. Deutsche Nikotinamid Interventions-Studie. 893 4

By subtraction strategy and polymerase chain reaction amplification, two novel cDNAs, designated IA-2 and IA-2 beta, were cloned, sequenced and expressed. Both are transmembrane proteins belonging to the protein tyrosine phosphatase family and are expressed in pancreatic islets. Serological studies revealed that a high percentage of patients with IDDM have autoantibodies to IA-2/IA-2 beta and that the presence of these autoantibodies in otherwise normal individuals is highly predictive in identifying those at risk of ultimately developing clinical diabetes. Moreover, many patients who are ICA positive, but who do not have Abs to GAD65, have Abs to IA-2/IA-2 beta. Enzymatic cleavage of IA-2/IA-2 beta and serological analysis showed that IA-2 is the precursor of the 40 kDa tryptic fragment and IA-2 beta is the precursor of the 37 kDa tryptic fragment, both previously shown to be autoantigens. It is concluded that IA-2/IA-2 beta are major autoantigens in IDDM and together with GAD65 are responsible for much of the reactivity of ICA with pancreatic islets. Tests for the detection of autoantibodies to recombinant IA-2/IA-2 beta and recombinant GAD65 are likely to replace the ICA immunofluorescence test for population screening.
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PMID:IA-2 and IA-2 beta are major autoantigens in IDDM and the precursors of the 40 kDa and 37 kDa tryptic fragments. 893 84

The goal of this study was to address whether antiislet autoantibodies appear sequentially or simultaneously before the onset of type I diabetes. We analyzed sequential serum samples from 155 siblings and offspring (aged < 7 yr) of patients with type I diabetes from the Denver Diabetes Autoimmunity Study in the Young study and from a separate group of first degree relatives (aged 2-40 yr) for autoantibodies reacting with three defined autoantigens: glutamic acid decarboxylase (GAD65), insulin, and ICA512/IA-2. The youngest age at which 1 of the 3 autoantibodies appeared was 1.1 yr, and the oldest was 60.9 yr. Of the total 26 autoantibody conversion events observed, in only 3 instances did more than 1 autoantibody appear simultaneously. Among individuals (n = 12) with sequential conversion to expression of multiple autoantibodies, anti-GAD65 autoantibodies or antiinsulin autoantibodies appeared first (4 expressed antiinsulin autoantibodies first, and 8 anti-GAD65 autoantibodies first). We conclude that antiislet autoantibodies usually appear sequentially and not simultaneously. This corroborates early suggestions that humoral autoimmunity to islets develops chronically in a process usually measured in months to years. As expression of multiple autoantibodies is associated with a high risk of progression to diabetes, and sequential appearance of autoantibodies can occur late in life, long term follow-up is necessary to fully delineate the relationship of diabetes risk to autoantibody expression.
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PMID:Antiislet autoantibodies usually develop sequentially rather than simultaneously. 895 25

Thirty-three IDDM sera that immunoprecipitated full-length IA-2 were tested for reactivity with different fragments of the IA-2 molecule. The fragments were prepared by PCR amplification of IA-2 cDNA and by expression in a rabbit reticulocyte transcription/translation system. Whereas all 33 sera reacted with the intracellular domain (amino acid 604 to 979), none of the sera reacted with the extracellular domain of IA-2 (amino acid 31 to 577). Analysis of the reactivity of IDDM sera with the different regions of the intracellular domain showed that 94% (31 of the 33) reacted with the COOH-terminus (amino acid 771 to 979), 40% reacted with the NH2-terminus (amino acid 604 to 776), and 40% reacted with the middle portion (amino acid 692 to 875). Of the 31 sera that reacted with the COOH-terminus, 14 of these reacted only with the COOH-terminus and with no other region. Of the 13 sera that reacted with the NH2-terminus, only one reacted exclusively with the NH2-terminus. Treatments of the different domains of IA-2 with trypsin showed that only the COOH-terminus was resistant to trypsin, arguing that it is from this region of the IA-2 molecule that the 40-kDa tryptic fragment from insulinoma cells is derived. From these experiments, it is concluded that the major antigenic determinant of IA-2 is located at the COOH-terminus and that minor antigenic determinants are located at the NH2-terminus and middle portion of the intracellular domain.
Diabetes 1997 Jan
PMID:Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. 897 Oct 79

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.
Diabetes 1997 Feb
PMID:Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. 900 Jul

Islet cell antigen (ICA) 512 also termed IA-2 is a novel autoantigen of type 1 diabetes, which has a tyrosine phosphatase-like domain. We have assessed autoantibody RIAs using a series of ICA512/IA-2 constructs to produce in vitro synthesized 35S-methionine-labeled proteins. Levels of ICA512/IA-2 (256-979, truncated aminoterminus) autoantibodies were strongly correlated with those of the full-length ICA512/IA-2 (1-979) autoantibodies (r = 0.96, P < 0.0001) and ICA512/IA-2 (687-979) autoantibodies (r = 0.98, P < 0.0001). RIAs using these 3 constructs had increased sensitivity relative to our initially reported ICA512 autoantibody RIA (amino acids 389-948, truncated carboxy- and aminoterminus). Only 2 of 38 sera examined in this study reacted with an aminoterminus ICA512/IA-2 (1-577) construct. The mean SD score (SD score = (index of unknown sample-mean index of controls)/SD of controls) using the ICA512/IA-2 (256-979) construct was significantly higher than the SD score obtained with other ICA512/IA-2 constructs (P < 0.001). Amongst patients with new-onset diabetes and prediabetic relatives, using RIAs for autoantibodies reacting with ICA512/IA-2 (256-979), insulin, and glutamic acid decarboxylase 65, 98% expressed one or more of these autoantibodies and 78% expressed two or more, whereas no control (n = 208) expressed more than a single autoantibody. A combined ICA512/IA-2 (256-979), glutamic acid decarboxylase 65 autoantibody RIA with differential autoantigen labeling (35S-methionine, 3H-leucine) has been developed that uses 96-well plate membrane filtration and Top Counter beta counting. Concordance between results of dual and single RIAs was greater than 90%. This simple combined autoantibody assay should facilitate large-scale autoantibody screening.
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PMID:Evaluation of islet cell antigen (ICA) 512/IA-2 autoantibody radioassays using overlapping ICA512/IA-2 constructs. 902 21


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