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

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

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

Insulin is a key hormone regulating glucose homeostasis and has many cellular effects on metabolism, growth, and differentiation. Insulin action is mediated through a specific cell-surface receptor. The first step following insulin binding consists in receptor autophosphorylation and stimulation of its tyrosine kinase activity. Among the multiple substrates, the insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate for insulin. IRS-1 binds several Src homology 2 (SH2) proteins through its multiple tyrosine phosphorylation sites: phosphatidylinositol 3-kinase (PI 3-kinase), the Ras guanine-nucleotide-releasing complex Grb2-SOS, the tyrosine phosphatase Syp, and the adapter protein Nck. IRS-1 is essential for many, but not all of the insulin's biological responses. Recently, a primary alternative substrate, i.e. IRS-2, was purified and cloned. Numerous biochemical abnormalities of the insulin signaling system lead to insulin resistance. No doubt, the recent data about the molecular mechanisms of insulin action will provide new insights into the pathophysiology and therapy of diabetes and other insulin resistant states.
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PMID:[The insulin transduction system]. 898 14

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

Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS mRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.
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PMID:The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. 905 45

Cytoplasmic islet cell antibodies (ICAs) are the classical serological markers for diagnosis and prediction of IDDM, but high technical demands have limited the widespread use of the histochemical ICA test. To investigate whether combined analysis of autoantibodies to two defined islet antigens can replace the histochemical ICA test, we established quantitative radioimmunoassays for autoantibodies to glutamate decarboxylase (GAD65-A), the tyrosine phosphatase IA2/ICA512 (IA2-A), and the cytoplasmic part of IA2 (IA2c-A). The GAD65-A and IA2c-A profiles of 920 sera from healthy individuals and from patients with IDDM, other organ-specific autoimmune diseases, and polyendocrine autoimmune syndrome were compared with the ICA profiles from these same individuals. Combined analysis of GAD65-A and IA2c-A detected 93-100% of the ICA+ sera, and, at equal specificity, improved the diagnostic sensitivity (85%) for IDDM compared with that of ICA (74%). This effect was especially pronounced in children with disease onset before 16 years of age (91% sensitivity). To replace ICA testing in risk assessment for IDDM, we designed a strategy adapted to study groups with low antibody prevalence. A combined radioimmunoassay for single-step detection of GAD65-A and IA2c-A was developed, and positive sera were reanalyzed to define their single autoantibody specificity. We identified 93% of the ICA+ sera from 204 first-degree relatives of IDDM patients. Single-step detection reduced costs and effort by more than 40% compared with separate testing, allowing an efficient large-scale screening of sera for GAD65-A and IA2c-A in IDDM. In sum, GAD65-A and IA2c-A detected much ICA reactivity, and their combined evaluation and detection is suitable to replace the histochemical ICA test.
Diabetes 1997 Apr
PMID:Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test. 907 95

The purpose of this study was to test for the presence (alone or in combination) of 4 autoantibodies directed against beta cells in the sera of children at diagnosis of the overt clinical phase of insulin-dependent diabetes mellitus. Children recorded in 1989 in the population-based French Registry of Incidence of Insulin-Dependent Diabetes Mellitus were included in the present study. One hundred and thirty-eight sera were tested for islet cell antibodies (ICA), insulin autoantibodies (IAA) and antibodies against glutamic acid decarboxylase (GAD-Ab) and tyrosine phosphatase (IA2-Ab). IAA showed significantly lower sensitivity (36%) than the other antibodies (ICA: 84%; GAD-Ab: 74%; IA2-Ab: 81%). In the age-range of the registry, the prevalence rates for the 4 antibodies were not significantly affected by age. IAA and GAD-Ab were significantly associated with ICA, whereas GAD-Ab and/or IA2-Ab was(were) associated with 93% sensitivity at diagnosis. Sensitivity was 100% with the 4 antibodies combined. No significant association was found between the antibodies and HLA DR phenotypes. This study shows that a combination of the 4 major autoantibodies allows all children with insulin-dependent diabetes to be identified.
Diabetes Metab 1997 Apr
PMID:Sensitivity at diagnosis of combined beta-cell autoantibodies in insulin-dependent diabetic children. French Registry of IDDM in Children Study Group. 913 5

Pancreatic islet beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is an autoimmune T cell-mediated process. Peripheral blood T cells, which proliferate to islet antigens such as glutamic acid decarboxylase (GAD), (pro)insulin or tyrosine phosphatase IA-2, can be detected in at-risk, first degree relatives of people with IDDM. However, cross-sectional studies cannot define the relationship between T cell responses and progression to IDDM. Longitudinal studies were therefore undertaken on 50 at-risk, first degree relatives tested at least yearly for up to 4 years, during which time five developed IDDM. Peripheral blood T cell responses to a GAD67(aa208-404)-glutathione-S-transferase (GST) fusion protein, GST, insulin and tetanus toxoid were measured, together with antibodies to islet cells, GAD, insulin and IA-2. High levels of antibodies to GAD or insulin were generally associated with low T cell responses to these antigens. Relatives who developed IDDM were characterized by high levels of antibodies to insulin and/or islet cells, and high T cell responses to GAD67-GST and tetanus, but not insulin, in the 24 months before clinical diagnosis. Cross-sectionally, T cell responses to GAD67(aa208-404)-GST and to full-length GAD65-GST were highly correlated (r=0.75, P<0.002). In conclusion, increased cellular immunity to the mid region of GAD67 was a marker of late pre-clinical IDDM, but appears to reflect a more general, transient state of cellular immune hyperresponsiveness.
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PMID:High T cell responses to the glutamic acid decarboxylase (GAD) isoform 67 reflect a hyperimmune state that precedes the onset of insulin-dependent diabetes. 918 78

Insulin-dependent diabetes (IDD), being an autoimmune disease, offers several opportunities for immunological interventions that may result either in the reduction of disease severity or in delaying diabetes onset. Among the various experimental preventative approaches, parenteral immunization with islet-specific autoantigens appears to be practically simpler and promising. We have previously shown that immunization with insulin, insulin B chain and B chain epitope (p9-23), but not insulin A chain, in incomplete Freund's adjuvant (IFA) and in alum (with B chain) delayed/prevented diabetes onset in NOD mice. Here we demonstrate the protective efficacy of affinity purified GAD65 in IFA. While both insulin B chain and GAD65 significantly delayed the onset of diabetes (P=0.001), a recently described tyrosine phosphatase (IA-2) antigen did not (P=0.38). Interestingly, B chain immunization reduced the incidence of cyclophosphamide (CY)-accelerated diabetes by about 50-55%. We also provide further evidence that B chain, upon increased adsorption to alum, could improve on its protective capacity in NOD mice.
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PMID:Immunization therapies in the prevention of diabetes. 921 56


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