Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IA-2 (insulinoma-associated protein 2), a major autoantigen in type 1 diabetes, is a receptor-tyrosine phosphatase-like protein associated with the membrane of secretory granules of neural and endocrine-specific cells. Loss of IA-2 activity in the mouse results in reduced insulin release and additional phenotypes, consistent with a general effect on neurosecretion and hormone release. To gain further insight into the cellular mechanisms of IA-2 function, we have studied the Caenorhabditis elegans homolog, CeIA-2 encoded by the ida-1 gene. Using two independent putative null alleles of ida-1, we demonstrate that animals lacking CeIA-2 activity are viable and exhibit subtle defects. Genetic studies of mutants in ida-1 and several genes involved in neurosecretory vesicle cargo release and signaling highlight two roles for CeIA-2. First, CeIA-2 has a specific and novel genetic interaction with UNC-31/CAPS, a protein that has been shown in other systems to regulate dense-core vesicle cargo release. Second, loss of CeIA-2 activity enhances weak alleles in the insulin-like signaling pathway. These results suggest that CeIA-2 may be an important factor in dense-core vesicle cargo release with parallels to insulin signaling in mammals.
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PMID:Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion in Caenorhabditis elegans. 1504 51

Insulinoma-associated protein (IA)-2beta, also known as phogrin, is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is located in dense-core secretory vesicles. In patients with type 1 diabetes, autoantibodies to IA-2beta appear years before the development of clinical disease. The genomic structure and function of IA-2beta, however, is not known. In the present study, we determined the genomic structure of IA-2beta and found that both human and mouse IA-2beta consist of 23 exons and span approximately 1,000 and 800 kb, respectively. With this information, we prepared a targeting construct and inactivated the mouse IA-2beta gene as demonstrated by lack of IA-2beta mRNA and protein expression. The IA-2beta(-/-) mice, in contrast to wild-type controls, showed mild glucose intolerance and impaired glucose-stimulated insulin secretion. Knockout of the IA-2beta gene in NOD mice, the most widely studied animal model for human type 1 diabetes, failed to prevent the development of cyclophosphamide-induced diabetes. We conclude that IA-2beta is involved in insulin secretion, but despite its importance as a major autoantigen in human type 1 diabetes, it is not required for the development of diabetes in NOD mice.
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PMID:Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. 1522 Jan 91

Active T cell recognition of islet antigens has been postulated as the pathogenic mechanism in human type 1 diabetes, but evidence is scarce. If T cells are engaged, they are expected to display increased clonal size and exhibit a T helper (Th)1/Th2 differentiation state. We used a peptide library that covers tyrosine phosphatase IA-2, a target antigen expressed in pancreatic beta cells, to probe 8 diabetic patients and 5 HLA-matched controls. When tested in a high resolution IFNgamma/IL-4 double color ELISPOT assay directly ex vivo, the number of IA-2-reactive IFNgamma producing cells was 17-fold higher in patients than in controls and IL-4 producing cells were not present. An average of 9 peptides was recognized in the patients vs. one in the controls. Determinant recognition primarily involved CD4+ cells and showed high variability among the patients. Furthermore, anti-CD28 antibody signal enhances quantitative assessment of effector T cells in T1D patients. In vitro expansion with peptides and IL-2 results in detection of responding cells in the controls and loss of disease specificity of the T cell response. Together these data provide strong evidence for the active targeting of IA-2 by Th1 memory effector cells in human type 1 diabetes.
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PMID:Increased in vivo frequency of IA-2 peptide-reactive IFNgamma+/IL-4- T cells in type 1 diabetic subjects. 1523 52

During pregnancy, maternal type 1 diabetes-associated autoantibodies may cross the placenta. It is proposed that insulin antibodies (IA) allow transfer of insulin across the placenta, contributing to fetal hyperinsulinemia and macrosomia. We assessed the prevalence of IA, the tyrosine phosphatase IA-2, and glutamic acid decarboxylase (GADA) in cord blood from offspring of mothers with type 1 diabetes (ODM, n = 138) and control mothers (control, n = 47) and further assessed cross-sectional relationships of antibody titers to birth weight and fetal insulin. In ODM, antibodies were frequently present in cord blood; 124 ODM (95%) were positive for IA, 82 (59%) were positive for GADA antibodies, and 61 (44%) were positive for IA-2 antibodies. In controls, GADA and IA-2 antibodies were absent, whereas seven controls (15%) were positive for IA at low titers (P < 0.0001 ODM vs. controls for all).ODM with IA (IA positive) or without IA (IA negative) had similar birth weights (mean +/- sd: IA positive, 3.8 +/- 0.7 kg; IA negative, 4.0 +/- 0.6 kg; P = 0.31) and cord insulin concentrations (IA positive: median, 112 pmol/liter; interquartile range, 62-219 pmol/liter; IA negative: median, 114 pmol/liter; interquartile range, 59-194 pmol/liter; P = 0.96). Similarly, the presence of GADA and/or IA-2 autoantibodies (n = 103) was not associated with differences in birth weight or insulin concentrations. Antibody titers were not associated with birth weight or insulin as continuous variables in either controls or ODM. Islet autoantibodies and IA are a common finding in cord blood of ODM, but we found no evidence that they influence offspring insulin concentrations or weight at birth.
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PMID:Type 1 diabetes-related antibodies in the fetal circulation: prevalence and influence on cord insulin and birth weight in offspring of mothers with type 1 diabetes. 1524 Jun 28

Patients with type 1 diabetes mellitus (DM1) are at high risk to develop further autoimmune disorders, which are mostly characterized by the presence of organ-specific antibodies in serum and a subclinical disease course. Diabetes-related (glutamic acid decarboxylase, tyrosine phosphatase, IA-2) and thyroid-specific (thyroperoxidase, thyroglobulin) as well as antibodies to 20S proteasome, and anti-nuclear antibodies, were measured at DM1 onset in 147 children and adolescents. Patients were followed prospectively for the development of autoimmune thyroiditis (TSH elevation and/or sonographic thyroid gland enlargement in the presence of thyroid antibodies) up to 12 years, median observation time 4.4 years. Eight of 147 (5.4%) patients developed autoimmune thyroiditis. The cumulative incidence (+/-SE) at 5 years was 0.08+/-0.03. The prevalence of thyroid antibodies was 16.7%, of DM-related 88.4%, 20S proteasome 21.9%, and anti-nuclear antibodies 20.0%. There was a positive correlation between thyroid and anti-nuclear antibodies (p <0.001). Clinical course of DM1 and remission duration were not influenced by the presence of autoantibodies. However, in contrast to patients without antibodies, those with positive antibodies had significantly (p <0.001) elevated cumulative incidence of autoimmune thyroiditis at 5 years: thyroperoxidase 0.40+/-0.13, thyroglobulin 0.38+/-0.15, and anti-nuclear antibodies 0.29+/-0.12, respectively. These data underline that autoimmunity in patients with DM1 is not only restricted to beta-cell antigens at the onset of disease. In particular, patients with positive thyroid and anti-nuclear antibodies are at high risk to develop autoimmune thyroiditis during the first 5 years of DM1.
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PMID:Prevalence of 20S proteasome, anti-nuclear and thyroid antibodies in young patients at onset of type 1 diabetes mellitus and the risk of autoimmune thyroiditis. 1530 Oct 45

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves' disease, 104 unrelated subjects with autoimmune Addison's disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves' disease alleles compared to 67 of 858 (7.8%) control alleles (chi(2) = 17.2, p = 3.4 x 10(-5)' odds ratio = 1.88, 5-95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison's disease alleles vs 7.8% of controls (chi(2) = 4.63, p = 0.031; odds ratio = 1.69, 5-95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.
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PMID:The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. 1553 53

The genetic susceptibility for gestational diabetes (GDM) was estimated by comparisons of genotypes within human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene A (MICA) in 199 women with GDM and 213 healthy women. At least one of ICA, glutamic acid decarboxylase antibodies, or islet cell antigen-2 antibodies/tyrosine phosphatase antibodies was found in 6.0% (12/199) of women with GDM and were considered as autoimmune GDM, whereas the remaining 187 were considered as nonautoimmune GDM. HLA genotyping was done with polymerase chain reaction and sequence-specific oligonucleotides. MICA polymorphism was determined with polymerase chain reaction and fragment size determination. HLA-DR3-DQ2/x or DR4-DQ8/x and MICA5.0/5.1 were more frequent in autoimmune GDM compared with controls; 92% versus 46% and 42% versus 13% and conferred increased risk (odds ratio [OR] = 13; 95% confidence interval [CI] 1.7-104) and (OR = 4.7; 95%CI 1.4-16). Four other genotypes were more frequent in nonautoimmune GDM compared with controls: HLA-DR7-DQ2/y, 24% versus 14%; DR9-DQ9/y, 9.6% versus 1.9%; DR14-DQ5/y, 7.5% versus 0.94%; and MICA5.0/z, 24% versus 13% and gave increased risk: OR = 2.0; 95%CI 1.2-3.4, OR = 5.6; 95%CI 1.8-17, OR = 8.5; 95%CI 1.9-38, and OR = 2.0; 95%CI 1.2-3.4, respectively. We concluded that autoimmune diabetes with onset during pregnancy is associated with the type 1 diabetes-associated genotypes and also with MICA5.0/5.1, whereas DR7-DQ2/y, DR9-DQ9/y, DR14-DQ5/y, and MICA5.0/z are risk factors for nonautoimmune GDM.
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PMID:Different HLA-DR-DQ and MHC class I chain-related gene A (MICA) genotypes in autoimmune and nonautoimmune gestational diabetes in a Swedish population. 1560 71

Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.
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PMID:Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. 1571 22

Islet tyrosine phosphatase 2 (IA-2) is one of the major autoantigens in type 1 diabetes. The aim of this work was to evaluate which IA-2 construct(s) among those usually employed has the highest sensitivity and specificity for detecting IA-2 autoantibodies in autoimmune diabetes and whether the combination of different IA-2 constructs into a single assay allows the detection of immunoreactivities otherwise not detectable by a single construct. For this purpose, we tested the single immunoreactivities of IA-2 FL(aa 1-979), IA-2(BDC)(aa 256-556:630-979), IA-2 IC(aa 605-979), IA-2(aa 256-760), IA-2(aa 761-928), and of 7 combinations of these fragments in the sera of 203 newly diagnosed type 1 diabetic patient (DM: 109 males,94 females, mean age 12.9 +/- 7.5 years) and 43 prediabetic subject (PDM: 20 males, 23 females, mean age 10.3 +/- 6.0 years) sera. IA-2 IC was the single construct that showed the highest sensitivity and specificity both in DM and PDM subjects; however, all of the other IA-2 constructs investigated detected additional immunoreactivities with respect to it. The combined use into the same assay of IA-2 IC, IA-2 FL, and IA-2 (256-760) constructs allowed detection of IA-2 Abs in additional 13.3% DM and 30.4% PDM subjects compared to the single IA-2 IC construct, suggesting this methodology as a new, highly sensitive approach to the study of IA-2 autoimmunity in type 1 diabetes.
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PMID:IA-2 combined epitope assay: a new, highly sensitive approach to evaluate IA-2 humoral autoimmunity in type 1 diabetes. 1589 93

Type 1 diabetes associated genes account for less than 50% of disease susceptibility. Human enteroviruses have been implicated as environmental factors that might trigger and/or accelerate this autoimmune disorder. We now report of a 12-year-old girl that developed pancreatic autoimmunity and type 1 diabetes after enteroviral infection. Diabetes-associated autoimmunity was evaluated by measurement of several islet cell related autoantibodies. Neutralizing antibodies to different enteroviruses were determined in the case and eight children suffering from aseptic meningitis during a large scale epidemic. Several types of diabetes-associated antibodies were detected post-infection in the adolescent with newly diagnosed type 1 diabetes, including islet cell antibodies (ICA) and tyrosine phosphatase antibodies (IA2A). ICA but not IA2A appeared in the non-diabetic enterovirus-infected subjects. Based on virological studies, type 1 diabetes pathogenesis process could have been triggered by echovirus 30 infections. This study provides the first evidence of an association between echovirus 30 infection with the presence of pancreatic autoimmunity and type 1 diabetes. Our data suggest that echovirus 30 Cuban strain could be considered a potentially diabetogenic enteroviral variant.
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PMID:Islet cell related antibodies and type 1 diabetes associated with echovirus 30 epidemic: a case report. 1590 5


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