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

Environmental agents are proposed to play a role in triggering or exacerbating pancreatic islet autoimmunity in people genetically predisposed to type 1 diabetes. However, with few exceptions, these agents remain enigmatic. Clues to environmental agents may be found by investigating population/geographic clusters or 'hotspots' of high disease incidence. We were alerted to a small community where the incidence of type 1 diabetes appeared to be five-fold higher than expected. Because type 1 diabetes is now recognized to have a subclinical phase during which anti-islet antibodies can be detected, we aimed to identify and characterize a reservoir of children with subclinical disease in this community. Venous blood samples were collected from 1906/2347 (81%) local school children during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%) children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were undetectable, whereas high-titer ICAs persisted. The latter were found in two distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr, had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes associated with susceptibility to type 1 diabetes, and lower first-phase insulin responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age cohort of the index clinical cases, had few antibodies other than ICA, non-susceptibility HLA genes and normal FPIRs. During follow-up, three children, all from the younger group with multiple antibodies and FPIRs less than the first percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two age groups of subclinical disease suggests that if environmental agents triggered islet autoimmunity they did not act constantly on the community. Furthermore, the absence of multiple autoantibodies and/or HLA susceptibility genes in the older group, the source of index clinical cases, implies they are a residual subgroup with slow or absent progressive beta-cell destruction. This study illustrates that the natural history of type 1 diabetes may be elucidated by analyzing age-related subclinical disease in the general population.
Pediatr Diabetes 2000 Dec
PMID:Screening for preclinical type 1 diabetes in a discrete population with an apparent increased disease incidence. 1501 15

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.
Diabetes 2004 Jul
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

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

Islet cell autoantigen 512 (ICA512)/IA-2 is a receptor tyrosine phosphatase-like protein associated with the insulin secretory granules (SGs) of pancreatic beta-cells. Here, we show that exocytosis of SGs and insertion of ICA512 in the plasma membrane promotes the Ca(2+)-dependent cleavage of ICA512 cytoplasmic domain by mu-calpain. This cleavage occurs at the plasma membrane and generates an ICA512 cytosolic fragment that is targeted to the nucleus, where it binds the E3-SUMO ligase protein inhibitor of activated signal transducer and activator of transcription-y (PIASy) and up-regulates insulin expression. Accordingly, this novel pathway directly links regulated exocytosis of SGs and control of gene expression in beta-cells, whose impaired insulin production and secretion causes diabetes.
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PMID:Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in {beta}-cells. 1559 45

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

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.
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PMID:Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. 1575 12

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

This work was intended to study if the coexistence of thyroid and Langerhans islets autoimmunity is associated with a different nature and course of diabetes in young adult diabetic patients. We followed the laboratory and clinical course of diabetes and the thyroid gland status of 47 young adults with Type I diabetes over a 9-year period starting from the onset of diabetes (ranging from 18 to 35 years of age). The patients were divided into subgroup I (with thyroid peroxidase and thyroglobulin antibodies, n = 13), subgroup II (thyroid peroxidase antibody only, n = 10), and subgroup III (without thyroid autoimmunity, n = 24). Out of the 22 females followed, 10 (46 %) and 5 (23 %) were in subgroups with thyroid autoimmunity (TA), I and II, respectively. On the contrary, out of the 25 men followed, 17 (68 %) were in group III. Within the 9 years, insulin secretion nearly ceased (C-peptide < 0.03 nmol/L) in all of the patients of subgroup I and 70 % of subgroup II, but only in 46 % of patients in subgroup III (I : II p < 0.01, I : III, p < 0.01, II : III, p < 0.05). The cumulative incidence of antiGAD > 1 U/mL (CIS, RIA) in subgroup I was higher (92 %) than in subgroups II (80 %) and III (53 %); I : III, p < 0.05. The cumulative incidence of tyrosine phosphatase antibodies (anti-IA2, BRAHMS, RIA) was insignificantly higher in subgroups I and II when compared with subgroup III (62 %, 60 %, and 42 %). The study of organ-specific and systemic autoantibodies showed their highest cumulative incidence in subgroup I, i.e., in patients with the most expressed manifestations of TA and the lowest one in subgroup III, i.e., diabetic patients without TA. Our results suggest that overall thyroid autoimmunity in young adult patients with Type I diabetes was associated not only with female gender, but also with more pronounced Langerhans islets autoimmunity and significantly faster cessation of endogenous insulin secretion; it was associated with therapeutical doses of insulin as well.
Exp Clin Endocrinol Diabetes 2005 Jul
PMID:Differences in type I diabetes mellitus of young adults with and without thyroid autoimmunity. 1602 2

Zinc ions have an insulin-like (insulinomimetic) effect. A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. Modulation of insulin signaling by zinc chelating agents and the recognition of temporal and spatial fluctuations of zinc suggest a physiological role of zinc in insulin signal transduction. Tyrosine phosphatases seem to be regulated jointly by insulin-induced redox (hydrogen peroxide) signaling, which results in their oxidative inactivation, and by their zinc inhibition after oxidative zinc release from other proteins. In diabetes, the significant oxidative stress and associated changes in zinc metabolism modify the cell's response and sensitivity to insulin. Zinc deficiency activates stress pathways and may result in a loss of tyrosine phosphatase control, thereby causing insulin resistance.
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PMID:Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. 1615 25


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