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)

With regard to progression to diabetes, ICA cross-reactive with mouse pancreas, antibodies to the M(r) 64,000 islet antigen (64K), antibodies immunotrapping brain GAD activity, and IAA were analysed in 53 ICA-positive first-degree relatives of IDDM patients and 18 ICA-positive schoolchildren without a family history of diabetes. Sera from 29 (55%) relatives did not bind to mouse pancreas, whereas 24 (45%) displayed cross-species reaction. ICA titres on human and mouse pancreas were weakly correlated in the overall population (p < 0.05) but more strongly (p < 0.01) in only those subjects who displayed antibodies on tissues from both species. GAD and 64K antibodies were detected in 31% and 35% of relatives. In schoolchildren, the frequencies of cross-species reactive ICA (22%), GAD antibodies (6%), 64K antibodies (22%), and IAA (6%), were lower (p < 0.05) than in relatives. A strong correlation (p < 0.0001) was observed between GAD and 64K antibodies. GAD or 64K antibodies were strongly correlated with ICA on human pancreas (p < 0.0001) but poorly with ICA on mouse pancreas (p = 0.05). After pre-incubation of sera with brain homogenate, ICA titres were unaffected on mouse pancreas but reduced on human pancreas. ICA-positive subjects who displayed neither cross-species reactive ICA nor GAD or 64K antibodies were more frequent (p < 0.05) among schoolchildren than relatives, whereas subjects who displayed all antibody specificities were more numerous (p < 0.04) in relatives. All relatives with ICA binding only to human pancreas, as well as all schoolchildren, permanently displayed an AIRG higher than the first control percentile and remained non-diabetic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined analysis of islet cell antibodies which cross-react with mouse pancreas, antibodies to the M(r) 64,000 islet protein, and antibodies to glutamate decarboxylase in subjects at risk for IDDM. 805 87

To learn more about the preclinical phase of IDDM we observed for a median period of 46.5 months (range 0.5-69 months) a group of 57 siblings positive for ICA and/or IAA when first screened within 6 months of the diagnosis of the proband. Sequential blood samples and IVGTTs were obtained at intervals of 6-12 months. Seventeen siblings (29.8%) presented with IDDM during the observation period. The duration of the known preclinical period ranged from 0.5 to 51 months (median 29 months). The converters were younger than the other siblings (P < 0.05) and had higher initial ICA levels (P < 0.01). In addition they had a lower FPIR in the first IVGTT (P < 0.001). On all subsequent tests the converters had higher ICA levels and a lower FPIR (P < 0.05 or less), a lower glucose elimination rate from the third test onwards (P < 0.01 or less) and higher IAA levels at 3 years (P < 0.05). Some variation could be observed in the FPIR in the converters with an initial increase and subsequent decrease (P < 0.05 for both). Their levels of complement-fixing ICA increased up to 18 months (P < 0.05) and IAA levels up to 3 years (P < 0.01). Those high risk siblings who progress to clinical IDDM are characterized by young age, strong and increasing signs of islet-cell specific autoimmunity, reduced insulin secreting capacity and emerging glucose intolerance. The present observations seem to be incompatible with the hypothesis of beta-cell destruction occurring at a constant, predictable rate.
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PMID:Natural history of preclinical IDDM in high risk siblings. Childhood Diabetes in Finland Study Group. 806 40

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.
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PMID:Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. 866 50

Prediction of type 1 diabetes is largely based on islet cell antibodies, but may be improved by combined analysis with other markers. We conducted a screening of first-degree relatives of type 1 diabetic patients in Germany using islet cell antibodies (ICA, indirect immunofluorescence on human pancreas) and insulin autoantibodies (IAA, radioimmunoassay) as screening markers. Of 1460 relatives tested, 2.3% (n = 33) were identified to be ICA+ (> or = 10 JDFu) and 1.9% (n = 27) to be IAA+ (> or = 50 nU/ml) in at least two subsequent serum samples. Of 44 antibody-positive relatives, 17 (39%) progressed to clinical insulin-dependent diabetes mellitus (IDDM) within 5 years. Life-table analysis showed a 58% risk of IDDM for ICA+ and 46% risk for IAA+ individuals. ICA combined with IAA gave a risk of 67% (p < 0.02 compared with ICA-, n.s. compared with IAA-). Of all relatives who progressed to clinical IDDM, only one was negative for ICA, but 6 were negative for IAA, resulting in a sensitivity of 94% for ICA and 65% for IAA. All antibody-positive relatives were characterized for HLA DR and DQ markers by genotyping. Relatives with 2 non DR3/ non-DR4 (DRx/x) alleles had no risk of IDDM, although they were consistently positive for one or more antibody specificities. We conclude that IAA screening is less sensitive than screening with ICA and relatives who lack ICA rarely progress to clinical disease. HLA analysis may be useful among antibody-positive relatives to define subgroups with a low risk of progression to exclude those from future intervention trials.
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PMID:Prediction of type 1 diabetes. 880 28

Little is known concerning the natural history of beta-cell autoimmunity in infants and toddlers, especially in those without a first degree IDDM relative. A population-based cohort of Colorado infants at increased IDDM risk due to their HLA genotype has been identified through a PCR-based HLA screening of cord blood and is being prospectively studied. We report the distribution of insulin (IAA), GAD65 (GAA), and ICA512 autoantibody levels in 312 children aged 9 months and in 131 children aged 15 months from this cohort, without family history of IDDM. The levels of IAA, GAA and ICA512 did not differ by the HLA genotype (DR3/4,DQB1*0302 vs. DR3/3, vs. DR2/DR4,DQB1*0302 vs. DRx/4,DQB1*0302, where x is not DR3 or DR2), by ethnicity (non-Hispanic whites vs. other ethnic groups), or by age (9 vs. 15 months). The 95th and 99th percentiles of the IAA distribution were respectively 40 and 61 nU/ml at the age of 9 months and 38 and 59 nU/ml at the age of 15 months. The 95th and 99th percentiles of the GAA distribution were respectively 0.020 and 0.046 at the age of 9 months and 0.022 and 0.098 at the age of 15 months. We propose to use IAA levels greater than 60 nU/ml and GAA index greater than 0.05 to define the presence of beta-cell autoimmunity in children younger than 2 years.
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PMID:Beta-cell autoantibodies in infants and toddlers without IDDM relatives: diabetes autoimmunity study in the young (DAISY). 881 78

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.
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PMID:Value of ICA512 antibodies for prediction and diagnosis of type 1 diabetes. 881 40

The aim of the study was to evaluate the frequency of islet cell (ICA) and insulin (IAA) antibodies and of HLA antigen typing in a group of subjects diagnosed with gestational diabetes mellitus (GDM) in a screening-diagnostic program during pregnancy. ICA, complement-fixing (CF) ICA and other autoantibodies, absolute number and percentage of lymphocyte subpopulations, and HLA antigens were evaluated in 68 women with GDM and compared with those of matched controls. ICA were found in 2 (2.9%) and IAA in 1 (1.5%). Both ICA-positive women had CF-ICA; one of them was receiving insulin therapy. while the other was on a special diet. No correlations were found between ICA and IAA, nor between IAA and insulin treatment. As far as lymphocyte subsets were concerned, we found a significant increase in the absolute number of total and activated (CD3+HLA-DR+) T lymphocytes and a significant increase in the absolute number and percentage of suppressor/cytotoxic T lymphocytes (CD8) and NK lymphocytes (CD57) in GDM patients compared with normal pregnant controls. Concerning frequency for HLA A, B, C, DR antigens in the GDM population, only Cw7 was found to be significantly increased and A10 significantly decreased in comparison with controls. Our study suggests that GDM is a heterogeneous disorder in which few patients present with the immunologic and genetic markers of type 1 diabetes.
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PMID:An immunological and genetic study of patients with gestational diabetes mellitus. 887 Aug 16

Antibodies to glutamic acid decarboxylase (anti-GAD) predict the progression of adults masquerading as NIDDM to insulin dependency and predict the eventual occurrence of IDDM in healthy pregnant women in Finland. Almost 80% of prediabetic and newly diagnosed IDDM cases are positive for anti-GAD. However, approximately 20% of these groups do not have a humoral response to GAD so it cannot be claimed that anti-GAD is the exclusive autoimmune phenomenon. Nevertheless, 94% of children with newly diagnosed IDDM that we studied had an autoimmune response to either GAD, ICA or IAA, singly or in combination. The anti-GAD assay also has a substantial role in the diagnosis and classification of diabetes presenting in adult life since a proportion of adults who present with apparent NIDDM actually have a slowly evolving autoimmune insulitis, a condition we have called latent autoimmune diabetes in adults (LADA). It appears likely that anti-GAD will be predictive for IDDM in both first degree relatives and the general population. As a result of the cost and relative ease of performance, it will provide a practical alternative to ICA, particularly in population screening. Comparisons of testing for anti-GAD and ICA as predictors of IDDM using large population groups are now in progress in our laboratory.
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PMID:Antibodies to glutamic acid decarboxylase in the prediction of insulin dependency. 901 81

IA-2 has been identified as an autoantigen that is recognized by immunoglobulins from insulin-dependent diabetic (IDDM) patients. Using a liquid phase radiobinding assay, we performed an IA-2-autoantibody (IA-2-Ab) assay in 474 IDDM patients and 482 non-diabetic control subjects aged 0-3 years. IA-2-Ab were detected in 58% of the patients and 0.8% of control subjects. Their prevalence in patients was lower than that of islet cell autoantibodies (ICA; 73%) or glutamic acid decarboxylase (M(r) 65 kDa)-autoantibodies (GAD65-Ab; 82%) but higher than that of insulin autoantibodies (IAA; 42%). IA-2-Ab were more frequent in patients under age 20 years (70%) than between 20 and 40 years (45%; p < 0.001). In the whole IDDM group, 92% of patients were positive for at least one of the three molecular assays, which is higher than the positivity for the ICA assay (73%). Only 1% was negative in the molecular assays and positive in the ICA assay. IA-2-Ab levels were positively correlated with ICA titres (p < 0.001) and HLA DQ A1*0301-DQ B1*0.02 (p < 0.003) by multivariate analysis. In a group of 481 non-diabetic siblings (age 0-39 years) of IDDM patients only 7 were IA-2-Ab positive (1.5%). All seven were under age 20 years and positive for at least two other autoantibodies and for DQ A1*0301-DQB1*0302. Four of these seven developed IDDM during the 6-70-month follow-up period. The positive predictive value of IA-2-Ab (57%) was higher than that of ICA, GAD65-Ab or IAA alone, or in combination (< or = 20%) but these calculations are restricted by the relatively short observation period and the small number of cases. The only IA-2-Ab-negative case of pre-diabetes was also negative for IAA and GAD65-Ab, while it was strongly positive for ICA. In conclusion, IA-2-Ab show a high diagnostic specificity for IDDM and are predictive markers of impending diabetes in siblings of patients. In combination with other molecular antibody assays they may replace ICA testing in future. Our data also indicate that other autoantibodies than IA-2-Ab, GAD65-Ab and IAA contribute to ICA.
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PMID:IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. The Belgian Diabetes Registry. 902 24

In general, reliable and reproducible ICA results are available only from research laboratories that routinely perform ICA testing. Regarding IAA testing, IAA ELISA must be avoided. There are numerous GADA procedures available that definitely have different sensitivities for GADA detection. IA-2A testing is very new and is performed in only a few research laboratories. Islet autoantibody testing should be performed only as part of research protocols. At the present time, we know much more about the prediction of IDDM than its prevention. Once safe and credible methods are available to prevent IDDM, islet autoantibody screening may become as common as childhood immunizations.
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PMID:Autoimmune diabetes. The role of autoantibody markers in the prediction and prevention of insulin-dependent diabetes mellitus. 931 71


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