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)

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients <40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
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PMID:CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. 935 55

Insulin-dependent diabetes mellitus (IDDM) is preceded by the presence of antibodies against islet proteins including a protein tyrosine phosphatase (PTP) designated IA-2. Recently, we cloned a novel PTP named IAR which shares 43% sequence identity with IA-2 and is recognised by antibodies from a majority of patients with IDDM. The aim of the present study was to determine whether IAR antibodies (IAR Ab) or IA-2 antibodies (IA-2 Ab) are associated with progression to IDDM in first-degree relatives "at-risk" for IDDM (operationally defined as those with islet cell antibodies [ICA] > or = 20JDFU or insulin autoantibodies [IAA] > or = 100 nU/ml), and to examine combinations of IAR Ab and IA-2 Ab in these subjects. The sensitivity and specificity of these antibodies were also examined in patients with recent-onset IDDM. Using Cox's Proportional Hazards Model, the number of siblings with IDDM was associated with progression to IDDM in "at-risk" relatives, but other covariables (age, sex, number of affected offspring or parents) were not significantly associated. Using number of affected siblings as a covariable, both IAR and IA-2 antibodies were significantly associated with progression to IDDM (p < 0.005). Combinations of both antibodies, however, did not result in a significantly stronger association with progression to IDDM. The threshold of positivity for IAR Ab (0.5 units) and IA-2 Ab (3.0 units) assays was adjusted to give the same specificity (97.9%) for each assay in 144 healthy control subjects, to allow standardised comparisons. Levels of IAR Ab and IA-2 Ab were strongly correlated in 53 recent-onset IDDM patients (r = 0.70, p < 0.0001) but 11.3% had IAR Ab in the absence of IA-2 Ab and 16.9% had IA-2 Ab in the absence of IAR Ab. The sensitivity for IDDM (defined as the proportion of IDDM patients positive) was 56.6% for IAR Ab and 62.3% for IA-2 Ab. We conclude that there is considerable overlap in IA-2 Ab and IAR Ab positivity, although either antibody can occur independently in IDDM patients. Both IAR Ab and IA-2 antibodies are associated with progression to IDDM in first-degree relatives at-risk of IDDM, but the use of IAR and IA-2 antibodies in combination are not significantly more strongly associated with progression than single antibodies. IAR Ab may play an important role in the prediction of IDDM.
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PMID:Antibodies to the protein tyrosine phosphatases IAR and IA-2 are associated with progression to insulin-dependent diabetes (IDDM) in first-degree relatives at-risk for IDDM. 975 10

Soluble CD23 (sCD23), a recently discovered multifunctional cytokine, is a 25-kDa molecule released by autoproteolysis from the 45-kDa CD23 molecule which is found mainly on the surface of B lymphocytes. In the present study we aimed to evaluate, in association with humoral immune and metabolic markers, the changes in CD23 antigen expression on B lymphocytes and levels of sCD23 in the peripheral blood of subjects at high risk of type 1 diabetes. The study was carried out in 28 first-degree relatives of type 1 diabetes patients (versus a control group of 28 age- and sex-matched healthy volunteers) using antibodies against different B-cell antigens: ICA, GADA, IAA, IA-2. Flow cytometry was used to measure the percentage of CD20+ (B lymphocytes) and CD20+CD23+ lymphocyte subsets, and sCD23 levels in serum were determined by enzyme immunoassay. Prediabetic subjects had a significantly (P<0.01) lower percentage of CD20+CD23+ lymphocytes in comparison with healthy age- and sex-matched controls. Expression of CD23+ on B lymphocytes was similar in subjects with ICA only and with two or more antibodies against pancreatic antigens. In the prediabetic group, the median concentration of sCD23 was lower than in the control group and was statistically significant (P < 0.02) in the subgroup of subjects with the most impaired function of pancreatic beta-cells (the lowest values of first phase of insulin release). In conclusion, our study suggests that CD23 molecule expression on B lymphocytes and sCD23 levels in peripheral blood could be additional markers for monitoring the development of type 1 diabetes and play a role in determining the efficacy of prevention trials. However, further prospective studies are needed.
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PMID:CD23 antigen expression on B lymphocytes and soluble CD23 levels in peripheral blood of high-risk type 1 diabetes subjects. 1002 61

The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.
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PMID:Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. 1007 44

The possible relation between HLA-DQ genotypes and both frequencies and levels of autoantibodies associated with IDDM was assessed by examining HLA-DQB1 alleles and antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase-related IA-2 molecule (IA-2A) in 631 newly diagnosed diabetic children under the age of 15 years. ICA were found in 530 children (84.0%), while close to half of the subjects (n = 307; 48.7%) tested positive for IAA. GADA were detected in 461 index cases (73.1%), with a higher frequency in those older than 10 years (78.9% versus 69.2% in the younger ones; P = 0.006). More than 85% of the children (n = 541; 85.7%) tested positive for IA-2A. Altogether there were only 11 children (1.7%) who had no detectable autoantibodies at diagnosis. There were no differences in the prevalence of ICA or GADA between four groups formed according to their HLA-DQB1 genotype (DQB1*0302/02, *0302/X (X = other than *02), *02/Y (Y = other than *0302) and other DQB1 genotypes). The children with the *0302/X genotype had a higher frequency of IA-2A and IAA than those carrying the *02/Y genotype (93.8% versus 67.3%, P < 0.001; and 49.0% versus 33.6%, P = 0.002, respectively). The children with the *02/Y genotype had the highest GADA levels (median 36.2 relative units (RU) versus 14.9 RU in those with *0302/X; P = 0.005). Serum levels of IA-2A and IAA were increased among subjects carrying the *0302/X genotype (median 76.1 RU versus 1.6 RU, P = 0.001; and 50 nU/ml versus 36 nU/ml, P = 0.004) compared with those positive for *02/Y. Only three out of 11 subjects homozygous for *02 (27.3%) tested positive for IA-2A, and they had particularly low IA-2A (median 0.23 RU versus 47.6 RU in the other subjects; P < 0.001). The distribution of HLA-DQB1 genotypes among autoantibody-negative children was similar to that in the other patients. These results show that DQB1*0302, the most important single IDDM susceptibility allele, is associated with a strong antibody response to IA-2 and insulin, while GAD-specific humoral autoimmunity is linked to the *02 allele, in common with a series of other autoimmune diseases as well as IDDM. We suggest that IA-2A may represent beta cell-specific autoimmunity, while GADA may represent a propensity to general autoimmunity.
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PMID:Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). The Childhood Diabetes in Finland Study Group. 1020 8

We analyzed 747 children, younger than 15 yr of age, with newly diagnosed diabetes, for antibodies to glutamic acid decarboxylase (GADA), the IA-2 protein (IA-2A), insulin (IAA), and islet cells, to evaluate the influence of positivity for GADA, IA-2A, IAA, or multiple (> or = 3) autoantibodies at diagnosis, on the clinical presentation and natural course of the disease over the first 2 yr and to characterize autoantibody-negative patients. At diagnosis, 73.2% of the children tested positive for GADA, 85.7% for IA-2A, 54.2% for IAA, and 72.6% for multiple autoantibodies. Only 17 subjects (2.3%) had no detectable autoantibodies. The patients testing positive for multiple autoantibodies were younger than the remaining children (P < 0.001). A similar age difference was seen when comparing IAA-positive and -negative patients (P < 0.001). There was no significant difference between the GADA-positive and -negative subjects in the degree of metabolic decompensation at diagnosis, whereas those testing positive for IA-2A had reduced serum C-peptide concentrations (P = 0.003), and those positive for IAA had lower glycated hemoglobin values. The patients with no detectable autoantibodies had higher serum C-peptide levels (P = 0.007) at diagnosis than did the other subjects. The children initially positive for IA-2A had decreased serum C-peptide concentrations at 24 months (P = 0.045), and their daily insulin dose was higher at 18 (P = 0.005) and 24 months (P < 0.001). The patients who tested positive for multiple autoantibodies at diagnosis had decreased serum C-peptide levels (P < 0.001) and higher insulin doses (P = 0.005) at 12, 18, and 24 months. A lower proportion of them were also in clinical remission at 12 and 18 months (P = 0.01). Autoantibody-negative subjects needed less exogenous insulin at 6 and 18 (P = 0.01) and at 24 months (P < 0.001) than the other subjects, and a higher proportion of them were in clinical remission at 18 months (P < 0.001). We conclude that positivity for multiple diabetes-related autoantibodies is associated with accelerated beta-cell destruction and an increased requirement for exogenous insulin over the second year of clinical disease, indicating that multiple autoantibodies reflect an aggressive progression to total beta-cell destruction. Patients testing negative for diabetes-associated autoantibodies at diagnosis seem to have a milder degree of beta-cell destruction, but their metabolic decompensation is similar to that seen in other affected children, suggesting that they do represent classical type 1 diabetes.
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PMID:Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. 1032 75

We report here our prospective study of 15,224 non-diabetic, first-degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2beta autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2betaA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5-year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2beta A. Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant beta-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.
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PMID:Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2beta predict immune-mediated (Type 1) diabetes in relatives. 1033 Feb 99

There is increasing evidence that CD3 + cells bearing gammadelta T-cell receptor (represent the minor subpopulation of the T-cells in the peripheral blood in humans) are involved in autoimmunity development. Gammadelta T-cell receptor (TCR)+ /CD8+ T-cells have been recently found to play a critical role in the pathogenesis and prevention of autoimmune diabetes in the animal model. The aim of the present study was the estimation the gammadelta T-cell subpopulation levels in the peripheral blood of subjects with preclinical and overt type 1 diabetes and their possible associations with the humoral immunity, metabolic parameters and pancreatic B-cells function. The study was carried out in three groups of subjects: 26 first degree relatives of type 1 diabetes patients (prediabetics) with the combinations of autoantibodies against pancreatic B-cells (ICA, GADA, IA-2A, IAA), 22 patients with a recent onset of type 1 diabetes and age and sex-matched 24 healthy volunteers (control group). A decrease was observed in the absolute numbers and percentages of gammadelta+ /CD8+ and gammadelta+ /CD8- T-cell subpopulations in peripheral blood in the prediabetics with the impaired first phase of insulin secretion in comparison to relatives with autoantibodies but still with normal B-cells function, patients with clinical diabetes and healthy controls. In conclusion, the study suggests that the gammadelta T-cells play an important role in the development of insulin-dependent diabetes mellitus (IDDM). It is possible that their levels in the peripheral blood could be an additional marker of preclinical detection of the disease, but further prospective studies in high risk of IDDM subjects are needed.
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PMID:Gammadelta T-cells alterations in the peripheral blood of high risk diabetes type 1 subjects with subclinical pancreatic B-cells impairment. 1042 34

It has been reported that there is a heterogeneity in the clinical course of Japanese patients with type 1 diabetes. To elucidate the associations of expression of autoantibodies to multiple islet antigens with age of onset and mode of diagnosis of diabetes in Japanese patients with type 1 diabetes, autoantibodies against the protein tyrosine phosphatase-like molecules ICA512 (IA-2) and phogrin (IA-2beta) (ICA512/phogrin-A), GAD (GADA), insulin (IAA), and islet cell cytoplasm (ICA) were determined in sera from 73 Japanese patients with type 1 diabetes obtained within 14 days of diagnosis. Patients were divided into groups based on the age of onset (</=10 years, n=24 and >10 years, n=49) or the mode of onset (abrupt onset, n=59 and urinary screening identified, n=14). Of 73 new-onset patients with type 1 diabetes, 43 (59%) and 32 (44%) had ICA512A and phogrin-A levels exceeding the 99th percentile of 184 normal control subjects, respectively. Forty-five patients (62%) were positive for either ICA512A or phogrin-A. The frequencies for other autoantibodies were 71% for GADA, 48% for IAA, and 62% for ICA. The frequency of ICA512/phogrin-A was significantly higher in patients with an age of onset less than 10 years (83%) than in patients aged >10 years (51%, P<0.01). The positivity of ICA512/phogrin-A was less in patients whose diabetes was diagnosed by the urine glucose screening test (21%, P<0.001) than in abrupt onset patients (71%). Combined analysis (>/=1 antibody) of GADA, IAA, and ICA512/phogrin-A detected 88% of abrupt onset and 93% of screening-positive patients vs. 70% and 29%, respectively, for ICA (P<0.0005). These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis.
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PMID:Autoantibodies to multiple islet autoantigens in patients with abrupt onset type 1 diabetes and diabetes diagnosed with urinary glucose screening. 1047 94

A pair of correspondent adhesion molecules: LFA-1 (CD11aCD18) and ICAM-1 (CD54) was shown to be involved in autoimmune insulitis in animal models. Anti-LFA-1 or anti-ICAM-1 monoclonal antibodies administered in vivo had a very strong preventive effect on the development of spontaneous diabetes with a marked reduction of insulitis. On the other hand elevated levels of the soluble form of ICAM-1 (sICAM-1) were documented in subjects at risk for type 1 diabetes. Recently sICAM-1 was shown to play an immunoregulatory role as an inhibitor of islet insulitis. The aim of the present study was to evaluate CD11a + mononuclear cells (lymphocytes and monocytes) and soluble sICAM-1 levels in the peripheral blood of subjects with preclinical and overt type 1 diabetes to assess their role in the development of the autoimmune process and their possible associations with the humoral autoimmune markers. The study was carried out in three groups of subjects: 26 first degree relatives of type 1 diabetes patients (prediabetics) with the combinations of autoantibodies against pancreatic B cells (ICA, GADA, IA-2A, IAA), 22 patients with a recent onset of type 1 diabetes and age and sex-matched 24 healthy volunteers (control group). We observed an increased fluorescence intensity of CD11a on mononuclear cells in overt diabetes subjects and a positive correlation between CD11a fluorescence intensity on monocytes and ICA titre. The highest sICAM-1 levels we obtained in the peripheral blood in the prediabetics in comparison to patients with clinical diabetes and the healthy controls. We found a positive correlation between slCAM-1 and values of ICA, GADA and a total number of antibodies present. In conclusion our study suggests that LFA-1 and sCAM-1 play an important role in the pathogenesis of type 1 diabetes. The assessment of the CD11a bearing monocytes and sICAM-1 levels are potential markers of the preclinical stage of the autoimmune diabetes, but further prospective studies in high risk diabetes type 1 subjects are needed.
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PMID:CD11a expression and soluble ICAM-1 levels in peripheral blood in high-risk and overt type 1 diabetes subjects. 1054 Oct 54


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