UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse results from a T lymphocyte mediated destruction of the insulin-producing beta cells of the pancreas and serves as a model for human type I diabetes. The NOD mouse develops insulitis at 4 weeks of age and diabetes later in life. It has previously been shown that a T helper 1 (Th1) response to the islet antigen, glutamic acid decarboxylase (GAD65, henceforth GAD) spontaneously develops in NOD mice concurrent with the onset of lymphocytic infiltration into the islets (insulitis). The proliferative T cell response in the spleen is initially confined to the carboxy-terminal region of GAD65 (peptides 509-528 and 524-543) followed by a progression to nearby determinants and a variety of upstream determinants. We have produced a set of overlapping synthetic peptides spanning the 509-543 region of GAD and surveyed the responses raised by immunization with peptide GAD(524-543), which is the more immunogenic of the two peptides. NOD mice immunized with GAD(524-543) demonstrate splenic proliferative responses to 524-538 and 527-541 but not to 521-535 or 530-543. Four T cell hybridomas were produced from spleen cells of GAD(524-543)-immunized NOD female mice. Each hybridoma displayed a unique cytokine profile when stimulated with peptides 524-538 and 527-541, assaying IL-2, IFN-gamma, and IL-5 production by peptide-stimulated hybridomas. To identify MHC and TCR contact residues critical for the stimulation of the hybridomas, a truncated peptide (GAD 526-538) and a panel of analogue peptides were synthesized containing single-amino acid substitutions. Hybridoma 35.13.2 was non-responsive to the truncated peptide and all of its variants. However, the four residues 530 (A), 531 (P), 536 (R), and 537 (M) were found to be critical for the activation of the three remaining hybridomas, suggesting that these positions in the GAD-524-543 determinant were MHC binding residues or conserved TCR contact sites.
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PMID:T cells with multiple fine specificities are used by non-obese diabetic (NOD) mice in the response to GAD(524-543). 881 72

The autoimmune disease insulin-dependent diabetes is thought to result from T-cell mediated destruction of pancreatic beta cells. We analysed the relation between humoral and cellular immunity to multiple islet cell antigens, including human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase (ICA512/IA2), human pancreas and RIN cells in 28 patients with newly diagnosed type 1 diabetes and 9 antibody-positive (Ab+) relatives at high risk for type 1 diabetes. Of newly diagnosed patients, all showed reactivity to at least one recombinant islet cell antigen, by elevated cellular or humoral (or both) immune responses. Fifty-seven percent of patients and relatives showed T-cell reactivity to more than one islet cell antigen and 68% revealed humoral immunity to more than one islet cell antigen. Increased T-cell response to one single islet cell antigen was observed in 32% and positive antibody response in 25% of diabetic patients and relatives. Further-more, we found that T-cell reactivity to GAD was associated with T-cell reactivity to RIN cells, whereas reactivity to ICA512 and insulin was not associated with any other T-cell response. Likewise, antibody response to ICA512/IA2 correlated with antibodies to human pancreas (ICA), whereas antibody response to GAD or insulin was not related to any other antibody response. No positive or inverse correlation, however, was detected between T cell and humoral immunity, except for a positive association of antibodies and T-cell reactivity to insulin. Our data suggest that both humoral and cellular immune reactivity to multiple islet cell antigens are present in patients with newly diagnosed type 1 diabetes and in high risk relatives, but the two immune responses are individually activated.
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PMID:Relation between cellular and humoral immunity to islet cell antigens in type 1 diabetes. 881 82

The role of T-cells in the pathogenesis of IDDM has been an area of much interest, and investigators have recently acquired new tools for studies on T-cells with the advent of T-cell clones that are reactive with islet antigens. Derived from NOD mice, diabetogenic T-cell lines and clones have for the most part been CD4+ and T-helper 1 (Th1)-like in their cytokine production. Some CD8+ cytotoxic clones have also been reported, although these have generally not transferred diabetes in the absence of CD4+ T-cells. The T-cell clones that have been described can also be separated on the basis of their antigen reactivity. While many of the T-cell lines and clones described react with islets, isolated islet cells, or islet membrane preparations, others have known antigen specificities, reacting with defined islet cell proteins such as insulin, GAD, and heat shock proteins. Particularly in the case of insulin-reactive clones, diabetogenicity has also been demonstrated. In light of the many possible T-cell reactivities that may arise from the islet lesion, the question of whether there is a dominant initiating antigen is a particularly intriguing one.
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PMID:Diabetogenic T-cell clones. 882 63

Twenty islet cell antibody (ICA)-positive patients, aged 19-38 years, with IDDM were randomized at onset to treatment with either diazoxide, a K+ channel opener that inhibits the release of insulin, or placebo for 3 months, in addition to multiple insulin injection therapy. The patients who were given diazoxide displayed higher residual insulin secretion than the placebo group after 1 year (basal C-peptide level, 0.40 +/- 0.04 vs. 0.25 +/- 0.04 [mean +/- SE] nmol/l; P < 0.021) and at an 18-month follow-up (0.37 +/- 0.06 vs. 0.20 +/- 0.01 nmol/l, P < 0.033). Metabolic control did not differ between the two groups. During the course of the study, no differences in islet cell or GAD autoantibodies were detected between the two groups. The results of this study warrant further trials to explore the potential of inducing target cell rest in order to halt the loss of insulin-producing cells during the early course of the disease.
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PMID:Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes. 882 81

Although anti-glutamic acid decarboxylase antibodies (GADAb) have been reported to be a useful diagnostic and predictive marker of insulin-dependent diabetes mellitus (IDDM, type 1 DM) in Caucasians, a precise analysis of GADAb in Japanese children has not been reported. We examined the clinical significance and time course of GADAb in Japanese IDDM children, who have different genetic backgrounds from Caucasians. Twenty-three of 34 (67.6%) sera from recent-onset (< 6 months) IDDM, and 16 of 49 (32.7%) sera from long-standing (> or = 2 years) IDDM patients were positive for GADAb. This prevalence of GADAb in IDDM patients was significantly higher than in normal controls and the other groups including non-insulin-dependent DM, autoimmune thyroid disease and congenital hypothyroidism, and was also significantly higher in recent-onset than in long-standing IDDM. Time course analysis suggested that autoimmune response against GAD could follow different courses in individual cases after the initiation of insulin therapy. The incidence of GADAb was significantly higher in females than in males in the older age group (11-15 years). Other clinical features including residual pancreatic beta-cell function after diagnosis were demonstrated to be similar between GADAb-positive and -negative patients. In conclusion, this study using the newly established radioimmunoassay (RIA) for GADAb revealed a high prevalence of autoimmune reactivity to GAD in Japanese IDDM children. These results, using this RIA procedure, might assist in laying the groundwork for future trials of immunomodulation therapy for IDDM in Japan.
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PMID:Clinical significance and time course of antibodies to glutamic acid decarboxylase in Japanese children with type I (insulin-dependent) diabetes mellitus. 882 99

The prevalence and titre of epitope-specific autoantibodies to glutamic acid decarboxylase (GAD65) in 155 insulin-dependent diabetic (IDDM) and 9 GAD65 antibody (Ab)-positive healthy children were determined using four GAD65/67 chimaeric molecules which discriminate among the N-terminal (N), middle (M) and C-terminal (C) epitopes of GAD65. Radioligand binding assays for IgGAb used immunoprecipitation of in vitro translated 35S-GAD. We found autoantibodies to GAD65 in 116 of 155 (75%), to GAD67 in 19 of 155 (12%) (p < 0.0001) and to the GAD65-N-67 chimaera in 25 of 155 (16%) (p < 0.0001) IDDM sera. GAD67Ab were found almost exclusively (17 of 19, 89%) in GAD65Ab-positive sera and the levels of GAD67Ab correlated with those of GAD65Ab (r2 = 0.5913; p = 0.009). GAD65Ab directed to GAD65-M were found in 104 of 155 (67%), to GAD65-C in 104 of 155 (67%) and to GAD65-M + C in 116 of 155 (75%) of IDDM sera, and indicated reactivity to at least two distinct epitopes. Among the nine GAD65Ab-positive healthy children, two (22%) were also positive with GAD67, nine (100%) with GAD65-M + C, seven (78%) with GAD65-M, eight (89%) with GAD65-C and two (22%) with GAD65-N-67. Titres of GAD65Ab (p = 0.007), GAD65-C-Ab (p = 0.002) and GAD65-C + M-Ab (p = 0.003), but not of GAD65-M-Ab (p = 0.101) were significantly higher in IDDM than in healthy children. We conclude that GAD65Ab in IDDM and healthy children are directed to middle and C-terminal epitopes, and propose that levels of antibodies specifically directed to the carboxy-terminal end of GAD65 may distinguish IDDM from healthy children.
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PMID:Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM. 887 94

We evaluated the frequency of antibodies to glutamic acid decarboxylase (GAD-Ab) in Japanese patients diagnosed initially as having non-insulin-dependent diabetes mellitus (NIDDM) and investigated a possible link between the presence of GAD-Ab and development of the insulin-dependent (ID) state. The population sample consisted of 583 Japanese NIDDM patients (age at onset > 30 years) who were initially non-ketotic and did not require insulin treatment during at least 6 months of observation. GAD-Ab were measured using radioimmunoassay. The clinical characteristics of GAD-Ab+ patients were carefully examined at four-year intervals from the onset of diabetes. We also examined the ID state by measuring the level of postprandial serum C-peptide and i.v. glucagon-stimulated serum C-peptide. The overall prevalence of GAD-Ab in Japanese NIDDM patients was 3.8%. The frequency of GAD-Ab+ did not significantly decrease with a long history of diabetes. GAD-Ab+ patients had a lower body mass index, compared with GAD-Ab- (20.8 +/- 2.9 vs 23.0 +/- 3.7, P < 0.005), lower postprandial C-peptide levels (0.7 +/- 0.6 vs 1.4 +/- 1.2, P < 0.01), and an early commencement of insulin therapy (3.6 +/- 4.7 vs 8.3 +/- 6.6, P < 0.01). GAD-Ab+ patients who had already developed the ID state had characteristically higher titers of GAD-Ab (421.4 +/- 359.1) and a higher frequency of islet cell antibodies (ICAs) (77.8%), compared with GAD-Ab+ NID patients (titer: 60.2 +/- 86.9, P < 0.005, 23.1%, P < 0.05, respectively). GAD-Ab+ ICAs+ patients showed higher frequencies of ID state at any diabetic duration compared with GAD- ICAs-, while GAD-Ab+ ICAs- patients did not differ in the frequency of the ID state from GAD- ICAs-. Our results suggest that the presence of both GAD-Ab and ICAs represents a high risk for IDDM in GAD-Ab+ NIDDM patients.
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PMID:Clinical evaluation of non-insulin-dependent diabetes mellitus patients with autoantibodies to glutamic acid decarboxylase. 893 85

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.
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PMID:Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. 900 Jul

In the Asian populations, it is not uncommon for adult patients with NIDDM to eventually lose beta-cell function and develop IDDM. Accepting that IDDM is an autoimmune disease, which occurs on a genetic background, it could by hypothesized that by measuring autoantibody prevalence and HLA DQ gene polymorphism, known important prediagnostic markers of IDDM, the prevalence of adult-onset IDDM in patients with previously undiagnosed NIDDM patients could be estimated. To do this, anti-GAD prevalence and HLA DQ A1 and DQ B1 polymorphisms after PCR amplification of genomic DNA were analyzed in 121 newly diagnosed diabetic patients of Yonchon cohort and compared to the results with those of 100 matched health control subjects. We also compared the results with those of other populations to assess the difference of genotype distribution. The overall prevalence of anti-GAD antibodies was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 controls had positive antibodies. Among those who were positive, their titer of antibodies to GAD were not high. No statistically significant differences in the distribution of either mean levels of anti-GAD or DQA1 and DQB1 alleles were found comparing NIDDM patients to controls. Interestingly, the frequency of DQB1*non-Asp-57 and DQA1*Arg-52 alleles in the Korean adult control population was similar to that of US Caucasians (DQB1*non-Asp-57: 0.431 vs. 0.475; DQA1*Arg-52: 0.492 vs. 0.463). The low prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 susceptibility alleles among recent-onset NIDDM patients, not different compared to controls suggests that diabetes in Korean adults is unlikely to have an autoimmune component to its pathogenesis.
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PMID:Low prevalence of immunogenetic markers of IDDM in adult Koreans with diabetes detected on OGTT. 901 68

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

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