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)

IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.
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PMID:Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus. 890 50

Enteroviruses are proposed as initiating factors in the etiology of Type 1 diabetes mellitus (Type 1 DM). Molecular mimicry between the autoantigen glutamic acid decarboxylase 65 (GAD65) and the coxsackievirus B4 (CVB4) nonstructural protein P2C is frequently cited as a mechanism by which this virus triggers the disease, but little is known about the immunogenicity of this viral protein in humans, mainly due to the problem of obtaining highly pure preparations of P2C. We generated large amounts of highly pure, soluble P2C protein, coupled to the fusion partner maltose binding protein (MBP-P2C) using the PMAL-c2 bacterial expression plasmid and a two-step purification system comprising amylose resin and ion exchange. Using purified viral protein we show that specific T-cell responses against P2C are detected in the blood of healthy donors and Type 1 DM patients. Proliferation responses to P2C were detected only in subjects also demonstrating T-cell proliferation to CVB4 Vero cell lysates. However, in additional cases T-cell responses to P2C were detectable through the release of interferon-gamma or interleukin-4 in individuals who did not make proliferative responses. Taken together, our data show that the P2C nonstructural protein of CVB4 is targeted by T cells during the antiviral immune response and may trigger the production of T helper 1 and T helper 2 cytokines. The availability of pure, immunogenic P2C should allow the putative role of antiviral responses in the development of autoimmune diabetes to be investigated.
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PMID:T-Cell reactivity to the P2C nonstructural protein of a diabetogenic strain of coxsackievirus B4. 1093 88

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, P(tdt)=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; P(tdt)=6.5 x 10(-4) and P(tdt)=2.4 x 10(-4), respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all P(tdt)>/=0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-estradiol (E(2)) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by approximately 70% in the absence of E(2) (P(c)=0.004), but not with E(2) present (P(c)=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E(2) present, but was derepressed by addition of E(2), P(c)=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E(2) as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E(2) levels in puberty.
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PMID:Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females. 1271 74

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.
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PMID:Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. 1577 95

The aim of this study was to identify in the Brazilian population the frequency of human leukocyte antigen (HLA) DQ2.5 and DQ8 haplotypes conferring risk for type 1 diabetes (T1D), and to validate a new genotyping method aimed at cost reduction and automation. A total of 184 children and adolescents with T1D and 184 healthy individuals from Recife (northeastern Brazil) were analyzed using the conventional polymerase chain reaction-sequence-specific primers HLA genotyping and a newly described Tag-single-nucleotide polymorphism real-time polymerase chain reaction. The Tag-single-nucleotide polymorphism-based HLA genotyping method was successfully validated, proved to be robust, with limited cost and thus could be successfully used for the identification of genetic susceptibility for T1D in areas with limited financial resources. Our findings report for the first time the distribution of DQ2.5 and DQ8 HLA risk haplotypes associated with T1D in northeastern Brazil and evidence a major risk for developing T1D when the heterozygous DQ2.5/DQ8 or the homozygous DQ2.5/DQ2.5 haplotypes are present.
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PMID:Rapid genetic screening for major human leukocyte antigen risk haplotypes in patients with type 1 diabetes from Northeastern Brazil. 2003 15

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.
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PMID:Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations. 2225 88

The aim of the article was to study the occurrence of periodontal diseases in children with type I diabetes mellitus. The examination of 78 children revealed periodontal diseases in 40 children with type I diabetes. OHI-S, CPITN, PMA indices were determined. Pathological changes in periodontal tissues were revealed in 100% of cases. The following were identified: gingival hemorrhage (100%), over - and under-gingival dental tartar (100%), inflammation of gingival papilla (87,5%) marginal (80%) and alveolar gingiva (55%). Spread of periodontal disease among children with I type diabetes is characterized as high and is equal to 100%. Degree of periodontal sickness is evaluated as average and is M=2,28; SD=0,47 according to CPITN index. Treatment and preventive measures should be carried out taking into account major somatic disease.
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PMID:[Periodontal disease in children with diabetes mellitus type 1]. 2541 12

The SEARCH Nutrition Ancillary Study aims to investigate the role of dietary intake on the development of long-term complications of type 1 diabetes in youth, and capitalise on measurement error (ME) adjustment methodology. Using the National Cancer Institute (NCI) method for episodically consumed foods, we evaluated the relationship between sugar-sweetened beverage (SSB) intake and cardiovascular risk factor profile, with the application of ME adjustment methodology. The calibration sample included 166 youth with two FFQ and three 24 h dietary recall data within 1 month. The full sample included 2286 youth with type 1 diabetes. SSB intake was significantly associated with higher TAG, total and LDL-cholesterol concentrations, after adjusting for energy, age, diabetes duration, race/ethnicity, sex and education. The estimated effect size was larger (model coefficients increased approximately 3-fold) after the application of the NCI method than without adjustment for ME. Compared with individuals consuming one serving of SSB every 2 weeks, those who consumed one serving of SSB every 2 d had 3.7 mg/dl (0.04 mmol/l) higher TAG concentrations and 4.0 mg/dl (0.10 mmol/l) higher total cholesterol and LDL-cholesterol concentrations, after adjusting for ME and covariates. SSB intake was not associated with measures of adiposity and blood pressure. Our findings suggest that SSB intake is significantly related to increased lipid levels in youth with type 1 diabetes, and that estimates of the effect size of SSB on lipid levels are severely attenuated in the presence of ME. Future studies in youth with diabetes should consider a design that will allow for the adjustment for ME when studying the influence of diet on health status.
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PMID:Sugar-sweetened beverage intake and cardiovascular risk factor profile in youth with type 1 diabetes: application of measurement error methodology in the SEARCH Nutrition Ancillary Study. 2617 13

Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.
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PMID:Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility. 2691 20

We have previously developed a methodology to produce protein microspheres (MS) that can be loaded with proteins of interest in living cells through their C or N-terminal tagging with the so-called IC-Tag. The IC-Tagging method has many applications ranging from the production of immobilized enzymes for industrial use to the production of subunit vaccines due to its intrinsic adjuvancy. Here we show the adaptation of the IC-Tagging to work inside the endoplasmic reticulum and bacteria, allowing us to produce properly modified viral glycoproteins. Additionally, we were able to express the Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), whose expression remained elusive to date possibly due to its toxicity when over-expressed. IGRP is an antigen of enormous pharmaceutical interest as it is specifically targeted during the autoimmune response taking place in both the Non-Obese Diabetic (NOD) mice and type 1 diabetes (T1D) patients leading to the destruction of insulin-producing beta cells.
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PMID:IC-Tagging methodology applied to the expression of viral glycoproteins and the difficult-to-express membrane-bound IGRP autoantigen. 3039 11


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