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)

A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P = 7.9 x 10(-5)). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk.
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PMID:A haplotype-based analysis of the PTPN22 locus in type 1 diabetes. 1700 57

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self-tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self-antigens (oxytocin, neurotensin, insulin-like growth factor 2 [IGF-2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF-2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF-2 is so difficult to break by active immunization. The high level of tolerance to IGF-2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11-25 of IGF-2 (homologous to the autoantigen insulin B9-23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF-2 and other thymus self-antigens related to type 1 diabetes (T1D) should be preferred to insulin for the design of novel specific antigen-based preventive approaches against T1D.
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PMID:Thymus-dependent T cell tolerance of neuroendocrine functions: principles, reflections, and implications for tolerogenic/negative self-vaccination. 1719 74

The identification of genes mediating susceptibility to type 1 diabetes (T1D) remains a challenging task. Using a positional cloning approach based on the analysis of nonobese diabetic (NOD) mice congenic over the Idd6 diabetes susceptibility region, we found that the NOD allele at this locus mediates lower mRNA expression levels of the lymphoid restricted membrane protein gene (Lrmp/Jaw1). Analysis of thymic populations indicates that Lrmp is expressed mainly in immature thymocytes. The Lrmp gene encodes a type 1 transmembrane protein that localizes to the ER membrane and has homology to the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate gene, which negatively regulates intracellular calcium levels. We hypothesize that the observed decrease in expression of the Lrmp gene in NOD mice may constitute a T1D susceptibility factor in the Idd6 region.
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PMID:The Idd6.2 diabetes susceptibility region controls defective expression of the Lrmp gene in nonobese diabetic (NOD) mice. 1735 98

The discovery that a single-nucleotide polymorphism (SNP) in lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, is associated with type 1 diabetes (T1D) has now been verified by numerous studies and has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus, Graves' disease, generalized vitiligo and other human autoimmune diseases. In this paper, we discuss the association of PTPN22 with autoimmunity, the biochemistry of the PTPN22-encoded phosphatase, and the molecular mechanism(s) by which the disease-predisposing allele contributes to the development of human disease.
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PMID:Protein tyrosine phosphatase PTPN22 in human autoimmunity. 1772 39

The missense PTPN22 C1858T polymorphism recently emerged as an important population-independent risk factor for type 1 diabetes (T1D) and other autoimmune diseases. The PTPN22 gene encodes the lymphoid tyrosine phosphatase (LYP), a negative regulator of signal transduction through the T-cell receptor. Although the frequency of the polymorphism is variable among different ethnic groups, the association between PTPN22 *T1858 and T1D has been replicated in several populations. Here, we contribute the first replication of the association between PTPN22 and T1D in populations from continental Italy, carried out in two independent samples of T1D patients (N = 216 and 82) and controls (N = 271 and 89). Our data also suggest that T1D carriers of the *T1858 allele could be at increased risk for other comorbid autoimmune disorders.
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PMID:Association between PTPN22 C1858T and type 1 diabetes: a replication in continental Italy. 1817 48

The 620Trp variant of the LYP protein, encoded by the lymphoid tyrosine phosphatase 22 gene (PTPN22), is associated with autoimmunity. In this study we aimed at characterising the role of this variant on lymphocyte activation. We analysed cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) and CD4(+)T cells in a cohort of clinically non-diabetic, multiple autoantibody-positive children, healthy controls and in children with type 1 diabetes (T1D). We found a decreased proliferation and IL-2 production of CD4(+)T cells after anti-CD3/anti-CD28 stimulation (p=0.04 for IL-2) among T1D patients. In addition, a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers. In contrast, no effect of this polymorphism on tuberculin and tetanus toxoid induced PBMC proliferation and cytokine secretion was observed in autoantibody positive children, healthy controls and children with newly-diagnosed T1D. In conclusion, the LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients. In accordance with our previous findings on the key role of this variant on disease progression, this mechanism is likely to contribute to the development of beta-cell specific autoimmunity.
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PMID:Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant. 1829 86

Improvement over current methods of beta cell viability assessment is highly warranted in order to efficiently predict the viability and function of beta cells prior to transplantation into type 1 diabetes patients. Dispersed human islet cells were stained with the cell-permeable zinc-selective dye, FluoZin-3-AM, along with the mitochondrial membrane potential indicator [(tetramethylrhodamine ethylester (TMRE)] and the thiol-binding dye, monochlorobimane (mBcl), and analyzed by flow cytometry. Islets were subjected to various experimental conditions to validate the usefulness of this method to accurately determine the viability and function of beta cells. Staining with FluoZin-3 revealed the presence of higher amounts of chelatable zinc ions in beta cells than in lymphoid cells and fibroblasts. An intracellular zinc chelator competitively inhibited the binding of FluoZin-3 to zinc ions. Mitochondrial depolarization or oxidative stress minimally affected the binding of mBcl and FluoZin-3, respectively, to thiols and zinc ions. The combination of FluoZin-3, TMRE, and mBcl was sufficient and necessary for the determination of the viability and function of beta cells. The data demonstrate the usefulness of the zinc-specific dye and the indicators of mitochondrial function and thiol levels, to accurately estimate the beta cell viability and function. This novel flow cytometry method has implications for islet transplantation in type 1 diabetes patients.
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PMID:A novel method for the detection of viable human pancreatic beta cells by flow cytometry using fluorophores that selectively detect labile zinc, mitochondrial membrane potential and protein thiols. 1841 18

The prevalence of overweight (body mass index, BMI, between 25 and 30 kg/m2) and obesity (BMI of 30 kg/m2 or higher) is increasing rapidly worldwide, especially in developing countries and countries undergoing economic transition to a market economy. One consequence of obesity is an increased risk of developing type II diabetes. Overall, there is considerable evidence that overweight and obesity are associated with risk for some of the most common cancers. There is convincing evidence of a positive association between overweight/obesity and risk for adenocarcinoma of the oesophagus and the gastric cardia, colorectal cancer, postmenopausal breast cancer, endometrial cancer and kidney cancer (renal-cell). Premenopausal breast cancer seems to be inversely related to obesity. For all other cancer sites the evidence of an association between overweight/obesity and cancer is inadequate, although there are studies suggesting an increased risk of cancers of the liver, gallbladder, pancreas, thyroid gland and in lymphoid and haematopoietic tissue. Far less is known about the association between diabetes mellitus type I (also called insulin dependent diabetes mellitus or juvenile diabetes), type II diabetes (called non-insulin dependent diabetes mellitus or adult onset diabetes mellitus) and cancer risk. The most common type of diabetes mellitus, type II, seems to be associated with liver and pancreas cancer and probably with colorectal cancer. Some studies suggest an association with endometrial and postmenopausal breast cancer. Studies reporting on the association between type I diabetes mellitus, which is relatively rare in most populations and cancer risk are scanty, but suggest a possible association with endometrial cancer. Overweight and obesity, as well as type II diabetes mellitus are largely preventable through changes in lifestyle. The fundamental causes of the obesity epidemic-and consequently the diabetes type II epidemic-are societal, resulting from an environment that promotes sedentary lifestyles and over-consumption of energy. The health consequences and economic costs of the overweight, obesity and type II diabetes epidemics are enormous. Avoiding overweight and obesity, as well as preventing type II diabetes mellitus, is an important purpose to prevent cancer and other diseases. Prevention of obesity and type II diabetes should begin early in life and be based on the life-long health eating and physical activity patterns. Substantial public investments in preventing overweight, obesity and type II diabetes mellitus are both appropriate and necessary in order to have a major impact on their adverse health effects including cancer.
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PMID:Obesity and diabetes epidemics: cancer repercussions. 1863 86

Prior to the development of type 1 diabetes, T cells are primed in the pancreatic lymph nodes (PLN) where they interact with APC displaying beta cell-derived peptides. The details concerning the regulation of autoreactive T cell responses in the PLN are unclear. BDC2.5/B6g7 TCR transgenic mice represent a simplified model of type 1 diabetes, in which beta cell-specific CD4+ T cells expressing a diabetogenic transgenic TCR are first activated in the PLN and subsequently home to the pancreas where they mediate killing of beta cells. DNAX-activating protein of 12 kDa (DAP12) is an adaptor molecule carrying an ITAM motif. It associates with receptors on lymphoid and myeloid cells, including APC. We here show that introduction of a DAP12 null mutation in BDC2.5/B6g7 mice accelerated diabetes development and promoted an augmented activation state of PLN T cells expressing the transgenic TCR. Transferred BDC2.5 T cells proliferated more efficiently in the PLN of DAP12-deficient B6g7 recipients, which correlated with a decreased impact of co-transferred BDC2.5+CD4+CD25+ T cells. We propose that signaling through a DAP12-associated receptor on APC facilitates activation of Treg in the PLN and by this contributes to the maintenance of peripheral tolerance to beta cell-derived antigens.
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PMID:Increased diabetes development and decreased function of CD4+CD25+ Treg in the absence of a functional DAP12 adaptor protein. 1892 76

FoxP3(+) regulatory T cells (Tregs) protect against autoimmunity, type 1 diabetes (T1D) in particular, prompting the hypothesis that a deficiency in Tregs is a critical determinant of diabetes susceptibility in NOD mice. However, tests of this hypothesis have yielded contradictory results. We confirmed that NOD mice, compared with reference strains, do not have a primary deficit in Treg numbers in the lymphoid organs, whether in prediabetic mice of any age or in animals with recent-onset diabetes. NOD Tregs did show a defect in standard in vitro T cell suppression assays, particularly at low suppressor/effector ratios. Gene expression profiling revealed the vast majority of transcripts constituting the "Treg signature" to be normally distributed in NOD Tregs versus CD4(+) T conventional (Tconv) cells, although there were a few differences affecting one or the other population. According to results from criss-cross experiments, the functional inefficacy was not rooted in NOD Tregs, which suppressed as well as their C57BL/6 (B6) counterparts, but rather in NOD Tconv, which were less prone to suppression than were B6 Tconv cells. They also responded more effectively to anti-CD3/28 monoclonal antibody (mAb) stimulation in vitro or to a natural pancreatic antigen in vivo. This difference was independent of autoimmune inflammation, did not map to the idd3 region, and was not due to the overproduction of interleukin-21 in NOD mice. That the immune dysregulation in this T1D model is rooted in the ability of effector T cells to be regulated, rather than in Tregs themselves, has implications for proposed therapeutic interventions.
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PMID:The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. 1907 38


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