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)

Public anxiety over gluten has fuelled widespread demand for gluten-free food, yet coeliac disease remains significantly underdiagnosed and some confusion remains regarding optimal diagnostic practices. Small bowel histology is the gold standard for diagnosis. High-quality commercial enzyme-linked immunosorbent assays for transglutaminase immunoglobulin A and deamidated gliadin immunoglobulin A and G are sensitive tools for screening, but almost 10% of coeliac disease is seronegative and serological testing is unreliable in the very young, in people already following a gluten-reduced diet, and those using immunosuppressive medications. HLA DQA and DQB genotyping to show that alleles encoding HLA DQ2 and DQ8 are absent virtually excludes coeliac disease. Confirming histological remission reduces the risks of later complications, such as osteoporosis and cancer. Monitoring remission by serology is unreliable. Because gluten is an exogenous antigen and the small intestine is readily accessible, the immunopathogenesis of coeliac disease is better understood than other strongly major histocompatibility complex class II-associated diseases, such as type 1 diabetes mellitus. Therapeutic targets have been identified and drugs are under development to supplement or even replace gluten-free diet. With greater awareness and non-dietary therapeutics, diagnosis and treatment of coeliac disease will be increasingly prominent in medical practice.
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PMID:Coeliac disease: current approach and future prospects. 1950 13

Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.
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PMID:Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family. 2441 6

The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.
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PMID:Matrix metalloproteinases, T cell homing and beta-cell mass in type 1 diabetes. 1925 Oct 49

Alan J Lewis, PhD, joined the Juvenile Diabetes Research Foundation (JDRF) as President and CEO in January 2009. JDRF is a leader in setting the agenda for diabetes research worldwide, and is the largest charitable funder and advocate of Type 1 research. Prior to joining JDRF, Dr Lewis served as President, CEO and Director of Novocell, Inc., since 2006. Novocell is a stem cell engineering company dedicated to creating, delivering and commercializing cell and drug therapies to treat diabetes and other chronic diseases. Previously, Dr Lewis served as CEO and Director of Signal Pharmaceuticals before its acquisition in 2000 by Celgene, a biopharmaceutical company focused on the discovery, development and commercialization of small-molecule drugs for cancer and immunological diseases. He then served as President of the Signal Research Division at Celgene. Dr Lewis previously held the position of Vice President of Research at Wyeth-Ayerst, where he spent 15 years leading research efforts in diabetes, CNS, cardiovascular, inflammatory, allergy and bone metabolism diseases. Dr Lewis currently serves as a Director of BioMarin Pharmaceutical, Inc., Cytochroma, Inc., BIOCOM, and the Scottish Stem Cell Network. Dr Lewis received a BSc. in Physiology and Biochemistry from Southampton University, Southampton, Hampshire, UK, a Ph.D. in Pharmacology from the University of Wales, Cardiff, UK and completed his postdoctoral training at Yale University. He is also an Honorary Fellow and Chair of the Life Sciences Department at the University of Wales in Swansea, UK.
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PMID:Working for a cure for Type 1 diabetes. An interview. 1931 31

We report a case of a 13-year-old female with Langerhans cell histiocytosis (LCH) and primary hypothyroidism followed by type 1 diabetes mellitus (DM), both of which are rare complications. In LCH diagnosis, imaging studies showed an enlargement of the thyroid gland, suggesting the involvement of LCH cells. While the pancreas appeared normal, insulin secretion markedly deteriorated 11 months after cessation of chemotherapy. Even without direct pancreatic involvement, there is a possibility that LCH could induce DM as a part of its long-term complications. In particular, thyroid involvement may be related to the onset of DM.
Pediatr Blood Cancer 2009 Aug
PMID:A case of multisystem Langerhans cell histiocytosis with primary hypothyroidism followed by type 1 diabetes mellitus. 1936 15

Previous reports have shown that DNA methylation profiles within primary human malignant tissues are altered when these cells are transformed into cancer cell lines. However, it is unclear if similar differences in DNA methylation profiles exist between DNA derived from peripheral blood leukocytes (PBLs) and corresponding Epstein-Barr Virus transformed lymphoblastoid cell lines (LCLs). To assess the utility of LCLs as a resource for methylation studies we have compared DNA methylation profiles in promoter and 5' regions of 318 genes in PBL and LCL sample pairs from patients with type 1 diabetes with or without nephropathy. We identified a total of 27 (approximately 8%) genes that revealed different DNA methylation profiles in PBL compared with LCL-derived DNA samples. In conclusion, although the profiles for most promoter regions were similar between PBL-LCL pairs, our results indicate that LCL-derived DNA may not be suitable for DNA methylation studies at least in diabetic nephropathy.
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PMID:Comparative analysis of DNA methylation profiles in peripheral blood leukocytes versus lymphoblastoid cell lines. 1944 41

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
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PMID:A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. 1986 6

This qualitative study aimed to gain an in-depth understanding of the adaptation of children and families to childhood chronic illness. Considering ecological theories and child empowerment, we departed from the usual practice of relying solely on parental report by also soliciting children's views. Eighteen children aged 7-14 with cancer, chronic renal failure or type 1 diabetes, and 21 of their parents, participated. The inclusion of several conditions enabled the examination of data from a categorical versus non-categorical perspective. Focus groups supplemented by individual interviews explored participants' views about challenges and the processes they considered important in enhancing adaptation to a chronic illness. Children, as well as parents, provided rich material. Thematic analysis revealed 11 main themes. Six concerned the impact of the illness on various aspects of life. The other main themes were the meaning of disease, stress-processing, social support, future concerns and psychosocial interventions. There were many similarities and some differences between parent and child reports. Many issues were common across illness groups, consistent with a non-categorical approach, though there were some illness-specific issues, especially for those with cancer. Positive as well as negative material emerged. Implications for clinical services are discussed.
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PMID:Parental and child perspectives on adaptation to childhood chronic illness: a qualitative study. 1991 42

Meta-analysis of genomic coordinates of SNP variations identified in genome-wide association studies (GWAS) of up to 712,253 samples (comprising 221,158 disease cases, 322,862 controls, and 168,233 case/control subjects of obesity GWAS) reveals that 39% of SNPs associated with 22 common human disorders are located within intergenic regions. Chromatin-state maps based on H3K4me3-H3K36me3 signatures show that many intergenic disease-linked SNPs are located within the boundaries of the K4-K36 domains, suggesting that SNP-harboring genomic regions are transcribed. Here we report identification of 13 trans-regulatory RNAs (transRNAs) 100 to 200 nucleotides in length containing intergenic SNP sequences associated with Crohn's disease, rheumatoid arthritis, type 1 diabetes, vitiligo, hypertension and multiple types of epithelial malignancies (prostate, breast, ovarian and colorectal cancers). We demonstrate that NALP1 loci intergenic SNP sequence, rs2670660, is expressed in human cells and may contribute to clinical manifestations of autoimmune and autoimflammatory phenotypes by generating distinct allelic variants of transRNAs. Stable expression of allele-specific sense and anti-sense variants of transRNAs markedly alters cellular behavior, affect cell cycle progression, and interfere with monocyte/macrophage transdifferentiation. On a molecular level, forced expression of allele-specific sense and anti-sense variants of transRNAs asserts allele-specific genome-wide effects on abundance of hundreds microRNAs and mRNAs. Using lentiviral gene transfer, microarray and Q-RT-PCR technologies, we identify rs2670660 allele-specific gene expression signatures (GES) which appear useful for detecting the activated states of innate immunity/inflammasome pathways in approximately 700 clinical samples from 185 control subjects and 350 patients diagnosed with nine common human disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, Huntington disease, autism, Alzheimer disease, obesity, prostate and breast cancers. Microarray analysis of clinical samples demonstrates that rs2670660 allele-specific GES are engaged in patients' peripheral blood mononuclear cells (PBMC) which encounter pathological conditions in coherent tissues of a human body during immune surveillance and homeostasis monitoring. These data indicate that expression of transRNAs encoded by specific intergenic sequences can trigger activation of innate immunity/inflammasome pathways and contribute to clinical development of autoinflammatory and autoimmune syndromes. Documented in this work single-base substitution-driven molecular and biological antagonisms of intergenic SNP-containing transRNAs suggest a guiding mechanism of selection and retention of phenotype-compatible intergenic variations during evolution. According to this model, random genetic variations which generate transRNAs asserting antagonistic phenotype-altering effects compared to ancestral alleles will be selected and retained as SNP variants.
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PMID:Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders. 1992 86

The acute leukaemias account for about 30% of all malignancy seen in childhood across the Western world. A peak incidence of precursor B cell ALL has emerged as socio-economic conditions have improved in countries worldwide. From twin studies and the use of neonatal blood spots it has been possible to back track the first initiating genetic events within critical haemopoietic cells to foetal development in utero for most precursor B cell ALL and some cases of AML. These events may occur as part of normal foetal development. Whether other factors (environmental or constitutional) are involved to increase the chance of these first genetic changes happening is unclear. For some leukaemias (e.g. infant MLL positive ALL) the first event appears adequate to create a malignant clone but for the majority of ALL and AML further 'genetic' changes are required, probably postnatal. Many environmental factors have been proposed as causative for leukaemia but only ionising irradiation and certain chemicals, e.g. benzene and cytotoxics (alkylators and topoisomerase II inhibitors) have been confirmed and then principally for acute myeloid leukaemia. It appears increasingly likely that delayed, dysregulated responses to 'common' infectious agents play a major part in the conversion of pre-leukaemic clones into overt precursor B cell ALL, the most common form of childhood leukaemia. Constitutional polymorphic alleleic variants in immune response genes (especially the HLA Class II proteins) and cytokines may play a role in determining the type of immune response. High penetrance germ-line mutations are involved in only about 5% of childhood leukaemias (more in AML than ALL). There is little evidence to support any role of viral transformation in causation, unlike in animals. Other environmental factors for which some evidence exists include non-ionising electromagnetic radiation and electric fields, although their mode of action in leukaemogenesis remains unclear. There is no single cause for childhood leukaemia and for most individuals a combination of factors appears to be necessary; all involving gene-environment interactions. To date few clear preventative measures have emerged, except the complete avoidance of first trimester X-rays in pregnancy; a healthy diet with adequate oral folic acid intake both preconception and early in pregnancy; and the early exposure of children to other children outside the home to facilitate stimulation and maturation of the natural immune system. Here then are clear echoes of the "hygiene hypothesis" regarding the initiation of allergies, autoimmune disease and type I diabetes mellitus in children and young people.
Cancer Treat Rev 2010 Jun
PMID:Aetiology of childhood leukaemia. 2022 94


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