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 2-yr-old boy presented initially with type 1 diabetes (T1D). Over the next 9 yrs, he developed multiple autoimmune conditions including Evans' syndrome, alopecia, and autoimmune bowel disease. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome was considered, but no mutations were found in the autoimmune regulator-1 (AIRE-1) gene, making this diagnosis unlikely, and he did not fulfill the clinical criteria for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. We describe the challenges created by the combination of these diseases and how introduction of insulin pump therapy revolutionized his care.
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PMID:Life-threatening autoimmunity with diabetes: management with an insulin pump. 1465 74

Coeliac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically predisposed individuals. Patients with CD have an increased prevalence of other autoimmune disorders, including type 1 diabetes (T1D) and Graves' disease (GD). CD shares with these conditions certain HLA susceptibility alleles. A number of studies have also shown association of autoimmune diseases, including CD, with the CD28-cytotoxic T lymphocyte antigen 4 (CTLA4)-inducible costimulator (ICOS) region of chromosome 2q33, but until recently the precise causal variant has remained unknown. Recently, it was shown that, in GD, CT60 (+6230G>A), a single nucleotide polymorphism (SNP) at the end of the CTLA4 transcript, is associated with an alteration in the ratio of splice forms of the CTLA4 gene and that this ratio affects disease susceptibility. A similar but weaker association was found with T1D. There is also an independent association of GD and T1D with the SNP MH30 (-23 327G>C), which possibly affects promoter region function. Hypothesizing that CT60 and MH30 may be causal variants in other autoimmune disorders, we investigated these SNPs in CD using 149 family trios and 100 unrelated/unaffected controls. No association was detected with either SNP using both the transmission disequilibrium test (TDT) and case-control methods. Our study appears to have good power to detect moderate genetic effects, but possibly these SNPs exert too weak an effect on risk of CD to have been detected in our sample. Alternatively, the previously noted association of CD with the CTLA4 gene region may be due to different causal variants. Unlike T1D and GD, CD is not a true autoimmune disease, and CD has different associations at the CTLA4 exon 1 SNP +49G>A from all other autoimmune disorders. MH30, CT60, and other SNPs in the region may still warrant further investigation in other CD samples.
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PMID:Coeliac disease: investigation of proposed causal variants in the CTLA4 gene region. 1467 97

The long-term consequences of screening for celiac disease in diabetic children are not known. Routine screening is not practiced in our pediatric diabetic population. This study of the incidence of the most severe and specific long-term complication of untreated celiac disease, i.e., enteropathy-associated T-cell lymphoma (EATCL) and its association with diabetes, is done in order to justify our strategy not to practice routine screening. In the first phase of this study, a questionnaire was sent to all Swiss pathologists. The second phase consisted of a search in the cancer registry of the canton of Zurich. The incidence of EATCL in the general population of a Swiss region and the theoretical risk for a diabetic patient to develop this type of lymphoma were calculated. Ten cases of EATCL were found. Five had a long history of malabsorption, three of them since childhood. The mean age of the patients was 61.9 yr. None suffered from diabetes mellitus. The incidence of EATCL was 0.07/100,000 inhabitants/year. The expected risk for EATCL in patients with type 1 diabetes is 12.4/100,000 diabetic patients over a period of 60 yr. The data suggest that the risk for EATCL is small in diabetic patients. Therefore, we restrict the investigation for celiac disease to patients with typical and atypical symptoms, but do not perform routine screening.
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PMID:Incidence of enteropathy-associated T-cell lymphoma in celiac disease: implications for children and adolescents with type 1 diabetes. 1501 74

Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome). FOXP3 is necessary for the differentiation of a key immune suppressive subset of T-cells, the CD4+CD25+ regulatory T-cells. Previously, we reported a significant male-female bias in the common, multifactorial form of type 1 diabetes in Sardinia and evidence of linkage of chromosome Xp11 to the disease. These findings indicate that FOXP3 is a prime functional and positional candidate locus for the common form of type 1 diabetes. In the present study, we initially scanned 82 kb of the FOXP3 region for common polymorphisms, including sequencing all of the coding and functionally relevant portions of the gene in 64 Sardinian individuals. Then the most informative polymorphisms in 418 type 1 diabetic families and in 268 male case and 326 male control subjects were sequentially genotyped and tested for disease association. There is no evidence that variants in the FOXP3 regions analyzed are associated with type 1 diabetes and account for the male-female bias observed in Sardinia. Our data indicate that allelic variation in or near the coding regions of the FOXP3 gene does not have a major role in the inherited susceptibility to the common form of type 1 diabetes.
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PMID:No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population. 1522 Feb 19

IPEX syndrome is a genetic autoimmune disease characterized by immune-mediated polyendocrinopathy, enteropathy, and X-linked inheritance. We describe a case of IPEX in which lymphocyte phenotypes were assessed at birth, before initiation of Cyclosporin A therapy, and at frequent intervals to 18 months of age. We performed flow cytometry for lymphocyte subtypes and for activation markers (HLA-DR, CD25, and CD69 or CD71). The ratios of both T to B cells and CD4+ to CD8+ cells were elevated at birth, but CD4+ cells were not activated. HLA-DR+ and CD25+ activated T-cells increased in association with two episodes of clinical deterioration: colitis and the onset of type I diabetes mellitus. These results indicate that measures of activation, particularly HLA-DR+ and CD25+ frequency, correlate well with the development of early active disease and may presage clinical episodes. Continuous maintenance of immunosuppression, once started, appears critical for prevention of permanent tissue damage.
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PMID:Prospective immunological profiling in a case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). 1527 Aug 55

Type 1 diabetes mellitus (T1D) remains the most intensively studied, and thus the best paradigm, of MHC-associated diseases. Accumulating evidence suggests that MHC susceptibility for T1D is recessive, with susceptibility alleles more common than protective alleles. Updated allele-level and nucleotide sequence analysis of MHC class II T1D susceptibility markers of conserved extended haplotypes underscore the uncertainty surrounding the actual T1D MHC susceptibility locus. Recent studies have established that disease concordance in dizygotic twins is the same as that in siblings generally, for both T1D and the MHC-associated autoimmune disease gluten-sensitive enteropathy, leaving little room for a differential environmental trigger. Epigenetic mechanisms are probably involved in many MHC-associated phenomena, including autoimmunity, and appear to be the best explanation for incomplete penetrance.
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PMID:The genetics of HLA-associated disease. 1534 14

In diabetes-prone BioBreeding rats, an enteropathy often precedes the onset of auto-immune insulitis. The present study draws attention to quantitative and qualitative alterations of intestinal mucins in this animal model of type 1 diabetes mellitus. Male and female diabetes-resistant (BBc) and diabetes-prone (BBdp) BioBreeding rats fed, from one to two weeks after weaning onwards, either a plant-based diabetes-promoting diet (NTP) or a hydrolysed casein diabetes-protective diet (HC), were sacrificed at 11-14 weeks of age. Proteins and total mucins, as well as acid and neutral mucins, were measured in a segment of the intestinal tract, located 25-30 cm below the pylorus. No significant difference between BBc and BBdp rats was found when fed the HC diet. However, the NTP diet lowered both total and neutral mucins, whilst failing to affect significantly acidic mucins. The effects of the NTP diet were more pronounced in BBdp rats than in BBc rats. It is speculated that the quantitative and qualitative changes evoked by the NTP diet in BBdp rats may play a role in the alteration of gut permeability found under the same experimental conditions.
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PMID:Quantitative and qualitative alterations of intestinal mucins in BioBreeding rats. 1558 35

The incidence of common polygenic diseases, such as type 1 diabetes, bronchial asthma, and gluten-sensitive enteropathy, is increasing. Although this is usually attributed to environmental factors, it is possible that this rising incidence also has a genetic basis. The hypothesis is put forth that, in the past, these diseases, with their increased morbidity and mortality, were selected against. In contrast to monogenic diseases, the incidence of polygenic diseases can be reduced by selection against susceptibility alleles of any of the genetic loci necessary for disease to occur. In different isolated populations, different disease susceptibility loci may have been selected against. Parents who derive from different isolated populations in which there are inversely different susceptibility allele frequencies because of selection or genetic drift, would be expected to have offspring with an increased risk for that polygenic disease. It is shown mathematically that the incidence of a hypothetical polygenic disease increases under these circumstances. The increased risk in these offspring results from a kind of genetic complementation in which they have inherited a more complete set of susceptibility alleles at all susceptibility loci than is carried by either of their parents. Hallmarks of this hypothesized phenomenon would be increased heterozygosity for specific population markers (whether susceptibility alleles or not) among the disease-affected offspring and a paucity of such heterozygotes among their parents. The parents and patients would also be expected to give more evidence of ethnic or subethnic disparity than that observed in controls.
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PMID:Mendelian inheritance of polygenic diseases: a hypothetical basis for increasing incidence. 1582 28

Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.
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PMID:Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. 1562 18

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immune regulation characterized by the early onset of one or more autoimmune diseases in boys. IPEX is caused by mutations in FOXP3, and is thus the homologue of the scurfy mutant mouse. The gene product, Scurfin, is required for the development of CD4+CD25+ T regulatory cells. In the absence of T regulatory cells, activated CD4+ T cells instigate multi-organ damage resulting in type 1 diabetes, enteropathy, eczema, hypothyroidism, and other autoimmune disorders. While effective therapies are currently limited, studies in the scurfy mouse are revealing aspects of pathophysiology and genetics that will lead to novel approaches for treating IPEX and other autoimmune disorders. Females carrying Foxp3 mutations are unaffected. In new experiments we show that female scurfy mice that are also heterozygous in trans for the X-linked recessive common gamma chain knockout contract autoimmune disease, proving that murine Foxp3 is subject to X-inactivation and providing an example of gene-gene interaction causing autoimmune disease in females. One explanation for the lesser disease severity in these females is proposed.
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PMID:IPEX and FOXP3: clinical and research perspectives. 1624 87


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