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

The identification of causative genes for the autoimmune disease type 1 diabetes (T1D) in humans and candidate genes in the NOD mouse has made significant progress in recent years. In addition to sharing structural aspects of the MHC class II molecules that confer susceptibility or resistance to T1D, genes and pathways contributing to autoimmune pathogenesis are held in common by the two species. There are data demonstrating a similar need to establish central tolerance to insulin. Gene variants for the interacting molecules IL2 and CD25, members of a pathway that is essential for immune homeostasis, are present in mice and humans, respectively. Variation of two molecules that negatively regulate T cells, CTLA-4 and the tyrosine phosphatase LYP/PEP, are associated with susceptibility to human and NOD T1D. These observations underscore the value of the NOD mouse model for mechanistic studies on human T1D-associated molecular and cellular pathways.
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PMID:Type 1 diabetes genes and pathways shared by humans and NOD mice. 1625 8

Autoimmune recurrence and subsequent diabetes after pancreas transplantation has been described. In this cross-sectional study 91 type 1 diabetic patients were examined after successful pancreas/kidney transplantation (SPK). We studied the prevalence of autoantibodies to insulin (IAA), glutamate decarboxylase (GAD) and tyrosine phosphatase (IA-2) as well as parameters of pancreas graft function. Graft recipients were grouped according to immunoreactivity: group 1: no immunoreactivity; group 2: immunoreactivity to one antigen; group 3: immunoreactivity to two or three antigens. Twenty-five percent of graft recipients displayed no immunoreactivity, 39% displayed positivity for one antigen and 36% were positive for two or three antigens. There were no significant differences concerning fasting glucose, HbA1(c), glucose tolerance and renal function between the groups. Patients with cyclosporine (n = 42) as first-line immunosuppression displayed more often immunoreactivity to IA-2 and IAA than patients treated with tacrolimus (n = 49) (31% vs. 14%, P = 0.04; 67% vs. 47%, P = 0.04). In addition methylprednisolone therapy was related to less immunoreactivity to IA-2. Immunological markers for type 1 diabetes can be determined in the majority of pancreas graft recipients despite adequate immunosuppression. However, immunoreactivity was not associated with impaired graft function. Patients with cyclosporine for immunosuppression and withdrawal of glucocorticoids therapy were more often immunoreactive to IAA and IA-2.
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PMID:Insulin and islet autoantibodies after pancreas transplantation. 1629 55

We underwent a project aimed to define the clinical and immunological characteristics of type 1 diabetes (T1D) in a Colombian population. This was a multicenter and cross-sectional study. Patients were systematically interviewed and their medical records reviewed, using a questionnaire that sought information about demographic, clinical and immunological characteristics. Glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase antibodies (IA-2A) and insulin antibodies (IAA) were examined by radioimmunoassay. There were 107 patients with T1D. Male:female ratio was 1:1. Half of the patients developed diabetes ketoacidosis at onset. GADA, IA-2A, and IAA were detected in 45%, 40%, and 69% of the cases, respectively. GADA positive patients were older and had a less duration of disease than patients without these autoantibodies (p<0.01). Association between breast feeding with the presence of antibodies or clinical characteristics was not observed. The results highlight some differences of T1D expression according to geographic location and ethnicity. Differences in age at onset and clinical variables may point to an environmental factor or deficient access to health care system. Genetic studies underway will provide important information in this population. These results might help to define public health policies in our population to improve T1D diagnosis, patients' quality of life and their outcome.
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PMID:Clinical and immunological characteristics of type 1 diabetes mellitus in a northwestern Colombian population. 1632 57

We studied environmental risk factors which might contribute to the development of beta-cell autoantibodies in healthy children. Here, we investigated 6000 randomly selected children from the large All Babies in Southeast Sweden (ABIS) cohort, including 17 055 newborns recruited between 1997 and 1999. Questionnaires at birth and at 1 yr of age and the levels of autoantibodies to glutamic acid decarboxylase (GADA) and autoantibodies to tyrosine phosphatase (IA-2A) at 1 yr of age were analyzed. The 99th percentile cutoff for autoantibodies was proposed to identify children at risk of type 1 diabetes (T1D) and the 90th percentile cutoff to identify children in whom beta-cell autoimmunity has been induced. Using the 90th percentile cutoff level, 1156 children had either IA-2A (n = 574) or GADA (n = 582), while 126 children had both GADA and IA-2A. When the 99th percentile cutoff level was used, 114 children had either IA-2A (n = 57) or GADA (n = 57), and six children had both GADA and IA-2A. In logistic regression analysis, celiac disease in grandparents [odds ratio (OR) 2.2] and maternal gastrointestinal infection (OR 1.1) represented a risk for simultaneous occurrence of both IA-2A and GADA above the 90th percentile. Birth in spring (March to May) (OR 1.5) and male gender (OR 1.3) were risk factors for induction of IA-2A. Mother's low education represented a risk for induction of IA-2A (OR 1.5) and GADA (OR 1.4). T1D in first-degree relatives increased the risk for beta-cell autoimmunity above the 99th percentile (OR 2.6), whereas type 2 diabetes in grandparents was associated with GADA (OR 2.1). Exposure to cow's milk formulas <2 months of age implied an OR of 2.9 for IA-2A above the 99th percentile.
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PMID:Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children. 1639 Mar 88

Growing evidence has implicated members of the genus Enterovirus of the family Picornaviridae in the etiology of some cases of type 1 diabetes (T1D). To contribute to an understanding of the molecular determinants underlying this association, we determined the complete nucleotide sequence of a strain of echovirus 3 (E3), Human enterovirus B (HEV-B) species, isolated from an individual who soon after virus isolation developed autoantibodies characteristic of T1D. The individual has remained positive for over 6 years for tyrosine phosphatase-related IA-2 protein autoantibodies and islet cell autoantibodies, indicating an ongoing autoimmune process, although he has not yet developed clinical T1D. The sequence obtained adds weight to the observation that recent enterovirus isolates differ significantly from prototype strains and provides further evidence of a role for recombination in enterovirus evolution. In common with most HEV-B species members, the isolate exhibits 2C and VP1 sequences suggested as triggers of autoimmunity through molecular mimicry. However, comparisons with the E3 prototype strain and previously reported diabetogenic and nondiabetogenic HEV-B strains do not reveal clear candidates for sequence features of PicoBank/DM1/E3 that could be associated with autoantibody appearance. This is the first time a virus strain isolated at the time of commencement of beta-cell damage has been analyzed and is an invaluable addition to enterovirus strains isolated previously at the onset of T1D in the search for specific molecular features which could be associated with diabetes induction.
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PMID:Molecular analysis of an echovirus 3 strain isolated from an individual concurrently with appearance of islet cell and IA-2 autoantibodies. 1645 97

Type 1 diabetes results from a specific destruction of the insulin-producing beta-cells of the pancreas. The disease is characterized by the appearance of specific autoantibodies against islet cell antigens. Autoantibodies to insulin, glutamic acid decarboxylase, tyrosine phosphatase IA-2 and cytoplasmic islet cell antibodies are useful markers for the differential diagnosis of type 1 diabetes when clinical and metabolic criteria alone do not allow definite classification. Autoimmune diagnostics is of particular importance in adults to discriminate between type 1 and type 2 diabetes and to assess the diagnosis of latent autoimmune diabetes in adults.
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PMID:Autoimmune diagnostics in diabetes mellitus. 1647 96

We studied dietary risk factors by analysing a questionnaire administered at birth, 1 year and 2(1/2) years of age, as well as the level of glutamic acid decarboxylase autoantibodies (GADA) and tyrosine phosphatase autoantibodies (IA-2A), in 7208 2(1/2)-year-old children from the All Babies in Southeast Sweden cohort, using the 95th percentile cut-off for autoantibodies to identify children at risk of type 1 diabetes. A total of 657 children had either IA-2A (n 360) or GADA (n 335), and thirty-eight children had both GADA and IA-2A. In univariate analysis, male gender and maternal coeliac disease implied a risk of possessing IA-2A. Maternal type 2 diabetes, a high consumption of fresh cows milk at the age of 1 year and a late introduction of gluten were associated with a risk of GADA. Early cessation of breast-feeding (< 2 months of age) was associated with a risk of the simultaneous occurrence of both IA-2A and GADA. In logistic regression analysis, a high consumption of milk at the age of I year (odds ratio 2.6)represented a risk for GADA, and maternal coeliac disease (odds ratio 2.9) represented a risk for IA-2A. The combination of an early introduction of cows milk formula and a late introduction of gluten-containing food gave an odds ratio of 6.0 for positivity for at least one autoantibody at 1 and 21 years of age. The induction of autoantibodies by the age of 2(1/2) years has a male preponderance and is more common in children with maternal type 2 diabetes or maternal coeliac disease. Dietary risk factors for the induction of beta-cell autoantibodies in 21-year-old children are a short duration of breast-feeding, an early introduction of cows milk formula and a late introduction of gluten, as well as a high consumption of milk at the age of I year.
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PMID:Dietary risk factors for the emergence of type 1 diabetes-related autoantibodies in 21/2 year-old Swedish children. 1709 93

We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.
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PMID:Role of PTPN22 in type 1 diabetes and other autoimmune diseases. 1669 61

Human type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic beta cells and is modeled in many respects by the lymphopenic and spontaneously diabetic BioBreeding (BB) DRlyp/lyp rat. Previously, preonset expression profiling of whole DRlyp/lyp pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DRlyp/lyp rats as well as those of diabetes-inducible BB DR(+/+) rats potentially recruit innate cells through eotaxin expression. Here we determine that lifelong eotaxin expression begins before 40 days of life and is localized specifically to beta cells. In this report, we find that PLN mast cells are more abundant in DRlyp/lyp compared with related BB DR(+/+) rats (2.1 +/- 0.9% vs 0.9 +/- 0.4% of total cells, p < 0.0001). DRlyp/lyp PLN mast cell gene expression profiling revealed an activated population and included significant overrepresentation of transcripts for mast cell protease 1, cationic trypsinogen, carboxypeptidase A, IL-5, and phospholipase Cgamma. In the DR(+/+) rat, which develops T1DM upon depletion of T regulator cells, mast cells displayed gene expression consistent with the negative regulation of degranulation, including significant overrepresentation of transcripts encoding tyrosine phosphatase SHP-1, lipid phosphatase SHIP, and E3 ubiquitin ligase c-Cbl. To recapitulate the negative mast cell regulation observed in the DR(+/+) rats, we treated DRlyp/lyp rats with the mast cell "stabilizer" cromolyn, which significantly (p < 0.05) delayed T1DM onset. These findings are consistent with a growing body of evidence in human and animal models, where a role for mast cells in the initiation and progression of autoimmune disease is emerging.
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PMID:Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. 1708 46

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.
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PMID:Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene. 1723 19


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