UMLS:C0011854 - FACTA Search

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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

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 aim was to estimate the prevalence of the serological markers of pancreatic autoimmunity in a cohort of Italian patients with type 1 diabetes mellitus occurring after 20 years of age in order to determine the prevalence of autoimmune diabetes and the most sensitive autoantibody combination to be employed for the diagnosis. We investigated 57 patients (31 males and 26 females) at clinical diagnosis of type 1 diabetes. 35 patients were 21-40 years and 22 were 41-72 years of age. Autoantibodies to islet-cells (ICA) were detected by indirect immunofluorescence, while those against glutamic acid decarboxylase (GADA), tyrosine-phosphatase (IA2A) and insulin (IAA) were detected by radiobinding assays. A positive test for at least one of the pancreatic autoantibodies was found in 45 of the 57 patients (78.9%). Coupling two antibody tests, GADA and/or IAA were found in 73.7%, ICA and/or GADA in 71.9%, while GADA and/or IA2A were found in 70.2% of the patients. The most frequently positive test was for GADA (66.7%). In general, the frequency of diabetes-related antibodies was higher in the 21-40-year-old group compared to the 41-72-year-old group and in females than males. Based on the detection of pancreatic autoantibodies determination, the great majority of the adult patients with recent onset type 1 diabetes were found to be autoimmune in nature. The best cost/benefit combination is provided by coupling the detection of GADA and ICA.
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PMID:Pancreatic autoantibodies in Italian patients with newly diagnosed type 1 diabetes mellitus over the age of 20 years. 1714 85

Breast-feeding has been suggested to have a protective effect against the development of type 1 diabetes. In the present study, we investigated the relation between duration of breast-feeding and beta-cell autoantibodies in 5-year-old non-diabetic children who participated in a prospective population-based follow-up study (the All Babies in Southeast Sweden study). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tryosine phosphatase-like IA-2 (IA-2A) were measured by radiobinding assays. A short duration of total breast-feeding was associated with an increased risk of GADA and/or IAA above the ninety-fifth percentile at 5 years of age (OR 2.09, 95% CI 1.45, 3.02; P<0.000) as well as with an increased risk of IAA above the ninety-fifth percentile at this age (OR 2.89, 95% CI 1.81, 4.62, P<0.000). A short duration of exclusive breast-feeding was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 2.01, 95% CI 1.08, 3.73; P=0.028) as well as with an increased risk of IA-2A above the ninety-ninth percentile (OR 3.50, 95% CI 1.38, 8.92, P=0.009) at 5 years of age. An early introduction of formula was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 1.84, 95% CI 1.01, 3.37; P=0.047) at 5 years of age. The positive association between a short duration of both total and exclusive breast-feeding, as well as an early introduction of formula, and positivity for beta-cell autoantibodies in children from the general population suggest that breast-feeding modifies the risk of beta-cell autoimmunity, even years after finishing breast-feeding.
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PMID:Short duration of breast-feeding as a risk-factor for beta-cell autoantibodies in 5-year-old children from the general population. 1721 66

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

A gain-of-function mutant of the lymphoid phosphatase Lyp (PTPN22) has recently been implicated in type 1 diabetes and other autoimmune diseases, suggesting that small-molecule inhibitors of Lyp could be useful for the treatment of autoimmunity. Virtual ligand screening (VLS) was applied in the search for hit compounds. Two different docking algorithms, FlexX and ICM, were used to screen a library of 'drug-like' molecules against two different 3D structures, representing the catalytic site of Lyp in both the inactive 'open' and active 'closed' conformations. The top-scoring compounds of each VLS run were tested for their inhibitory activity against recombinant Lyp. Interestingly, VLS with both active and inactive conformations yielded very potent hits, with IC(50) values in the sub- and low-micromolar range. Moreover, many of these hits showed high docking scores only with one conformation. For instance, this was the case with several 2-benzamidobenzoic acid derivatives, which specifically docked into the inactive open form. Tryptophan fluorescence measurements further support a binding mode in which these compounds seem to stabilize the phosphatase in its inactive conformation.
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PMID:In silico screening for PTPN22 inhibitors: active hits from an inactive phosphatase conformation. 1917 73

The proline-, glutamic acid-, serine- and threonine-rich (PEST) family of protein tyrosine phosphatases (PTPs) includes proline-enriched phosphatase (PEP)/lymphoid tyrosine phosphatase (LYP), PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind C-terminal Src kinase (Csk), a PTK also involved in inactivating Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells, PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of PTP-PEST to dephosphorylate cytoskeletal proteins such as Cas, focal adhesion associated-kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a PTP-PEST- and PTP-HSCF-interacting protein, PSTPIP1, were identified in humans with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind PTP-PEST and PTP-HSCF, suggesting that these two PTPs may be negative regulators of inflammation.
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PMID:PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. 1929 Sep 36

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet beta cells and/or insulin resistance in liver, muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B (PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway, insulin secretion and autoreactive attack to pancreatic beta cells. Genetic mutation or overexpression of these phosphotases has been found to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B, a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model and PTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares more than 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substrates overlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP may have role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic beta cell apoptosis. The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutant have impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanism of R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. A receptor tyrosine phosphatase, PTPIA-2/beta is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/beta autoantibodies is valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2 are involved in type 2 diabetes via regulation of insulin production, beta cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulin response and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic and therapeutic strategies for diabetes.
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PMID:[Research progress of several protein tyrosine phosphatases in diabetes]. 2040 54

Elevated IL-12 production and higher rate of CD4(+) T conventional (Tconv) cell proliferation in NOD mice have been implicated in the progression of type 1 diabetes. However, the underlying mechanisms remain largely unknown, even though enhanced activation of the IkappaB kinase (IKK)/NF-kappaB pathway has been revealed to mediate IL-12 overproduction. In this study, we report that deviated p38 MAPK activation also contributes to elevated IL-12 production with a mechanism involving MAPK-activated protein kinase-2-mediated stabilization of IL-12p40 mRNA. Aberrant p38 activation induced by various inflammatory stimuli in IL-12-overproducing cells is not due to defective MAPK phosphatase-1 induction in NOD mice. Deviated IKK and MAPKs activation also occurs in NOD CD4(+) Tconv cells, which is associated with higher rates of proliferation. All of the above evidence suggests that the signaling defects occur at the level of MAPK kinase kinase (MAK3K or MEKK). Further exploration shows that MEKK3, but not other MAP3Ks, is overexpressed in NOD IL-12-overproducing cells and CD4(+) Tconv cells independent of autoimmune inflammation. MEKK3 knockdown leads to reversal of the deviated IKK and MAPKs activation, resulting in reduced IL-12 production and decreased CD4(+) Tconv cell proliferation. Thus, this study provides a molecular mechanism of the hyperresponsiveness of IL-12-overproducing cells and CD4(+) Tconv cells in NOD mice.
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PMID:MEKK3 overexpression contributes to the hyperresponsiveness of IL-12-overproducing cells and CD4+ T conventional cells in nonobese diabetic mice. 2072 Feb 1

Insulin dependent diabetes mellitus (Type 1 diabetes, T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells by proinflammatory autoreactive T cells. In the past, several therapeutic approaches have been exploited by immunologists aiming to regulate the autoimmune response; this can occur by deleting lymphocyte subsets and/or re-establishing immune tolerance via activation of regulatory T cells. The use of broad immunosuppressive drugs was the first approach to be explored. Subsequently, antibody-based immunotherapies failed to discriminate between autoreactive versus non-autoimmune effectors. Antigen-based immunotherapy is a third approach developed to manipulate beta cell autoimmunity. This approach allows the selective targeting of disease-relevant T cells, while leaving the remainder of the immune system intact. Animal models have been successfully employed to prevent or treat T1D by injection of either the self proteins or peptides derived from them. Peptide immunotherapies have been mainly experimented in the NOD mouse spontaneous model of disease. In this review we therefore report the main approaches that rely on the use of peptides obtained from relevant autoantigens such as glutamic acid decarboxylase, isoform 65 (GAD65), insulin, proinsulin and islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP). Protective peptides have proven to be effective in treating or delaying the diabetic process. We also highlight the main difficulties encountered in extrapolating data to guide clinical translational investigations in humans.
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PMID:Peptide immunotherapies in Type 1 diabetes: lessons from animal models. 2114 10

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