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)

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

Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn's disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell-specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases.
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PMID:Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease. 2208 Aug 63

The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). The Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased risk of T1D since 1993. Of the 1692 DAISY children genotyped for VDR rs1544410, VDR rs2228570, VDR rs11568820, PTPN2 rs1893217, and PTPN2 rs478582, 111 developed IA, defined as positivity for GAD, insulin or IA-2 autoantibodies on 2 or more consecutive visits, and 38 IA positive children progressed to T1D. Proportional hazards regression analyses were conducted. There was no association between IA development and any of the gene variants, nor was there evidence of a VDR*PTPN2 interaction. Progression to T1D in IA positive children was associated with the VDR rs2228570 GG genotype (HR: 0.49, 95% CI: 0.26-0.92) and there was an interaction between VDR rs1544410 and PTPN2 rs1893217 (p(interaction)=0.02). In children with the PTPN2 rs1893217 AA genotype, the VDR rs1544410 AA/AG genotype was associated with a decreased risk of T1D (HR: 0.24, 95% CI: 0.11-0.53, p=0.0004), while in children with the PTPN2 rs1893217 GG/GA genotype, the VDR rs1544410 AA/AG genotype was not associated with T1D (HR: 1.32, 95% CI: 0.43-4.06, p=0.62). These findings should be replicated in larger cohorts for confirmation. The interaction between VDR and PTPN2 polymorphisms in the risk of progression to T1D offers insight concerning the role of vitamin D in the etiology of T1D.
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PMID:Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). 2296 18