Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.
...
PMID:Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus. 889 33

Recently, human endogenous retrovirus type K (HERV-K [IDDMK(1,2)22]) was isolated from an IDDM patient's beta-cell supernatant and shown to be implicated in expression as a superantigen. Furthermore, HERV-K RNA was found in plasma samples from newly diagnosed patients but not in those from healthy control subjects. We had earlier identified the presence of a HERV-K long terminal repeat element of the HLA DQ gene (DQ-LTR) to be positively associated with IDDM, which led us to investigate whether DQ-LTR is related to transcription of the putative retroviral superantigen. Additionally, we sought immunological evidence to determine whether those retroviral antigens could evoke an antibody response. Patients with IDDM (n = 14), Hashimoto's thyroiditits (n = 5), and Graves' disease (n = 12), as well as healthy control subjects (n = 12), were investigated, as were four nuclear families of Graves' disease patients and two of IDDM patients. RNA was isolated from plasma and peripheral blood lymphocytes and subjected to reverse transcription-polymerase chain reaction for transcripts of the env region of the HERV-K (IDDMK(1,2)22) sequence. We identified env transcripts in both plasma and peripheral blood lymphocytes in all individuals studied: patients with recent-onset or long-standing IDDM, their relatives, and healthy control subjects, as well as patients with thyroid autoimmune disorders. Furthermore, we screened the sera of patients (n = 62) and control subjects (n = 35) for evidence of humoral immunity against HERV-K by Western blot specific for the ENV protein. Similar frequencies of antibody-positives were observed both in patients with IDDM (29%) and in healthy control subjects (26%). We conclude that neither the ubiquitous HERV-K transcripts nor the comparable percentage of ENV protein antibodies are associated with IDDM. An earlier, presymptomatic antibody response against HERV-K (IDDMK(1,22)22) ENV cannot be ruled out. However, the superantigen hypothesis of an endogenous retrovirus in beta-cell autoimmunity awaits confirmation.
...
PMID:IDDM patients neither show humoral reactivities against endogenous retroviral envelope protein nor do they differ in retroviral mRNA expression from healthy relatives or normal individuals. 989 47

Indoleamine 2,3-dioxygenase (IDO) catalyzes the breakdown of the amino acid tryptophan into kyneurenine. It has been shown that IDO production by placental trophoblasts prevents the attack of maternal T-cells activated in response to the paternal HLA alleles expressed by the tissues of the fetus. In this article, we show that adenoviral gene transfer of IDO to pancreatic islets can sufficiently deplete culture media of tryptophan and consequently inhibit the proliferation of T-cells in vitro. Experiments in vivo have also demonstrated that transplantation of IDO-expressing islets from prediabetic NOD mouse donors into NODscid recipient mice is associated with a prolongation in islet graft survival after adoptive transfer of NOD diabetogenic T-cells. This protection is attributed to the depletion of tryptophan at the transplantation site beneath the kidney capsule. These results suggest that local modulation of tryptophan catabolism may be a means of facilitating islet transplantation as a therapy for type 1 diabetes.
...
PMID:Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. 1181 42

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, alpha-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.
...
PMID:Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. 1538 98

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves' disease, 104 unrelated subjects with autoimmune Addison's disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves' disease alleles compared to 67 of 858 (7.8%) control alleles (chi(2) = 17.2, p = 3.4 x 10(-5)' odds ratio = 1.88, 5-95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison's disease alleles vs 7.8% of controls (chi(2) = 4.63, p = 0.031; odds ratio = 1.69, 5-95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.
...
PMID:The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. 1553 53

Cells at the maternal-fetal interface express indoleamine 2,3 dioxygenase (IDO) to consume all local tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells. Thus it makes sense to consider IDO induction towards tolerance for autoimmune diseases in general. Approaches to cell specific therapeutic IDO induction with NAD precursor supplementation to prevent the collateral non-T cell pathogenesis due to chronic TNFalpha-IDO activated tryptophan depletion in autoimmune diseases are reviewed. Tryptophan is an essential amino acid most immediately because it is the only precursor for the endogenous biosynthesis of nicotinamide adenine dinucleotide (NAD). Both autoimmune disease and the NAD deficiency disease pellagra occur in women at greater than twice the frequency of occurrence in men. The importance of IDO dysregulation manifest as autoimmune pellagric dementia is genetically illustrated for Nasu-Hakola Disease (or PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of tryptophan causing neurodegeneration. Administration of NAD precursors rescued entire mental hospitals of dementia patients literally overnight in the 1930's and NAD precursors should help Nasu-Hakola patients as well. NAD depletion mediated by peroxynitrate PARP1 activation is one of the few established mechanisms of necrosis. Chronic elevation of TNFalpha leading to necrotic events by NAD depletion in autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete NAD. Pharmacological doses of NAD precursors repeatedly provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases. Distinct among the NAD precursors, nicotinic acid specifically activates the g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic prostaglandins PGE(2) and PGD(2). Next, PGD(2) is converted to the anti-inflammatory prostaglandin, 15d-PGJ(2). These prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma respectively. Nicotinamide prevents type 1 diabetes and ameliorates multiple sclerosis in animal models, while nothing is known about the therapeutic potential of nicotinamide riboside. Alternatively the direct targeting of the non-redox NAD-dependent proteins using resveratrol to activate SIRT1 or PJ34 in order to inhibit PARP1 and prevent autoimmune pathogenesis are also given consideration.
...
PMID:Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. 1743 Jan 13

Niacin (nicotinic acid and nicotinamide) is a vitamin used as a source of the NAD+ and NADP+ coenzymes required for many metabolic processes. Its low dietary levels induce the development of pellagra. Niacin has been used for decades in the treatment of patients with disturbed lipid and lipoprotein metabolism, this being the main cause of atherosclerotic changes in cardiovascular diseases. It is still the most efficacious drug in terms of its ability to increase HDL cholesterol content accompanied by a decrease in all atherogenic lipoproteins (VLDL, LDL, and L(a)) as well as fatty acids and triglycerides. Niacin also increases adiponectin level, which might result in additional atheroprotection. There are studies confirming the beneficial action of niacin against migraine and hyperphosphatemia associated with renal failure, ethanol-induced neurodegeneration, and loss of beta-cell function in type 1 diabetes. Moreover, it augments plasma tryptophan concentrations in HIV-infected patients and thyroid radiosensitivity to 131I. Inhibition of the invasion of hepatoma cells has also been proven. However, it is necessary to point out that the currently applied niacin preparations might exhibit such side effects as cutaneous flushing, gastrointestinal disturbances, and hepatotoxicity, particularly during treatment with sustained-release niacin preparations. The recent discovery of the G-protein-coupled receptor GPR109A, which mediates the antilipolytic effects induced by nicotinic acid in adipocytes as well as cutaneous vasodilation, allows the development of new agents interacting with this receptor. In view of these observations, niacin therapy must be accompanied by control of the choice of niacin preparation and its dose in order to eliminate or at least limit its side effects.
...
PMID:[Niacin in therapy]. 1755 32

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.
...
PMID:In silico screening for PTPN22 inhibitors: active hits from an inactive phosphatase conformation. 1917 73

Type I diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells, and effective treatment of the disease might require rescuing beta cell function in a context of reinstalled immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional beta cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-beta-dependent emergence of autoantigen-specific regulatory T cells and recovery of beta cell function in the diabetic recipients.
...
PMID:Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone. 1982 46

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is the third major locus affecting risk of type I diabetes (T1D), after HLA-DR/DQ and INS. The most associated single-nucleotide polymorphism (SNP), rs2476601, has a C->T variant and results in an arginine (R) to tryptophan (W) amino acid change at position 620. To assess whether this, or other specific variants, are responsible for T1D risk, the Type I Diabetes Genetics Consortium analyzed 28 PTPN22 SNPs in 2295 affected sib-pair (ASP) families. Transmission Disequilibrium Test analyses of haplotypes revealed that all three haplotypes with a T allele at rs2476601 were overtransmitted to affected children, and two of these three haplotypes showed statistically significant overtransmission (P=0.003 to P=5.9E-12). Another haplotype had decreased transmission to affected children (P=3.5E-05). All haplotypes containing the rs2476601 T allele were identical for all SNPs across PTPN22 and only varied at centromeric SNPs. When considering rs2476601 'C' founder chromosomes, a second haplotype (AGGGGC) centromeric of PTPN22 in the C1orf178 region was associated with protection from T1D (odds ratio=0.81, P=0.0005). This novel finding requires replication in independent populations. We conclude the major association of PTPN22 with T1D is likely due to the recognized non-synonymous SNP rs2476601 (R620W).
...
PMID:rs2476601 T allele (R620W) defines high-risk PTPN22 type I diabetes-associated haplotypes with preliminary evidence for an additional protective haplotype. 1995 96


1 2 3 4 Next >>

---