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)

Cardiovascular disease and the development of coronary artery disease play a pivotal role in increasing mortality in patients with type 1 diabetes. The aim of our study was to evaluate the effects of pancreas transplantation on atherosclerotic risk factors, endothelial-dependent dilation (EDD), and progression of intima media thickness (IMT) in patients with uremia and type 1 diabetes after kidney-alone (KA) or kidney-pancreas (KP) transplantation. A cross-sectional study comparing two groups of patients with type 1 diabetes was performed. Sixty patients underwent KP transplantation and 30 patients underwent KA transplantation. Age and cardiovascular risk profile were comparable in patients before transplantation. In all patients, atherosclerotic risks factors (lipid profile, fasting and post-methionine load plasma homocysteine, von Willebrand factor levels, D-dimer fragments, and fibrinogen) were assessed and Doppler echographic evaluation of IMT and endothelial function with flow-mediated and nitrate dilation of the brachial artery was performed. Twenty healthy subjects were chosen as controls (C) for EDD. Compared with patients undergoing KA transplantation, patients undergoing KP transplantation showed lower values for HbA1c (KP = 6.2 +/- 0.1% vs. KA = 8.4 +/- 0.5%; P < 0.01), fasting homocysteine (KP = 14.0 +/- 0.7 mcromol/l vs. KA = 19.0 +/- 2.0 micromol/l; P = 0.02), von Willebrand factor levels (KP = 157.9 +/- 8.6% vs. KA = 212.5 +/- 16.2%; P < 0.01), D-dimer fragments (KP = 0.29 +/- 0.02 microg/ml vs. KA = 0.73 +/- 0.11 microg/ml;P < 0.01), fibrinogen (KP = 363.0 +/- 11.1 mg/dl vs. KA = 397.6 +/- 19.4 mg/dl; NS), triglycerides (KP = 122.7 +/- 8.6 mg/dl vs. KA = 187.0 +/- 30.1 mg/dl; P = 0.01), and urinary albumin excretion rate (KP = 13.5 +/- 1.9 mg/24 h vs. KA = 57.3 +/- 26.3 mg/24 h; P < 0.01). Patients undergoing KP transplantation showed a normal EDD (KP = 6.21 +/- 2.42%, KA = 0.65 +/- 2.74%, C = 8.1 +/- 2.1%; P < 0.01), whereas no differences were observed in nitrate-dependent dilation. Moreover, IMT was lower in patients undergoing KP transplantation than in patients undergoing KA transplantation (KP = 0.74 +/- 0.03 mm vs. KA = 0.86 +/- 0.09 mm; P = 0.04). Our study showed that patients with type 1 diabetes have a lower atherosclerotic risk profile after KP transplantation than after KA transplantation. These differences are tightly correlated with metabolic control, fasting homocysteine levels, lower D-dimer fragments, and lower von Willebrand factor levels. Normal endothelial function and reduction of IMT was observed only in patients undergoing KP transplantation.
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PMID:Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes. 1124 68

To investigate the possible involvement of IDDMK1,2 22/HERV-K18 in childhood type I diabetes mellitus, we identified two nonsynonymous A/G polymorphisms in the superantigen-coding region of IDDMK1,2 22 at the 290- and 461-nucleotide (nt) positions from the initial methionine codon and compared their frequencies in 74 Japanese patients with type 1 diabetes and in 54 nondiabetic controls. Although the G substitution was observed more frequently at either site in the patients than it was in the controls (7% vs. 4% at 290 nt, and 29% vs. 20% at 461 nt), the differences were not statistically significant. A weak significance of difference in the frequency of 461G was obtained only in an early-onset group of patients manifesting the disease at 5 years of age or less (n = 24) when compared with controls (38% vs. 20%; P = 0.03). However, in addition to the common absence of a particular allele among the expected four alleles, remarkable differences in allele frequencies were present between Japanese and European populations. This first trial investigating the association of IDDMK1,12 22 with type 1 diabetes presents intriguing suggestions for the role of this region in the etiology of autoimmune and infectious diseases.
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PMID:Identification of nonsynonymous polymorphisms in the superantigen-coding region of IDDMK1,2 22 and a pilot study on the association between IDDMK1,2 22 and type 1 diabetes. 1177 84

The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG) --> Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG) --> Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the alpha2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and beta3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. =
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PMID:Variation in enterovirus receptor genes. 1262 50

A number of cytokines that finely regulate immune response have been implicated in the pathogenesis or protection of type 1 diabetes and other autoimmune diseases. It is, therefore, of pivotal importance to examine a family of proteins that serve as signal transducers and activators of transcription (STATs), which regulate the transcription of a variety of cytokines. We report here a defective gene (Stat5b) located on chromosome 11 within a previously mapped T1D susceptibility interval (Idd4) in the nonobese diabetic (NOD) mice. Our sequencing analysis revealed a unique mutation C1462A that results in a leucine to methionine (L327M) in Stat5b of NOD mice. Leu(327), the first residue in the DNA binding domain of STAT proteins, is conserved in all identified mammalian STAT proteins. Homology modeling predicted that the mutant Stat5b has a weaker DNA binding, which was confirmed by DNA-protein binding assays. The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2Rbeta and Pim1). Consequently, IL-2Rbeta and Pim1 proteins were shown by Western blotting to have lower levels in NOD compared with normal B6 mice. These proteins have been implicated in immune regulation, apoptosis, activation-induced cell death, and control of autoimmunity. Therefore, the Stat5b pathway is a key molecular defect in NOD mice.
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PMID:A mutant Stat5b with weaker DNA binding affinity defines a key defective pathway in nonobese diabetic mice. 1470 62

Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes.
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PMID:A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. 1512 4

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.
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PMID:Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. 1538 98

Reactive oxygen species are considered to play a role in the development of diabetes mellitus and its complications. Human MTH1 (mutT homologue 1) has 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase activity, which repairs oxidized forms of dGTP. This enzyme is known to have a thermolabile Met83 variant. We examined whether Val83Met polymorphism of human MTH1 gene is associated with type 1 diabetes mellitus. We recruited 156 type 1 diabetic patients (59 males and 97 females). The polymorphism was analyzed by restriction fragment length polymorphism analysis with Nsi I. The Met/Met genotype at codon 83 was very rare in both control and patient groups. Val/Met genotype tended to be more frequent in the whole type 1 diabetic patients than in controls. When subjects were divided into subgroups according to gender, there were no differences in the genotype and allele frequencies between patients and controls in males. On the other hand, in female type 1 diabetic patients, the Val/Met genotype was more frequent than in female controls (corrected P = 0.102). The Met allele was significantly more frequent in female type 1 diabetic patients than in female controls (corrected P = 0.022). Our results suggested that the Met allele at codon 83 of MTH1 gene might be involved in the development of type 1 diabetes mellitus in the Japanese female population.
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PMID:Association study of human MTH1 gene polymorphisms with type 1 diabetes mellitus. 1551 84

Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4(+) GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligand-mediated antagonism is inhibited in a dose-dependent manner by the presence of non-antagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.
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PMID:Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells. 1554 75

These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase.
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PMID:Proteomic changes associated with diabetes in the BB-DP rat. 1898 54

IA2 and phogrin are important targets of humoral and cell-mediated autoimmunity in type 1 diabetes in man. They belong to a conserved subfamily of transmembrane protein tyrosine phosphatases (PTPs) associated with the regulatory pathway of secretion. To examine potential cross-reactivity between PTP family members we tested sera from T1D patients for reactivity to IA2, and the Drosophila (FLYDA) and C. elegans (IDA) orthologs using radioimmunoprecipitation assays of (35)S Met-labeled in vitro translated products of the cytosolic domains of these proteins. Approximately 80% of sera reacted with at least one probe. Of these, 82.5% showed reactivity to human IA2, 74.1% to FLYDA, and 33.7% to IDA. The majority of sera that bound FLYDA and/or IDA also recognized IA2. This raises the possibility that in some cases reactivity to IA2 may have arisen by molecular mimicry.
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PMID:Conserved epitopes in the protein tyrosine phosphatase family of diabetes autoantigens. 1912 Mar 4


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