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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent (type 1) diabetes is characterized by progressive destruction of insulin-producing beta cells probably by autoreactive T lymphocytes. Viral infections, especially those caused by coxsackieviruses, are postulated to play a role in the pathogenesis of the disease in humans. One mechanism by which viral infections could initiate or accelerate diabetogenic processes is "molecular mimicry," induction of antiviral immune responses cross-reacting with epitopes in the beta-cell autoantigens. Tyrosine phosphatases (IA-2, IAR) represent a major target autoantigen in type 1 diabetes. Both humoral and cellular immune responses are directed to the carboxy-terminal (C-terminal) part of the protein. This region has a 5-amino acid sequence identity, followed by five amino acid similarity with the conservative motif in the VP1-protein of enteroviruses (PALTAVETGA/HT), which is a highly immunogenic B- and T-cell epitope in enterovirus infection-induced immune responses. This observation prompted us to investigate potential humoral cross-reactions between immune responses induced by tyrosine phosphatases and enteroviruses. The reactivities of various peptide- and virus-induced rabbit antisera clearly demonstrated that cross-reactions do exist, and in both directions. Using epitope mapping, we were able to show that several diabetes-linked epitopes in IA-2 were also recognized by CBV-4-induced antisera. Immunization of female NOD-mice with formalin-inactivated purified strain of coxsackievirus B4 (CBV-4-E2) induced an immune response that recognized the IA-2/IAR diabetogenic peptide. The results obtained with human paired sera, collected during enterovirus infection, indicated that enterovirus infection in humans may also occasionally induce a humoral response that cross-reacts with IA-2/IAR.
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PMID:Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR. 1179 86

Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.
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PMID:Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor. 1270 68

Loss of Protein Tyrosine Phosphatase 1B (PTP 1B) activity is known to enhance insulin sensitivity and resistance to weight gain. So potent and orally active PTP1B inhibitors could be potential pharmacological agents for the treatment of Type 2 diabetes and obesity. Classification models of PTP1B inhibitors are developed using a data set containing 128 compounds. Their inhibitory concentrations ranged from -1.59 to 1.68 log units. Initially a two-class (active, inactive) problem is tackled using a number of different methods. The data set was divided into active and inactive classes on the basis of inhibitory activity of the compounds. Molecular structure-based descriptors were calculated and used in the model development. Descriptors encoding the flexibility of the molecules were investigated. Classification models were generated using k-nearest neighbors (k-NN), linear discriminant analysis (LDA), and radial basis function neural network (RBFNN). All models are tested using an external prediction set, compounds not used anywhere during the model development procedure. A five-descriptor model is developed that produces a classification rate of 85.7% for an external prediction set. Then a three-class (active, moderately active, inactive) problem was explored. This time the data set was divided into highly active, moderate, and inactive classes on the basis of inhibitory activity of the compounds. The best classification rate achieved for an external prediction set was 85%. The classification rates achieved indicate that these models could serve as a screening mechanism, to identify potentially useful PTP 1B inhibitors. In addition multiple linear regression and computational neural network models are also developed for prediction of log IC(50) values. All QSAR models are tested using the same external prediction set.
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PMID:Classification of inhibitors of protein tyrosine phosphatase 1B using molecular structure based descriptors. 1276 47

Tyrosine dephosphorylation, serine phosphorylation, and proteasomal degradation of insulin receptor substrates (IRSs) are implicated in the negative regulation of insulin action. Here we show that simultaneous inhibition of IRS-1 tyrosine dephosphorylation and proteasomal degradation synergistically augments insulin-responsive glucose uptake. L6 skeletal muscle cells (L6 cells) were treated with inhibitors of protein-tyrosine phosphatases, proteasomal degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and IRS-1 mass were examined. Pretreatment of L6 cells with sodium orthovanadate (Na(3)VO(4)) plus the mTOR inhibitor rapamycin caused a 5-fold increase in insulin-responsive glucose uptake at 2 hours when compared to insulin alone. Evaluation of IRS-1 associated PI 3-kinase activity, IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours after insulin addition they were reduced by 70% from maximal activity. Likewise, IRS-1 mass was reduced by 50%. When L6 cells were pretreated with Na(3)VO(4) plus the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, respectively, over insulin alone. Finally, treatment of L6 cells with subtherapeutic amounts of vanadyl sulfate and rapamycin induced a synergistic 3-fold increase in insulin-induced glucose uptake at 2 hours. These findings indicate that vanadium and rapamycin synergize to enhance glucose uptake by preventing IRS-1 mass loss and IRS-1/PI 3-kinase complex decay and may offer a new approach to enhance glucose transport in diabetes.
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PMID:Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. 1280 89

Oxidative stress has been implicated in dysfunctional mitochondria in diabetes. Tyrosine nitration of mitochondrial proteins was observed under conditions of oxidative stress. We hypothesize that nitration of mitochondrial proteins is a common mechanism by which oxidative stress causes dysfunctional mitochondria. The putative mechanism of nitration in a diabetic model of oxidative stress and functional changes of nitrated proteins were studied in this work. As a source of mitochondria, alloxan-susceptible and alloxan-resistant mice were used. These inbred strains are distinguished by the differential ability to detoxify free radicals. A proteomic approach revealed significant similarity between patterns of tyrosine-nitrated proteins generated in the heart mitochondria under different in vitro and in vivo conditions of oxidative stress. This observation points to a common nitrating species, which may derive from different nitrating pathways in vivo and may be responsible for the majority of nitrotyrosine formed. Functional studies show that protein nitration has an adverse effect on protein function and that protection against nitration protects functional properties of proteins. Because proteins that undergo nitration are involved in major mitochondrial functions, such as energy production, antioxidant defense, and apoptosis, we concluded that tyrosine nitration of mitochondrial proteins may lead to dysfunctional mitochondria in diabetes.
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PMID:Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes. 1282 49

Recently, environmental chemicals have appeared in daily human life, and these chemicals have been incidentally taken in by humans. The serum concentrations of some of these chemicals have been found to be associated with the onset and incidence rate of diabetes mellitus. It has been suggested that one of the environmental chemicals, bisphenol A (BPA), has hormone-like activity. It has also been demonstrated that some hormones affect insulin resistance and fat distribution in the body. To study the effects of these environmental chemicals on glucose metabolism, the effect of BPA on glucose transport in mouse 3T3-F442A adipocytes was investigated. The 3T3-F442A adipocytes were incubated with various concentrations of BPA in a medium. Deoxyglucose uptake assay was performed with and without insulin. Immunoblot analysis was performed with a glucose transporter (GLUT) 4-specific antibody and antiphosphotyrosine antibody. The BPA treatment enhanced basal and insulin-stimulated glucose uptake, and caused an increased amount of GLUT4 protein. Thus, the enhanced glucose uptake resulting from the BPA treatment was at least partially due to the increased amount of GLUT4. Tyrosine phosphorylation of insulin receptor substrate-1 with insulin stimulation was not significantly affected. In conclusion, it was demonstrated that BPA, one of the chemicals that we intake incidentally, affects the glucose transport in adipocytes, and also that the environmental chemicals may be identified as one of the environmental factors that affect diabetes and obesity.
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PMID:Bisphenol A affects glucose transport in mouse 3T3-F442A adipocytes. 1470 28

Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptor's intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses. A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes. We review how circulating factors such as insulin itself, TNF-alpha, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes.
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PMID:Modulation of insulin action. 1472 54

Zinc ions have an insulin-like (insulinomimetic) effect. A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. Modulation of insulin signaling by zinc chelating agents and the recognition of temporal and spatial fluctuations of zinc suggest a physiological role of zinc in insulin signal transduction. Tyrosine phosphatases seem to be regulated jointly by insulin-induced redox (hydrogen peroxide) signaling, which results in their oxidative inactivation, and by their zinc inhibition after oxidative zinc release from other proteins. In diabetes, the significant oxidative stress and associated changes in zinc metabolism modify the cell's response and sensitivity to insulin. Zinc deficiency activates stress pathways and may result in a loss of tyrosine phosphatase control, thereby causing insulin resistance.
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PMID:Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. 1615 25

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.
Diabetes 2006 Jan
PMID:The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice. 1638 Apr 83

Protein Tyrosine Phosphatase 1B (PTP1B), an important negative regulator of insulin signaling, is thought to be an attractive therapeutic target for insulin resistance and type 2 diabetes. For the aim of screening PTP1B expression down-regulators, we established the drug screening cellular model based on transcriptional regulation of PTP1B. In this study, the promoter sequences of PTP1B were cloned into pGL3B-neo vector containing luciferase gene and neomycin resistance gene. The recombinant reporter gene vector pGL3B-neo /PTP1B was transfected into CV1 cells and therefore stable cell line, namely SPTP1B, was obtained. With the cell-based reporter gene assay, we detected more than one hundred compounds in microtiter wells. In the screening process, the compound CM107 which had extracted from the traditional Chinese medicinal herbs was identified to repress the activity of PTP1B promoter significantly in mode of dose-dependence.
Exp Clin Endocrinol Diabetes 2007 Jan
PMID:Establishment of a cell-based drug screening model for identifying down-regulators of Protein Tyrosine Phosphatase 1B expression. 1728 30


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