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)

Cytokines, in particular IL-1, released mainly by infiltrating macrophages, can be one of the key mediators of immune-induced beta-cell destruction in IDDM. IL-1 is able to induce suppression of insulin release and biosynthesis in cultured rat pancreatic islets. In addition, the cytokine shows clear cytotoxic effects leading to beta-cell death. The proposed mechanisms of action of IL-1 after binding to the beta-cell receptors are varied. Concerning the cytotoxic effects of the cytokine, the role of oxygen free radicals, mainly derived from arachidonate metabolism (see Fig. 1) is clear, and possibly potentiated by a cytosolic Na(+)-mediated alkalinization of the beta-cell exposed to the cytokine. In fact, an increased influx of Na+ may explain some of the cytotoxicity since it results in concomitant water uptake leading to swelling of the endoplasmic reticulum. NO formation also seems to be related to the cytokine-induced cytotoxicity since inhibition of the NO synthase abolishes the effects of the cytokine (see Fig. 1). In relation to the inhibitory effects of the cytokine on the beta-cell, different studies point toward almost all known second messenger systems already described for several hormones, such as cAMP formation, increased phospholipase C activity, changes in cytosolic Ca++, and altered gene transcription (see Fig. 1). Of particular interest is the protease activation associated with IL-1 (a serine protease) that seems to be clearly connected with the effects of the cytokine upon the beta-cell. In conclusion, the different studies devoted to the problem of IL-1 signal transduction on the beta-cell seem to indicate that the action of the cytokine on the pancreatic insulin-secreting cells is not associated with an individual second messenger system but rather seems to be related to a plurifactorial transduction system.
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PMID:Interleukin-1 and beta-cell function: more than one second messenger? 142 86

Arginine metabolism via nitric oxide (NO) synthase and other pathways was studied in coronary endothelial cells (EC) from the spontaneously diabetic BB rat, an animal model of human type I diabetes mellitus (IDDM). EC were prepared from insulin-treated diabetic BB (BBd) and non-diabetes-prone BB (BBn) rats. Basal NO synthesis was studied in EC cultured for 48 h in medium containing 0.4 mM L-arginine. At the end of the culture period, the medium was analyzed for nitrite and nitrate (two major end stable oxidation products of NO), and the cells were used to determine arginine uptake and metabolism and the activities of some arginine-degrading enzymes. For studies of arginine metabolism, cells were incubated at 37 degrees C for 1 h in Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 1 mM L(-)[1-14C]arginine or L(-)[1-14C]ornithine. The rates of production of nitrite plus nitrate by BBd EC were only 15% of those of BBn cells. This impaired NO synthesis in BBd EC was not due to alterations in arginine uptake, NO synthase activity, or intracellular arginine concentrations but might have resulted from a limited intracellular availability of cofactors of NO synthase. In addition to the arginine-NO pathway, arginine was found to be metabolized to urea, ornithine, and, to a much lesser extent, CO2 via arginase and ornithine aminotransferase. The activities of arginase and the formation of ornithine and urea from arginine were decreased by 90% in BBd compared with BBn cells. These results, coupled with the reduced NO synthesis, indicate metabolic defects in arginine metabolism in BBd EC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat. 748 63

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit the immune response, thereby regulating the rate of beta-cell destruction in IDDM.
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PMID:Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. 876 Mar 54

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin-secreting beta-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and beta-cell destruction during the development of IDDM. In this study, the effects of cytokines on the expression of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) by human islets were examined. In combination, the cytokines, human recombinant interleukin-1 beta (IL-1 beta), human recombinant tumor necrosis factor-alpha (TNF-alpha), and human recombinant interferon-gamma (IFN-gamma), induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) completely inhibits cytokine-induced nitrite formation and attenuates PGE2 production by human islets. L-NMMA does not inhibit cytokine-induced expression of COX-2 by human islets, suggesting that nitric oxide may directly activate cyclooxygenase, an effect that has been previously demonstrated for isolated rat islets. This combination of cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) also induces the expression of iNOS mRNA by human islets as demonstrated by both reverse transcriptase-polymerase chain reaction and Northern blot analysis. We further show that the tyrosine kinase inhibitors genistein and herbimycin A prevent IL-1 beta plus IFN-gamma-induced expression of COX-2 and iNOS and the production of PGE2 and nitric oxide by human islets. These results demonstrate that cytokines induce the expression of iNOS and COX-2 by human islets and that cytokine-induced expression of both COX-2 and iNOS by human islets appears to require the activation of a tyrosine kinase(s).
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PMID:Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets. 876 39

Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting beta cells found in islets of Langerhans. The biochemical mechanisms associated with beta-cell destruction have remained elusive. Cytokines, released from T lymphocytes, macrophages, and monocytes during islet insulitis, have been implicated as effector molecules that participate in beta-cell death. Recently, cytokine-induced expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide by beta cells has been suggested as one potential mechanism associated with beta-cell destruction. Treatment of rat islets with interleukin 1 (IL-1) results in a potent inhibition of insulin secretion followed by islet destruction. The inhibitory and destructive effects of this cytokine on islet function are completely prevented by the inhibition of iNOS enzymatic activity. Islets contain a heterogeneous population of both endocrine and nonendocrine cells including a low level of resident tissue macrophages ( approximately0.5% of all islet cells). The intraislet macrophage appears to one cellular source of IL-1. Activation of resident islet macrophages results in both the expression of iNOS and the release of IL-1. Intraislet macrophage production of nitric oxide (in the absence of IL-1) does not modulate beta-cell function; however, macrophage release of IL-1 and IL-1-induced iNOS expression by beta cells results in a potent inhibition of beta-cell function. These findings support a role for nitric oxide as a potential mediator of cytokine-induced inhibition of beta-cell function and implicate the intraislet macrophage as one cellular source of IL-1. Direct support for a role of nitric oxide in the development of diabetes includes the ability of inhibitors of iNOS to prevent or delay the development of this disease condition in animal models. Important to these studies has been the identification of selective inhibitors of iNOS. Many inhibitors of nitric oxide synthase have been developed; however, few selective inhibitors for the individual isoforms of NOS (inducible, endothelial, neuronal) have been described. Aminoguanidine has been identified as one of the first iNOS selective inhibitors. Aminoguanidine is over 50-fold more effective at inhibiting the enzymatic activity of iNOS than endothelial or neuronal NOS. The effects of aminoguanidine on the development of diabetes in the nonobese diabetic mouse using an adoptive transfer protocol has been evaluated. Aminoguanidine delays the onset of diabetes in this animal model by 7-10 days. These studies, which provide in vivo evidence implicating a role for nitric oxide in the development of autoimmune diabetes, also support the use of selective inhibitors of iNOS for the attenuation of disease conditions associated with the expression of iNOS and an increased production of nitric oxide.
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PMID:The Use of Aminoguanidine, a Selective iNOS Inhibitor, to Evaluate the Role of Nitric Oxide in the Development of Autoimmune Diabetes 881 41

The radical nitric oxide (NO) may be a mediator of beta-cell damage in IDDM. The cytokines IFN-gamma and IL-1beta are required for expression of the enzyme nitric oxide synthase (iNOS), and NO production by human pancreatic islets. In this study, possible mechanisms by which IFN-gamma participates in iNOS messenger RNA (mRNA) expression were evaluated in both rodent and human islets cells. Addition of IFN-gamma, before or after arrest of IL-1beta-induced iNOS gene transcription by actinomycin D, did not prolong iNOS mRNA half life in the rat insulin-producing cell line RINm5F (RIN cells). IFN-gamma also failed to modify IL-1beta-induced activation of the transcription factor kappaB (NF-kappaB) in RIN cells, as determined by electrophoretic mobility shift assay. However, IFN-gamma induced an early (30 min(-1) h) increase in interferon regulatory factor-1 (IRF-1) mRNA expression and a later (2 h) 19-fold increase in RIN cell nuclear IRF-1 protein content, an effect further potentiated by IL-1beta. The total cellular content of IRF-1 protein increased by 30- to 50-fold in human islets exposed for 2-8h to IFN-gamma or IFN-gamma + IL-1beta. IL-1beta alone induced a marginal and transient increase in IRF-1. It has been previously reported that nicotinamide prevents IL-1beta-induced IRF-1 expression in rat pancreatic islets. However, nicotinamide (20 mM) presently failed to prevent IL-1beta + IFN-gamma-induced IRF-1 protein expression in human pancreatic islets. In conclusion, the effects of IFN-gamma on iNOS expression can neither be explained by iNOS mRNA stabilization nor increased NF-kappaB activation. However, IFN-gamma induces an early increase in cellular IRF-1 content, and this may contribute to increased iNOS mRNA expression.
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PMID:Interferon-gamma-induced interferon regulatory factor-1 (IRF-1) expression in rodent and human islet cells precedes nitric oxide production. 920 13

1. Insulin-dependent diabetes mellitus is an autoimmune disease leading to pancreatic beta-cell destruction, an event that may, at least partially, be induced by the formation of nitric oxide. 2. Under the influence of cytokines, the enzyme nitric oxide synthase is induced. 3. Blockage of the inducible form of nitric oxide synthase has been found to protect against insulin-dependent diabetes mellitus in some animal models. 4. Aminoguanidine has been found to be a fairly specific inhibitor of cytokine-inducible nitric oxide synthase. 5. Aminoguanidine may reduce the blood flow to the pancreatic islets in vivo and, at higher concentrations, also impair insulin secretion by the beta-cells,--which may make the compound less useful in attempts to prevent insulin-dependent diabetes mellitus.
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PMID:Inhibition of nitric oxide formation by aminoguanidine: an attempt to prevent insulin-dependent diabetes mellitus. 934 12

Nitric oxide (NO) produced by platelet nitric oxide synthase (NOS) inhibits platelet activation by increased cytoplasmic cGMP levels. The aim of this study was to investigate platelet NOS activity in insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), which are characterized by enhanced platelet activation. HbA1c levels, platelet NOS and platelet membrane Na+/K+ ATPase activity were determined in 19 IDDM patients, 21 NIDDM patients and 31 healthy control subjects. NOS activity was measured by a spectrophotometric method based on NO-dependent oxidation of oxyhaemoglobin to met-haemoglobin. Na+/K+ ATPase activity was measured by the method of Kitao and Hattori. Both NOS and Na+/K+ ATPase activity were significantly reduced in diabetic subjects compared with control subjects. NOS showed a significant negative relation with HbA1c levels and a positive relation with Na+/K+ ATPase activity in diabetic patients. It is hypothesized that the decreased NOS activity might play a role in the pathogenesis of diabetic vascular complications.
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PMID:Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients. 949 37

Cytokines could contribute to beta-cell damage in Type I diabetes mellitus. The radical nitric oxide, generated by the inducible form of nitric oxide synthase (iNOS), is a potential mediator of cytokine-induced beta-cell dysfunction. In rat pancreatic islets and insulin-producing cell lines, interleukin-1beta (IL-1beta) induces expression of iNOS mRNA and increases NO production, an effect potentiated by interferon-gamma (IFN-gamma). In human islet cells both IL-1beta and IFN-gamma are required for iNOS expression. We have shown previously that both the transcription factors nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor-1 (IRF-1) are activated by cytokines in rodent and human islets but there is no direct information on the regulation of the iNOS promoter in insulin-producing cells. We presently investigated the effects of cytokines on iNOS transcriptional regulation in both rat insulin-producing RINm5F cells and in primary FACS-purified rat beta cells. Transient transfection experiments with the 1.5-kb rat promoter region and 5' deletants of it showed that a distal region extending up to -1002 bp, and containing a distal and a proximal nuclear factor-kappaB (NF-kappaB) binding site, a gamma-interferon activated site (GAS) and two adjacent IFN-stimulated response elements (ISRE), is required for IL-1beta induction and IFN-gamma potentiation of iNOS activation. Site-mutation analysis showed that both the distal and proximal NF-kappaB and GAS are necessary for IL-1beta-induced iNOS expression in RINm5F cells. In these cells IFN-gamma potentiation is mostly mediated by GAS and ISRE, suggesting a role for the IFN-gamma-induced transcription factors Stat1alpha (which binds GAS) and IRF-1 (which binds ISRE), which may cooperate with NF-kappaB induced by IL-1beta for iNOS activation. In primary beta cells both NF-kappaB binding sites are required for IL-1beta-induced iNOS promoter activation. In these cells IFN-gamma neither increased IL-1beta-induced iNOS promoter activity nor iNOS mRNA expression but it induced a twofold increase in NO production. The present results unveiled the nature of the promoter binding sites necessary for iNOS expression in rodent beta cells. This information could be relevant for the development of new strategies aimed at preventing cytokine-induced iNOS expression and consequent beta-cell damage.
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PMID:Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. 975 30

Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type 1 diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS-/-, background C57BL/6x129SvEv, H-2b) both to interleukin (IL)-1beta-induced beta-cell dysfunction in vitro and to multiple low-dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets. IL-1beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS-/-), and no impairment in islet function was observed. The iNOS-/- mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2b) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS-/- mice was only 23%. This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS-/- mice was observed when the animals were followed up to 42 days. Moreover, islets isolated from iNOS-/- mice were susceptible to the in vitro deleterious effects of STZ. In conclusion, the present study provides evidence that iNOS may contribute to beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo.
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PMID:Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. 1010 85


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