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)

Nitric oxide produced by inducible nitric oxide synthase in islets exerts inhibitory and cytotoxic effects on pancreatic beta cells and is therefore thought to be a potent mediator in the pathogenesis of Type I diabetes mellitus. Here, using isolated rat pancreatic islets, we show that high-concentration nicotinamide (20 mM), but not low-concentration nicotinamide (5 mM), attenuates the interleukin-1 beta-evoked inhibition of glucose-induced insulin secretion by preventing the induction of interferon regulatory factor-1, a transcriptional factor which plays an essential role in inducible nitric oxide synthase gene expression, and the interleukin-1 beta-induced nitric oxide formation. High-concentration nicotinamide also restored an interleukin-1 beta-induced decrease in ATP content in pancreatic beta cells, suggesting that interleukin-1 beta-induced nitric oxide inhibits the mitochondrial function. The present results show the molecular basis of the preventive effect of high-dose nicotinamide on Type I diabetes mellitus.
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PMID:Nicotinamide inhibits IRF-1 mRNA induction and prevents IL-1 beta-induced nitric oxide synthase expression in pancreatic beta cells. 748 87

Endothelial dysfunction is known to occur in chemically-induced animal models of diabetes. The BB diabetic rat is a genetic diabetes-prone model which more closely resembles Type I diabetes mellitus. In this study, we examined the role of superoxide anion radical and cyclooxygenase activity on endothelial dysfunction in aorta of the spontaneous diabetic BB rat. Vascular endothelial function was studied in vitro in aortic rings from 8-wk diabetic rats and age-matched nondiabetic littermates. There was no alteration in reactivity to norepinephrine as a result of diabetes. Relaxation to acetylcholine (but not nitroglycerin) was impaired in diabetic rings. Relaxation to acetylcholine was abolished by 100 microM L-nitroarginine but unaltered by an equimolar concentration of aminoguanidine (an inducible nitric oxide synthase inhibitor) in both control and diabetic rings. Incubation with 10 microM indomethacin did not alter relaxation to acetylcholine in either control or diabetic rings. In contrast, addition of 20 U/ml superoxide dismutase enhanced relaxation to acetylcholine in diabetic rings but had no effect on relaxation to acetylcholine in control rings. Thus, nitric oxide-mediated, endothelium-dependent relaxation is diminished in aortic rings of the genetic diabetic BB rat. Furthermore, superoxide anion radicals but not cyclooxygenase products play an important role in endothelial dysfunction in this genetic diabetic model.
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PMID:Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat. 863 17

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

In type 1 diabetes, autoimmune destruction of pancreatic beta-cells has been attributed to cytokines released from infiltrating immunocytes. Exposure of isolated islets to cytokines leads to nitric oxide (NO) production, which can damage beta-cells. Because ductal cells are closely associated with human beta-cells, we examined whether they can contribute to this process. Isolated human ductal cells were cultured for 48 h with various cytokines. The combination of interleukin-1beta (IL-1beta) plus interferon-gamma (IFN-gamma) increased nitric oxide production 12-fold while stimulating mRNA expression of inducible nitric oxide synthase (iNOS). In this condition, 10-20% of cells positive for the cytokeratin-19 duct marker also stained positive for iNOS protein, whereas no positive cells were found in control preparations. Comparison of the magnitude of iNOS mRNA expression and nitric oxide production in these cells with that in isolated human islets suggests that >50% of total islet nitric oxide production might originate from associated ductal cells. It is concluded that ductal cells are a potential source of nitric oxide production in human islets infiltrated by cytokine-releasing immunocytes.
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PMID:Contribution of ductal cells to cytokine responses by human pancreatic islets. 989 19

Nitric oxide is thought to contribute to beta cell destruction during islet inflammation in animal models of type I diabetes. In vitro, inhibition of inducible nitric oxide synthase protects islet cells from the damaging effects of inflammatory cells or cytokines. However, the administration of several inducible nitric oxide synthase inhibitors to prediabetic animals had variable effects on disease progression. An alternative approach is to prevent the lethal consequences of nitric oxide action at the level of islet cells. We observed that the suppression of poly-(ADP-ribose)-polymerase ensures survival of islet cells exposed to nitric oxide. Cells could also be rendered resistant by the induction of endogenous stress proteins in particular of heat shock protein 70. Nitric oxide is not only a strong cytotoxic agent, but is also able to modulate immune reactions by interfering with Th1/Th2 reactivities. This may occur via induction of the interleukin-12 antagonist IL-12(p40)2. Development of type 1 diabetes is known to be correlated with a shift from a Th2 status during benign insulitis to a Th1 status during destructive insulitis. This shift was found dependent on local interleukin-12 gene expression. Indeed, administration of a natural interleukin-12 antagonist suppressed the progression of islet inflammation and concomitant upregulation of the inducible nitric oxide synthase.
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PMID:Strategies of protection from nitric oxide toxicity in islet inflammation. 993 Sep 25

Immune-mediated beta-cell damage induces diverse intracellular signals, leading to transcription of different genes which may either contribute to beta-cell repair and/or defence or lead to cell death. The cytokine interleukin-1beta (IL-1) is a potential mediator of beta-cell dysfunction and damage in type 1 diabetes mellitus. To understand the molecular actions of this cytokine upon beta-cells, this study aimed at the cloning of genes induced in FACS-purified rat pancreatic beta-cells by a 6- or 24-h exposure to IL-1 by using differential display of mRNA with reverse transcription-polymerase chain reaction (DDRT-PCR). Among these cytokine-induced genes, a gene encoding for rat serine protease inhibitor (SPI-3) was isolated. SPI-3 may be involved in cellular defence responses against inflammatory stress. RT-PCR analysis confirmed that SPI-3 mRNA expression in rat beta-cells is increased by IL-1 at an early stage (2 h), with maximal accumulation during 6-12 h and decline after 24 h. Similar observations were made in mouse pancreatic islets and in the rat insulinoma cell line RINm5F. IFN-gamma neither increased SPI-3 gene expression nor potentiated its induction by IL-1 in rat beta-cells. The stimulatory effects of IL-1 on SPI-3 mRNA expression were decreased by co-incubation with an inhibitor of gene transcription (actinomycin D), an inhibitor of protein synthesis (cycloheximide) or an inhibitor of NF-kappaB activation (PDTC). On the other hand, a blocker of inducible nitric oxide synthase (iNOS) activity (N(G)-methyl-L-arginine) did not prevent IL-1-induced SPI-3 expression. Thus, SPI-3 mRNA expression following IL-1 exposure depends on gene transcription, protein synthesis and activation of the nuclear transcription factor NF-kappaB, but it is independent of NO formation.
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PMID:IL-1beta induces serine protease inhibitor 3 (SPI-3) gene expression in rat pancreatic beta-cells. Detection by differential display of messenger RNA. 1054 73

Activated T-cells and macrophages infiltrate pancreatic islets early in the pathogenesis of type 1 diabetes. Their secretion of different pro-inflammatory cytokines such as interleukin (IL)-1beta, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha affects beta-cell function. Here we report that a combination of these cytokines inhibits insulin release, stimulates inducible nitric oxide synthase (iNOS), and upregulates the surface expression of Fas in NIT-1 beta-cells and intact mouse islets. Using iNOS-deficient and Fas-deficient islets, respectively, we investigated the relative contribution of NO and Fas upregulation in cytokine-induced beta-cell damage. Interestingly, inhibition of insulin release did not occur in the absence of NO production. However, de novo expression of Fas-specific mRNA and Fas cell surface expression were detected and thus appear to be NO-independent. The lack of NO production partially protected islets from cytokine-induced apoptosis but had no effect on cell death induced by cell surface cross-linking of Fas with soluble Fas ligand (FasL). The absence of FasL on alpha-cells and the degree of apoptosis observed in Fas-deficient islets exclude the possibility of cytokine-induced fratricide. In conclusion, pro-inflammatory cytokines exert a cytotoxic effect on beta-cells via an NO-dependent pathway and, in parallel, render beta-cells susceptible to Fas:FasL-mediated, NO-independent cell death triggered by activated T-cells.
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PMID:Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage. 1061 48


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