UMLS:C0011854 - FACTA Search

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

Proinflammatory cytokines are believed to be important in pancreatic beta-cell destruction in the development of type 1 diabetes. They act by upregulation of genes including Fas and inducible nitric oxide synthase (iNOS), which have both been shown to lead to beta-cell death in vitro. We used mice deficient in the interleukin (IL)-1 receptor (IL-1R) to assess the contribution of IL-1 to different models of diabetes. IL-1R-deficient islets were protected from the damaging effects of tumor necrosis factor (TNF) and interferon (IFN)-gamma in vitro, and beta-cell expression of iNOS was reduced, suggesting that IL-1 mediates the induction of iNOS by TNF and IFN-gamma. IL-1 action was not required for induction of class I major histocompatibility complex or Fas by TNF and IFN-gamma. IL-1R-deficient nonobese diabetic (NOD) mice developed diabetes significantly slower than wild-type mice. IL-1R deficiency did not affect diabetes in 8.3 TCR transgenic NOD mice but prolonged the time to diabetes in BDC2.5 TCR transgenic NOD mice. We conclude that IL-1R deficiency slows progression to diabetes in NOD mice but on its own does not prevent diabetes.
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PMID:IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. 1469 5

Local excess of nitric oxide (NO) has been implicated in beta-cell damage, thus, a possible approach to the treatment of autoimmune IDDM is the selective inhibition of inducible nitric oxide synthase (iNOS). A series of variously substituted hexahydropyridazine-1-carbothioamides, -carbothioimidic acid esters and -carboximidamides was synthesized and dose-dependently evaluated as potential inhibitors of iNOS. The screening of the title compounds was performed with insulin-producing RIN-5AH cells and a combination of IL1-1 beta and IFN-gamma as inducers of cellular NO production. The structure-activity analysis revealed that the variation of substituents in the position 1 of the hexahydropyridazine strongly influences the inhibitory activity to iNOS as well as being critical for RIN cell survival. Among the compounds tested, the hexahydropyridazine-1-carbothioamides showed particularly significant inhibitory effects. However, for an efficient iNOS inhibition substitution at the nitrogen of the 1-carbothioamide group is important. Thus, the introduction of aliphatic chains such as propyl or butyl and of cyclic moieties such as cyclohexyl, 3-methoxyphenyl, and 4-methoxyphenyl (IC(50): 0.5-2.1 mM), respectively, provided compounds with similar inhibitory activity to aminoguanidine (IC(50): 0.3 mM), a common standard substance used for the selective inhibition of iNOS. However, the 1-carboximidamides, which represent more structurally related semicyclic derivatives of aminoguanidine, caused only incomplete iNOS inhibition. The hexahydropyridazine-1-carbothioimidic acid esters caused dose- and substituent-dependent damage of RIN-5AH cells. The toxicity of the synthesized compounds increased markedly if aliphatic substituents at the exocyclic N atom(s) were replaced by variously substituted aromatic rings.
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PMID:Synthesis, structural investigations and biological evaluation of novel hexahydropyridazine-1-carboximidamides, -carbothioamides and -carbothioimidic acid esters as inducible nitric oxide synthase inhibitors. 1498 Jun 20

During the development of type 1 diabetes, pancreatic beta-cells are subject to an immune attack, leading to their apoptotic or necrotic cell death. Apoptotic beta-cells are also present during periods of tissue remodeling, such as in early life. Macrophages should clear apoptotic cells silently without production of pro-inflammatory cytokines. The aim of the present study was to investigate the cytokine pattern of NOD macrophages exposed to apoptotic or necrotic cells in vitro. In contrast to the limited response of macrophages from C57BL/6 or NOR mice, NOD macrophages reacted aberrantly to both necrotic and apoptotic cells, with secretion of inappropriately high amounts of IL1beta and TNFalpha. Further exploration of the macrophage behavior showed an excessive response of NOD macrophages when exposed to LPS (high iNOS and IL12p40 levels), accompanied by hyper-activation of NF-kappaB(p65). In contrast, NOD macrophages failed to up-regulate IL1beta and IL12p40 in response to IFNgamma. This failure correlated with low protein levels and a low phosphorylation state of STAT1alpha. We conclude that NOD macrophages have severely aberrant cytokine expression patterns that could contribute to the initiation or continuation of an immune attack towards the pancreatic beta-cells and thus onset and progression of type 1 diabetes.
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PMID:NOD macrophages produce high levels of inflammatory cytokines upon encounter of apoptotic or necrotic cells. 1523 48

Apoptosis is probably the main form of beta-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to beta-cell destruction through nuclear factor-kappaB (NF-kappaB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are beta-cell toxic also via NF-kappaB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced beta-cell apoptosis and determine whether TNFalpha, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-kappaB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified beta-cells by oleate, palmitate, and/or cytokines (IL-1beta, interferon-gamma, TNFalpha). Palmitate and IL-1beta induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFalpha did not potentiate FFA toxicity in primary beta-cells. The NF-kappaB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1beta but not by FFAs. Cytokines activated NF-kappaB in INS-1E and beta-cells, but FFAs did not. Moreover, FFAs did not enhance NF-kappaB activation by TNFalpha. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced beta-cell death but the mechanisms involved are different. Whereas cytokines induce NF-kappaB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-kappaB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of beta-cell death in T1DM and T2DM.
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PMID:Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. 1529 38

Cytokines that are released by infiltrating inflammatory cells around the pancreatic islets are involved in the pathogenesis of type 1 diabetes mellitus. Specifically, interleukin-1beta (IL-1beta) stimulates inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction, leading to the beta-cell damage. In activating this pathway, nuclear factor-kappaB (NF-kappaB) plays a crucial role, and many of the IL-1beta-sensitive genes contain NF-kappaB binding sites in their promoter regions. We have recently shown that epicatechin, which is a flavonoid, had a protective effect on pancreatic beta-cells in both streptozotocin-treated rats and islets. In the present study, the effects of epicatechin on IL-1beta-induced beta-cell damage were examined. RINm5F cells and islets were pretreated with epicatechin and next incubated with IL-1beta. The released nitrite, iNOS protein and mRNA expression levels were then measured. IkappaBalpha protein, nuclear translocation of NF-kappaB, and NF-kappaB DNA binding activity were also determined. Following the transient transfection of an iNOS promoter into the cells, the iNOS promoter activity was measured. ATP- or D-glucose-induced insulin release was measured in RINm5F cells and islets, respectively. Epicatechin significantly reduced IL-1beta-induced nitrite production, iNOS protein and mRNA expressions, and it also inhibited IL-1beta-induced IkappaBalpha protein degradation, NF-kappaB activation, and iNOS promoter activity. Epicatechin partly restored the IL-1beta-induced inhibition of insulin release. These results suggest that epicatechin inhibits the IL-1beta-induced iNOS expression by down-regulating NF-kappaB activation, and protecting beta-cells from IL-1beta.
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PMID:Inhibitory effects of epicatechin on interleukin-1beta-induced inducible nitric oxide synthase expression in RINm5F cells and rat pancreatic islets by down-regulation of NF-kappaB activation. 1545 Sep 43

Nitric oxide (NO) is involved in the destruction of beta-cells during the development of type I diabetes mellitus (DM). We demonstrated the possibility of rescuing beta-cells by intervention with thymoquinone (TQ) using streptozotocin (STZ) rat diabetic model. The hyperglycemic and hypoinsulinemic responses to STZ were significantly abrogated in rats cotreated with TQ, and this abrogating effect has persisted for 1 month after stopping of TQ treatment. Unlike observations recorded after diabetic chronicity of 1month, where there was a significant reduction of both serum and pancreatic nitrites, a significant increase in both nitrites was observed within the first 3 days in STZ rats, with or without lipopolysaccharide (LPS) stimulation, compared with controls and the TQ-cotreated. In vitro production of nitrite was significantly higher by 3-day-diabetic macrophages with or without stimulation compared to control or TQ-treated ones. However, 1-month-diabetic macrophages showed insignificant decrease of nitrite which turned significant upon stimulation. TQ has no effect on either IkB degradation or NF-kB activation; however, it significantly inhibited both p44/42 and p38 mitogen-activated protein kinases (MAPKs) which contribute to the transcriptional machinery of inducible nitric oxide synthase and NO production. These data emphasize the protective value of TQ against development of type I DM via NO inhibitory pathway.
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PMID:Successful abrogation by thymoquinone against induction of diabetes mellitus with streptozotocin via nitric oxide inhibitory mechanism. 1558 81

IL-1beta is an important mediator in the pathogenesis of type 1 diabetes both in vivo and in vitro and it has been shown to induce islet beta-cell apoptosis. Most of the IL-1beta effects seem to be mediated by NF-kappaB transcription factor activation, but its role in the induction of islet beta-cell apoptosis has not yet been clarified. Taking advantage of the protease inhibitor TPCK (N-tosyl-L-phenylalanine chloromethyl ketone), which specifically inhibits the nuclear transcription factor NF-kappaB activation, we studied the role of NF-kappaB in the rIL-1beta treated rat pancreatic islets. Our results show that TPCK blocked rIL-1beta-mediated early increase of MnSOD activity and beta-cell defence/repair protein expression, suggesting a protective role for NF-kappaB at the beginning of IL-1beta treatment; but, in a second phase, NF-kappaB induces a sustained decrease of specific beta-cell proteins like insulin, GLUT-2 and PDX-1 with a concomitant increase of aspecific proteins and iNOS transcription. The appearance of iNOS expression correlates with increased levels of nitrite + nitrate levels and appearance of mitochondrial damage detected either at morphological and biochemical level. After 36 h of IL-1beta treatment islet beta-cells begin to undergo apoptosis. Since IL-1beta induction of apoptosis is completely prevented by TCPK treatment, this finding underscores the central role of NF-kappaB in this process. Thus, our results clearly indicate that NF-kappaB regulates MnSOD genes expression and MnSOD activity, which protects islet beta-cells by IL-1beta damage. Furthermore, when the IL-1beta stress impairs islet beta-cell function, NF-kappaB activation regulates the entrance of islet beta-cell into the cell death program.
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PMID:A biphasic role of nuclear transcription factor (NF)-kappaB in the islet beta-cell apoptosis induced by interleukin (IL)-1beta. 1562 24

Cytokines have been implicated in pancreatic beta-cell destruction leading to type 1 diabetes. Exposure to interleukin-1beta (IL-1beta) of pancreatic beta-cells induces expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and prostaglandin E2 (PGE2) may impair beta-cell function. Using NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), we have further investigated the relation between NO formation and COX-2 expression. IL-1beta stimulated the formation of NO and PGE2 by pancreatic beta-cells. L-NMMA completely inhibited IL-1beta-induced NO formation and attenuated PGE2 production. COX-2 gene transcription level and protein expression were determined by real-time PCR, Western blot and luciferase analysis. L-NMMA inhibited IL-1beta-induced promoter activity, gene transcription and protein expression of COX-2 in pancreatic beta-cells. Therefore, we concluded that NO-affected COX-2 activity is directly linked to COX-2 gene transcription and protein expression in pancreatic beta-cells. The identification of a novel interaction of NO on the COX signaling pathway in beta-cells provides a strategy of intervention for further evaluating the role of NO and PGE2 in autoimmune diabetes.
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PMID:Potential role of NO in modulation of COX-2 expression and PGE2 production in pancreatic beta-cells. 1568 72

The IDDM (LEW.1AR1/Ztm-iddm) rat is a type 1 diabetic animal model characterized by a rapid apoptotic pancreatic beta-cell destruction. Here we have analyzed the time course of islet infiltration, changes in the cytokine expression pattern, and beta-cell apoptosis in the transition from the pre-diabetic to the diabetic state. Transition from normoglycemia to hyperglycemia occurred when beta-cell loss exceeded 60-70%. At the early stages of islet infiltration, macrophages were the predominant immune cell type in the peripherally infiltrated islets. Progression of beta-cell loss was closely linked to a severe infiltration of the whole islet by CD8+ T-cells. With progressive islet infiltration, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were expressed in immune cells but not in beta-cells. This proinflammatory cytokine expression pattern coincided with the expression of inducible nitric oxide synthase (iNOS) and procaspase 3 in beta-cells and a peak apoptosis rate of 6.7%. Islet infiltration declined after manifestation of clinical diabetes, yielding end-stage islets devoid of beta-cells and immune cells without any sign of cytokine expression. The observed coincidence of IL-1beta and TNF-alpha expression in the immune cells and the induction of iNOS and procaspase 3 mRNA expression in the beta-cells depicts a sequence of pathological changes leading to apoptotic beta-cell death in the IDDM rat. This chain of events provides a mechanistic explanation for the development of the diabetic syndrome in this animal model of human type 1 diabetes.
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PMID:Immune cell infiltration, cytokine expression, and beta-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat. 1598 5

The proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) are toxic to pancreatic beta-cells and are implicated in the pathogenesis of type 1 diabetes. We have previously found that GH and prolactin (PRL) stimulate both proliferation and insulin production in pancreatic beta-cells and rat insulin-producing INS-1 cells. Here we report that human (h) GH can prevent the apoptotic effects of IL-1beta, IFN-gamma and TNF-alpha in INS-1 and INS-1E cells. Using adenovirus-mediated gene transfer, we found that the anti-apoptotic effect of hGH is abrogated by expression of a dominant negative signal transducer and activator of transcription (STAT5) mutant in INS-1E cells. hGH and the cytotoxic cytokines was found to additively increase suppressor of cytokine signalling-3 mRNA expression after 4 h of exposure. In order to identify possible targets for the STAT5-mediated protection of INS-1E cells, we studied the effect of hGH on activation of the transcription factors STAT1 and nuclear factor-kappaB (NF-kappaB) by IFN-gamma and IL-1beta+TNF-alpha respectively. Gel retardation experiments showed that hGH affects neither IFN-gamma+TNF-alpha-induced STAT1 DNA binding nor IL-1beta and IFN-gamma+TNF-alpha-induced NFkappaB DNA binding. The lack of influence of hGH on cytokine-mediated activation of STAT1 and NFkappaB is in accordance with the finding that hGH had only a minor effect on cytokine-induced inducible nitric oxide synthase (iNOS) gene expression and in fact augmented the IL-1beta-stimulated nitric oxide production. As the anti-apoptotic Bcl-xL gene has been shown to harbour a STAT5-binding element we measured the expression of Bcl-xL as well as the pro-apoptotic Bax. We found that hGH increased the Bcl-xL/Bax ratio both in the absence and in the presence of cytotoxic cytokines. In conclusion, these results suggested that GH and PRL protect beta-cells against cytotoxic cytokines via STAT5-dependent mechanisms distal to iNOS activation possibly at the level of Bcl-xL.
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PMID:STAT5 activation by human GH protects insulin-producing cells against interleukin-1beta, interferon-gamma and tumour necrosis factor-alpha-induced apoptosis independent of nitric oxide production. 1621 38

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