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

This study was conducted to investigate the possible involvement of Fas in beta-cell death in insulitis of Type 1 (insulin-dependent) diabetes mellitus. Although primary cultured Balb/c mouse islet cells did not express Fas mRNA, 4-12 hours of treatment with 10(2)-10(3) U/l of mouse interleukin-1 alpha (IL-1 alpha) induced the expression of Fas mRNA. Surface Fas expression was detected by immunofluorescence flow cytometry using a non-cytolytic anti-Fas monoclonal antibody after 6 or 12 h of incubation with 10(3) U/l of IL-1 alpha. Primary islet cells were resistant to an agonistic anti-Fas monoclonal antibody. However, 12 h pretreatment with IL-1 alpha sensitized islet cells to its cytolytic effect. Significant cell death was observed 24 h after the addition of anti-Fas, and progressively increased until 72 h, when specific 51Cr release was 72 +/- 6%. Agarose gel electrophoresis of DNA extracted from cells exposed to IL-1 alpha and agonistic anti-Fas showed internucleosomal DNA fragmentation, a hallmark of apoptotic cell death. Since the Fas antibody showed no cross-reactive activity of tumour necrosis factor (TNF), the cytotoxic effect was not mediated by TNF receptors. A protein synthesis inhibitor cycloheximide augmented Fas-mediated islet cell death. The Fas-mediated killing of islet cells was not L-arginine-dependent, or blocked by N(G)-monomethyl-L-arginine. beta-TC1 cells also expressed Fas mRNA when exposed to IL-1 alpha or IL-1 alpha plus interferon-gamma. These observations suggest that Fas-mediated apoptosis may be a mechanism of islet cell death in autoimmune insulitis.
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PMID:Mouse islet cell lysis mediated by interleukin-1-induced Fas. 893 96

Cytokines produced by mononuclear leukocytes infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokines may damage islet beta-cells by inducing oxygen free radical production in the beta-cells. Lipid peroxidation and aldehyde production are measures of oxygen free radical-mediated cell injury. In the current study, we used a HPLC technique to measure levels of different aldehydes produced in rat islets incubated with cytokines. The cytokine combination of interleukin-1beta (10 U/ml), tumor necrosis factor-alpha (10(3) U/ml), and interferon-gamma (10(3) U/ml), and the oxidant, t-butylhydroperoxide, induced significant increases in islet levels of the same aldehydes: butanal, pentanal, 4-hydroxynonenal (4-HNE), and hexanal. Cytokine-induced aldehyde production was associated with islet beta-cell destruction. Thus, cytokine-induced increases in malondialdehyde (MDA; at 4 h) and 4-HNE (at 8 h) preceded islet cell destruction (at 16 h), and the addition of 4-HNE, hexanal, MDA, and pentanal (1-200 microM) to th islets, but not other aldehydes at similar concentrations, produced dose-dependent destruction of islet beta-cells. Furthermore, an antioxidant (lazaroid U78518E) prevented cytokine-induced increases in 4-HNE, hexanal, and MDA and significantly inhibited cytokine-induced decreases in insulin and DNA in the islets. In contrast, N(G)-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in 4-HNE, hexanal, and MDA or decreases in insulin and DNA in the islets. These results suggest that cytokines may damage islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and, consequently, the formation of cytotoxic aldehydes in the islet cells.
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PMID:Destruction of rat pancreatic islet beta-cells by cytokines involves the production of cytotoxic aldehydes. 894 Mar 48

In order to clarify the nature of T lymphocytes infiltrating the pancreatic islets of patients with insulin-dependent diabetes mellitus (IDDM), we analysed T cell receptor (TCR) gene transcripts expressed in pancreatic biopsy specimens of patients with recent-onset IDDM. We also investigated the expression of cytokines (interferon-gamma: IFN-gamma; tumour necrosis factor-alpha: TNF-alpha; interleukin-4: IL-4; interleukin-6: IL-6) in the same specimens. The TCR V beta repertoire was not restricted either in the pancreas or the peripheral lymphocytes of IDDM patients. In contrast, the TCR V alpha repertoire was restricted in the pancreas, but not in the peripheral blood lymphocytes, of IDDM patients. The sequence analysis of the complementarity-determining region 3 (CDR3) of the TCR alpha revealed the presence of dominant clonality in alpha chains of T cells in the patients. IFN-gamma mRNA was highly expressed in the pancreas of IDDM patients, while IL-4 mRNA was deficient. A lower level of expression of IL-6 mRNA was detected in the IDDM pancreas than in the control tissue. These results indicate that T cells bearing a distinct TCR alpha chain are selectively retained and activated within the pancreas of recent-onset IDDM.
Diabetes Res Clin Pract 1996 Sep
PMID:Dominant TCR alpha-chain clonotypes and interferon-gamma are expressed in the pancreas of patients with recent-onset insulin-dependent diabetes mellitus. 896 89

The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different, experimental conditions with a purified polyclonal antibody (Ab), antirat IFN gamma. The results show that when administered at doses of 100 or 200 micrograms/week from the 30/33th until the 105th day of age, the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFN gamma Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFN gamma Ab (500 micrograms or 1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 micrograms/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BB rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.
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PMID:Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-gamma antibody. 897 15

The present study was initiated to characterize thyrotropin receptor (TSH-R) expression in thyroids from patients with Graves' disease, as well as parameters that influence TSH-R expression either causally, such as interferon-gamma (IFN-gamma), the leading candidate among the cytokines thought to play a key role in the initiation of autoimmune thyroid disease, or therapeutically, such as iodide, which is used to prepare patients for surgery. Our data show that there is an average 4-fold increase of TSH-R mRNA levels in the thyroids of Graves' patients coming to surgery, which is paralleled by an increase in TSH-R protein levels and TSH binding capacity. The increase does not appear to be related to IFN-gamma since IFN-gamma transcripts are barely detectable in most Graves' patients. Iodide treatment causes a 2-fold decrease in TSH-R expression in association with significant decreases in major histocompatibility complex (MHC) class I and class II gene expression. These last data are compatible with a recently enunciated "transcription factor hypothesis" according to which abnormally high TSH-R and MHC class I and class II gene expression in Graves' thyroids are the result of a loss of the normal negative regulation of these genes necessary to allow the normal growth and function of the gland, yet preserve self-tolerance.
Exp Clin Endocrinol Diabetes 1996
PMID:Iodide, cytokines and TSH-receptor expression in Graves' disease. 898 Oct 6

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-kappa B activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1 beta, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 microM) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-beta but failed to block IL-1 beta-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic beta-cells, an effect not associated with inhibition of NF-kappa B activation.
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PMID:Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. 898 32

Recently, interferon-gamma-inducing-factor (IGIF) has been described as a novel monokine that is a more potent interferon-gamma (IFN-gamma) inducer than IL-12. By cloning IGIF from affected tissue and studying IGIF gene expression, we describe for the first time a close association of this cytokine with an autoimmune disease. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide. IGIF mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IGIF mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-gamma mRNA, and subsequently diabetes. Interestingly, these kinetics mimick that of IL-12p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IGIF cDNA from pancreas RNA followed by sequencing revealed identity with the IGIF sequence cloned from Kupffer cells and in vivo preactivated macrophages. When extending our study to macrophages of the spleen we observed that NOD mouse macrophages responded to cyclophosphamide with IGIF gene expression while macrophages from Balb/c mice treated in parallel did not. The IGIF gene position is located within the Idd2 interval on mouse chromosome 9 and therefore it is a candidate for the Idd2 susceptible gene. We conclude that IGIF expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development.
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PMID:Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. 902 80

Autoimmune mediated destruction of beta cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their beta cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner, 1996, J. Exp. Med. 183:2143-2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction. Here we provide evidence that killing of beta cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-gamma (IFN-gamma)-deficient mice, beta cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-gamma and express LCMV NP or GP in their beta cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, beta cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-gamma, presumably through enhancement of major histocompatibility complex expression and antigen presentation.
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PMID:Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. 905 53

Nitric oxide has been shown to mediate beta-cell destruction in rodent islets exposed to interleukin 1 beta in culture. The inhibitory effect is potentiated by tumour necrosis factor-alpha and interferon-gamma. Cytokine stimulation leads to gene transcription and translation of inducible nitric oxide synthase, the biosynthetic enzyme of nitric oxide. In the non-obese diabetic mouse, progressive invasion of pancreatic islets by immune cells may lead to local production of inflammatory cytokines, resulting in inducible nitric oxide synthase expression within the islets. In this study, the ontogeny of this enzyme and its cellular expression were examined in pancreatic sections of female non-obese diabetic mice by double-label immunofluorescence. Light and confocal microscopy were employed to study the up-regulation, co-localization and immunocytoplasmic distribution of the enzyme in female non-obese, diabetic and Swiss mice following cytokine treatment. From day 40 to day 220 a small number of beta-cells and a proportion of macrophages, usually in peri-islet and exocrine areas, expressed the enzyme. At onset of diabetes, an increasing number of macrophages within and surrounding the islets were positive for the enzyme. Treatment of day 60 female non-obese diabetic mice with interleukin 1 beta alone and in combination with tumour necrosis factor-alpha and/or interferon-gamma resulted in a significant influx of macrophages into the pancreas, while this was lower in female Swiss mice treated similarly. Cytokine administration led to intense but sometimes eccentric immunocytoplasmic labelling for the enzyme in a considerable proportion of macrophages and beta-cells. Macrophages positive for inducible nitric oxide synthase were located in peri- and intra-islet areas, being distal and adjacent to enzyme-positive and negative beta-cells. Treatment with tumour necrosis factor-alpha and/or interferon-gamma did not lead to enzyme up-regulation. These results show that in the non-obese diabetic mouse there is low and sustained expression of islet inducible nitric oxide synthase in the prediabetic period, which is followed by an increase around onset. However, treatment of female non-obese diabetic and Swiss mice with interleukin-1 beta, alone or together with tumour necrosis factor-alpha and/or interferon-gamma leads to a marked expression of this enzyme within macrophages and beta-cells.
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PMID:Inducible nitric oxide synthase in pancreatic islets of the non-obese diabetic mouse: a light and confocal microscopical study of its ontogeny, co-localization and up-regulation following cytokine administration. 908 45

The mouse pancreatic beta TC3 and beta TC6-F7 cell lines were used to characterize the effects of interferon-gamma (IFN-y) on beta-cell phenotype and function. Initially, intracellular and secreted insulin were compared in glucose-stimulated cells over time. A significant reduction in insulin content and secretion was observed on a per-cell basis in glucose-stimulated beta TC3 and beta TC6-F7 cells after 12 h of exposure to IFN-gamma. The steadystate level of pre-proinsulin mRNA expression was not affected by IFN-gamma. Thus, we postulate that IFN-gamma's inhibitory actions occur after transcription of pre-proinsulin genes. Time-course analysis of IFN-gamma-regulated mRNA expression of the two intra-MHC-encoded subunits of the proteasome (low-molecular-mass polypeptide [Lmp]-2 and Lmp-7) revealed a correlation between their induction and the inhibitory effects of IFN-gamma on glucose-stimulated insulin production. Increased expression of Lmp-2 and Lmp-7 mRNA was accompanied by a corresponding induction of LMP2 and LMP7 protein expression. Subsequently, major histocompatibility complex (MHC) class I cell-surface expression was significantly increased in IFN-gamma-treated beta TC3 and beta TC6-F7 cells. Exposure of IFN-gamma-treated beta-cells to a peptide aldehyde inhibitor of the proteasome (MG132) significantly attenuated MHC class I cell-surface expression but did not prevent the negative effects of IFN-gamma on glucose responsiveness. Enhanced expression of the MHC class I antigen processing and presentation pathway and diminished insulin production appear to be distinct pathological alterations in beta-cells exposed to the insulitic cytokine IFN-gamma.
Diabetes 1997 May
PMID:Interferon-gamma independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic beta-cell lines. 913 43


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