Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During insulin-dependent diabetes mellitus, islet invading immune cells destroy beta cells over a prolonged asymptomatic pre-diabetic period. Cytokines synthesised and secreted by specific immune cells within the islet infiltrate may be crucial effectors of beta cell destruction or protection during the disease. Interleukin-1beta may be a key cytokine which may act in concert with other cytokines in initiating and/or promoting beta cell destruction. We have examined this hypothesis in NOD mice by assessing the intra-islet expression and co-localization of interleukin-1beta at different time-points following cyclophosphamide administration. We have also tested the effects of long-term oral nicotinamide given to NOD mice in suppressing intra-islet expression of the cytokine in this accelerated model. Cyclophosphamide was administered to day 95 female NOD mice. Pancreatic tissues were examined by dual-label confocal immunofluorescence microscopy for the expression and co-localization of interleukin-1beta at days 0, 4, 7, 11 and at onset of diabetes (day 14). Diabetes developed in 7/11 mice 14 days after administration of cyclophosphamide while nicotinamide completely prevented the disease. At day 0, interleukin-1beta immunolabelling was observed in selective intra-islet macrophages, several somatostatin cells and in a few beta cells. However, at day 4, it was seen mostly in somatostatin and some beta cells. At day 7, an increasing number of interleukin-1beta cells were observed within the islets and co-localized to several somatostatin cells, beta cells and macrophages. The mean number of intra-islet interleukin-1beta cells reached a peak at day 11 and was significantly higher than at day 7 (p = 0.05) and at day 14 (onset of diabetes; p = 0.03). At day 11, interleukin-1beta immunolabelling was also present in selective macrophages which co-expressed inducible nitric oxide synthase. At onset of diabetes, some macrophages, residual beta cells and somatostatin cells showed immunolabelling for the cytokine. Exposure of NOD mice to oral nicotinamide was associated with a considerably reduced expression of interleukin-1beta cells within the islet at day 11 (p = 0.002). We conclude that cylophosphamide treatment enhances the expression of interleukin-1beta in selective macrophages, somatostatin and beta cells during the course of the disease. Its expression reaches a maximum immediately prior to onset of diabetes. Interleukin-1beta present in intra-islet macrophages, somatostatin and beta cells may influence its expression by autocrine and paracrine means. Interleukin-1beta expression within islet macrophages may also up-regulate inducible nitric oxide synthase within the same macrophage or adjacent macrophage populations. These intra-islet molecular events may corroborate with other local cytotoxic processes leading to beta cell destruction. Oral nicotinamide may attenuate intra-islet expression of interleukin-1beta and thus inducible nitric oxide synthase during prevention of Type 1 diabetes in this animal model. The expression of interleukin-1beta in specific islet endocrine cell-types shown in this study requires further investigation.
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PMID:Immunoexpression of interleukin-1beta in pancreatic islets of NOD mice during cyclophosphamide-accelerated diabetes: co-localization in macrophages and endocrine cells and its attenuation with oral nicotinamide. 1175 8

Peroxynitrite, a marker of oxidative stress, is elevated in conditions associated with vascular endothelial cell dysfunction, such as atherosclerosis, preeclampsia, and diabetes. However, the effects of peroxynitrite on endothelial cell function are not clear. The endothelium-derived enzymes nitric oxide synthase (NOS) and prostaglandin H synthase (PGHS) mediate vascular reactivity and contain oxidant-sensitive isoforms (iNOS and PGHS-2) that can be induced by nuclear factor (NF)-kappaB activation. We investigated the effect(s) of peroxynitrite on NOS and PGHS pathways in endothelial cells. We hypothesized that peroxynitrite will increase levels of iNOS and PGHS-2 through activation of NF-kappaB. Western immunoblots of endothelial cells show that 3-morpholinosydnonimine (SIN-1; 0.5 mM), a peroxynitrite donor, increased iNOS protein mass, which can be inhibited by pyrroline dithiocarbamate (an NF-kappaB inhibitor) (167 +/- 24.2 vs. 78 +/- 19%, P < 0.05, n = 6). SIN-1 treatment also significantly increased NF-kappaB translocation into endothelial cell nuclei (135 +/- 10%, P < 0.05). Endothelial NOS, PGHS-1, and PGHS-2 protein levels were not altered by SIN-1. However, prostacyclin synthase protein mass, but not mRNA, was significantly reduced in SIN-1-treated endothelial cells (78 +/- 8.9%, P < 0.05). Our results illustrate novel mechanisms through which peroxynitrite may modulate vascular endothelial function.
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PMID:Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells. 1178 51

Nitric oxide (NO) is a multifunctional mediator that has been implicated in the short-term hemodynamic alterations that occur in acute streptozocin (STZ)-induced diabetes. We investigated the role of NO produced by inducible nitric oxide synthase (iNOS) in chronic STZ diabetic nephropathy. Diabetes was induced in C57BL/6 and iNOS knockout (KO) mice with two intraperitoneal injections of STZ, 100 mg/kg. Animals were maintained without insulin treatment for 40 weeks. There were no significant differences between the strains in blood urea nitrogen (BUN), serum creatinine or glucose concentration, or urinary protein excretion during the entire observation period. Urinary nitrite + nitrate excretion was significantly lower in iNOS KO mice compared to control animals at all time points; in C57 mice, urinary nitrite declined progressively with more prolonged duration of diabetes. Renal hypertrophy (kidney weight/body weight) was noted in both strains of mice. However, histopathological assessment of renal tissue specimens at 16 and 40 weeks demonstrated increased mesangial hypercellularity and expansion as well as more prominent tubulointerstitial fibrosis in iNOS KO versus C57 mice. These changes were accompanied by increased interstitial deposition of type I collagen at 16 and 40 weeks in iNOS KO mice. Glomerular basement membrane staining for type IV collagen was also increased at 40 weeks in diabetic iNOS KO mice. While iNOS protein was undetectable in any of the kidney specimens obtained from either strain, eNOS was present throughout the course of chronic STZ diabetes. Moreover, eNOS expression was significantly increased by approximately 40% at 16 and 40 weeks of observation in iNOS KO versus C57 mice. There was no difference in renal cortical malondialdehyde content between the strains early or late in the disease course. In time control animals, there was no evidence of renal histopathological damage in iNOS KO or C57 mice after 40 weeks. We conclude that iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic STZ nephropathy. This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.
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PMID:Chronic diabetic nephropathy: role of inducible nitric oxide synthase. 1179 30

Cytokines have been implicated in pancreatic beta-cell destruction leading to type 1 diabetes. In vitro, a combination of gamma-interferon (IFN-gamma) and interleukin-1 (IL-1) stimulate inducible nitric oxide synthase (iNOS) expression in islets, and the resulting increased production of nitric oxide (NO) causes islet cell destruction. Islets contain macrophages, ductal cells, and endothelial cells that, when activated, may mediate islet cell damage by producing either NO themselves or cytokines that then stimulate NO production by beta-cells. The aim of this study was to determine whether beta-cell damage mediated by cytokine-induced NO production is dependent on beta-cell production of NO, or whether NO produced by other cells in the islet is capable of destroying beta-cells. To address this aim, we used transgenic mice expressing a dominant-negative IFN-gamma receptor in beta-cells (RIP-Delta(gamma)R). RIP-Delta(gamma)R islets are resistant to IL-1 + IFN-gamma-induced inhibition of insulin secretion and DNA damage, indicating that beta-cell IFN-gamma responsiveness is required for IL-1 + IFN-gamma-mediated beta-cell damage. Although islets isolated from RIP-Delta(gamma)R mice are resistant to functional damage, these islets produce NO in response to IL-1 + IFN-gamma, but at a lower concentration than that produced by wild-type islets. beta-Cells appear to be the primary cellular source of IL-1 + IFN-gamma-induced iNOS expression in wild-type islets. In contrast, IL-1 + IFN-gamma fail to stimulate iNOS expression by insulin-expressing cells in islets isolated from RIP-DeltagammaR mice. IL-1 + IFN-gamma-induced expression of iNOS was detected in non-beta-cells in both wild-type and RIP-DeltagammaR islets. These findings support the hypothesis that NO must be produced by beta-cells to induce damage.
Diabetes 2002 Feb
PMID:Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta-cell nitric oxide production. 1181 37

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. After 72 h exposure of human pancreatic islets to a cytotoxic cytokine combination of interleukin 1 beta (50 U/ml), tumor necrosis factor alpha (1,000 U/ml), and interferon gamma (1,000 U/ml), an increase of cell death vs. control islets was demonstrated by TUNEL and cell death detection ELISA method. Islet death was associated with apoptosis and mitochondrial swelling as evidenced by electron microscopy. This effect was correlated with a marked decrease of Bcl-2 mRNA expression (without any major change of Bax mRNA) and a marked increase of inducible nitric oxide synthase mRNA. Since peripheral benzodiazepine receptors constitute the aspecific mitochondrial permeability transition pore, and that it has been suggested to be involved in cytokine-induced cell death, we evaluated the effects of the cytotoxic cytokines on PBR density and mRNA expression. We demonstrated that cytokine treatment of human islets induced an increase of maximum density of (3)H1-(2-chlorophenyl-N-methyl-1-methylpropyl)-3- isoquinolinecarboxamide binding sites, (5,110+/-193 vs. 3,421+/-336 fmol/mg proteins, P<0.05) with no significant change in the affinity constant value (9.45+/-0.869 vs. 8.7+/-1.159 nM). Moreover, an increase of the expression of peripheral benzodiazepine receptor mRNA was observed, suggesting an increased transcription from the coding gene. These results suggest a possible role of peripheral benzodiazepine receptors in the organism response to tissue damage associated with inflammatory mediator production.
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PMID:Upregulation of mitochondrial peripheral benzodiazepine receptor expression by cytokine-induced damage of human pancreatic islets. 1181 68

15-deoxy-delta (12,14)prostaglandin J(2) (15d-PGJ(2)) has been identified as a natural ligand of the PPARgamma subtype. PPAR activation in nonadipose tissues seems to inhibit iNOS and COX2 expression. Vasoactive compounds like nitric oxide and prostaglandins are increased in pancreatic tissue from streptozotocin-diabetic rats. We hypothesize that 15d-PGJ(2) may regulate the production of these proinflammatory compounds that lead to beta cell destruction in the diabetic pathology. In this work we evaluated Ca(2+)-dependent (cNOS) and Ca(2+)-independent (iNOS) activity, nitrate/nitrite levels, 15-dPGJ(2) and prostaglandin E(2) (PGE(2)) levels in isolated pancreatic islets, and 15d-PGJ(2) levels in plasma from control and streptozotocin-diabetic rats. Our results show that cNOS is predominant in control, while iNOS isoform is increased in the diabetic islets (P < 0.01). 15d-PGJ(2) 10(-5)M inhibits cNOS and iNOS activity both in control and diabetic islets (P < 0.05). Nitrate/nitrite and PGE(2) levels are higher in diabetic than in control islets (P < 0.05 and P < 0.01, respectively). 15d-PGJ(2) 10(-5)M decreases nitrate/nitrite and PGE(2) levels both in control and in diabetic islets. Bisphenol A diglycidyl ether (BADGE), a recently described PPARgamma antagonist, seems to act as a PPARgamma agonist, diminishing nitrate/nitrite and PGE2 levels in control and diabetic islets. 15d-PGJ(2) production is lower in islets from diabetic animals compared to control (P < 0.05). Our observations suggest that 15d-PGJ(2) is able to diminish the production of vasoactive proinflammatory agents in pancreatic islets. The diminished 15d-PGJ(2) levels in the diabetic islets are probably related to the diminished capacity to limit the inflammatory response due to experimental diabetes in the rat.
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PMID:Streptozotocin-pancreatic damage in the rat: modulatory effect of 15-deoxy delta12,14-prostaglandin j(2) on nitridergic and prostanoid pathway. 1189 Jul 46

Complications of diabetes have a genetic influence. Since increased inducible nitric oxide synthase (iNOS) gene ( NOS2A) expression can contribute to tissue damage, NOS2A is a worthy candidate for such a role. We therefore tested a 4-bp insertion/deletion (+/-) polymorphism 0.7 kb upstream of NOS2A for association with complications in type 2 diabetes patients, and also performed transient transfection experiments to examine the effect of this variant on promoter activity in kidney cells in culture. We investigated 379 Caucasian type 2 diabetes patients of British/European descent, 93 of whom had microalbuminuria, 26 overt nephropathy, 46 retinopathy, and 73 clinical neuropathy. Genotyping for the variant was carried out by PCR and automated Genescan analysis. Transient transfection studies involved the renal HEK 293 cell line and luciferase reporter gene constructs containing 1.1 kb of 5'-flanking DNA from '+' or '-' allele homozygotes. We found that the '+' allele frequency in patients without microalbuminuria was 12%, but was 23% in those with microalbuminuria ( P=0.0005), and was 26% in those with nephropathy ( P=0.0007), 22% in those with retinopathy ( P=0.037), and 23% in those with neuropathy ( P=0.045). The odds ratios for homozygote +/+ to have microalbuminuria or nephropathy were 2.4 (95% CI 1.4-4.2, P=0.0023) and 5.4 (95% CI 1.8-16, P=0.0009), respectively. Luciferase reporter gene constructs containing 1 kb of NOS2A promoter DNA for each allele were made and sequence analysis confirmed that the +/- variation was the only sequence difference present. Transient transfection of these into HEK 293 cells revealed 25 times higher reporter gene activity for the '+' allele compared with the '-' allele. Gel shift analysis with 30mer oligonucleotides corresponding to each allele showed specific binding to nuclear extracts, being greater for the '+' allele. Thus the '+' allele of the NOS2A promoter variant may confer higher iNOS expression, and could contribute to complications of type 2 diabetes, especially in the approximately 5% of patients homozygous for this variant.
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PMID:Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes. 1190 46

In an effort to better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of beta-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.
Diabetes 2002 May
PMID:Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. 1197 40

This study investigated the time course of NADH oxidase, a source of superoxide in the vascular endothelium, inducible nitric oxide synthase (iNOS), and peroxynitrite (ONOO(-)) in the BBZ/Wor rat, a spontaneous model of noninsulin dependent diabetes (NIDDM). Colloidal gold-labeled immunocytochemical studies of iNOS and nitrotyrosine, a marker for OONO(-), were done on sections of retinas from male BBZ/Wor rats in which NADH oxidase was localized by cerium derived cytochemistry at three time points: pre-diabetes (prior to the onset of hyperglycemia); new onset diabetes (2-6 days after onset of hyperglycemia); and chronic diabetes (4-18 months after onset of hyperglycemia). Control retinas were from age matched non-diabetic BB(DR)/Wor rats. The percentage of blood vessels positive for NADH oxidase increased significantly (P = 0.05) in new onset (64.2 +/- 6.5%) and chronic diabetes (83.2 +/- 11.4%), as compared to pre-diabetes (25.8 +/- 5.6%) and nondiabetic controls (33.6 +/- 15.9%). The percentage of blood vessels positive for iNOS immunoreactivity was significantly higher in new onset diabetic retinas (69.6 +/- 5.88%, P = 0.0001; 8.9 +/- 3.29 colloidal gold particles (cgp) /50 microm(2)) than in chronic diabetic retinas (49.9 +/- 9.75%; 7.9 +/- 5.12 cgp) and both were significantly higher (P = 0.0001) than in prediabetic (3.7 +/- 0.81%; 0.4 +/- 0.56 cgp) and nondiabetic control retinas (8.7 +/- 4.66%; 1.2 +/- 1.40 cgp). In new onset diabetes, levels of nitrotyrosine immunoreactivity (60.8 +/- 16.91 cgp) were significantly higher (P = 0.0001) than those in chronic diabetes (29.5 +/- 4.31 cgp); both were significantly higher (P = 0.0001) than those in prediabetic (8.2 +/- 1.70 cgp) and nondiabetic retinas (9.0 +/- 1.87 cgp). There was no cumulative increase in nitrotyrosine in the chronic diabetic retinas as a function of time. In rats with diabetes there was disruption of the inner blood-retinal barrier. These results suggest that iNOS and ONOO(-) may contribute to retinal damage in diabetes from the onset of hyperglycemia in NIDDM.
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PMID:Time course of NADH oxidase, inducible nitric oxide synthase and peroxynitrite in diabetic retinopathy in the BBZ/WOR rat. 1200 47

Ischemic proliferative retinopathy (e.g., diabetes mellitus, retinopathy of prematurity, or retinal vein occlusion) is a major cause of blindness worldwide. Apart from neovascularization, ischemic proliferative retinopathy leads to retinal degeneration. Apoptosis has been ascribed to be the leading mechanism in ischemic retinal degeneration. We showed recently that inducible nitric oxide synthase (iNOS) is expressed in the avascular retina in proliferative retinopathy in vivo and that iNOS expression in retinal glial cells is responsible for retinal neuronal cell death in vitro. Here we show that retinal apoptosis and subsequent degeneration occur in the murine model of ischemic proliferative retinopathy. Furthermore, because NO can have beneficial or detrimental effects in the retina, we analyzed the role of iNOS on retinal apoptosis in ischemic proliferative retinopathy. Using iNOS knock-out mice and iNOS inhibitor 1400W, we demonstrate in vivo that iNOS expression induces apoptosis locally in the inner nuclear layer of the avascular retina and that protein nitration may be involved in this process. These findings are the first evidence for retinal apoptosis in an animal model of ischemic proliferative retinopathy, demonstrating that iNOS plays a crucial role not only in retinal neovascular disease but also in retinal degeneration. We show that it is an ideal target to protect the hypoxic retina from degeneration and to improve its vascularization.
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PMID:Inducible nitric oxide synthase mediates retinal apoptosis in ischemic proliferative retinopathy. 1201 18


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