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

We present here the first report of a metalloporphyrin-based antioxidant that can prevent or delay the onset of autoimmune diabetes. Type 1 diabetes is an autoimmune process whereby T-cells recognize pancreatic beta-cell antigens and initiate a leukocyte infiltrate that produces proinflammatory cytokines and reactive oxygen species (ROS), ultimately leading to beta-cell destruction. Because islet beta-cells have a reduced capacity to scavenge free radicals, they are very sensitive to ROS action. Metalloporphyrin-based superoxide dismutase (SOD) mimics scavenge ROS and protect cells from oxidative stress and apoptosis. To investigate the effect of SOD mimics and the role of oxidative stress in the development of autoimmune diabetes in vivo, we used a diabetogenic T-cell clone, BDC-2.5, to induce rapid onset of diabetes in young nonobese diabetic-severe combined immunodeficient mice (NOD.scid). Disease was significantly delayed or prevented altogether by treatment of recipient mice with an SOD mimic, AEOL-10113, before transfer of the BDC-2.5 clone. To investigate the mechanisms of protection, in vitro assays for T-cell proliferation and gamma-interferon (IFN-gamma) production were carried out using the T-cell clone BDC-2.5. We found that the SOD mimic significantly inhibited antigen-presenting cell-dependent T-cell proliferation and IFN-gamma production in vitro. In addition, pretreatment of lipopolysaccharide (LPS)-stimulated peritoneal macrophages with SOD mimic inhibited the LPS-dependent increase in TNF-alpha as well as the NADPH oxidase-dependent release of superoxide. Finally, this compound protected NIT-1 insulinoma cells from interleukin-1beta and alloxan cytotoxicity in vitro.
Diabetes 2002 Feb
PMID:A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. 1181 41

Professional phagocytes, comprising polymorphonuclear neutrophils and monocyte/macrophage cells, play an important role in the host defense. Any defect in their function exposes the organism to microbial intruders terminating in fatal diseases. The functional responses of the phagocytes to bacterial and fungal infections include chemotaxis, actin assembly, migration, adhesion, aggregation, phagocytosis, degranulation, and reactive oxygen species production. Superoxide generation by phagocytic NADPH oxidase is an imperative step toward bacterial killing. Phagocytes participate in inflammatory reactions and exert tumoricidal activity. They are supported by serum factors such as immunoglobulins, cytokines, complement, the acute phase reactant C-reactive protein, production of antibacterial proteins, and others. In addition to their principal task to eliminate bacteria, they are engaged in removing damaged, senescent, and apoptotic cells. Engulfed cell debris, large particles such as latex beads, fat, and oil droplets, are examples of phagocytic activity illustrated in the present review with transmission and scanning electron microscope micrographs. Numerous factors, such as diseases and stressful conditions, affect the engulfing activity of the professional phagocytes. Our experience regarding the impaired phagocytic capacity of cells in patients with diabetes and chronic renal failure is discussed. The results obtained in our laboratory from experiments detecting the effect of strenuous physical exercise, hypothermia, fasting, and abdominal photon irradiation on the phagocytic capacity of human polymorphonuclear neutrophils and rat peritoneal macrophages are hereby summarized and the reports on those subjects in the recent literature are reviewed. A variety of assays are applied for quantifying phagocytosis. Flow cytometry based on incubation of phagocytic cells with fluorescent conjugated particles and measuring the amount of fluorescence as an indicator of the engulfing capacity of the cells is a useful method. A direct visualization of the ingested particles using light or electron microscopy is a valuable tool for estimation of phagocytic function. In our hands, the use of semithin sections of embedded phagocytes following their incubation with latex particles provided satisfactory results for measuring the total number of phagocytic cells, as well as the internalizing capacity of each individual cell. Microbiological assays, the nitroblue tetrazolium test, quantitation of antibody- and antigen-mediated phagocytosis, as well as methods reviewed in detail in other reports are additional applications for determination of this intricate process.
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PMID:Phagocytosis--the mighty weapon of the silent warriors. 1211 25

An accelerated accumulation of advanced glycation end products (AGEs) occurs in diabetes secondary to the increased glycemic burden. In this study, we investigated the contribution of AGEs to intravascular oxidant stress by examining their action on the neutrophil burst of reactive oxygen species (ROS); this may be a significant donor to the overall vascular redox status and to vasculopathy. AGEs exerted a dose-dependent enhancement on the neutrophil respiratory burst in response to a secondary mechanical stimulus (up to 265 +/- 42%, P = 0.022) or chemical stimulation with formyl-methylleucylphenylalanine 100 nmol/l (up to 218 +/- 19%, P < 0.001), although they possessed no ability to augment the neutrophil respiratory burst alone. This phenomenon was both immediate and reversible and depended on the simultaneous presence of AGEs with the additional stimulus. It appeared to work through an upregulation of the neutrophil NADPH oxidase, the enzyme responsible for ROS generation, as seen by a diphenyleneiodonium-dependent suppression of basal and augmented ROS output. Moreover, this action of AGEs was found to be complementary to that of neutrophil priming agents, also known to upregulate neutrophil ROS production, implying the presence of distinct intracellular transduction pathways mediating the effect of these two classes of agents.
Diabetes 2002 Sep
PMID:Augmentation of the neutrophil respiratory burst through the action of advanced glycation end products: a potential contributor to vascular oxidant stress. 1219 80

Diabetes is a major risk factor for premature atherosclerosis, and oxidative stress appears to be an important mechanism. Previously, we showed that diabetic monocytes produce increased superoxide anion (O(2)(-)), and alpha-tocopherol (AT) supplementation decreases this. The aim of this study was to elucidate the mechanism(s) of O(2)(-) release and inhibition by AT under hyperglycemic (HG) conditions in monocytes. O(2)(-) release, protein kinase C (PKC) activity, and translocation of PKC-alpha and -betaII and p47phox were increased in THP-1 cells (human monocytic cell line) under HG (15 mmol/l glucose) conditions, whereas AT supplementation inhibited these changes. AT, NADPH oxidase inhibitors (apocynin and diphenyleneiodonium chloride [DPI]), and an inhibitor to PKC-alpha and other isoforms (2,2',3,3',4,4'-hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether [HBDDE]) but not PKC-beta II (LY379196) decreased O(2)(-) release and p47phox translocation. Antisense oligodeoxynucleotides to PKC-alpha and p47phox but not to PKC-betaII inhibited HG-induced O(2)(-) release and p47phox translocation in THP-1 cells. Under HG conditions, reactive oxygen species release from monocytes was not inhibited by agents affecting mitochondrial metabolism but was inhibited in human endothelial cells. We conclude that under HG conditions, monocytic O(2)(-) release is dependent on NADPH oxidase activity but not the mitochondrial respiratory chain; HG-induced O(2)(-) release is triggered by PKC-alpha, and AT inhibits O(2)(-) release via inhibition of PKC-alpha.
Diabetes 2002 Oct
PMID:Alpha-tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-alpha. 1235 46

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress
Diabetes 2002 Nov
PMID:Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. 1240 19

Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelial dysfunction in diabetes. To clarify whether glucose-modified HDL affects the function of endothelial cells, we first examined herein the level of H(2)O(2) generation from cultured human aortic endothelial cells (HAECs) exposed to a glycated oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation for 48 hours with 100 microg/mL of gly-ox-HDL induced significant release of H(2)O(2) from cells and gly-ox-HDL-induced H(2)O(2) formation was inhibited in the presence of diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, stimulation of HAECs with gly-ox-HDL for 48 hours elicited a marked downregulation of catalase and Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD), suggesting H(2)O(2) formation by gly-ox-HDL to be due to a disturbance involving oxidant and antioxidant enzymes in the cells. Treatment of HAECs with gly-ox-HDL attenuated the expression of endothelial nitric oxide synthase (eNOS), but not inducible nitric oxide synthase (iNOS), and this was followed by decreased production of nitric oxide (NO) by the cells. Furthermore, in vitro experiments with glycated HDL (gly-HDL) in the presence of 2 mmol/L EDTA and Cu(2+)-oxidized HDL suggested the effect of gly-HDL on endothelial function to be possibly potentiated by additional oxidative modification. Taking all of the above findings together, gly-ox-HDL may lead to the deterioration of vascular function through altered production of reactive oxygen species and reactive nitrogen species in endothelial cells.
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PMID:Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells. 1252 61

Oxidative stress is associated with diabetes mellitus: a role of vascular NADPH oxidase as a source of superoxide has been demonstrated. We determined whether in type 2 diabetes mononuclear cells, NADPH oxidase and the inducible hemeoxygenase (HO-1) gene expressions are activated. In monocytes from 25 outpatients with type 2 diabetes, p22(phox) gene expression was higher (0.71 +/- 0.09 p22(phox)/beta-actin gene expression ratio) than that observed in 19 controls (0.56 +/- 0.09, P < 0.001). Similarly, HO-1 gene expression was significantly higher in diabetic patients (0.77 +/- 0.12 HO-1/beta-actin gene expression ratio) than in controls (0.41 +/- 0.14, P < 0.001). The p22(phox) and HO-1 gene expressions were also determined during (plasma glucose 363 +/- 40 mg/dl) and after (125 +/- 11 mg/dl) metabolic decompensation in 10 type 2 diabetic patients. The correction of the metabolic milieu was associated with a 19% +/- 3% (P < 0.01) and 30% +/- 3% (P < 0.01) decrease in the p22(phox) and HO-1 gene expressions, respectively. In a multivariate analysis, age was independently associated to p22(phox) gene expression in circulating monocytes in type 2 diabetics [13% (adjusted R(2)), P < 0.05]. Decompensated type 2 diabetes is associated with increased p22(phox) and HO-1 gene expressions in circulating monocytes; the metabolic normalization reduces but does not normalize this activation. These findings suggest that these cells, which play a crucial role in the earliest events of atherosclerotic lesion, are subjected to an increased oxidative stress.
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PMID:Monocyte NADPH oxidase subunit p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress. 1267 69

Metformin (dimethylbiguanide) is an antihyperglycemic agent used in type 2 diabetes. Beyond its action on glycemic control, metformin exhibits other intrinsic effects that could play a role in prevention against diabetes complications. Some studies thus reported an improvement in the antioxidant status in patients treated with metformin. This might be in part related to its property to limit formation of advanced glycation end products (AGEs) and to decrease the overproduction of free radicals in diabetic subjects. The aim of this study was to investigate the in vitro ability of metformin to modulate the action of reactive oxygen species (ROS) generated either by water gamma radiolysis or by stimulated human leukocytes. Our results showed that metformin at pharmacologically relevant concentrations was in vitro able to scavenge hydroxyl ((.)OH) but not superoxide (O(.-)(2)) free radicals and that hydrogen peroxide did not react with metformin. Nevertheless, when polymorphonuclear cells (PMN) are stimulated by phorbol myristate acetate (PMA), or above all by formyl methionine leucyl phenylalanine (fMLP), a systematic (although nonsignificant) decrease of the ROS-induced chimiluminescence (CL) was observed. These results suggest that metformin could directly scavenge ROS or indirectly act by modulating the intracellular production of superoxide anion, of which NADPH oxidase constitutes the major source. This could contribute to the additional benefits of metformin, especially those related to the improvement in the cardiovascular outcomes in diabetes.
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PMID:An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. 1275 88

High glucose (HG) is the underlying factor contributing to long term complications of diabetes mellitus. The molecular mechanisms transforming the glomerular mesangial cell phenotype to cause nephropathy including diacylglycerol-sensitive protein kinase C (PKC) are still being defined. Reactive oxygen species (ROS) have been postulated as a unifying mechanism for HG-induced complications. We hypothesized that in HG an interaction between ROS generation, from NADPH oxidase, and PKC suppresses mesangial Ca2+ signaling in response to endothelin-1 (ET-1). In primary rat mesangial cells, growth-arrested (48 h) in 5.6 mM (NG) or 30 mm (HG) glucose, the total cell peak [Ca2+]i response to ET-1 (50 nM) was 630 +/- 102 nM in NG and was reduced to 159 +/- 15 nM in HG, measured by confocal imaging. Inhibition of PKC with phorbol ester down-regulation in HG normalized the ET-1-stimulated [Ca2+]i response to 541 +/- 74 nM. Conversely, an inhibitory peptide specific for PKC-zeta did not alter Ca2+ signaling in HG. Furthermore, overexpression of conventional PKC-beta or novel PKC-delta in NG diminished the [Ca2+]i response to ET-1, reflecting the condition observed in HG. Likewise, catalase or p47phox antisense oligonucleotide normalized the [Ca2+]i response to ET-1 in HG to 521 +/- 58 nM and 514 +/- 48 nM, respectively. Pretreatment with carbonyl cyanide m-chlorophenylhydrazone or rotenone did not restore Ca2+ signaling in HG. Detection of increased intracellular ROS in HG by dichlorofluorescein was inhibited by catalase, diphenyleneiodonium, or p47phox antisense oligonucleotide. HG increased p47phox mRNA by 1.7 +/- 0.1-fold as measured by reverse transcriptase-PCR. In NG, H2O2 increased membrane-enriched PKC-beta and -delta, suggesting activation of these isozymes. HG-enhanced immunoreactivity of PKC-delta visualized by confocal imaging was attenuated by diphenyleneiodium chloride. Thus, mesangial cell [Ca2+]i signaling in response to ET-1 in HG is attenuated through an interaction mechanism between NADPH oxidase ROS production and diacylglycerol-sensitive PKC.
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PMID:High glucose-suppressed endothelin-1 Ca2+ signaling via NADPH oxidase and diacylglycerol-sensitive protein kinase C isozymes in mesangial cells. 1282 78

Enhanced tissue angiotensin (Ang) II levels have been reported in diabetes and might lead to cardiac dysfunction through oxidative stress. This study examined the effect of blocking the Ang II type 1 (AT1) receptor on high glucose-induced cardiac contractile dysfunction. Rat ventricular myocytes were maintained in normal- (NG, 5.5 mmol/L) or high- (HG, 25.5 mmol/L) glucose medium for 24 hours. Mechanical and intracellular Ca2+ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening (+/-dL/dt), and intracellular Ca2+ decay (tau). HG myocytes exhibited normal PS; decreased +/-dL/dt; and prolonged TPS, TR90, and tau. Interestingly, the HG-induced abnormalities were prevented with the AT1 blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 micromol/L). The only effect of AT1 blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT1 antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 micromol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 micromol/L) or apocynin (100 micromol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47phox and the AT1 but not the AT2 receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47phox was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT1 blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT1 receptor-mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.
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PMID:AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. 1284 13


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