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

The susceptibility of mitochondria from liver and kidney of diabetic and normal rats to in vitro oxidative damage was assessed. Mitochondria were isolated from diabetic rats 4 weeks after streptozotocin injection and from age-matched, normal rats. Liver mitochondria from diabetic rats were less susceptible to oxidative damage (induced by Fe3+/adenosine 5'-diphosphate (ADP) xanthine/xanthine oxidase), as assessed by the formation of thiobarbituric acid reacting substances (TBARS) and sulfhydryl loss, than were mitochondria from normal rats. The decreased susceptibility of liver mitochondria from diabetic rats to oxidative damage correlated with a sevenfold increase in mitochondrial alpha-tocopherol levels. Activities of the antioxidant enzymes, glutathione reductase, glutathione peroxidase, and superoxide dismutase, were lower in liver mitochondria from diabetic compared to normal rats. Manipulation of dietary alpha-tocopherol, to counteract the increased intake of alpha-tocopherol due to diabetes-associated polyphagia, failed to lower liver mitochondrial alpha-tocopherol to the levels found in normal rats. Mitochondria from kidney of diabetic rats were equally as susceptible to in vitro oxidative damage as kidney mitochondria from normal rats. They had increased levels of superoxide dismutase and glutathione peroxidase but identical levels of alpha-tocopherol compared to mitochondria from normal rats. Dietary manipulation of alpha-tocopherol had no effect on kidney mitochondrial levels of the nutrient.
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PMID:Decreased susceptibility of liver mitochondria from diabetic rats to oxidative damage and associated increase in alpha-tocopherol. 845 24

Pretreatment of porcine aortic endothelial cells with high D-glucose results in enhanced endothelium-derived relaxing factor (EDRF) formation (39%) due to increased endothelial Ca2+ release (57%) and Ca2+ entry (97%) to bradykinin. This study was designed to investigate the intracellular mechanisms by which high D-glucose affects endothelial Ca2+/EDRF response. The aldose-reductase inhibitors, sorbinil and zopolrestat, failed to diminish high D-glucose-mediated alterations in Ca2+/EDRF response, suggesting that aldose-reductase does not contribute to high D-glucose-initiated changes in Ca2+/EDRF signaling. Pretreatment of cells with the nonmetabolizing D-glucose analog, 3-O-methylglucopyranose (3-OMG), mimicked the effect of high D-glucose on Ca2+ release (41%) and Ca2+ entry (114%) to bradykinin, associated with elevated EDRF formation (26%). High D-glucose and 3-OMG increased superoxide anion (O2-) formation (133 and 293%, respectively), which was insensitive to inhibitors of cyclooxygenase (5,8,11,14-eicosatetraynoic acid [ETYA], indomethacin), lipoxygenase (ETYA, gossypol, nordihydroguaiaretic acid [NDGA]), cytochrome P450 (NDGA, econazole, miconazole), and nitric oxide (NO) synthase (L-omega N-nitroarginine), while it was diminished by desferal, a metal chelator. The gamma-glutamyl-cysteine-synthase inhibitor, buthioninesulfoximine (BSO), also increased formation of O2- by 365% and mimicked the effect of high D-glucose on Ca2+/EDRF signaling. The effects of high D-glucose, 3-OMG, and BSO were abolished by co-incubation with superoxide dismutase. Like high D-glucose, pretreatment with the O2(-)-generating system, xanthine oxidase/hypoxanthine, elevated bradykinin-stimulated Ca2+ release (+10%), Ca2+ entry (+75%), and EDRF (+73%). We suggest that prolonged exposure to pathologically high D-glucose concentration results in enhanced formation of O2-, possibly due to metal-mediated oxidation of D-glucose within the cells. This overshoot of O2- enhances agonist-stimulated Ca2+/EDRF signaling via a yet unknown mechanism.
Diabetes 1996 Oct
PMID:High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. 882 76

Susceptibility of islet cells to damage by hydrogen peroxide, superoxide, and nitric oxide was determined on islets isolated from humans, pigs, and rats. Islets were incubated for 20 hr at 37 degrees C with different concentrations of hydrogen peroxide, hypoxanthine/xanthine oxidase, or nitroprusside sodium, respectively. Islet cell damage was then measured as trypan blue-uptake. Rat islets showed a higher sensitivity than human or pig islets to damage by reactive oxygen species or nitric oxide. These results indicate that pig islets may be a more suitable model than rat islets to study inflammatory islet cell damage in diabetes and clinical islet transplantation.
Exp Clin Endocrinol Diabetes 1995
PMID:Different toxic effects of hydrogen peroxide, nitric oxide, and superoxide on human, pig, and rat islets of Langerhans. 883 70

In order to examine the mechanisms of the beneficial effects of vanadate on cardiac dysfunction in chronic diabetes, rat hearts were perfused with xanthine plus xanthine oxidase, an oxyradical generating system in the absence or presence of vanadate. The heart failed to generate contractile force and increased the resting tension markedly within 5 min of perfusion with xanthine plus xanthine oxidase. These changes were prevented by the addition of 4 microM vanadate in the perfusion medium. The protective effects of vanadate on the loss of developed tension and increased resting tension due to xanthine plus xanthine oxidase were dose-dependent (0.1-5 microM). Perfusion of the hearts with glucose-free medium did not abolish the protective actions of vanadate. The sarcolemmal Ca(2+)-pump (ATP-dependent Ca2+ uptake and Ca(2+)-stimulated ATPase) and Na(+)-dependent Ca2+ uptake activities were decreased upon perfusing the hearts with a medium containing xanthine plus xanthine oxidase for 5 min; these effects were prevented by the addition of 2-4 microM vanadate in the perfusion medium. The signals for superoxide radicals produced by xanthine plus xanthine oxidase, as detected by electron paramagnetic resonance spectroscopic technique, were inhibited by 5-100 microM vanadate. These results suggest that vanadate is an oxyradical scavenger and thus may prevent heart dysfunction under some pathological conditions by its antioxidant action.
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PMID:Protective effect of vanadate on oxyradical-induced changes in isolated perfused heart. 892 51

1. Some cardiovascular disturbances which occur in diabetics are a consequence of alterations in vascular contractility as well as in endothelium-dependent relaxation. 2. Calcium dobesilate (DOBE) is a drug used in diabetic retinopathy and its mechanism of action is not yet understood. 3. The aim of this study was to investigate the effects of DOBE on synthesis and release of endothelium-dependent relaxing factor (EDRF) and endothelium-dependent hyperpolarizing factor (EDHF) in rabbit isolated aorta. 4. Endothelium-dependent relaxation induced by acetylcholine (ACh) (10(-8)-(10(-5) M) increased in the presence of DOBE 10(-5) M only when vascular endothelium was kept intact. 5. NG-nitro-L-arginine methyl ester (L-NAME; 10(-8)-10(-4) M progressively decreased the enhancing effect of DOBE on endothelium-dependent relaxation whereas it was progressively increased by L-Arg. 6. DOBE 10(-5) M increased in a non-significant manner endothelium-dependent relaxation induced by ACh when the arteries were incubated with both L-NAME 10(-4) M and indomethacin 10(-5) M. 7. DOBE (10(-6) M and 10(-5) M) was able to scavenge superoxide anion radicals generated by the hypoxanthine/xanthine oxidase reaction. 8. These results provide evidence that DOBE is able to affect the vascular disorders associated with diabetes mellitus since it enhances the synthesis of endothelium-dependent relaxing factors.
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PMID:Effects of calcium dobesilate on the synthesis of endothelium-dependent relaxing factors in rabbit isolated aorta. 920 38

Insulin-induced increases in blood flow are hypothesized to enhance overall glucose uptake by skeletal muscle. Whether the insulin-mediated changes in blood flow are associated with altered blood flow distribution and increased capillary recruitment in skeletal muscle is not known. In the present study, the effects of insulin on hemodynamic parameters in rat skeletal muscle in vivo were investigated. Mean arterial blood pressure, heart rate, femoral blood flow, hind leg vascular resistance, and glucose uptake were measured in control and euglycemic insulin-clamped (10 mU x min(-1) x kg[-1]) anesthetized rats. Blood flow distribution within the hind leg muscles was assessed by measuring the metabolism of 1-methylxanthine (1-MX), an exogenously added substrate for capillary xanthine oxidase. Insulin treatment had no effect on heart rate but significantly increased arterial blood pressure (12 mmHg) and femoral blood flow (80%) and decreased hind leg vascular resistance (31%). Changes were similar in magnitude and in time of onset to those reported in humans. Insulin treatment increased hind leg glucose uptake approximately fourfold and also increased hind leg 1-MX metabolism by 50%, suggesting increased exposure to endothelial xanthine oxidase. To ascertain whether the increased 1-MX metabolism was simply due to increased bulk femoral blood flow, epinephrine was infused at a dose (0.125 microg x min(-) x kg[-1]) chosen to match the insulin-induced increase in femoral blood flow. This dose of epinephrine had no significant effects on arterial blood pressure or heart rate but increased femoral blood flow and lowered hind leg vascular resistance to a similar extent as insulin. Epinephrine did not significantly alter 1-MX metabolism as compared with control animals. These results demonstrate that insulin increases total hind leg blood flow and metabolism of 1-MX, suggesting a recruitment of capillary blood flow in rat hind leg not mimicked by epinephrine.
Diabetes 1997 Sep
PMID:Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. 928 35

The effects of acute hyperglycemia on endothelial Ca2+ signaling, formation of endothelium-derived relaxing factor (EDRF) and bioactivity of EDRF were investigated. Hyperglycemia increased 2,5-tert-butyl-1,4-hydrochinone (BHQ)-initiated Ca2+ signaling and EDRF formation in a concentration-dependent manner. The effect of elevated D-glucose on Ca2+/EDRF response could be diminished by co-incubation with the antioxidants vitamin E, probucol, GSH, vitamin C and superoxide dismutase. Convincingly, hyperglycemic conditions yielded an increase in superoxide anion release from endothelial cells and the superoxide anion-generating mixture xanthine oxidase/hypoxanthine mimicked the effect of hyperglycemia on Ca2+/EDRF signaling. Besides an enhanced formation of the vasodilatatory NO compound EDRF, hyperglycemia enhanced NO degradation by endothelial cells and, thus, reduced bioactivity of EDRF. We suggest that vasoactivity during acute hyperglycemia depends on the superoxide anion scavenging properties of the vascular wall. In acute hyperglycemia and early stages of diabetes, radical scavenging capacity may be suitable to protect NO degradation, resulting in an enhanced vasodilation. In contrast, decreased free radical scavenging properties of the vasculature in prolonged hyperglycemia and in later stages of diabetes might promote NO degradation by an overshoot of superoxide anions, resulting in an attenuation of endothelium-dependent vasodilation.
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PMID:Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia. 949 99

Although the involvement of free radicals in the development of endothelial dysfunction under pathological conditions, like diabetes and hypercholesterolemia, has been proposed frequently, there is limited knowledge as to how superoxide anions (O2-) might affect endothelial signal transduction. In this study, we investigated the effects of preincubation with the O2(-)-generating system xanthine oxidase/hypoxanthine (XO/HX) on mechanisms for Ca2+ signaling in cultured porcine aortic endothelial cells. Incubation of cells with XO/HX yielded increased intracellular Ca2+ release and capacitative Ca2+ entry in response to bradykinin and ATP in a time- and concentration-dependent manner. This effect was prevented by superoxide dismutase but not by the tyrosine kinase inhibitor tyrphostin A48. In addition, capacitative Ca2+ entry induced by the receptor-independent stimulus 2,5-di-(tert-butyl)-1,4-benzohydroquinone or thapsigargin was enhanced in O2(-)-exposed cells (+38% and +32%, respectively). Increased Ca2+ release in response to bradykinin in XO/HX-pretreated cells might be due to enhanced formation of inositol-1,4,5-trisphosphate (+140%). Exposure to XO/HX also affected other signal transduction mechanisms involved in endothelial Ca2+ signaling, such as microsomal cytochrome P450 epoxygenase and membrane hyperpolarization to Ca2+ store depletion with thapsigargin (+103% and +48%, respectively) and tyrosine kinase activity (+97%). A comparison of bradykinin-initiated intracellular Ca2+ release and thapsigargin-induced hyperpolarization with membrane viscosity modulated by XO/HX (decrease in viscosity) or cholesterol (increase in viscosity) reflected a negative correlation between bradykinin-initiated Ca2+ release and membrane viscosity. Because intracellular Ca2+ is a main regulator of endothelial vascular function, our data suggest that O2- anions are involved in regulation of the vascular endothelium.
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PMID:Effects of superoxide anions on endothelial Ca2+ signaling pathways. 974 37

To determine the importance of different antioxidative enzymes for the defense status of insulin-producing cells, the effects of stable overexpression of glutathione peroxidase (Gpx), catalase (Cat), or Cu/Zn superoxide dismutase (SOD) in insulin-producing RINm5F cells on the cytotoxicity of hydrogen peroxide (H2O2), hypoxanthine/xanthine oxidase (H/XO), and menadione have been investigated. Single overexpression of Cat or Gpx provided less protection than the combined expression of Cat plus SOD or Cat plus Gpx, while single overexpression of SOD either had no effect on the toxicity of the test compounds or increased it. RINm5F cells were also susceptible to butylalloxan, a lipophilic alloxan derivative that is selectively toxic to pancreatic beta-cells. Overexpression of enzymes, both alone and in combination, did not protect against butylalloxan-induced toxicity while SOD overexpression increased it, as evident from a half maximally effective concentration (EC50) value. The addition of Cat to the culture medium completely prevented the toxic effects of H2O2 and H/XO but had no significant effect on the toxicity of menadione or butylalloxan. Extracellular SOD had no effect on the toxicity of any of the test compounds. The results of this study show the importance of a combination of antioxidant enzymes in protecting against the toxicity of reactive oxygen species. Thus, overexpression of Cat and Gpx, alone or in combination with SOD, by use of molecular biology techniques can protect insulin-producing cells against oxidative damage. This may represent a strategy to protect pancreatic beta-cells against destruction during the development of autoimmune diabetes and emphasizes the importance of optimal antioxidative enzyme equipment for protection against free radical-mediated diseases.
Diabetes 1998 Oct
PMID:Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. 975 95

1. Nonenzymatic protein glycosylation is a possible mechanism contributing to oxidative stress and vascular disease in diabetes. In this work, the influence of 14%-glycosylated human oxyhaemoglobin (GHHb), compared to the non-glycosylated protein (HHb), was studied on several growth parameters of rat cultured vascular smooth muscle cells (VSMC). A role for reactive oxygen species was also analysed. 2. Treatment of VSMC for 48 h with GHHb, but not with HHb, increased planar cell surface area in a concentration dependent manner. The threshold concentration was 10 nM, which increased cell size from 7965+/-176 to 9411+/-392 microm2. Similarly, only GHHb enhanced protein content per well in VSMC cultures. 3. The planar surface area increase induced by 10 nM GHHb was abolished by superoxide dismutase (SOD; 50 200 u ml(-1)), deferoxamine (100 nM-100 microM), or dimethylthiourea (1 mM), while catalase (50 200 u ml(-1)) or mannitol (1 mM) resulted in a partial inhibition of cell size enhancement. 4. When a known source of oxygen free radicals was administered to VSMC, the xanthine/xanthine oxidase system, the results were analogous to those produced by GHHb. Indeed, enhancements of cell size were observed, which were inhibited by SOD, deferoxamine, or catalase. 5. These results indicate that, at low concentrations, GHHb induces hypertrophy in VSMC, this effect being mediated by superoxide anions, hydrogen peroxide, and/or hydroxyl radicals. Therefore, glycosylated proteins can have a role in the development of the structural vascular alterations associated to diabetes by enhancing oxidative stress.
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PMID:Vascular smooth muscle cell hypertrophy induced by glycosylated human oxyhaemoglobin. 983 96


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