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)

Oxidative stress and the resulting change in cell redox state are proposed to contribute to pathogenic alterations in ion channels that underlie electrical remodeling of the diseased heart. The present study examined whether K(+) channel remodeling is controlled by endogenous oxidoreductase systems that regulate redox-sensitive cell functions. Diabetes was induced in rats by streptozotocin, and experiments were conducted after 3-5 wk of hyperglycemia. Spectrophotometric assays of ventricular tissue extracts from diabetic rat hearts revealed divergent changes in two major oxidoreductase systems. The thioredoxin (TRX) system in diabetic rat heart was characterized by a 52% decrease in TRX reductase (TRXR) activity from control heart (P < 0.05), whereas TRX activity was 1.7-fold greater than control heart (P < 0.05). Diabetes elicited similar changes in the glutaredoxin (GRX) system: glutathione reductase was decreased 35% from control level (P < 0.05), and GRX activity was 2.5-fold greater than in control heart (P < 0.05). The basal activity of glucose-6-phosphate dehydrogenase, which generates NADPH required by the TRX and GRX systems, was not altered by diabetes. Voltage-clamp studies showed that the characteristically decreased density of the transient outward K(+) current (I(to)) in isolated diabetic rat myocytes was normalized by in vitro treatment with insulin (0.1 microM) or the metabolic activator dichloroacetate (1.5 mM). The effect of these agonists on I(to) was blocked by inhibitors of glucose-6-phosphate dehydrogenase. Moreover, inhibitors of TRXR, which controls the reducing activity of TRX, also blocked upregulation of I(to) by insulin and dichloroacetate. These data suggest that K(+) channels underlying I(to) are regulated in a redox-sensitive manner by the TRX system and the remodeling of I(to) that occurs in diabetes may be due to decreased TRXR activity. We propose that oxidoreductase systems are an important repair mechanism that protects ion channels and associated regulatory proteins from irreversible oxidative damage.
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PMID:Redox regulation of Ito remodeling in diabetic rat heart. 1553 26

In diabetes, cell death and resultant cardiomyopathy have been linked to oxidative stress and depletion of antioxidants like glutathione (GSH). Although the de novo synthesis and recycling of GSH have been extensively studied in the chronically diabetic heart, their contribution in modulating cardiac oxidative stress in acute diabetes has been largely ignored. Additionally, the possible contribution of cellular efflux in regulating GSH levels during diabetes is unknown. We used streptozotocin to make Wistar rats acutely diabetic and after 4 days examined the different processes that regulate cardiac GSH. Reduction in myocyte GSH in diabetic rats was accompanied by increased oxidative stress, excessive reactive oxygen species, and an elevated apoptotic cell death. The effect on GSH was not associated with any change in either synthesis or recycling, as both gamma-glutamylcysteine synthetase gene expression (responsible for bio syn thesis) and glutathione reductase activity (involved with GSH recycling) remained unchanged. However, gene expression of multidrug resistance protein 1, a transporter implicated in effluxing GSH during oxidative stress, was elevated. GSH conjugate efflux mediated by multidrug resistance protein 1 also increased in diabetic cardiomyocytes, an effect that was blocked using MK-571, a specific inhibitor of this transporter. As MK-571 also decreased oxidative stress in diabetic cardiomyocytes, an important role can be proposed for this transporter in GSH and reactive oxygen species homeostasis in the acutely diabetic heart.
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PMID:Increased efflux of glutathione conjugate in acutely diabetic cardiomyocytes. 1557 48

Diabetes mellitus is characterized by hyperglycemia and, in chronic disease, by microvascular pathologies, especially in the kidney, peripheral nerve, and eye. Although hyperglycemia can be controlled with insulin and/or antihyperglycemic medications, diabetic retinopathy continues to be the leading cause of blindness in the United States. Because increased oxidative stress may be a cause of retinopathy, this study examined the hypothesis that administration of exogenous antioxidants can restore a more balanced oxidative condition. Normal and 30-day streptozotocin-induced diabetic Sprague-Dawley rats received daily intraperitoneal doses (10 mg/kg) of beta-carotene, alpha-lipoic, and Pycnogenol individually or in combinations for 14 days, after which retinae were dissected and fractionated for the assay of activities of glutathione reductase, glutathione peroxidase, gamma-glutamyl transferase, and superoxide dismutase. In normal rats, treatment with antioxidant combinations led to a decrease in gamma-glutamyl transferase activity; beta-carotene plus pycnogenol treatment decreased the activity of both glutathione-related enzymes. Decreased retinal gamma-glutamyl transferase activity of diabetic rats was normalized by the administration of pycnogenol alone or in combination with beta-carotene. In diabetic rats, retinal glutathione reductase activity increased after treatment with beta-carotene alone or with pycnogenol. Treatment with pycnogenol and alpha-lipoic acid alone or in combination decreased the activity of glutathione peroxidase, while this activity was increased after treatment with a combination of all antioxidants. Elevated activity of superoxide dismutase in diabetic retina was normalized by treatment with alpha-lipoic acid and with pycnogenol and beta-carotene in combination, but not with all three together. Antioxidants can access the retina and, once there, can alter antioxidant enzyme activities. In both normal and diabetic rats, combinations of antioxidants have different effects on retinal antioxidant enzyme activities than do individual antioxidants.
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PMID:Effects of antioxidant treatment on normal and diabetic rat retinal enzyme activities. 1571 25

Reactive oxygen species are, at least partly, involved in the diabetogenic agent-induced dysfunction of pancreatic beta-cells because the expression of antioxidative and redox proteins is low. We examined the levels of antioxidant/redox proteins, peroxiredoxins-1, -4, and -6 and glutathione reductase (GR), by immunohistochemistry and found that the expression of GR was very high in pancreatic islet cells compared to exocrine cells. When diabetes was induced by an intravenous injection of streptozotocin, the pre-administration of 1,3-bis[2-chloroethyl]-1-nitrosourea, an irreversible inhibitor of GR, made islet cells more vulnerable to streptozotocin. These data point to a pivotal role of the glutathione redox system in pancreatic islet cells against diabetogenic stress.
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PMID:Glutathione reductase is expressed at high levels in pancreatic islet cells. 1572 Aug 26

Diabetes induced by streptozotocin (50 mg/kg body wt, i.p.) in the rats substantially increased the plasma glucose and malondialdehyde levels along with corresponding decrease in the antioxidants levels. Supplementation of vitamin E (200 mg/kg body wt., ip) for 5 weeks resulted in non-significant decrease in the blood glucose levels but plasma malondialdehyde levels were reduced to below normal levels. Plasma vitamin E, vitamin C, uric acid and red blood cell glutathione levels were also restored to near normal levels on vitamin E supplementation to diabetic rats as compared to control (diabetic) rats. The activities of antioxidant enzymes, catalase (EC 1.11.1.6), glutathione peroxidase (GSHPx EC 1.11.1.9), and glutathione reductase (GR EC 1.6.4.2) were also concomitantly restored to near normal levels by vitamin E supplementation to diabetic rats. The results clearly demonstrated that vitamin E supplementation augments the antioxidant defense mechanism in diabetes and provides evidence that vitamin E may have a therapeutic role in free radical mediated diseases.
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PMID:Effect of vitamin E supplementation on diabetes induced oxidative stress in experimental diabetes in rats. 1578 20

In this study, the antioxidative properties of repaglinide were examined in tissues of alloxan-induced diabetic rabbits. Glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and protein carbonyl groups (PCG) were measured after 4 and 8 weeks treatment with repaglinide (0.3 mg/kg daily). In liver, diabetic versus control values (mean +/- S.E.M., p<0.05) for GSH-Px were 181.0 +/- 5.4 mU/mg protein versus 203.1 +/- 1.9 mU/mg protein and 187.4 +/- 6.6 mU/mg protein versus 240.9 +/- 18.8 mU/mg protein. The respective values for GSH were 33.7 +/- 0.4 nmol/mg protein versus 49.0 +/- 1.6 nmol/mg protein and 37.7 +/- 1.0 nmol/mg protein versus 41.2 +/- 0.7 nmol/mg protein. In diabetic kidney, GSSG-R activity (20.6 +/- 1.6 mU/mg protein versus 32.4 +/- 1.5 mU/mg protein and 23.6 +/- 0.6 mU/mg protein versus 36.3 +/- 0.3 mU/mg protein) and GSH level (16.6 +/- 0.5 nmol/mg protein versus 23.2 +/- 0.9 nmol/mg protein and 17.9 +/- 0.5 nmol/mg protein versus 23.2 +/- 0.6 nmol/mg protein) were reduced compared to control. PCG level was elevated in diabetic liver (0.58 +/- 0.02 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein at 4 weeks and 0.64 +/- 0.04 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein at 8 weeks) and in diabetic kidney (0.32 +/- 0.03 nmol/mg protein versus 0.11 +/- 0.02 nmol/mg protein and 0.35 +/- 0.03 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein). Repaglinide did not affect the glucose level but reduced to some extent the oxidative stress enhanced by chronic hyperglycemia. In diabetic kidney, it restored to control values GSSG-R activity (45.4 +/- 2.0 mU/mg protein at 4 weeks and 41.1 +/- 0.07 mU/mg protein at 8 weeks), GSH level (27.0 +/- 0.8 and 26.8 +/- 0.9 nmol/mg protein), and partly PCG level (0.17 +/- 0.02 nmol/mg protein at 8 weeks). The treatment partly affected GSH-Px activity (262.7 +/- 17.6 mU/mg protein) and GSH level (40.4 +/- 1.4 nmol/mg protein) in diabetic liver. This study shows that repaglinide produces measurable antioxidative effects at therapeutic dose.
Diabetes Res Clin Pract 2005 May
PMID:Effects of repaglinide on oxidative stress in tissues of diabetic rabbits. 1586 Feb 35

Vanadium compounds are potent in controlling elevated blood glucose levels in experimentally induced diabetes. However the toxicity associated with vanadium limits its role as therapeutic agent for diabetic treatment. A vanadium compound sodium orthovanadate (SOV) was given to alloxan-induced diabetic Wistar rats in lower doses in combination with Trigonella foenum graecum, a well-known hypoglycemic agent used in traditional Indian medicines. The effect of this combination was studied on lens morphology and glucose metabolism in diabetic rats. Lens, an insulin-independent tissue, was found severely affected in diabetes showing visual signs of cataract. Alterations in the activities of glucose metabolizing enzymes (hexokinase, aldose reductase, sorbitol dehydrogenase, glucose-6-phosphate dehydrogenase) and antioxidant enzymes (glutathione peroxidase, glutathione reductase) besides the levels of related metabolites, [sorbitol, fructose, glucose, thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH)] were observed in the lenses from diabetic rats and diabetic rats treated with insulin (2 IU/day), SOV (0.6 mg/ml), T. f. graecum seed powder (TSP, 5%) and TSP (5%) in combination with lowered dose of vanadium SOV (0.2 mg/ml), for a period of 3 weeks. The activity of the enzymes, hexokinase, aldose reductase and sorbitol dehydrogenase was significantly increased whereas the activity of glucose-6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase decreased significantly in lenses from 3 week diabetic rats. Significant increase in accumulation of metabolites, sorbitol, fructose, glucose was found in diabetic lenses. TBARS measure of peroxidation increased whereas the levels of antioxidant GSH decreased significantly in diabetic condition. Insulin restored the levels of altered enzyme activities and metabolites almost to control levels. Sodium orthovanadate (0.6 mg/ml) and Trigonella administered separately to diabetic animals could partially reverse the diabetic changes, metabolic and morphological, while vanadate in lowered dose in combination with Trigonella was found to be the most effective in restoring the altered lens metabolism and morphological appearance in diabetes. It may be concluded that vanadate at lowered doses administered in combination with Trigonella was the most effective in controlling the altered glucose metabolism and antioxidant status in diabetic lenses, these being significant factors involved in the development of diabetic complications, that reflects in the reduced lens opacity.
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PMID:Efficacy of lower doses of vanadium in restoring altered glucose metabolism and antioxidant status in diabetic rat lenses. 1588 58

The direct effect and the interaction of diabetic angiopathy and metabolic control on free radical and antioxidant activity indices was investigated in 48 patients with type 2 diabetes mellitus. Conjugated dienes (CD) and thiobarbituric acid-reacting substances (TBARS) levels were 34 and 178% of control values, respectively. An approximate two-fold decrease in plasma thiols (PSH) and erythrocyte lysate thiols (LSH) concentrations, parameters reflecting protein oxidative damage, was found. Impairment of blood antioxidant potential in diabetic patients was reflected by an 81% increase in superoxide dismutase (SOD) activity, a 30% decrease in catalase (CT), 20% decrease in glutathione peroxidase (GPx) and glutathione reductase (GR) activities as well as by lowered total antioxidant status (TAS). CD, TBARS and SOD values were positively correlated with plasma glucose concentration and glycated hemoglobin level. A negative correlation existed between levels of LSH, PSH, CT, GPx or TAS and both glucose and HbA(1c). Blood glucose control and vascular complications had strong independent effects on prooxidant-antioxidant status, apart from blood glucose and GR activity. In addition, glycemic control and diabetic vasculopathy interact in their influence on most of the free radical and antioxidant indices, except for CD, LSH levels and CT activity. Thus, we observed different mechanisms by which vascular complications and glucose control affect blood free radical indices and antioxidant status parameters in type 2 diabetic patients.
Diabetes Res Clin Pract 2005 Jun
PMID:Effects of metabolic control and vascular complications on indices of oxidative stress in type 2 diabetic patients. 1593 62

We have shown that a single dose of streptozotocin (STZ) (50 mg/kg body weight) injected into rats caused significant changes in some antioxidant enzyme activities, such as glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase activities, and acid-soluble sulfhydryl levels of the liver tissue with respect to the control rats. Furthermore, these alterations in the activities of the antioxidant enzymes were accompanied by significant changes in the ultrastructure of the liver tissue; mainly intercellular biliary canaliculi were distended and contained stagnant bile, swollen mitochondria in hepatocytes and disoriented and disintegrating cristae, dilatation of the rough endoplasmic reticulum (rER) with detachment of ribosomes, and dissociation of polysomes. Both diabetic and normal rats were treated with sodium selenite (5 micromol/kg/d, intra peritoneally) for 4 wk following 1 wk of diabetes induction. This treatment of diabetic rats improved significantly diabetes-induced alterations in liver antioxidant enzymes. Moreover, treating of diabetic rats with sodium selenite prevented primarily the variation in staining quality of hepatocytes nuclei, increased density and eosinophilia of the cytoplasm, focal sinusoidal dilatation and congestion, and increased numbers of mitochondria with different size and shape. In summary, treatment of diabetic rats with sodium selenite has beneficial effects on both antioxidant system and the ultrastructure of the liver tissue. These findings suggest that diabetes-induced oxidative stress can be responsible for the development of diabetic complications and antioxidant treatment can protect the target organs against diabetes.
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PMID:Selenium treatment protects diabetes-induced biochemical and ultrastructural alterations in liver tissue. 1603 59

Intracellular free zinc concentration ([Zn2+]i) is very important for cell functions, and its excessive accumulation is cytotoxic. [Zn2+]i can increase rapidly in cardiomyocytes because of mobilization of Zn2+ from intracellular stores by reactive oxygen species (ROS). Moreover, ROS have been proposed to contribute to direct and/or indirect damage to cardiomyocytes in diabetes. To address these hypotheses, we investigated how elevated [Zn2+]i in cardiomyocytes could contribute to diabetes-induced alterations in intracellular free calcium concentration ([Ca2+]i). We also investigated its relationship to the changes of metallothionein (MT) level of the heart. Cardiomyocytes from normal rats loaded with fura-2 were used to fluorometrically measure resting [Zn2+]i (0.52 +/- 0.06 nM) and [Ca2+]i (26.53 +/- 3.67 nM). Fluorescence quenching by the heavy metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine was used to quantify [Zn2+]i. Our data showed that diabetic cardiomyocytes exhibited significantly increased [Zn2+]i (0.87 +/- 0.05 nM ) and [Ca2+]i (49.66 +/- 9.03 nM), decreased levels of MT and reduced glutathione, increased levels of lipid peroxidation and nitric oxide products, and decreased activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Treatment (4 wk) of diabetic rats with sodium selenite (5 micromol.kg body wt(-1).day(-1)) prevented these defects induced by diabetes. A comparison of present data with previously observed beneficial effects of selenium treatment on diabetes-induced contractile dysfunction of the heart can suggest that an increase in [Zn2+]i may contribute to oxidant-induced alterations of excitation-contraction coupling in diabetes. In addition, we showed that oxidative stress is involved in the etiology of diabetes-induced downregulation of heart function via depressed endogenous antioxidant defense mechanisms.
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PMID:Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle. 1621 42


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