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

Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic beta-cells has not been previously described. We measured the levels of 8-OHdG and 4-hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic beta-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE-modified proteins in the pancreatic beta-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic beta-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (alpha-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic beta-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic beta-cells.
Diabetes 1999 Apr
PMID:Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. 1010 16

Recent studies have clarified that reactive oxygen species (ROS) are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. The breakthrough of these fruitful accomplishments was the discovery of an enzyme, superoxide dismutase, by McCord and Fridovich in 1968. In the 1970s and 80s, biochemists and radiation biologists were attracted by the role of ROS in its irreversible damage to biological molecules. In the 1990s, ROS were further found to be a reversible modulator of protein structure as well, and this led to a recent rapid data accumulation on the association of ROS and transcription factors. At the same time, methods to localize ROS-induced damage in paraffin-embedded tissues have been established. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. The present article reviews histochemical and immunohistochemical methods to localize ROS-induced damage in tissues and cells, further comments on the association of ROS with transcription factors, and shows a prospective view of ROS-induced carcinogenesis.
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PMID:Reactive oxygen species-induced molecular damage and its application in pathology. 1035 61

Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes adverse alterations in beta cell function, a phenomenon termed glucose toxicity and one that may play a secondary pathogenic role in type 2 diabetes. However, no mechanism of action has been definitively identified for glucose toxicity in beta cells. To ascertain whether chronic oxidative stress might play a role, we chronically cultured the beta cell line, HIT-T15, in medium containing 11.1 mM glucose with and without the antioxidants, N-acetyl-L-cysteine (NAC) or aminoguanidine (AG). Addition of NAC or AG to the culture medium at least partially prevented decreases in insulin mRNA, insulin gene promoter activity, DNA binding of two important insulin promoter transcription factors (PDX-1/STF-1 and RIPE-3b1 activator), insulin content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress. To ascertain the effects of these drugs on diabetes, NAC or AG was given to Zucker diabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 12 weeks of age. Both drugs prevented a rise in blood oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insulin secretion as well as decrements in beta cell insulin content, insulin gene expression, and PDX-1 (STF-1) binding to the insulin gene promoter. We conclude that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes.
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PMID:Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. 1048 16

Recent studies demonstrate that cellular, molecular and morphological changes induced by stress in rats are accelerated when there is a pre-existing strain upon their already compromised adaptive responses to internal or external stimuli, such as may occur with uncontrolled diabetes mellitus. The deleterious actions of diabetes and stress may increase oxidative stress in the brain, leading to increases in neuronal vulnerability. In an attempt to determine if stress, diabetes or stress+diabetes increases oxidative stress in the hippocampus, radioimmunocytochemistry was performed using polyclonal antisera that recognize proteins conjugated by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). Radioimmunocytochemistry revealed that HNE protein conjugation is increased in all subregions of the hippocampus of streptozotocin (STZ) diabetic rats, rats subjected to restraint stress and STZ diabetic rats subjected to stress. Such increases were not significant in the cortex. Because increases in oxidative stress may contribute to stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization, we examined the stress/diabetes mediated HNE protein conjugation of the neuron specific glucose transporter, GLUT3. GLUT3 immunoprecipitated from hippocampal membranes of diabetic rats subjected to stress exhibited significant increases in HNE immunolabeling compared to control rats, suggesting that HNE protein conjugation of GLUT3 contributes to decreases in neuronal glucose utilization observed during diabetes and exposure to stress. Collectively, these results demonstrate that the hippocampus is vulnerable to increases in oxidative stress produced by diabetes and stress. In addition, increases in HNE protein conjugation of GLUT3 provide a potential mechanism for stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization.
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PMID:Oxidative stress and HNE conjugation of GLUT3 are increased in the hippocampus of diabetic rats subjected to stress. 1079 3

Lipid peroxidation due to oxidative stress is accelerated under hyperglycemic conditions such as diabetes mellitus. The effect of 4-hydroxy-2-nonenal (HNE) and other lipid peroxidation products on the ability of isolated rat pancreatic islets to secrete insulin was examined in this study. HNE concentration- and time-dependently deteriorated glucose-induced insulin secretion: insulin secretion was decreased by 50% when measured after incubation of islets with 100 microM HNE for 1 h. Other lipid peroxidation products, e.g. 2-hexenal and 2-butenal, also inhibited glucose-induced insulin secretion. HNE at 100 microM lowered alpha-ketoisocaproate-induced insulin secretion, whereas leucine-induced insulin secretion was stimulated. Insulin secretion induced by 10 mM glyceraldehyde was slightly decreased by HNE. On the other hand, HNE severely decreased insulin secretion induced by 10 mM glyceraldehyde and 2.8 mM glucose. Glucose utilization and glucose oxidation were significantly lowered in islets treated with HNE. The amounts of fructose 1,6-bisphosphate and dihydroxyacetone phosphate in islets were decreased by treatment with HNE, whereas the amount of fructose 6-phosphate was increased. Our study indicates that HNE and other lipid peroxidation products impair insulin secretion induced by glucose probably through affecting both the glycolytic pathway and the citric acid cycle.
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PMID:Inhibition of glucose-induced insulin secretion by 4-hydroxy-2-nonenal and other lipid peroxidation products. 1091 61

4-Hydroxy-2-nonenal (HNE) is one of the major lipid peroxidation products with cytotoxic and mutagenic activity. It further reacts with protein residues such as histidine to generate stable Michael adducts. To evaluate the status of oxidative stress in the serum of type 2 diabetes mellitus, we constructed a sandwich enzyme-linked immunosorbent assay to measure serum HNE-modified albumin by the use of a specific monoclonal antibody (HNEJ-2) against HNE-histidine adducts as well as an antibody against human serum albumin. Serum of type 2 diabetes outpatients revealed significantly higher levels of HNE-modified albumin (736.1 +/- 34.2 pmol/ml, n = 54) than the matched nondiabetics (611.4 +/- 39.1 pmol/ml, n = 30; means +/- SEM; p = 0.018). However, no significant correlation was observed in diabetic outpatients between the levels of HNE-modified albumin and clinical parameters such as fasted blood glucose, HbA1c, diabetes duration, or complications. Our data demonstrated the increased formation of serum HNE-modified albumin in type 2 diabetic outpatients in the milieu between liver and vascular lumina, indicating the presence of oxidative stress.
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PMID:Serum 4-hydroxy-2-nonenal-modified albumin is elevated in patients with type 2 diabetes mellitus. 1121 73

To cast light on the mechanisms underlying development of spontaneous pancreatitis lesions, tissues from WBN/Kob rats at various ages were histopathologically and immunohistochemically investigated with special reference to the existence of the lipid peroxidation products 4-hydroxy-2-nonenal (HNE), 4-hydroxy-2-hexenal (HHE), and malondialdehyde (MDA). Male 4-20-week-old WBN/Kob rats were killed to allow sampling of pancreatic tissues, which were fixed in cold acetone and 10% neutral-buffered formalin. and then processed for routine histopathology as well as immunohistochemistry for proteins modified by HNE, HHE, and MDA. Although no remarkable histologic changes were noted in younger animals, edema, hemorrhage, inflammatory cell infiltration, fibrosis, vacuolation of acinar cells, and ductular proliferation were observed in exocrine pancreatic tissue from animals at 10-15 weeks of age. In animals aged 20 weeks, the lesions had progressed remarkably and deposits of hemosiderin were apparent with fibrosis. Immunohistochemical examination for lipid peroxidation product-modified proteins showed HNE and MDA to be negative in all pancreatic tissues, but HHE was positive in the areas involving atrophy of acinar cells and fibrosis in the islets. The results of the present study thus provide support for the conclusion that lipid peroxidation during spontaneous pancreatitis in WBN/Kob rats may possibly be involved in the development of diabetes in this model.
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PMID:Involvement of lipid peroxidation in spontaneous pancreatitis in WBN/Kob rats. 1134 45

There is increasing evidence that lipid peroxidation is involved in many of the pathophysiologies associated with cardiovascular diseases, such as atherosclerosis and the long-term complications of diabetes. Among the products which originate from the peroxidation of cellular membrane lipids, 4-hydroxy-2-nonenal (HNE) is believed to be largely responsible for the cytopathological effects observed during oxidative stress in vivo. Here we found that HNE dramatically inhibited the expression of adhesion molecules induced by inflammatory stimuli in human aortic endothelial cells. The inhibition was found to be accompanied by a significant reduction of NF-kappaB activation followed by nuclear localization. This and the observation that the HNE treatment of the cells resulted in a rapid reduction of intracellular glutathione levels suggest that redox regulation of NF-kappaB may be involved in the modulation of the endothelial response by reactive aldehydes.
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PMID:4-Hydroxy-2-nonenal is a powerful endogenous inhibitor of endothelial response. 1140 96

Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic beta-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of beta-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of beta-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of beta-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of beta-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280+/-82 vs. 914+/-238 pmol/l (120 min, at 16 weeks; P<0.05); glucose, 44.6+/-2.4 vs. 35.2+/-2.6 mmol/l (120 min, at 16 weeks; P<0.05). Thus, our present observations demonstrate the potential usefulness of probucol for treatment of type 2 diabetes.
Diabetes Res Clin Pract 2002 Jul
PMID:Probucol preserves pancreatic beta-cell function through reduction of oxidative stress in type 2 diabetes. 1200 24

Diabetes mellitus evoked by streptozotocine in rats is associated with the oxidative stress. We examined the effect of Schiff's base 2,5-dihydroxybenzaldehyde with a well-known antidiabetic drug aminoguanidine, 2,5-dihydroxybenzilideneaminoguanidine (BAG) on the production of markers of oxidative stress such as 4-hydroxy-2-nonenal (4HNE) and conjugated dienes in diabetic rats. BAG administration did not affect glucose level in diabetic rats but significantly decreased the production of 4HNE and conjugated dienes. On the other hand, BAG caused the elevation of conjugated dienes and an insignificant increase of 4HNE levels in the control animals.
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PMID:Effects of aminoguanidine Schiff's base on biomarkers of the oxidative stress, 4-hydroxy-2-nonenal and conjugated dienes, in the model diabetes mellitus. 1253 56


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