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

Streptozotocin-induced diabetes in rats is accompanied by development of diabetic complications such as neuropathies. It was shown that aldose reductase inhibitors (A1-1576, sorbinil and unithiol) administration partially normalized not only polyol pathway. Aldose reductase inhibitors partially restored Na+, K(+)-ATP-ase activity in sciatic nerve of diabetic rats and redox state of nicotinamide adenine dinucleotides. The sorbitol level increases in streptozotocin-diabetic rats as compared to control. Administration of aldose reductase inhibitors to diabetic rats is accompanied by partial reduction of sorbitol level in sciatic nerve. The results obtained confirm the important role of a dose reductase inhibitors, as antidiabetic drugs, in the improvement of diabetic neuropathy.
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PMID:[Role of aldose reductase inhibitors in the development of peripheral neuropathy in experimental diabetes]. 950 66

The duration of diabetes, age and genetic predispositions are admitted agents of risk in diabetic neuropathy. The reasons of diabetic neuropathy are suspected in cooperation with various factors among which metabolic disturbances and ischaemia are the most important. The abnormal activation of sorbitol tract is very significant agent of development of diabetic neuropathy. The excess of sorbitol which is accumulating also in nervous tissue causes its damage in osmotic way. At the same time decreasing concentration of myoinositol reduces ATP-ase Na+/K+ activity which is important in impulse conduction. The overproduction of free oxygenic radical (oxidative lesion) and nitrogen oxide (vasodilator) deficiency is inducted by hyperglycaemia and the activation of aldolase reductase. Metabolic disturbances cause the decrease of carnitine concentration what deteriorates nerve sensitivity on growth factor. The activation of sorbitol tract leads to nonenzymatic proteins glycation which causes thickening of basement membrane and proliferation of endothelium cells. In this way increased vascular resistance decreases tissue perfusion and induces nerve hypoxia. The impairment of nerve blood supply depends on altered in diabetes rheological properties. They are inconveniently changed through hyperglycaemia, hyperlypidaemia, dysproteinaemia and excessive aggregation and rigidity of morphotic elements of blood.
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PMID:[Contemporary views on the pathogenesis of diabetic neuropathy]. 968 30

Since a number of pathological processes such as septic shock, inflammation, graft rejection, diabetes, etc. are associated with a release of nitric oxide (NO), rapid and accurate methods of monitoring of NO concentration are of interest. Various methods for measurement of nitrite and nitrate (NO2-, NO3- ) -- the stable metabolites of NO -- are commonly used for this purpose. In this paper we have shown that the proper Griess procedure for nitrite determination significantly increases the sensitivity of this method. This procedure, supplemented with deproteinization and reduction of nitrates to nitrites in the presence of NADPH-sensitive reductase, can be successfully applied for measurement of NOx levels in human body fluids (serum, urine and CSF). Deproteinization of samples with methanol/diethylether is required and does not influence the sensitivity of detection of NO metabolites. The recovery of the method is 88%+/-6% (n = 30). The NOx concentrations measured by this procedure ranged from 25.0 to 39.0 micromol/l in blood, 4.6 to 14.6 micromol/l in CSF and 0.37 to 2.52 mmol/l (adjusted to creatinine concentration) in urine. The coefficient of variation for this method was between 1.3-2.2%. This method can also be recommended for measurement of NOx produced by cells in tissue cell culture.
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PMID:Determination of nitrite/nitrate in human biological material by the simple Griess reaction. 969 86

To address the problem of the pathogenesis in diabetic neuropathy, rats were made diabetic by streptozotocin administration, and discrete brain regions, such as cortex, cerebellum, brainstem, thalamus, and hypothalamus, were sampled for assay of activities of electron transport chain complexes I-IV at 1 and 3 mo after induction of diabetes. Significant decrease was seen in activities of dinitrophenylhydrazine DNPH-coenzyme Q reductase (complex I), coenzyme Q cytochrome-c reductase (complex III), and cytochrome-c oxidase (complex IV) from discrete brain regions with more pronounced changes in complex I. The decline in the complex I, III, and IV activity was more severe in the 3-mo group. Succinate dehydrogenase (SDH) coenzyme Q reductase (complex II), which is an enzyme shared by tricarboxylic acid (TCA) cycle and electron transport chain, showed a significant increase under the same set of conditions. These results suggest that the bioenergetic impairment has an important role in the pathophysiology of diabetes.
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PMID:The impact of diabetes on CNS. Role of bioenergetic defects. 1034 74

Cardiovascular disease is the leading cause of death and the leading source of healthcare expenditure in the US and most other industrialised countries. Cholesterol lowering by pharmacological means prevents atherosclerotic plaque progression and has been shown to reduce both fatal and nonfatal coronary events in patients with or without coronary artery disease (CAD). Because of their excellent efficacy and safety profiles, the introduction of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known an 'statins') in 1987 raised hopes for demonstrating the survival benefit of cholesterol reduction. In the past decade, several large-scale placebo-controlled trials with statin therapy have revisited the relationship between cholesterol reduction, cardiovascular disease and mortality. The West of Scotland Coronary Prevention Study (WOSCOPS) [pravastatin] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [lovastatin] have shown significant cardiovascular disease reduction in primary prevention trials of patients with elevated and normal cholesterol levels, respectively. The Scandinavian Simvastatin Survival Study (4S), the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study and the Cholesterol and Recurrent Events (CARE) trial [pravastatin] have shown significant cardiovascular disease reduction in patients with a previous history of CAD with high, moderate and normal cholesterol levels, respectively. Three of these studies (4S, WOSCOPS and LIPID) have shown significant reduction in all-cause mortality, while all the statin secondary prevention trials (4S, CARE and LIPID) have demonstrated significant reduction in cerebrovascular disease/ Earlier cholesterol reduction cost-effectiveness studies with nonstatin treatments (bile acid resins, fibrates, niacin and diet) suggested that only patients at extremely high risk could be treated with lipid therapy in a cost-effective manner. More recently, rigorous outcomes evidence demonstrates that statins, particularly for simvastatin for secondary prevention and lovastatin for primary prevention, have a broadly favourable cost-effectiveness profile. Based on US medical price levels and the available clinical trial data on statins, it would be cost effective [e.g. cost less than $US50,000/year of life saved] to intervene with statin therapy in any patient with an annual CAD risk exceeding 1%. This includes all patients with pre-existing CAD or diabetes mellitus, and many more primary prevention patients than are currently contemplated by the US National Cholesterol Education Panel treatment guidelines. Achieving such a goal will require enormous changes in patient education, clinical perspective, healthcare practice and healthcare finances. But any proven opportunity for saving the lives of 25% of those dying from cardiovascular disease each year deserves to be considered with the utmost seriousness and urgency.
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PMID:Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease. 1034 58

Recent lipid intervention studies led to the implementation of lipid lowering therapy in the cardiovascular risk management. These secondary as well as primary prevention studies share the effect of HMG-CoA-reductase inhibition. Despite varying product properties there seem to be no major differences in risk reduction between the drugs. One could argue the main action of the statins, lipid lowering, is the most prominent mode of action. A new study (AirForce/Texas Coronary Atherosclerosis Prevention Study) extended that to patients with relatively low total cholesterol levels (mean 221 mg/dl with a slightly lowered LDL-C of 37 mg/dl, LDL-C of 150 mg/dl) successfully treated with lovastatin in primary prevention. That supports the concept to reach lipid levels as low as possible in the longer term, even if the absolute clinical event reduction in primary prevention is not so impressive. On the contrary, in secondary prevention: in the AVERT-study in patients with a 82% mean stenosis in one vessel PTCA-treated patients with conventional drug therapy were compared to such without PTCA and aggressive lipid lowering therapy (resulting LDL-C 77 mg/dl). One could be surprised that the "intervention group" was not better, though representing the usual clinical procedere. Interestingly, borderline significant (p < 0.046 at a level of significance of p < 0.045), results were in favor for the drug treated group. Such data could, if confirmed in further investigations, change cardiovascular disease management to aggressive lipid lowering prior to or instead invasive management, especially in initial therapy of CVD and diabetes mellitus type II.
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PMID:[Statins--attaining goal values--with reference to recent studies]. 1040 6

Glyoxal, methylglyoxal (MG), and 3-deoxyglucosone (3-DG) are physiological alpha-oxoaldehydes formed by lipid peroxidation, glycation, and degradation of glycolytic intermediates. They are enzymatically detoxified in cells by the cytosolic glutathione-dependent glyoxalase system (glyoxal and MG only) and by NADPH-dependent reductase and NAD(P)+-dependent dehydrogenase. In this study, the changes in the cellular and extracellular concentrations of these alpha-oxoaldehydes were investigated in murine P388D1 macrophages during necrotic cell death induced by median toxic concentrations of hydrogen peroxide and 1-chloro-2,4-dinitrobenzene (CDNB). Alpha-oxoaldehyde concentrations were determined by derivatization with 1,2-diamino-4,5-dimethoxybenzene. There were relatively small increases in cellular and extracellular glyoxal concentration, except that extracellular glyoxal was decreased with hydrogen peroxide. The cytosolic concentration of 3-DG and the cytosolic and extracellular concentrations of MG, however, increased markedly. Aminoguanidine inhibited alpha-oxoaldehyde accumulation and prevented cytotoxicity induced by hydrogen peroxide and CDNB. The accumulation of glyoxal and MG in toxicant-treated cells was a likely consequence of decreased in situ activity of glyoxalase 1. The effect was marked for MG but not for glyoxal, suggestive of a greater metabolic flux of MG formation than of glyoxal. The accumulation of 3-DG in toxicant-treated cells was probably due to the decreased availability of pyridine nucleotide cofactors for the detoxification of 3-DG. Impairment of alpha-oxoaldehyde detoxification is cytotoxic, and this may contribute to toxicity associated with GSH oxidation and S conjugation in oxidative stress and chemical toxicity, and to chronic pathogenesis associated with diabetes mellitus where there is oxidative stress and the formation of glyoxal, MG, and 3-DG is increased.
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PMID:Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity. 1041 1

1. The aim of this study was to examine the mechanism of impaired platelet-mediated endothelium-dependent vasodilation in diabetes. Exposure of human platelets to high glucose in vivo or in vitro impairs their ability to cause endothelium-dependent vasodilation. While previous data suggest that the mechanism for this involves increased activity of the cyclo-oxygenase pathway, the signal transduction pathway mediating this effect is unknown. 2. Platelets from diabetic patients as well as normal platelets and normal platelets exposed to high glucose concentrations were used to determine the role of the polyol pathway, diacylglycerol (DAG) production, protein kinase C (PKC) activity and phospholipase A2 (PLA2) activity on vasodilation in rabbit carotid arteries. 3. We found that two aldose-reductase inhibitors, tolrestat and sorbinil, caused only a modest improvement in the impairment of vasodilation by glucose exposed platelets. However, sorbitol and fructose could not be detected in the platelets, at either normal or hyperglycaemic conditions. We found that incubation in 17 mM glucose caused a significant increase in DAG levels in platelets. Furthermore, the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) caused significant impairment of platelet-mediated vasodilation. The PKC inhibitors calphostin C and H7 as well as inhibitors of PLA2 activity normalized the ability of platelets from diabetic patients to cause vasodilation and prevented glucose-induced impairment of platelet-mediated vasodilation in vitro. 4. These results suggest that the impairment of platelet-mediated vasodilation caused by high glucose concentrations is mediated by increased DAG levels and stimulation of PKC and PLA2 activity.
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PMID:Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation. 1043 97

3-Deoxyglucosone (3-DG) is synthesized via the Maillard reaction and the polyol pathway, and is detoxified to 3-deoxyfructose and 2-keto-3-deoxygluconic acid. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as imidazolone, pyrraline, N'-(carboxymethyl)lysine and pentosidine, among which imidazolone is the AGE most specific for 3-DG. As demonstrated by using gas chromatography-mass spectrometry or high-performance liquid chromatography, plasma 3-DG levels are markedly increased in diabetes and uremia. Although the plasma 3-DG levels had been controversial, it was clearly demonstrated that its plasma level depends on the deproteinization method by which either free or total 3-DG, presumably bound to proteins, is measured. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway, and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG, which may be due to the loss of 3-DG reductase activity in the end-stage kidneys, may lead to high plasma 3-DG level. The elevated 3-DG levels in plasma and erythrocytes may promote the formation of AGEs such as imidazolone, as demonstrated by immunohistochemistry and immunochemistry using an anti-imidazolone antibody. Although AGE-modified proteins prepared in vitro exhibit a variety of biological activities, known AGE structures have not yet been demonstrated to show any biological activities. Because 3-DG is potent in the formation of AGEs and has some biological activities, such as cellular toxicity, it may be more important in the development of diabetic and uremic complications than the known AGE structures. By demonstrating that treatment with an aldose reductase inhibitor reduces the erythrocyte levels of 3-DG and AGEs, such as imidazolone, light is shed on the mystery of how aldose reductase inhibitors may prove beneficial in diabetic complications. These evidences suggest that 3-DG plays a principal role in the development of diabetic and uremic complications.
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PMID:3-Deoxyglucosone: metabolism, analysis, biological activity, and clinical implication. 1049 86

In this review, we describe the physiological, genetic and pathological factors regulating the reductive metabolism of drugs with a ketone group. Acetohexamide (AH) was chosen as a model drug with a ketone group. Species differences of AH reductase activity were observed in liver cytosol and microsomes of animals tested. AH reductase activity in liver microsomes of rats was much higher in males than females. The activity was not detectable until 4 weeks of age after birth in both sexes, but increased markedly at puberty only in males. AH reductase activity in liver microsomes of male rats was decreased by testectomy, and restored by the treatment with testosterone propionate, indicating that the sex-related difference and postnatal development of the activity are regulated by androgens. There was a strain difference of AH reductase activity in liver microsomes of male rats. Of rat strains tested, only Wistar-Imamichi strain was found to lack male-specific microsomal enzyme activity. The inheritance pattern of AH reductase activity in liver microsomes of rats was determined by mating the genetic deficiency Wistar-Imamichi strain with Fischer-344 strain. Streptozotocin-induced diabetes significantly decreased AH reductase activity in liver microsomes of male rats. Furthermore, the physiological role of AH reductase present in liver microsomes of male rats was examined. We propose the possibility that the male-specific microsomal enzyme physiologically functions as a 20 beta-hydroxysteroid dehydrogenase.
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PMID:[Physiological, genetic and pathological factors regulating the reductive metabolism of drugs with a ketone group]. 1059 Jul 11


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