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

Dicarbonyl and oxidative stress may play important roles in the development of diabetes complications, and their response to hyperglycemia could determine individual susceptibility to diabetic nephropathy. This study examines the relationship of methylglyoxal, 3-deoxyglucosone (3DG), and oxidative stress levels to diabetic nephropathy risk in three populations with diabetes. All subjects in the Overt Nephropathy Progressor/Nonprogressor (ONPN) cohort (n = 14), the Natural History of Diabetic Nephropathy study (NHS) cohort (n = 110), and the Pima Indian cohort (n = 45) were evaluated for clinical nephropathy, while renal structural measures of fractional mesangial volume [Vv(Mes/glom)] and glomerular basement membrane (GBM) width were determined by electron microscopy morphometry in the NHS and Pima Indian cohorts. Methylglyoxal and 3DG levels reflected dicarbonyl stress, while reduced glutathione (GSH) and urine 8-isoprostane (8-IP) measured oxidative stress. Cross-sectional measures of methylglyoxal production by red blood cells incubated in 30 mmol/l glucose were increased in nephropathy progressors relative to nonprogressors in the ONPN (P = 0.027) and also reflected 5-year GBM thickening in the NHS cohort (P = 0.04). As nephropathy progressed in the NHS cohort, in vivo levels of methylglyoxal (P = 0.036), 3DG (P = 0.004), and oxidative stress (8-IP, P = 0.007 and GSH, P = 0.005) were seen, while increased methylglyoxal levels occurred as nephropathy progressed (P = 0.0016) in the type 2 Pima Indian cohort. Decreased glyceraldehyde-3-phosphate dehydrogenase activity also correlated with increased methylglyoxal levels (P = 0.003) in the NHS cohort. In conclusion, progression of diabetic nephropathy is significantly related to elevated dicarbonyl stress and possibly related to oxidative stress in three separate populations, suggesting that these factors play a role in determining individual susceptibility.
Diabetes 2005 Nov
PMID:Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. 1624 55

This study was conceived in an effort to understand cause and effect relationships between hyperglycemia and diabetic retinopathy. Numerous studies show that hyperglycemia leads to oxidative stress in the diabetic retinas, but the mechanisms that generate oxidative stress have not been resolved. Increased electron pressure on the mitochondrial electron transfer chain, increased generation of cytosolic NADH, and decreases in cellular NADPH have all been cited as possible sources of reactive oxygen species and nitrous oxide. In the present study, excised retinas from control and diabetic rats were exposed to euglycemic and hyperglycemic conditions. Using a microwave irradiation quenching technique to study retinas of diabetic rats in vivo, glucose, glucose-derived metabolites, and NADH oxidation/reduction status were measured. Studying excised retinas in vitro, glycolytic flux, lactate production, and tricarboxylic acid cycle flux were evaluated. Enzymatically assayed glucose 6-phosphate and fructose 6-phosphate were only slightly elevated by hyperglycemia and/or diabetes, but polyols were increased dramatically. Cytosolic NADH-to-NAD ratios were not elevated by hyperglycemia nor by diabetes in vivo or in vitro. Tricarboxylic acid cycle flux was not increased by the diabetic state nor by hyperglycemia. On the other hand, small increases in glycolytic flux were observed with hyperglycemia, but glycolytic flux was always lower in diabetic compared with control animals. An observed decrease in activity of glyceraldehyde-3-phosphate dehydrogenase may be partially responsible for slow glycolytic flux for retinas of diabetic rats. Therefore, it is concluded that glucose metabolism, downstream of hexokinase, is not elevated by hyperglycemia or diabetes. Metabolites upstream of glucose such as the sorbitol pathway (which decreases NADPH) and polyol synthesis are increased.
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PMID:Analysis of glucose metabolism in diabetic rat retinas. 1638 Mar 92

Insulin dependent diabetes mellitus (IDDM; type I) is a chronic disease stemming from little or no insulin production and elevated blood glucose levels. IDDM is associated with osteoporosis and increased fracture rates. The mechanisms underlying IDDM associated bone loss are not known. Previously we demonstrated that osteoblasts exhibit a response to acute (1 and 24 h) hyperglycemia and hyperosmolality. Here we examined the influence of chronic hyperglycemia (30 mM) and its associated hyperosmolality on osteoblast phenotype. Our findings demonstrate that osteoblasts respond to chronic hyperglycemia through modulated gene expression. Specifically, chronic hyperglycemia increases alkaline phosphatase activity and expression and decreases osteocalcin, MMP-13, VEGF and GAPDH expression. Of these genes, only MMP-13 mRNA levels exhibit a similar suppression in response to hyperosmotic conditions (mannitol treatment). Acute hyperglycemia for a 48-h period was also capable of inducing alkaline phosphatase and suppressing osteocalcin, MMP-13, VEGF, and GAPDH expression in differentiated osteoblasts. This suggests that acute responses in differentiated cells are maintained chronically. In addition, hyperglycemic and hyperosmotic conditions increased PPARgamma2 expression, although this increase reached significance only in 21 days chronic glucose treated cultures. Given that osteocalcin is suppressed and PPARgamma2 expression is increased in type I diabetic mouse model bones, these findings suggest that diabetes-associated hyperglycemia may modulate osteoblast gene expression, function and bone formation and thereby contribute to type I diabetic bone loss.
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PMID:Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. 1661 59

Hyperglycaemia, triose phosphate decomposition and oxidation reactions generate reactive aldehydes in vivo. These compounds react non-enzymatically with protein side chains and N-terminal amino groups to give adducts and cross-links, and hence modified proteins. Previous studies have shown that free or protein-bound carbonyls inactivate glyceraldehyde-3-phosphate dehydrogenase with concomitant loss of thiol groups [Morgan, Dean and Davies (2002) Arch. Biochem. Biophys. 403, 259-269]. It was therefore hypothesized that modification of lysosomal cysteine proteases (and the structurally related enzyme papain) by free and protein-bound carbonyls may modulate the activity of these components of the cellular proteolytic machinery responsible for the removal of modified proteins and thereby contribute to a decreased removal of modified proteins from cells. It is shown that MGX (methylglyoxal), GO (glyoxal) and glycolaldehyde, but not hydroxyacetone and glucose, inhibit catB (cathepsin B), catL (cathepsin L) and catS (cathepsin S) activity in macrophage cell lysates, in a concentration-dependent manner. Protein-bound carbonyls produced similar inhibition with both cell lysates and intact macrophage cells. Inhibition was also observed with papain, with this paralleled by loss of the active site cysteine residue and formation of the adduct species S-carboxymethylcysteine, from GO, in a concentration-dependent manner. Inhibition of autolysis of papain by MGX, along with cross-link formation, was detected by SDS/PAGE. Treatment of papain and catS with the dialdehyde o-phthalaldehyde resulted in enzyme inactivation and an intra-molecular active site cysteine-lysine cross-link. These results demonstrate that reactive aldehydes inhibit cysteine proteases by modification of the active site cysteine residue. This process may contribute to the accumulation of modified proteins in tissues of people with diabetes and age-related pathologies, including atherosclerosis, cataract and Alzheimer's disease.
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PMID:Evidence for inactivation of cysteine proteases by reactive carbonyls via glycation of active site thiols. 1667 91

Endothelium-derived nitric oxide (NO) plays an important role in the prevention of platelet aggregation and adhesion to the vascular wall. Endothelial nitric oxide synthase (eNOS) and L-arginine/NO pathway are both present in human platelets. Platelet-derived NO inhibits excessive activation and aggregation of platelets. However, the expression level of the eNOS gene in human platelets has yet to be elucidated. The current study investigates the individual expression level of platelet eNOS mRNA using the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) detection method. eNOS mRNA expression was examined in platelets isolated from 50 subjects: 11 male smokers, 15 male nonsmokers, and 24 female non-smokers. After extraction of platelet total RNA, eNOS (target) and GAPDH (internal control) mRNA expression levels were quantitated using real-time RT-PCR. The expression levels of eNOS mRNA (relative copy numbers) were significantly lower in male smokers (59+/-17) than in male nonsmokers (195+/-71, P < .03), and higher in female nonsmokers (285+/-60) than in the male nonsmokers (195+/-71, P < .03). By multiple linear regression analysis, cigarette smoking (P = .008) and diabetes mellitus (P = .047) were found to be significantly negative predictors, and antioxidant (vitamin E) treatment (P = .01) was a significantly positive predictor of platelet eNOS mRNA expression. Age, other medications, and other risk factors for coronary artery disease were not significant. Using this method, eNOS mRNA abundance in human platelets was detected and quantitated in real-time. The intraplatelet eNOS mRNA expression levels were significantly decreased in cigarette smokers. Low platelet NO synthesis in smokers may result in the augmentation of platelet aggregation and thrombus formation, developing into acute coronary syndromes.
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PMID:The effects of long-term smoking on endothelial nitric oxide synthase mRNA expression in human platelets as detected with real-time quantitative RT-PCR. 1716 95

In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes and its complications are described. In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all of which are believed to be the main molecular mechanisms of diabetic complications. Glomerular hyperfiltration, one of the characteristics of early diabetic nephropathy, may be caused by mitochondrial ROS through activation of COX-2 gene transcription, followed by PGE2 overproduction. In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppresses the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH2-terminal kinases (JNK), increases serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. These results suggest the importance of mitochondrial ROS in the pathogenesis of diabetes mellitus and its complications through modification of various cellular events in many tissues, including vessels, kidney, pancreatic beta cells, and liver.
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PMID:Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. 1718 77

In addition to hyperglycemia, diabetes is associated with increased levels of circulating free fatty acids, lactate, and branched chain amino acids, all of which produce an excessive reduced form of pyridine nucleotides NADH (reductive stress) in the cytosol and mitochondria. Our studies suggest that cytosolic NADH reductive stress under high glucose is largely caused by increased flux of glucose through polyol (sorbitol) pathway consisting of aldose reductase and sorbitol dehydrogenase. Inhibition of aldose reductase that blocks the polyol pathway has been shown to ameliorate diabetic neuropathy in humans. Cytosolic NADH reductive stress is predicted to increase production of diglycerides, reactive oxygen species, and methylglyoxal. Recent studies indicate that increasing NADH affects gene expression through the NADH activating transcriptional co-repressor, C-terminal binding protein (CtBP). In addition, it has been shown that the NADH utilizing enzyme, glyceraldehyde-3-phosphate dehydrogenase, participates as transcriptional regulator. These findings testify to the importance of NADH redox balance in cell biology and pathogenesis of diabetes and its complications. For example, through CtBP, the high NADH to NAD(+) ratio decreases an expression of SirT1, the protein inducing longevity and anti-apoptosis. This review covers metabolic cascades causing reductive stress and oxidative stress in diabetes after a brief introduction of the redox concept.
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PMID:Pyridine nucleotide redox abnormalities in diabetes. 1750 15

Abnormal endothelial function plays a pivota role in the pathogenesis of diabetic complications. Due to lack of autoregulation of glucose transport in the presence of high extracellular glucose concentrations, intracellular hyperglycaemia induces a series of metabolic changes that ultimately lead to the genesis of both microvascular complications (the hallmark of chronic hyperglycaemic states) and macrovascular damage. In type 2 diabetes, the abnormalities associated with insulin resistance and the metabolic syndrome phenotype (such as high blood pressure, dyslipidaemia, abnormal levels of circulating adipokines and free fatty acids e.g.) also contribute to accelerate the endothelial damage sustained as a result of chronic exposure to hyperglycaemia. Only recently was a unifying theory proposed to account for the four major abnormal pathways activated by chronic hyperglycaemia and thought to damage the endothelial cell and to trigger the downstream micro- and macrovascular complications associated with diabetes mellitus. This pathophysiological sequence revolves around the metabolic abnormalities triggered as a result of overproduction of superoxide by the mitochondrial electron transport chain and subsequent inhibition of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase by increased activity of nuclear poly(ADP-ribose)polymerase.
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PMID:Diabetes and the endothelium. 1754 90

S-(2-succinyl)cysteine (2SC) is a chemical modification of proteins formed by a Michael addition reaction between the Krebs cycle intermediate, fumarate, and thiol groups in protein--a process known as succination of protein. Succination causes irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vitro. GAPDH was immunoprecipitated from muscle of diabetic rats, then analyzed by ultra-performance liquid chromatography-electrospray ionization-mass spectroscopy. Succination of GAPDH was increased in muscle of diabetic rats, and the extent of succination correlated strongly with the decrease in specific activity of the enzyme. We propose that 2SC is a biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins may provide the chemical link between glucotoxicity and the pathogenesis of diabetic complications.
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PMID:Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. 1844 29

Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3-phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
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PMID:Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. 1921 Jul 48


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