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)

This is a report investigating the methylglyoxal (MG) bypass in animals, by which D-lactate is produced from triosephosphate via MG. Rats were made diabetic using streptozotocin or starved for 72 h. D-Lactate and various metabolites related to it, such as L-lactate, pyruvate, methylglyoxal, glucose, and inorganic phosphate, were measured in the blood plasma, liver, and skeletal muscle of the rats. Diabetic and starved rats had significantly higher levels of D-lactate in plasma, liver, and skeletal muscle compared with the control group. In contrast, pyruvate levels in plasma, liver, and skeletal muscle was markedly lower than normal in diabetic and starved rats. L-Lactate level lowered markedly in plasma, liver, and skeletal muscle of starved rats and elevated in liver of diabetic rats. Differences between plasma L-lactate level for diabetes and control were not significant. MG level was significantly elevated in plasma and depressed in livers and muscles of starved rats as well as livers of diabetic rats. Hepatic glycerol content was markedly increased in those states. Enzyme activities related to D- and L-lactate, such as pyruvate kinase, phosphofructokinase, aldolase, and glyoxalase I, were measured in the livers of these rats. Pyruvate kinase activity decreased in these states, but other enzyme activities showed no significant changes. D-Lactate was much more excreted than L-lactate in the urine of diabetic and fasted rats compared with normal rats.
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PMID:Concentrations of D-lactate and its related metabolic intermediates in liver, blood, and muscle of diabetic and starved rats. 148 Aug 18

The gene for glyoxalase I (E.C. 4.4.1.5), Glo, has two alleles, Glo1 and Glo2, which are autosomally inherited in a co-dominant manner. Glo1 allele-frequency is highest in native Alaskan-Eskimo and Indian populations and decreases geographically south and east, to minimum levels in Aboriginal-Australian populations and native tribes in Papua New Guinea. There was no correlation between Glo1 frequency and incidence of insulin-dependent diabetes mellitus (IDDM). The frequencies of GLO phenotypes, Glo 1-1, Glo 1-2 and Glo 2-2, are disturbed in IDDM and there is a suggestion that IDDM patients with or without chronic, clinical complications have characteristic phenotype frequencies.
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PMID:Population genetics of human glyoxalases. 175 72

Human red blood cells were fractionated by density, which correlates with cell age, and the activities of glyoxalase I and glyoxalase II were determined for each fraction. The activity of glyoxalase I and glyoxalase II both significantly increased during maturation of the red blood cells (P less than 0.001), except in the most dense, old cell fraction where both glyoxalase activities decreased. The increase in glyoxalase activity from the reticulocyte-rich fraction to mature erythrocytes was substantial and markedly different from other glycolytic enzymes which typically decrease. This suggests that glyoxalase activity changes markedly during and probably after the maturation of reticulocytes to erythrocytes. The decrease in glyoxalase activity from the mature to old red blood cell fractions may be caused by oxidative inactivation of glyoxalases. The decreased capacity to metabolise methylglyoxal may be an important factor in red blood cell senesence. This is expected to be particularly important in diabetes mellitus where the rate of methylglyoxal formation is increased during hyperglycaemia.
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PMID:Glyoxalase activity in human red blood cells fractioned by age. 272 76

Methylglyoxal and other alpha-oxoaldehydes are formed from glycolytic intermediates and may be involved in the development of diabetic microangiopathy. Glyoxalase I and glyoxalase II metabolise methylglyoxal to D-lactic acid, via the intermediate S-D-lactoylglutathione. The activities of the glyoxalase enzymes and the concentrations of methylglyoxal and S-D-lactoylglutathione were measured in erythrocytes of 45 control and 85 diabetic subjects (41 with retinopathy and 44 uncomplicated). The concentration of S-D-lactoylglutathione was increased in diabetic patients vs. controls (21.4 +/- 9.3 vs. 12.4 +/- 4.8 mumol/l, P less than 0.001), as was methylglyoxal (3.6 +/- 2.3 vs. 1.4 +/- 0.2 mumol/l, P less than 0.001). There were no significant differences in the activities of glyoxalase I and glyoxalase II between diabetic patients and controls. For insulin-dependent patients only, those without retinopathy had a higher activity of glyoxalase II than those with retinopathy (P less than 0.05). A group of age- and duration-matched insulin-dependent diabetic patients with retinopathy also had a higher activity of glyoxalase I compared with a group of diabetic patients without retinopathy (P less than 0.025). This study provides evidence for elevated concentrations of oxoaldehydes in diabetes mellitus which might have pathogenic significance.
Diabetes Res Clin Pract 1989 Aug 01
PMID:The human red blood cell glyoxalase system in diabetes mellitus. 277 50

The human red-blood-cell glyoxalase system was modified by incubation with high concentrations of glucose in vitro. Red-blood-cell suspensions (50%, v/v) were incubated with 5 mM- and 25 mM-glucose to model normal and hyperglycaemic glucose metabolism. There was an increase in the flux of methylglyoxal metabolized to D-lactic acid via the glyoxalase pathway with high glucose concentration. The increase was approximately proportional to initial glucose concentration over the range studied (5-100 mM). The activities of glyoxalase I and glyoxalase II were not significantly changed, but the concentrations of the glyoxalase substrates, methylglyoxal and S-D-lactoylglutathione, and the percentage of glucotriose metabolized via the glyoxalase pathway, were significantly increased. The increase in the flux of intermediates metabolized via the glyoxalase pathway during periodic hyperglycaemia may be a biochemical factor involved in the development of chronic clinical complications associated with diabetes mellitus.
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PMID:Modification of the glyoxalase system in human red blood cells by glucose in vitro. 319 89

In view of the demonstrated linkage of glyoxalase I (GLO) with HLA, we studied the possible association of Graves' disease and juvenile diabetes with GLO allotypes. Both these diseases are known to show significant HLA associations. The distributions of the two GLO allotypes in the two disease groups were identical to those found in the control group.
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PMID:Association of glyoxalase I allotypes with Graves' disease and diabetes mellitus. 689 68

Levels of aldose reductase, glyoxalase I, and glyoxalase II in mononuclear and polymorphonuclear cells from insulin-dependent diabetes mellitus (IDDM) patients with long term diabetic complications were compared to levels in IDDM patients without complications and to those in nondiabetic controls. Cells were isolated from 22 asymptomatic long term IDDM patients, 22 symptomatic IDDM patients, and 16 controls, using a double gradient centrifugation procedure. Aldose reductase was determined by Western blots using polyclonal antiserum to human aldose reductase purified from skeletal muscle. Glyoxalase I and glyoxalase II were determined spectrophotometrically. Aldose reductase in mononuclear cells from symptomatic IDDM patients is significantly elevated compared to that in asymptomatic IDDM patients (mean +/- SEM, 0.96 +/- 0.20 vs. 0.46 +/- 0.08 microgram/mg protein; P < 0.02). Aldose reductase was not detected in polymorphonuclear cells. Glyoxalase I in mononuclear and polymorphonuclear cells from symptomatic IDDM patients is significantly elevated compared to that in controls [mean for mononuclear cells, 0.46 +/- 0.03 vs. 0.37 +/- 0.03 mumol/min.mg (P < 0.05); mean for polymorphonuclear cells, 0.16 +/- 0.01 vs. 0.10 +/- 0.01 mumol/min.mg (P < 0.002)]. Glyoxalase II is significantly elevated only in polymorphonuclear cells from symptomatic IDDM patients compared to controls (mean, 0.13 +/- 0.01 vs. 0.063 +/- 0.016 mumol/min.mg; P < 0.005). Glutathione peroxidase and glutathione S-transferase were not significantly different in these populations. Aldose reductase, glyoxalase I, and glyoxalase II are involved in the metabolism of methylglyoxal, suggesting that methylglyoxal may play a role in the etiology of diabetic complications.
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PMID:Increased levels of methylglyoxal-metabolizing enzymes in mononuclear and polymorphonuclear cells from insulin-dependent diabetic patients with diabetic complications: aldose reductase, glyoxalase I, and glyoxalase II--a clinical research center study. 863 55

1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy). 2. The presence of diabetic complications correlated positively with duration of diabetes and patients age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1C in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant. 3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with D-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients. 4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes. 5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to alpha-oxoaldehydemediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that alpha-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention of diabetic complications by supplementation of reduced glutathione and/or alpha-oxoaldehyde-scavenging agents now deserve investigation.
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PMID:Negative association between erythrocyte reduced glutathione concentration and diabetic complications. 894 96

Advanced glycation end products (AGEs) from the Maillard reaction contribute to protein aging and the pathogenesis of age- and diabetes-associated complications. The alpha-dicarbonyl compound methylglyoxal (MG) is an important intermediate in AGE synthesis. Recent studies suggest that pyridoxamine inhibits formation of advanced glycation and lipoxidation products. We wanted to determine if pyridoxamine could inhibit MG-mediated Maillard reactions and thereby prevent AGE formation. When lens proteins were incubated with MG at 37 degrees C, pH 7.4, we found that pyridoxamine inhibits formation of methylglyoxal-derived AGEs concentration dependently. Pyridoxamine reduces MG levels in red blood cells and plasma and blocks formation of methylglyoxal-lysine dimer in plasma proteins from diabetic rats and it prevents pentosidine (an AGE derived from sugars) from forming in plasma proteins. Pyridoxamine also decreases formation of protein carbonyls and thiobarbituric-acid-reactive substances in plasma proteins from diabetic rats. Pyridoxamine treatment did not restore erythrocyte glutathione (which was reduced by almost half) in diabetic animals, but it enhanced erythrocyte glyoxalase I activity. We isolated a major product of the reaction between MG and pyridoxamine and identified it as methylglyoxal-pyridoxamine dimer. Our studies show that pyridoxamine reduces oxidative stress and AGE formation. We suspect that a direct interaction of pyridoxamine with MG partly accounts for AGE inhibition.
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PMID:Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal. 1205 89

Erythrocyte and lens reduced glutathione (GSH) levels are often lower in patients with diabetes whereas erythrocyte dicarbonyl levels are often higher. We hypothesise that high plasma carbohydrates may be metabolised by glycolytic and pentose phosphate pathways to form alpha-oxoaldehydes, which deplete cellular GSH. Our aims were: (1) to compare the effectiveness of various carbohydrates or metabolites at depleting erythrocyte GSH, (2) to determine if GSH loss is related to the autoxidation or metabolism of carbohydrates. It was found that erythrocyte GSH was depleted by 50% (ED-50) at t = 2.5 h when erythrocytes were incubated with the following: methylglyoxal (MG) 23 microM, glyoxal 75 microM, DL-glyceraldehyde 299 microM, deoxyribose 606 microM, xylitol 626 microM, and ribose 2 mM. The glycolytic inhibitors, sodium arsenate and KF prevented ribose, deoxyribose, xylitol and MG-induced GSH depletion in erythrocytes over 2 h. However, the antioxidant trolox and the ferric chelator detapac did not affect MG-induced GSH depletion. These data suggest that the carbohydrates or glyceraldehyde were metabolised to form carbonyls such as MG which depleted erythrocyte GSH as a result of catalysis by glyoxalase I. None of the carbohydrates were autoxidised to carbonyls over this time period. We speculate that as a result of GSH depletion, subsequent glycoxidative stress affects erythrocyte function and contributes to diabetic complications.
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PMID:Metabolism, not autoxidation, plays a role in alpha-oxoaldehyde- and reducing sugar-induced erythrocyte GSH depletion: relevance for diabetes mellitus. 1457 7


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