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)

1. Rat liver endoplasmic reticulum catalyzes the reduction of 4-dimethylaminoazobenzene (DAB) by NADPH to dimethyl-p-phenylenediamine and p-aminophenol. This azoreductase activity was inhibited by cyanide and cytochrome b5 antibody, but was resistant to carbon monoxide and SKF-525A (beta-diethylaminoethyl-diphenylpropylacetate). 2. DAB azoreductase activity was induced by 20-methylcholanthrene and phenobarbital, and increased in streptozotocin-induced diabetes or fasting. It was repressed by treatment with DAB and its 3'-methyl derivative, but not by several other derivatives with substitutions in the dimethylaminoazobenzene ring. 3. Azoreductase activity, NADPH-cytochrome P-450 reductase, cytochromes P-450 and b5 were measured in liver microsomes prepared from fasted animals and from animals treated with 20-methylcholanthrene, phenobarbital, streptozotocin or 3-aminotriazole plus allyl-isopropylacetamide. No direct correlation could be established between the variations of azoreductase activity and those of cytochromes P-450 and b5, and of NADPH-cytochrome P-450 reductase in these experimental situations. Since these known carriers do not seem to be the limiting factors for the azoreductase activity, the participation of an unknown carrier that can be repressed by dimethylaminoazobenzene is postulated. 4. Dimethylaminoazobenzene treatment did not reduce the rate of synthesis of microsomal proteins but rather increased the turnover rate of proteins with molecular weights of about 17, 30 an 35 kdal. Since streptozotocin increased the synthesis of proteins with molecular weights of 17, 32, and 48 kdal it is suggested that one of these proteins may correspond to the postulated carrier that is the limiting factor in DAB reduction.
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PMID:Effect of drugs and hormones on rat liver dimethylaminoazobenzene reductase activity. 621 56

L-Asparagine (2-10 mM) failed to affect insulin secretion from rat pancreatic islets incubated in the absence of exogenous nutrient or presence of D-glucose, but caused a dose-related and progressive enhancement of insulin release evoked by L-leucine, 2-aminobicyclo[2,2,1]heptane-2-carboxylate, or 2-ketoisocaproate. The secretory response to the combination of L-asparagine and L-leucine was augmented by theophylline and inhibited in the absence of extracellular Ca2+ or presence of either menadione or methylamine. L-Asparagine augmented leucine-stimulated 45Ca net uptake. The ATP content, rate of O2 uptake, and malate/pyruvate ratio were not significantly different in islets exposed to L-leucine alone or to both L-asparagine and L-leucine, respectively. In the sole presence of L-asparagine, however, the malate/oxalacetate ratio was decreased and the malate/pyruvate ratio increased, relative to basal values. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine might be due to an accelerated generation rate of cytosolic NADPH, rather than to any sizable increase in either islet respiration or steady-state cytosolic NADPH/NADP+ ratio.
Diabetes 1984 May
PMID:The stimulus-secretion coupling of amino acid-induced insulin release. Secretory and oxidative response of pancreatic islets to L-asparagine. 637 56

This study examined the effect of an aldose reductase inhibitor (Sorbinil, CP 45634, Pfizer, Sandwich, Kent, United Kingdom) on the metabolite profile of the lens during the first week after induction of diabetes with alloxan. The lens content of sorbitol, fructose, glycerol 3-phosphate, and glucose 6-phosphate was, respectively, 0.33 +/- 0.03, 0.55 +/- 0.05, 0.10 +/- 0.01, and 0.074 +/- 0.006 mumol/g (means +/- SEM) in the control group rising to 12.2 +/- 0.52, 3.20 +/- 0.10, 0.76 +/- 0.10, and 0.200 +/- 0.009 in lenses from alloxan-diabetic rats. Sorbinil treatment (40 mg/kg) decreased the lens content of sorbitol to 0.60 +/- 0.06, fructose to 0.85 +/- 0.08, and glycerol 3-phosphate to 0.36 +/- 0.03 mumol/g; glucose 6-phosphate remained unchanged. Significantly, the lens content of glutathione was decreased to 60% of the normal value in the diabetic group, but was sustained at normal levels with Sorbinil treatment. The ATP content of the lens was not altered by diabetes or Sorbinil treatment at this time interval. Sorbinil has no significant effect on the above metabolites in the normal rat lens. The effect of Sorbinil in restoring normal levels of glutathione and glycerol 3-phosphate may be a potentially important facet of the action of this drug. The interlocking of metabolic pathways by the redox state of NAD+/NADH and NADP+/NADPH, their derangement in diabetes, and the wider effects of Sorbinil on the network of reactions in the lens are discussed.
Diabetes 1983 May
PMID:The effect of an aldose reductase inhibitor (Sorbinil) on the level of metabolites in lenses of diabetic rats. 640 81

Isolated microvessels (primarily capillaries) from bovine retina and cerebral cortex, as well as cultured bovine retinal capillary pericytes and porcine and canine retinal capillary endothelial cells contain apparent aldose reductase activity. This conclusion is based on the ability of these cultured cells and vessel fragments to reduce DL-glyceraldehyde in preference to D-glucuronate at low (0.1 mM) substrate concentrations, in the presence of NADPH, and in the accumulation of high levels of sorbitol or galactitol when retinal pericytes and endothelial cells are cultured in media enriched in glucose or galactose. The quantitative similarities of these activities in bovine retinal and cerebral microvessels, as well as the quantitatively similar ability of these two sets of microvessels to oxidize 14C-labeled glucose with the label either in the C-1 or the C-6 position, suggests that aldose reductase may not be a major causal factor in diabetic retinopathy. This conclusion is suggested because, while these metabolic activities are similar in bovine retinal and cerebral microvessels, only the retinal microvasculature suffers major anatomic and functional damage in diabetes. This conclusion must be viewed with caution, however, because other metabolic pathways that we have not investigated may be altered by an excess of sugar alcohols, and be present in differing activities in retinal and cerebral microvessels; species differences may exist; and similar experiments have not been conducted using human microvessels.
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PMID:Aldose reductase activity in retinal and cerebral microvessels and cultured vascular cells. 641 48

Previous work has shown that induction of a high-affinity NADPH-dependent nitrosodimethylamine demethylase (NDMAd) in liver microsomes occurs in rats due to fasting, ethanol consumption, and streptozotocin-induced diabetes. Several lines of observations suggest that this is due to the induction of specific cytochrome P-450 isozymes. Induction of P-450 species by ethanol has also been observed by other investigators. Since each of the above altered metabolic states has in common elevated levels of ketone bodies, the possible role of acetone, a known inducer of NDMAd, in the induction of the demethylase activity was investigated. Levels of endogenous acetone in fasted rats correlated (r = 0.72) with a three- to fourfold increase in NDMAd activity. However, a dose-response experiment showed endogenous levels of acetone to be capable of causing at most 40% of the induction in fasted rats. This suggests that other ketone bodies or factors may have contributed to the induction. The induction of NDMAd by ethanol was enhanced by alcohol dehydrogenase inhibitors pyrazole and acetaldehyde oxime, suggesting that ethanol, rather than its metabolites, was responsible for the induction.
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PMID:Studies on the mechanisms of induction of N-nitrosodimethylamine demethylase by fasting, acetone, and ethanol. 670 8

The activity of enzymes with a regulatory function in the pathways of glycolysis, gluconeogenesis and NADP-generation was investigated in 50 placentae from normal pregnancies and deliveries, 23 placentae from women with gestational diabetes, and 12 placentae from insulin-dependent patients. In placentae from the gestational diabetic group, the activity of pyruvate kinase and of NADPH-generating enzymes was raised and the activity of enzymes connected to glucogenesis was unchanged. These alterations were attributed to the oversupply of glucose and insulin to morphologically normal and well-oxygenated placental tissue. In the placentae from the insulin-dependent group, the activity of pyruvate kinase was reduced, the activity of NADPH-generating enzymes was enhanced and the activity of those related to the gluconeogenesis was unchanged. It is suggested that this pattern of enzyme changes reflects a reduction in the glycolytic capacity in these placentae, which may be due to inhibition by products of enhanced fatty acid oxidation in diabetes, amino acids and/or by long-term anoxia as a result of uteroplacental circulatory disturbances. The possible relation of reduced energy-forming capacity of the placenta in diabetes to its transport function is discussed.
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PMID:Changes in activity of enzymes related to glycolysis, gluconeogenesis and lipogenesis in placentae from diabetic women. 672 31

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH4 production is close to the summed rates of L-[1-14C] leucine decarboxylation and alpha-ketoisocarproate production, whereas the rates of acetoacetate production and L-[U-14C]-leucine oxidation are compatible with conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO2. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD+ ratio (but not the NADPH/NADP+ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on 86Rb+ and 45Ca2+ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.
Diabetes 1980 Jun
PMID:The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine. 676 28

Mice were found to convert acetone to lactate at appreciable rates. The conversion of acetone to gluconeogenic precursors could provide additional glycolytic intermediates that would allow the more complete utilization of lipid stores and increase survival time during starvation. In mice that were starved for 3 days or were provided with acetone in the drinking water the acetone-metabolizing pathway was induced to levels severalfold normal. Mice heterozygous for obesity-producing mutations, either obese (ob/+) or diabetes (db/+), showed induction of the activity of this pathway to a significantly higher degree than did homozygous normal (+/+) mice of the same strain. This more effective conversion of acetone to lactate exhibited by heterozygous mice could account for their prolonged survival on a starvation regimen compared to that of normal homozygotes. The rate-limiting step in the pathway appears to be the conversion of acetone to a hydroxylated derivative. The enzyme system effecting this conversion is an NADPH-requiring microsomal oxygenase found in the liver.
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PMID:Acetone metabolism in mice: increased activity in mice heterozygous for obesity genes. 692 21

We examined the relationship between glucose-induced insulin release and the intermediary metabolism of islets from fed and fasted rats. Isolated islets were perifused and insulin release measured in the effluent. At various times after switching islets from 2.4 to 8.6 or 14.5 mM glucose or from 2.4 to 14.5 and back to 2.4 mM glucose, islets were quickly frozen, freeze dried, and subsequently analyzed for tissue content of glucose-6-P, fructose-1,6-P2 plus triose-P, Pi, ATP, ADP, 5'-AMP, NADH, NADPH, total NAD, and total NADP using enzymatic fluorometric procedures. When islets from fed rats were exposed to high glucose, there were concomitant increases of insulin release and islet content of glucose-6-P, fructose-1,6-P2 plus triose-P, NADH, and NADPH. During stimulation Pi and 5'-AMP content fell markedly. The total adenine nucleotide content remained constant. Similar secretory and metabolic changes occurred when 1.5 mM Pi was added to the perifusion fluid. When glucose-stimulated islets were switched back to low glucose for 10 min, all substances but fructose-1,6-P2 plus triose-P, 5'-AMP, NADPH, and possibly ATP returned to the prestimulatory level. Starvation of rats for 3 days blocked the secretory response to 8.6 mM glucose. Fructose-1,6-P2 plus triose-P rose but it did not attain the level existing in islets from fed rats. The ratios (ATP)/(5'-AMP) and (ATP)/(Pi)(adp) increased to the values observed in glucose-stimulated islets of fed rats. The metabolic changes in islets from fed rats exposed to high glucose are consistent with an activation of glycolysis occurring concomitantly with stimulated rates of insulin release. This occurs despite the decrease of important activators of glycolysis--Pi and 5'-AMP. The enhanced glycolysis possibly results from P-fructokinase activation by increased fructose-6-P levels. Activation of glycolysis with 8.6 mM glucose was not as pronounced in islets from starved rats. Despite the different secretory response of islets from fet and fasted rats, the changes of phosphorylation state in the islets, in particular, Pi and 5'-AMP levels, were similar.
Diabetes 1980 Jan
PMID:Effects of glucose on insulin release and on intermediary metabolism of isolated perifused pancreatic islets from fed and fasted rats. 699 11

In isolated rat pancreatic islets, glucose (5.6, 11.1, and 16.7 mM) significantly increased reduced glutathione (GSH) and decreased oxidized glutathione (GSSG) levels in a dose-related manner. This was paralleled by a concomitant increase of NADPH and a decrease of NADP. The change of the GSH level occurred as quickly as one minute after addition of glucose. Exogenous insulin (200, 400, and 800 microU/ml) significantly decreased islet GSH levels in the presence of 5.6 and 16.7 mM glucose and significantly inhibited the insulin-releasing effect of the thiol reagent parachloromercuribenzoate (p-CMB) and tolbutamide. These data, together with earlier observations, suggest that GSH levels in pancreatic islets are increased by glucose and decreased by exogenous insulin via their effects on the pentose phosphate shunt and NADPH. Our results are compatible with the hypothesis that glucose and exogenous insulin, by modifying the redox state of the NADPH/NADP and GSH/GSSG systems, modulate the sensitivity of the beta-cell to the insulin-triggering actions of glucose, p-CMB, and tolbutamide.
Diabetes 1980 Oct
PMID:Islet glutathione and insulin release. 700 64


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