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

Human and rat whole blood were shown to metabolize the aromatic amides acetanilide and phenacetin by deacetylation followed by reacetylation in vitro. Derivatives of the parent compounds labelled with deuterium in the N-acetyl group produced non-labelled material after incubation. The reaction was monitored by capillary gas chromatographic-mass spectrometric (GC-MS) analysis. There was no significant difference in the acetyl group exchange of these substrates using blood samples donated by non-diabetic volunteers or Type 2 diabetic patients (respective mean +/- SEM values = 4.0 +/- 0.2% and 4.2 +/- 0.3% for trideuteroacetanilide, 6.2 +/- 0.6% and 6.1 +/- 0.3% for trideuterophenacetin). Increasing the glucose concentration in the incubation medium by 50 mmol/L significantly (P less than 0.01) increased deacetylation-reacetylation of trideuteroacetanilide in each group (4.6 +/- 0.2% and 4.7 +/- 0.2% for non-diabetic and diabetic subjects, respectively). In rat blood the amount of deacetylation-reacetylation was much higher: 7.2 +/- 0.6% and 8.3 +/- 0.7% for trideuteroacetanilide and trideuterophenacetin, respectively. Induction of experimental diabetes using streptozotocin did not significantly change the extent of deacetylation-reacetylation of either deuterated substrate (10.1 +/- 2.1% and 9.5 +/- 1.1%). Elevation of the incubation glucose concentration by 50 mmol/L produced an increase in acetyl group exchange (for trideuteroacetanilide) in diabetic (14.3 +/- 2.2%) and non-diabetic (10.6 +/- 1.0%) rats. The donation of acetyl groups (transacetylation) was observed after incubation of blood samples from both diabetic and non-diabetic human subjects and rats with trideuterophenacetin and a molar excess of aniline. This reaction significantly (P less than 0.001) decreased the acetyl group exchange of trideuterophenacetin (these values were 4.5 +/- 0.4% and 3.4 +/- 0.6% using samples from non-diabetic human subjects and rats, respectively) and demonstrated the ability of whole blood to catalyse transacetylation (acetyl-CoA-independent acetylation). There was correlation between the amount of (unlabelled) acetanilide produced by acetylation with acetyl-CoA and the percentage present as trideuteroacetanilide. The proportion of trideuteroacetanilide was higher using rat blood (e.g. the values for non-diabetic subjects were 25.5 +/- 1.7% vs 8.5 +/- 0.3%; P less than 0.001) although the total amount of acetanilide produced was lower (0.54 +/- 0.14 nmol vs 1.82 +/- 0.23 nmol; P less than 0.05) than that observed using human blood.
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PMID:In vitro studies on the deacetylation-reacetylation of arylamides and the transacetylation of arylamines by human and rat whole blood. 204 56

There is evidence that hyperketonemia in insulin-dependent diabetes may be aggravated by a decreased disposal rate for ketone bodies. To test the hypothesis that this decrease may be induced by concomitant hyperglycemia through substrate competition at the acetyl-CoA level, 5 young insulin-dependent diabetic subjects received at 2-h iv infusion of 0.9 mmol 3-hydroxybutyrate.kg-1.h-1 at clamped 1. euglycemia (5 mmol/l) and 2. hyperglycemia (11 mmol/l) on separate occasions. To ensure similar metabolic conditions, a low-dose hyperinsulinemic euglycemic clamp was performed during the 5 h preceding the actual studies. Substrate fluxes in muscle were assessed through the forearm technique. The glucose infusion rate was 4.9 and 2.9 mg.kg-1.min-1, and the forearm arteriovenous difference for glucose was 0.72 during hyperglycemia and 0.39 mmol/l (p less than 0.05), during euglycemia. Hyperglycemia did not affect circulating levels of free insulin, glucagon, non-esterified fatty acids, 3-hydroxybutyrate (hyperglycemia: 665, euglycemia: 770 mumol/l, p greater than 0.05) or acetoacetate, nor forearm uptake of 3-hydroxybutyrate (hyperglycemia, 152, euglycemia: 168 mumol/l, p greater than 0.05). In conclusion, our results do not suggest any inhibitory role for hyperglycemia in the disposal of ketone bodies. In as much as extrapolation from the present well insulinized state is appropriate, the data indicate that alternative mechanisms may be involved in the observed impairment of ketone body clearance in hyperketonemic insulin-dependent diabetic patients.
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PMID:Lack of effects of hyperglycemia on the disposal of 3-hydroxybutyrate in insulin-dependent diabetic patients. 228 87

The discovery of a cold-labile cytosolic acetyl-CoA hydrolase of high activity in rat liver by Prass et al. [(1980) J. Biol. Chem. 255, 5215-5223] has questioned the importance of mitochondrial acetyl-CoA hydrolase for the formation of free acetate [Grigat et al. (1979) Biochem. J. 177, 71-79] under physiological conditions. Therefore this problem has been reevaluated by comparing various properties of the two enzymes. Cold-labile cytosolic acetyl-CoA hydrolase bands with an apparent Mr of 68000 during SDS/polyacrylamide gel electrophoresis, while the native enzyme elutes in two peaks with apparent Mr of 136000 and 245000 during gel chromatography in the presence of 2 mM ATP. The mitochondrial enzyme elutes under the same conditions with an apparent Mr of 157000. Under conditions where the cold-labile enzyme binds strongly to DEAE-Bio-Gel and ATP-agarose, the mitochondrial enzyme remains unbound. The cold-labile enzyme can be activated 14-fold by ATP, half-maximal activation occurring already at 40 microM ATP. AdoPP[NH]P, AdoPP[CH2]P and GTP have a similar though weaker effect. ADP as well as GDP can completely inhibit the cold-labile enzyme with 50% inhibition occurring for both nucleotides at about 1.45 microM. The binding of ATP and ADP is competitive. Acetyl phosphate and pyrophosphate have no effect on the activity of the cold-labile enzyme. The mitochondrial acetyl-CoA hydrolase is not affected by these nucleotides. CoASH is a strong product inhibitor (approximately equal to 80% inhibition at 40 microM CoASH) of the cold-labile enzyme, but only a weak inhibitor of the mitochondrial enzyme. Under in vivo conditions the activity of the cold-labile cytosolic acetyl-CoA hydrolase can be no more than 7% of the activity calculated for mitochondrial acetyl-CoA hydrolase under the same conditions. Accordingly the mitochondrial enzyme seems to be mainly responsible for the formation of free acetate by the intact liver, especially in view of the fact that the substrate specificity of the mitochondrial enzyme is much higher (activity ratios acetyl-CoA/butyryl-CoA 4.99 and 1.16 for the mitochondrial and the cold-labile enzyme respectively). Alloxan diabetes neither increased the activity of the cold-labile enzyme nor that of the mitochondrial enzyme. No experimental support has been found yet for the hypothesis that the acetyl-CoA hydrolase activity of the cold-labile enzyme represents the side-activity of an acetyl-transferase.
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PMID:On the regulation of cold-labile cytosolic and of mitochondrial acetyl-CoA hydrolase in rat liver. 285 46

Recent studies in man demonstrated a marked ketogenic effect of increased plasma norepinephrine concentrations as observed in diabetic ketoacidosis. Since this effect may have been due either to increased substrate supply for ketogenesis (lipolysis) or to direct hepatic activation of ketogenesis, the latter mechanism was examined in isolated rat hepatocytes. Incubation of hepatocytes with norepinephrine (10(-7) to 10(-4) M) resulted in a dose-dependent increase in conversion of the long-chain fatty acid [1-14C]palmitate into ketone bodies and CO2. Norepinephrine decreased [1-14C]palmitate conversion into triglycerides without affecting fatty acid uptake. Norepinephrine enhanced ketogenesis from [1-14C]palmitate in a physiologic range of fatty acid concentrations (0.5-2.5 mM), but failed to affect fatty acid esterification to phospholipids or mono- and diglycerides. In contrast to long-chain fatty acids, oxidation of the medium-chain fatty acid [1-14C]octanoate to ketone bodies was not enhanced by norepinephrine, whereas CO2 production increased. The effect of norepinephrine on [1-14C]fatty acid oxidation was blocked by the alpha 1 receptor blocker prazosin. The results demonstrate that norepinephrine diverts long-chain fatty acids into the pathways of oxidation and ketogenesis away from esterification, suggesting enhanced carnitine-dependent mitochondrial fatty acid uptake. The studies using octanoate indicated that norepinephrine also enhanced fatty acid oxidation by increasing the flux of acetyl-CoA through the Krebs cycle. The data suggest that stress-associated sympathetic activation and norepinephrine discharge, as observed in diabetic ketoacidosis, result in direct activation of ketogenesis in the liver.
Diabetes 1985 Aug
PMID:Effect of norepinephrine on ketogenesis, fatty acid oxidation, and esterification in isolated rat hepatocytes. 286 86

Significant increase in the activity of an acetyl-CoA hydrolase (ATP-stimulated, ADP-inhibited enzyme) in the supernatant fraction of rat liver was observed after 44-68 h of starvation (about 2-fold), and in the early stage of diabetes (about 1.6-fold), but not in the chronic stage of diabetes. The increased enzymatic activity in starved rats returned to the control level within 20 h when the animals were given laboratory chow, but not when they were given fat-free diet with a high carbohydrate content, and the enzyme activity was increased by the latter diet containing 1% thyroid powder. A single intraperitoneal injection of 3,3'5-triiodo-L-thyronine or 3,3',5,5'-tetraiodo-L-thyronine resulted in twice the normal enzyme activity two days later, and conversely 7 days after thyroidectomy, the enzyme activity was about 60% of the control level. A single subcutaneous injection of alpha-(p-chlorophenoxy)isobutyric acid, a hypolipidemic drug, doubled the enzyme activity in euthyroid rats, but not in thyroidectomized rats. Of the various tissues tested besides the liver, only the kidney had detectable ATP-stimulated and ADP-inhibited enzyme activity (5% of the activity in liver cytosol). The kidney enzyme had similar kinetic and immunochemical properties to the liver enzyme. Changes in the enzyme activity in the liver in various states were closely related to the amount of enzyme present, judging from results obtained by enzyme-linked immunosorbent assay. The physiological role of this enzyme (which hydrolyzes acetyl-CoA to acetate and CoASH) may be in maintenance of the cytosolic acetyl-CoA concentration and CoASH pool for both fatty acid synthesis and oxidation.
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PMID:Physiological changes in the activities of extramitochondrial acetyl-CoA hydrolase in the liver of rats under various metabolic conditions. 286 34

The metabolism of L-tryptophan by isolated liver cells prepared from control, adrenalectomized, glucocorticoid-treated, acute-diabetic, chronic-diabetic and insulin-treated chronic-diabetic rats was studied. Liver cells from adrenalectomized rats metabolized tryptophan at rates comparable with the minimum diurnal rates of controls, but different from rates determined for cells from control rats 4h later. Administration of dexamethasone phosphate increased the activity of tryptophan 2,3-dioxygenase (EC 1.13.11.11) 7-8-fold, and the flux through the kynurenine pathway 3-4-fold, in cells from both control and adrenalectomized rats. Increases in flux through kynureninase (EC 3.7.1.3) and to acetyl-CoA can be explained in terms of increased substrate supply from tryptophan 2,3-dioxygenase. The metabolism of tryptophan was increased 3-fold in liver cells isolated from acutely (3 days) diabetic rats, with a 7-8-fold increase in the maximal activity of tryptophan 2,3-dioxygenase. The oxidation of tryptophan to CO2 and metabolites of the glutarate pathway increased 4-5-fold, consistent with an increase in picolinate carboxylase (EC 4.1.1.45) activity. Liver cells isolated from chronic (10 days) diabetic rats metabolized tryptophan at rates comparable with those of cells from acutely diabetic rats, but with a 50% decrease in the activity of tryptophan 2,3-dioxygenase. The proportion of flux from tryptophan 2,3-dioxygenase to acetyl-CoA, however, was increased by 50%; this was indicative of further increases in the activity of picolinate carboxylase. Administration of insulin partially reversed the effects of chronic diabetes on the activity of tryptophan 2,3-dioxygenase and flux through the kynurenine pathway, but had no effect on the increased activity of picolinate carboxylase. The role of tryptophan 2,3-dioxygenase in regulating the blood tryptophan concentration is discussed with reference to its sensitivity to the above conditions.
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PMID:The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes. 389 9

1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O(2) consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood-brain barrier may be the rate-limiting step in their metabolism.
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PMID:Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. 427 4

1. In an attempt to define the importance of acetate as a metabolic precursor, the activities of acetyl-CoA synthetase (EC 6.2.1.1) and acetyl-CoA hydrolase (Ec 3.1.2.1) were assayed in tissues from rats and sheep. In addition, the concentrations of acetate in blood and liver were measured, as well as the rates of acetate production by tissue slices and mitochondrial fractions of these tissues. 2. Acetyl-CoA synthetase occurs at high activities in heart and kidney cortex of both species as well as in rat liver and the sheep masseter muscle. The enzyme is mostly in the cytosol fraction of liver, whereas it is associated with the mitochondrial fraction in heart tissue. Both mitochondrial and cytosol activities have a K(m) for acetate of 0.3mm. Acetyl-CoA synthetase activity in liver was not altered by changes in diet, age or alloxan-diabetes. 3. Acetyl-CoA hydrolase is widely distributed in rat and sheep tissues, the highest activity being found in liver. Essentially all of the activity in liver and heart is localized in the mitochondrial fraction. Hepatic acetyl-CoA hydrolase activity is increased by starvation in rats and sheep and during the suckling period in young rats. 4. The concentrations of acetate in blood are decreased by starvation and increased by alloxan-diabetes in both species. The uptake of acetate by the sheep hind limb is proportional to the arterial concentration of acetate, except in alloxan-treated animals, where uptake is impaired. 5. Acetate is produced by liver and heart slices and also by heart mitochondrial fractions that are incubated with either pyruvate or palmitoyl-(-)-carnitine. Liver mitochondrial fractions do not form acetate from either substrate but instead convert acetate into acetoacetate. 6. We propose that acetate in the blood of rats or starved sheep is derived from the hydrolysis of acetyl-CoA. Release of acetate from tissues would occur under conditions when the function of the tricarboxylic acid cycle is restricted, so that the circulating acetate serves to redistribute oxidizable substrate throughout the body. This function is analogous to that served by ketone bodies.
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PMID:Production and utilization of acetate in mammals. 444 81

1. The extractions of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo were calculated from measurements of their arterial and coronary sinus blood concentration. Elevation of plasma free fatty acid concentrations by infusion of intralipid and heparin resulted in increased extraction of free fatty acids and diminished extractions of glucose, lactate and pyruvate by the heart. It is suggested that metabolism of free fatty acids by the heart in vivo, as in vitro, may impair utilization of these substrates. These effects of elevated plasma free fatty acid concentrations on extractions by the heart in vivo were reversed by injection of dichloroacetate, which also improved extraction of lactate and pyruvate by the heart in vivo in alloxan diabetes. 2. Sodium dichloroacetate increased glucose oxidation and pyruvate oxidation in hearts from fed normal or alloxan-diabetic rats perfused with glucose and insulin. Dichloroacetate inhibited oxidation of acetate and 3-hydroxybutyrate and partially reversed inhibitory effects of these substrates on the oxidation of glucose. In rat diaphragm muscle dichloroacetate inhibited oxidation of acetate, 3-hydroxybutyrate and palmitate and increased glucose oxidation and pyruvate oxidation in diaphragms from alloxan-diabetic rats. Dichloroacetate increased the rate of glycolysis in hearts perfused with glucose, insulin and acetate and evidence is given that this results from a lowering of the citrate concentration within the cell, with a consequent activation of phosphofructokinase. 3. In hearts from normal rats perfused with glucose and insulin, dichloroacetate increased cell concentrations of acetyl-CoA, acetylcarnitine and glutamate and lowered those of aspartate and malate. In perfusions with glucose, insulin and acetate, dichloroacetate lowered the cell citrate concentration without lowering the acetyl-CoA or acetylcarnitine concentrations. Measurements of specific radioactivities of acetyl-CoA, acetylcarnitine and citrate in perfusions with [1-(14)C]acetate indicated that dichloroacetate lowered the specific radio-activity of these substrates in the perfused heart. Evidence is given that dichloroacetate may not be metabolized by the heart to dichloroacetyl-CoA or dichloroacetylcarnitine or citrate or CO(2). 4. We suggest that dichloroacetate may activate pyruvate dehydrogenase, thus increasing the oxidation of pyruvate to acetyl-CoA and acetylcarnitine and the conversion of acetyl-CoA into glutamate, with consumption of aspartate and malate. Possible mechanisms for the changes in cell citrate concentration and for inhibitory effects of dichloroacetate on the oxidation of acetate, 3-hydroxybutyrate and palmitate are discussed.
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PMID:Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. 476 52

1. The total acid-soluble carnitine concentrations of four tissues from Merino sheep showed a wide variation not reported for other species. The concentrations were 134, 538, 3510 and 12900nmol/g wet wt. for liver, kidney cortex, heart and skeletal muscle (M. biceps femoris) respectively. 2. The concentration of acetyl-CoA was approximately equal to the concentration of free CoA in all four tissues and the concentration of acid-soluble CoA (free CoA plus acetyl-CoA) decreased in the order liver>kidney cortex>heart>skeletal muscle. 3. The total amount of acid-soluble carnitine in skeletal muscle of lambs was 40% of that in the adult sheep, whereas the concentration of acid-soluble CoA was 2.5 times as much. A similar inverse relationship between carnitine and CoA concentrations was observed when different muscles in the adult sheep were compared. 4. Carnitine was confined to the cytosol in all four tissues examined, whereas CoA was equally distributed between the mitochondria and cytosol in liver, approx. 25% was present in the cytosol in kidney cortex and virtually none in this fraction in heart and skeletal muscle. 5. Carnitine acetyltransferase (EC 2.3.1.7) was confined to the mitochondria in all four tissues and at least 90% of the activity was latent. 6. Acetate thiokinase (EC 6.2.1.1) was predominantly (90%) present in the cytosol in liver, but less than 10% was present in this fraction in heart and skeletal muscle. 7. In alloxan-diabetes, the concentration of acetylcarnitine was increased in all four tissues examined, but the total acid-soluble carnitine concentration was increased sevenfold in the liver and twofold in kidney cortex. 8. The concentration of acetyl-CoA was approximately equal to that of free CoA in the four tissues of the alloxan diabetic sheep, but the concentration of acid-soluble CoA in liver increased approximately twofold in alloxan-diabetes. 9. The relationship between CoA and carnitine and the role of carnitine acetyltransferase in the various tissues is discussed. The quantitative importance of carnitine in ruminant metabolism is also emphasized.
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PMID:Relationships between carnitine and coenzyme A esters in tissues of normal and alloxan-diabetic sheep. 507 38


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