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1.
A possible mechanism for the anti-ketogenic action of alanine in the rat   总被引:6,自引:6,他引:0  
1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10μg/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70±11% decrease in [3-hydroxybutyrate] and a 58±9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72±9% decrease in the rate of production of ketone bodies and a 57±8% decrease in disappearance rate as assessed by [3-14C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.  相似文献   

2.
The marked decrease in blood non-esterified fatty acids and ketone bodies after vasopressin infusion into starved rats [Rofe & Williamson (1983) Biochem. J. 212, 231-239] was investigated. Vasopressin did not inhibit lipolysis in isolated rat adipocytes. The metabolic effects in vivo were still present after pretreatment of rats with indomethacin, indicating that the effect is not secondary to the release of prostaglandins. Vasopressin significantly decreased blood flow through the retroperitoneal, epididymal and mesenteric fat depots, by 80%, 76% and 46% respectively. The specific haemodynamic effect of vasopressin on adipose tissue is considered to be the primary cause of the major metabolic changes seen in the starved rat.  相似文献   

3.
Ketone-body metabolism in tumour-bearing rats.   总被引:3,自引:3,他引:0       下载免费PDF全文
During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.  相似文献   

4.
In order to clarify if vasopressin (VP) plays a role in the pathophysiology of hyperosmolar nonketotic diabetic coma (HNDC), VP has been infused to diabetic rats and plasma levels of glucose (PG), ketone bodies, FFA and glucagon were determined. High-dose VP infusion (1.2 U/kg/h) caused gradual elevation of PG (60%) and glucagon levels (600%), while ketone bodies showed transient decrease (20%) at 30 min. Under the suppression of endogenous glucagon secretion by constant infusion of somatostatin (100 micrograms/kg/h), high dose VP showed 25% increase in PG levels and 30% reduction of ketone body levels for the subsequent VP infusion for 1.5 hour. Low-dose VP infusion (0.06 U/kg/h) had no hyperglycemic effect, but suppressed ketosis (20%) in the same condition. There were no changes in plasma FFA concentrations, indicating no significant effect of VP on lipolysis. The results indicate that VP often elevated in HNDC may play an important role for the pathophysiology of HNDC through suppression of hepatic ketogenesis.  相似文献   

5.
An incremental insulin infusion technique to assess insulin action at physiological circulating levels in diabetic man is described. Insulin was infused during sequential one hour periods at rates of 0.01, 0.05 and 0.10 u/kg/h. Serum free insulin concentrations had reached a plateau by the second 30 minutes of each infusion period. Blood glucose concentrations fell at a similar rate during the two lower rates of insulin infusion, but the fall was significantly greater with the highest insulin infusion. Glucose production and utilisation were measured isotopically using a 3-3H glucose infusion technique. Glucose production was inhibited with the lowest insulin infusion rate and a marked increase in glucose metabolic clearance rate occurred with the highest insulin infusion. Key intermediary metabolites were measured and blood glycerol, total ketone bodies, and plasma non-esterified fatty acids fell with the lowest insulin infusion rate. It is concluded that this technique allows identification of the effect of insulin upon different metabolic processes.  相似文献   

6.
Acetoacetate was the sole ketone body formed when livers from starved rats were perfused with minimal concentrations of non-esterified fatty acid. Absence of 3-hydroxybutyrate was related to a low substrate potential, which caused a more oxidized redox state and a decreased [ATP]/[ADP] ratio. Only under conditions of comparable non-esterified fatty acid uptake was lipoprotein triacylglycerol production inversely related to ketogenesis.  相似文献   

7.
The role of leucine in ketogenesis in starved rats.   总被引:1,自引:1,他引:0       下载免费PDF全文
The quantitative significance of the conversion in vivo of L-[U-14C]leucine to ketone bodies was determined in rats starved for 3 or 48 h. In animals starved for 3 h, 4.4% of ketone-body carbon is derived from the metabolism of leucine, and in rats starved for 48 h the corresponding value is 2.3%. This conversion occurs rapidly, and the specific radioactivity of ketone bodies in blood is maximal at 2 min after the intravenous injection of labelled leucine for both periods of starvation. The flux of leucine in the blood is 1.01 and 1.04 mumol/min per 100 g body wt. respectively for animals starved for 3 and 48 h. The specific radioactivity of blood ketone bodies was compared at 2 min after the injection of labelled leucine, lysine and phenylalanine. The specific radioactivity was 4-5 fold higher with leucine than with lysine or phenylalanine.  相似文献   

8.
Rats subjected to laparotomy and handling of the liver were starved for 48 h, starting either immediately after surgery or 48 h later. Surgery enhanced the rise in plasma non-esterified fatty acid concentrations after starvation without affecting the responses of blood or liver ketone bodies. Thus in surgically stressed rats, blood and liver ketone body concentrations were inappropriately low for the blood fatty acid concentrations. In the control rats, starvation increased hepatic carnitine concentrations, mainly through increases in short-chain acylcarnitine. Surgical stress decreased or abolished these increases. This may possibly contribute to the blunted ketonaemic response observed after surgery.  相似文献   

9.
The effect of acetoacetate on plasma insulin concentration   总被引:12,自引:9,他引:3       下载免费PDF全文
1. Sodium acetoacetate was infused into the inferior vena cava of fed rats, 48h-starved rats, and fed streptozotocin-diabetic rats treated with insulin. Arterial blood was obtained from a femoral artery catheter. 2. Acetoacetate infusion caused a fall in blood glucose concentration in fed rats from 6.16 to 5.11mm in 1h, whereas no change occurred in starved or fed-diabetic rats. 3. Plasma free fatty acids decreased within 10min, from 0.82 to 0.64mequiv./l in fed rats, 1.16 to 0.79mequiv./l in starved rats and 0.83 to 0.65mequiv./l in fed-diabetic rats. 4. At 10min the plasma concentration rose from 20 to 49.9muunits/ml in fed unanaesthetized rats and from 6.4 to 18.5muunits/ml in starved rats. There was no change in insulin concentration in the diabetic rats. 5. Nembutal-anaesthetized fed rats had a more marked increase in plasma insulin concentration, from 30 to 101muunits/ml within 10min. 6. A fall in blood glucose concentration in fed rats and a decrease in free fatty acids in both fed and starved rats is to be expected as a consequence of the increase in plasma insulin. 7. The fall in the concentration of free fatty acids in diabetic rats may be due to a direct effect of ketone bodies on adipose tissue. A similar effect on free fatty acids could also be operative in normal fed or starved rats.  相似文献   

10.
The administration of glucose to 48 h-starved euthyroid or hyperthyroid rats led to decreased blood concentrations of fatty acids and ketone bodies in both groups, but fatty acid concentrations were higher and ketone-body concentrations lower in the latter group. Decreased ketonaemia was not due to increased ketone-body clearance. Flux through carnitine palmitoyltransferase 1 was increased, consistent with the effects of hyperthyroidism on enzyme activity demonstrated in vitro. Correlations between the concentrations of ketone bodies and long-chain acylcarnitine measured in freeze-clamped liver samples indicated that a lower proportion of the product of beta-oxidation was used for ketone-body synthesis. Citrate concentrations were unaffected by hyperthyroidism, but lipogenesis was increased. The results are discussed in relation to the factors controlling hepatic carbon flux and energy requirements after re-feeding.  相似文献   

11.
Uptake of radioactively labelled insulin by the mammary gland of the rat increased 12-fold in lactation compared with non-lactating controls. This uptake was decreased by the presence of unlabelled insulin, indicating that it occurred via insulin receptors. The plasma half-life of insulin is decreased in lactation from 9.4 min to 4.8 min, and the metabolic clearance rate for insulin increased from 7.26 to 13.03 ml/kg body wt. per min. The basal insulin and glucose concentrations in the plasma were decreased in lactation. Infusion of insulin at a dose which led to a small physiological rise in plasma insulin concentration increased lipogenic rates in the mammary gland by 100% without causing marked hypoglycaemia. It is concluded that the lactating mammary gland is a highly insulin-sensitive tissue and that the lower plasma insulin during lactation occurs primarily as a result of this sensitivity increasing extraction of glucose by the gland and thus producing a decrease in the plasma glucose concentration. It is suggested that a secondary result of the fall in plasma insulin concentration is the preferential direction of substrates (glucose and non-esterified fatty acids) towards the lactating mammary gland and away from adipose tissue and the liver.  相似文献   

12.
The relative importance of the main glucogenic and ketogenic substrates, and interactions between fatty acids availability and ketogenesis have been investigated in virgin or 21 day pregnant rats. Fed pregnant rats displayed elevated lactatemia and the production of lactate by portal-drained viscera was markedly reduced. In contrast, the production of alanine and propionate from digestion was almost similar in fed pregnant and virgin rats. The release of glucose by the liver in fed animals was higher in pregnant rats, and lactate was the main glucogenic substrate taken up whereas alanine uptake was reduced. The hepatic utilization of propionate was not different between the two groups of fed animals. Hepatic gluconeogenesis and lactate extraction were enhanced by starvation; the contribution of lactate to glucose release remained higher in pregnant than in virgin rats, whereas the contribution of alanine was lower, owing to its decreased availability in afferent blood. There was a large uptake of intestinally-derived acetate in fed rates, and a slight release, parallel to ketogenesis, was observed in starved pregnant rats. Free fatty acids were elevated and efficiently taken up by the liver in fed pregnant rats, but without any noticeable ketogenesis. Hepatic ketogenesis was enhanced in starved animals, with marked hyperketonaemia in pregnant rats. However, in those animals, the hepatic release of ketone bodies was not proportional to ketonaemia and was almost similar to the release in starved virgin rats.  相似文献   

13.
1. The infusion of sodium dichloroacetate into rats with severe diabetic ketoacidosis over 4h caused a 2mM decrease in blood glucose, and small falls in blood lactate and pyruvate concentrations. Similar findings had been reported in normal rats (Blackshear et al., 1974). In contrast there was a marked decrease in blood ketone-body concentration in the diabetic ketoacidotic rats after dichloroacetate treatment. 2. The infusion of insulin alone rapidly decreased blood glucose and ketone bodies, but caused an increase in blood lactate and pyruvate. 3. Dichloroacetate did not affect the response to insulin of blood glucose and ketone bodies, but abolished the increase of lactate and pyruvate seen after insulin infusion. 4. Neither insulin nor dichloroacetate stimulated glucose disappearance after functional hepatectomy, but both agents decreased the accumulation in blood of lactate, pyruvate and alanine. 5. Dichloroacetate inhibited 3-hydroxybutyrate uptake by the extra-splachnic tissues; insulin reversed this effect. Ketone-body production must have decreased, as hepatic ketone-body content was unchanged by dicholoracetate yet blood concentrations decreased. 6. It was concluded that: (a) dichloroacetate had qualitatively similar effects on glucose metabolism in severely ketotic rats to those observed in non-diabetic starved animals; (b) insulin and dichloroacetate both separately and together, decreased the net release of lactate, pyruvate and alanine from the extra-splachnic tissues, possibly through a similar mechanism; (c) insulin reversed the inhibition of 3-hydroxybutyrate uptake caused by dichloroacetate; (d) dichloroacetate inhibited ketone-body production in severe ketoacidosis.  相似文献   

14.
The extent to which normal and neoplastic tissues of the rate take up glucose was assessed by the 2-deoxy[U-14C]glucose tracer technique. Measurements of glucose uptake were made over 40 min in anaesthetized rats under conditions where the blood glucose concentration was constant. In fed tumour-bearing rats, the relative rates of glucose uptake per g wet wt. of tissue were tumour (100), small intestine (72), brain (61), heart (61), spleen (50), lung (42), adipose tissue (11) and muscle (8). Normal tissues of the fed tumour-bearing rats had decreased rates of glucose uptake as compared with the same tissues in fed non-tumour-bearing control rats. Blood glucose concentrations were similar in both groups, but insulin concentrations were decreased in tumour-bearing rats. Starvation decreased the rates of glucose uptake by normal tissues in both control and tumour-bearing rats, but the difference between the fed and starved states was greater in the control rats. Starvation did not decrease glucose uptake by the tumour. On an organ basis, the tumour (12-14% of body wt.) took up 4 times more glucose than did muscle (40% of body wt.).  相似文献   

15.
Isolated rat livers perfused in an open system exhibited a continous net release of free acetate. Upon intraportal infusion of hexanoate the net release of total ketone bodies and of free acetate increased significantly in livers from fed and 48 hours starved rats. The ratio ketone body production/acetate production during infusion of hexanoate was similar with livers from fed and starved rats. Livers from diabetic rats, however, did not only exhibit a higher rate of ketone body and acetate production, but also a significant decrease of the ratio ketone body production/acetate production. Intraportal infusion of oleate led also to an enhanced release of free acetate. An examination of the activities of 5 enzymes involved in ketone body and acetate metabolism showed no correlation with the higher rate of acetate production by diabetic livers.  相似文献   

16.
The synthesis of 4-3H-labelled ketone bodies, and their use along with 14C-labelled ketone-body precursors, is employed using an 'in vivo' rat infusion model to measure ketone-body turnover. The use of two isotopes is necessary to measure ketone-body turnover when ketogenesis may occur from more than one precursor such as glucose and fatty or amino acids. Requirements of isotopic equivalence in terms of metabolic similarity, valid stoichiometry and the lack of differences in the kinetics of relevant enzymes is demonstrated for the 4-3H- and 14C-labelled ketone bodies. The hypoketonaemic effect of L-alanine is shown by two distinct phases after the administration of L-alanine. During the first 12 min after alanine administration ther was a 50% decrease in acetoacetate and a 30% decrease in 3-hydroxybutyrate production, with no significant change in the utilization of either compound. The hypoketonaemic action of alanine during the following 16 min was primarily associated with an uptake of 3-hydroxybutyrate that was somewhat greater than the increase in its production. There were essentially equivalent decreases in production and utilization of acetoacetate, resulting in no significant net change in the level of this ketone body in the blood.  相似文献   

17.
The high energy demands of the heart are met primarily by the mitochondrial oxidation of fatty acids and glucose. However, in heart failure there is a decrease in cardiac mitochondrial oxidative metabolism and glucose oxidation that can lead to an energy starved heart. Ketone bodies are readily oxidized by the heart, and can provide an additional source of energy for the failing heart. Ketone oxidation is increased in the failing heart, which may be an adaptive response to lessen the severity of heart failure. While ketone have been widely touted as a “thrifty fuel”, increasing ketone oxidation in the heart does not increase cardiac efficiency (cardiac work/oxygen consumed), but rather does provide an additional fuel source for the failing heart. Increasing ketone supply to the heart and increasing mitochondrial ketone oxidation increases mitochondrial tricarboxylic acid cycle activity. In support of this, increasing circulating ketone by iv infusion of ketone bodies acutely improves heart function in heart failure patients. Chronically, treatment with sodium glucose co-transporter 2 inhibitors, which decreases the severity of heart failure, also increases ketone body supply to the heart. While ketogenic diets increase circulating ketone levels, minimal benefit on cardiac function in heart failure has been observed, possibly due to the fact that these dietary regimens also markedly increase circulating fatty acids. Recent studies, however, have suggested that administration of ketone ester cocktails may improve cardiac function in heart failure. Combined, emerging data suggests that increasing cardiac ketone oxidation may be a therapeutic strategy to treat heart failure.  相似文献   

18.
The effect of intravenous infusion of monoacetoacetin (glycerol monoacetoacetate) as a non-protein energy source was evaluated in burned rats. During 3 days of parenteral nutrition, in which animals received 14 g of amino acids/kg body wt. per day exclusively (group I) or with the addition of isoenergetic amounts (523 kJ/kg per day) of dextrose (group II), a 1:1 mixture of dextrose and monoacetoacetin (group III) or monoacetoacetin (group IV), significant decreases in urinary nitrogen excretion and whole-body leucine oxidation were observed in the three groups given additional non-protein energy as compared with group I. Serum ketone bodies (acetoacetate and 3-hydroxybutyrate) were decreased in rats given dextrose, whereas glucose and insulin increased significantly. Monoacetoacetin-infused animals (group IV) had high concentrations of ketone bodies without changes in glucose and insulin, whereas animals infused with both monoacetoacetin and glucose (group III) showed intermediate values. On day 4 of nutritional support, whole-body L-leucine kinetics were measured by using a constant infusion of L-[1-14C]leucine. In comparison with group I, the addition of dextrose or monoacetoacetin produced a significant decrease in plasma leucine appearance and release from whole-body protein breakdown. Gastrocnemius-muscle protein-synthesis rates were also higher in the three groups receiving additional non-protein energy. These findings suggest that monoacetoacetin can effectively replace dextrose as an intravenous energy source in stressed rats. Both fuels are similar in decreasing weight loss, nitrogen excretion, leucine release from whole-body protein breakdown and oxidation, in spite of differences in energy substrate and insulin concentrations.  相似文献   

19.
To assess the effect of chemical stimulation of the central nervous system (CNS) on ketogenesis, we injected neostigmine (5 x 10(-8)mol) into the third cerebral ventricle in normal rats fasted for 48 h and fed rats with diabetes induced by streptozotocin (STZ, 80 mg/kg). The hepatic venous plasma levels of ketone bodies (3-hydroxybutyrate and acetoacetate), free fatty acids (FFA), and glucose were measured for 120 min after the injection of neostigmine under pentobarbital anesthesia. In the normal rats, plasma glucose levels were significantly increased but neither ketone bodies nor FFA were affected by CNS stimulation with neostigmine. In contrast the plasma levels of ketone bodies and FFA were significantly increased in STZ-diabetic rats, while glucose levels remained unchanged. The intravenous infusion of somatostatin (1.0 microgram/kg/min) suppressed the increase in plasma ketone bodies following CNS stimulation in STZ-diabetic rats. These findings suggest that CNS stimulation with neostigmine may accelerate ketogenesis by promoting the lipolysis, which may be induced by glucagon, in fed diabetic rats but not in normal fasted rats.  相似文献   

20.
The present study was undertaken to evaluate quantitatively the turnover of serum triacylglycerol (triglyceride) in the starved rat and to determine whether serum triacylglycerol recycled to liver contributes a significant fraction of the total hepatic triacylglycerol turnover. Serum was labelled in vitro with [3H]trioleoylglycerol (glycerol [3H]trioleate) to provide uniform labelling of all lipoprotein species. By using the curves describing disappearance of isotope from serum and its appearance in liver, rate constants for movement of triacylglycerol out of serum (0.29 min-1) and the uptake of serum triacylglycerol by liver (0.22 min-1) were calculated. The total rate of movement (flux) of triacylglycerol in these processes, the product of rate constant and serum pool size, was calculated to be 0.39 and 0.29 mg/min per 100 g body wt. respectively. A model is postulated for whole-body triacylglycerol metabolism consistent with the present data as well as most observations in the literature. From the model it can be predicted that: (1) the entire turnover of liver triacylglycerol in the starved rat can be accounted for on the basis of contributions from serum non-esterified fatty acid and serum triacylglycerol; (2) the entire turnover of the serum triacylglycerol pool can be accounted for quantitatively on the basis of contributions from intestine and liver; (3) the release rate for triacylglycerol from liver should be 0.34 to 0.35 mg/min per 100 g body wt.; (4) triacylglycerol synthesized by liver from non-esterified fatty acid of serum and by intestine can account quantitatively for the irreversible disposal rate of triacylglycerol from serum.  相似文献   

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