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At least 19 recordsLinked to original sources
PubMed1981

Gluconeogenesis in rat liver parenchymal cells in primary culture: permissive effect of the glucocorticoids on glucagon stimulation of gluconeogenesis.

Primary cultures of parenchymal cells isolated from adult rat liver by a collagenase perfusion procedure and maintained as a monolayer in a serum-free culture medium were used to study gluconeogenesis and the role that the glucocorticoids play in the control of this pathway. These cells carried out gluconeogenesis from three-carbon precursors (alanine and lactate) in response to glucagon and dexamethasone added alone or in combination. Maximum glucose production was observed with cells pretreated for several hours with dexamethasone and glucagon prior to addition of substrate and glucagon (8- to 12-fold increase over basal glucose production). Half-maximum stimulation of gluconeogenesis was seen with 3.6 X 10(-10) M glucagon and 3.6 X 10(-8) M dexamethasone. Maximum stimulation was observed with 10(-7) M glucagon and 10(-6) M dexamethasone. The length of time of dexamethasone pretreatment was found to be important in demonstrating the effect of glucocorticoids on glucagon-stimulated gluconeogenesis. Treatment of cells with dexamethasone for 2 hours did not result in an increase in glucose production over identical experimental conditions in the absence of dexamethasone, whereas pretreatment for 5 hours (1.2-fold increase) or 15 hours (1.7-fold increase) did result in an increase in glucose production. The results establish that the adult rat liver parenchymal cells in primary culture are a valid model system to study hepatic gluconeogenesis. In addition, we have established directly that the glucocorticoids amplify the glucagon stimulation of gluconeogenesis.

Alanine↗
PubMed1980

Gluconeogenesis in rabbit liver. III. The influences of glucagon, epinephrine, alpha- and beta-adrenergic agents on gluconeogenesis in isolated hepatocytes.

1. Gluconeogenesis from various substrates has been demonstrated in hepatocytes from 48 h fasted rabbits. Maximum rates of gluconeogenesis (expressed as mumol glucose formed/30 min per 10(8) cells) are: D-fructose, 9.86; dihydroxyacetone, 5.28; L-lactate, 5.26; L-lactate/pyruvate, 3.83; pyruvate, 3.32; glycerol, 2.92; L-alanine, 2.24. 2. Gluconeogenesis from L-lactate is enhanced 1.3--1.5-fold over control values by glucagon, L-epinephrine, L-norepinephrine, dibutyryl cyclic AMP, L-phenylephrine and L-isoproterenol. Glucogenesis from both dihydroxyacetone and D-fructose is stimulated 1.7--2.0-fold of control values by glucagon, epinephrine and dibutyryl cyclic AMP. 3. Gluconeogenesis from lactate is enhanced by both alpha- and beta-adrenergic stimulations based on findings with alpha- and beta-agonists and antagonists. 4. Enhancement of gluconeogenesis by epinephrine and norepinephrine is apparently due to both alpha- and beta-adrenergic effects, as either propranolol or phentolamine partially inhibits such enhancement. The consistently more pronounced inhibition produced by propranolol implies that stimulation of glucose formation by catecholamines is more strongly beta-adrenergic related. Epinephrine-induced glycogenolysis in rabbit hepatocytes is severely inhibited by propranolol but insensitive to phentolamine, suggesting that glycogen breakdown is solely beta-adrenergic related. These observations contrast with those of others that stimulation of both gluconeogenesis and glycogenolysis by catecholamines while sensitive to both alpha- and beta-adrenergic stimulation in rats, at least young rats, is primarily alpha-adrenergic mediated, especially in adult rats.

Animals↗
PubMed1987

Evidence that the flux control coefficient of the respiratory chain is high during gluconeogenesis from lactate in hepatocytes from starved rats. Implications for the hormonal control of gluconeogenesis and action of hypoglycaemic agents.

1. Increasing concentrations of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), a mild respiratory-chain inhibitor [Halestrap (1987) Biochim. Biophys. Acta 927, 280-290], caused progressive inhibition of glucose production from lactate + pyruvate by hepatocytes from starved rats incubated in the presence or absence of oleate and gluconeogenic hormones. 2. No significant changes in tissue ATP content were observed, but there were concomitant decreases in ketone-body output and cytochrome c reduction and increases in NADH fluorescence and the ratios of [lactate]/[pyruvate] and [beta-hydroxybutyrate]/[acetoacetate]. 3. The inhibition by DCMU of palmitoylcarnitine oxidation by isolated liver mitochondria was used to calculate a flux control coefficient of the respiratory chain towards gluconeogenesis. In the presence of 1 mM-oleate, the calculated values were 0.61, 0.39 and 0.25 in the absence of hormone and in the presence of glucagon or phenylephrine respectively, consistent with activation of the respiratory chain in situ as previously suggested [Quinlan & Halestrap (1986) Biochem. J. 236, 789-800]. 4. Cytoplasmic oxaloacetate concentrations were shown to decrease under these conditions, implying inhibition of pyruvate carboxylase. 5. Inhibition of gluconeogenesis from fructose and dihydroxyacetone was also observed with DCMU and was accompanied by an increased output of lactate + pyruvate, suggesting that activation of pyruvate kinase was occurring. With the latter substrate, measurements of tissue ADP and ATP contents showed that DCMU caused a small fall in [ATP]/[ADP] ratio. 6. Two inhibitors of fatty acid oxidation, pent-4-enoate and 2-tetradecylglycidate, were shown to abolish and to decrease respectively the effects of hormones, but not valinomycin, on gluconeogenesis from lactate + pyruvate, without changing tissue ATP content. 7. It is concluded that the hormonal increase in mitochondrial matrix volume stimulates fatty acid oxidation and respiratory-chain activity, allowing stimulation of pyruvate carboxylation and thus gluconeogenesis to occur without major changes in [ATP]/[ADP] or [NADH]/[NAD+] ratios. 8. The high flux control coefficient of the respiratory chain towards gluconeogenesis may account for the hypoglycaemic effect of mild respiratory-chain inhibitors.

Adenosine Triphosphate↗
PubMed1985

Quinolinate inhibition of gluconeogenesis is dependent on cytosolic oxalacetate concentration. An explanation for the differential inhibition of lactate and pyruvate gluconeogenesis.

In isolated rat hepatocytes, the phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, quinolinate decreased gluconeogenesis from lactate more than from pyruvate (78 vs 44%). Quinolinate inhibition of PEPCK has been reported to be competitive with oxalacetate (OAA), and therefore higher cytosolic OAA concentrations could be expected to alleviate quinolinate inhibition of PEPCK and hence reduce its effect on gluconeogenesis. With pyruvate as a carbon source, the cytosolic concentration of OAA was higher than with lactate (40 vs 9.7 microM). The levels of OAA were manipulated metabolically by adding asparagine (which provides more cytosolic OAA through the urea cycle) or oleate (which increases malate efflux from the mitochondria). In each of the 8 conditions studied, quinolinate inhibition of gluconeogenesis was inversely related to the levels of OAA in the cytosol. Quinolinate inhibition of asparagine gluconeogenesis was not due to a non-specific effect on urea synthesis.

Animals↗
PubMed1983

Postnatal hypoglycaemia and gluconeogenesis in the newborn rat. Delayed onset of gluconeogenesis in prematurely delivered newborns.

The concentrations of glucose and lactate in the blood and of liver glycogen, and the phosphoenolpyruvate carboxykinase activity in liver and kidney of term and preterm newborn rats, were studied during the first 6 h post partum. Rates of lactate turnover and gluconeogenesis in vivo from [U-14C]lactate at 3 h and 6 h post partum were also quantified. The development of the prolonged postnatal hypoglycaemia observed after birth in the premature newborn rat is associated with lower rates of glucose production through glycogenolysis and gluconeogenesis; liver glycogenolysis was the main contributing factor to the glucose available during the neonatal period studied in both groups. Delayed induction of liver phosphoenolpyruvate carboxykinase activity was observed in premature newborn rats. Renal phosphoenolpyruvate carboxykinase activity increased 72% from birth in preterm newborns, but only a 25% increase was found in term newborns during the same experimental period. The gluconeogenesis in vivo from [U-14C]lactate paralleled the appearance of cytosolic phosphoenolpyruvate carboxykinase activity in the liver of both groups of newborns. Blood lactate concentrations remained higher in preterm than in term newborns. The postnatal utilization of lactate via the gluconeogenic pathway in either group of newborns was always less than 20% of the total lactate used. The results presented are discussed in relation to the development of postnatal hypoglycaemia and gluconeogenesis in the premature newborn rat.

Animals↗
PubMed1995

Isotopomer analysis of citric acid cycle and gluconeogenesis in rat liver. Reversibility of isocitrate dehydrogenase and involvement of ATP-citrate lyase in gluconeogenesis.

We conducted an extensive mass isotopomer analysis of citric acid cycle and gluconeogenic metabolites isolated from livers of overnight fasted rats perfused with 4 mM glucose, 0.2 mM octanoate, 1 mM [U-13C3]lactate, and 0.2 mM [U-13C3]pyruvate, in the anterograde or retrograde mode. In both perfusion modes, two distinct isotopomer patterns were observed: (i) those of phosphoenolpyruvate, glucose, malate, and aspartate and (ii) those of citrate, alpha-ketoglutarate, glutamate, and glutamine. Key citric acid cycle parameters and, hence, rates of gluconeogenesis, calculated (Lee, W.-N.P. (1989) J. Biol. Chem. 264, 13002-13004 and Lee, W.-N.P. (1993) J. Biol. Chem. 268, 25522-25526) from our mass isotopomer data did not only vary, but lead to conclusions inconsistent with Lee's citric acid cycle model. Compared to lactate and pyruvate uptake, which sets an upper limit to glucose production, rates of gluconeogenesis calculated (i) with the phosphoenolpyruvate and citrate data were similar, but those calculated (ii) with the glutamate data amounted to only 60%, which is unlikely. All these conclusions are independent of the perfusion modes. We provide evidence that the following processes contribute to the observed labeling discrepancy: (i) the reversibility of the isocitrate dehydrogenase reaction and (ii) an active citrate cleavage pathway for the transfer of the oxaloacetate carbon skeleton from mitochondria to the cytosol. Also, a good fit of our labeling data was obtained with a model of citric acid cycle and gluconeogenesis which we developed to incorporate the above reactions (Fernandez, C.A., and Des Rosiers, C. (1995) J. Biol. Chem. 270, 10037-10042). The following conclusions can be drawn from the calculated reaction rates: (i) about half of the lactate conversion to glucose occurs via the citrate cleavage pathway, (ii) the flux through the reversal of the isocitrate dehydrogenase reaction is almost as fast as that through the citrate synthase reaction, and (iii) the flux through citrate synthase and alpha-ketoglutarate dehydrogenase is 1.6- and 3.2-fold that through pyruvate carboxylase, respectively.

ATP Citrate (pro-S)-Lyase↗
PubMed1977

Gluconeogenesis in the guinea pig. Effect of glucagon on gluconeogenesis from lactate by isolated perfused guinea-pig liver.

Gluconeogenesis was stimulated by glucagon in fed but not fasted isolated perfused guinea pig livers. Both the amount and the rate of incorporation of radioactivity into glucose from L-[U-14C]lactate were increased in fed livers by the addition of glucagon to the perfusate. The glucagon-stimulated increase in gluconeogenesis was accompanied by an increase in oxygen consumption, an increase in the amount of lactate carbon converted to glucose and a decrease in the amount of lactate carbon converted to CO2. The results are interpreted to indicate that glucagon affects gluconeogenesis from lactate in fed livers by redirecting the fate of substrate from other products toward glucose.

Animals↗
PubMed1991

Metabolic adaptation of renal carbohydrate metabolism. IV. The use of site-specific liver gluconeogenesis inhibitors to ascertain the role of renal gluconeogenesis.

The in vitro and in vivo effects of several different inhibitors of carbohydrate metabolism have been studied. The in vitro addition of 5-methoxyindole-2-carboxylic acid (MICA), pent-4-enoic acid, and quinolinic acid to the perfusion medium significantly inhibited liver gluconeogenesis in 48-hour-starved rats (100% inhibition when MICA and quinolinic acid were added at 0.8 and 2.4 mM, respectively). In vivo the level of inhibition varied greatly depending upon whether MICA was administered by intragastric tube or intraperitoneal injection. In all cases the inhibitory capacity of MICA on liver gluconeogenesis was significantly higher when injected intraperitoneally. On the other hand, the administration of MICA produced a significant, dose-dependent, increase in renal gluconeogenesis in both fed and 48-hour-starved rats, more so when the inhibitor was administered by intraperitoneal injection.

Animals↗
PubMed1984

The permissive effects of glucocorticoid on hepatic gluconeogenesis. Glucagon stimulation of glucose-suppressed gluconeogenesis and inhibition of 6-phosphofructo-1-kinase in hepatocytes from fasted rats.

Production of [14C]glucose from [14C]lactate in the perfused livers of 24-h fasted adrenalectomized rats was not stimulated by 1 nM glucagon but was significantly increased by 10 nM hormone. Crossover analysis of glycolytic intermediates in these livers revealed a significant reduction in glucagon action at site(s) between fructose 6-phosphate and fructose 1,6-bisphosphate as a result of adrenalectomy. Site(s) between pyruvate and P-enolpyruvate was not affected. In isolated hepatocytes, adrenalectomy reduced glucagon response in gluconeogenesis while not affecting glucagon inactivation of pyruvate kinase. A distinct lack of glucagon action on 6-phosphofructo-1-kinase activity was noted in these cells. When hepatocytes were incubated with 30 mM glucose, lactate gluconeogenesis was greatly stimulated by glucagon. A reduction in both sensitivity and responsiveness to the hormone in gluconeogenesis was seen in the adrenalectomized rat. These changes were well correlated with similar impairment in glucagon action on 6-phosphofructo-1-kinase activity and fructose 2,6-bisphosphate content in hepatocytes from adrenalectomized rats incubated with 30 mM glucose. These results suggest that adrenalectomy impaired the gluconeogenic action of glucagon in livers of fasted rats at the level of regulation of 6-phosphofructo-1-kinase and/or fructose 2,6-bisphosphate content.

Adrenalectomy↗
PubMed1981

Gluconeogenesis in rabbit liver. IV. The effects of glucagon, epinephrine, alpha- and beta-adrenergic agents on gluconeogenesis and pyruvate kinase in hepatocytes given dihydroxyacetone or fructose.

1. Epinephrine, isoproterenol and phenylephrine each increases significantly gluconeogenesis (from dihydroxy-acetone or D-fructose) and glycogenolysis when added to hepatocytes from 48-h fasted rabbits. Such stimulation of both processes by epinephrine, isoproterenol or phenylephrine is negated by the beta-adrenergic antagonist propranolol but remains significant in the presence of the alpha-adrenergic antagonist phentolamine. Conversely, previous data suggest that catecholamine-induced stimulation of glucose formation from L-lactate is both alpha- and beta-adrenergic-sensitive. 2. Glucagon, epinephrine, isoproterenol, phenylephrine and dibutyryl cyclic AMP each inhibits significantly pyruvate kinase activity in rabbit hepatocytes. Inhibition of pyruvate kinase activity by epinephrine, isoproterenol or phenylephrine is negated by propranolol but insensitive to phentolamine. 3. These observations suggest that enhancement by epinephrine of glucose formation from either dihydroxyacetone or D-fructose is solely beta-adrenergic-regulated, just as is its inhibition of pyruvate kinase activity. Stimulation of gluconeogenesis by glucagon, epinephrine, isoproterenol, phenylephrine or dibutyryl cyclic AMP may be at least in part directly related to their ability to inhibit pyruvate kinase.

Animals↗
PubMed1969

Regulation of gluconeogenesis and lipogenesis. The regulation of mitochondrial pyruvate metabolism in guinea-pig liver synthesizing precursors for gluconeogenesis.

1. The carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase in guinea-pig liver mitochondria was determined by measuring the amount of (14)C from H(14)CO(3) (-) fixed into organic acids in the presence of pyruvate, ATP, Mg(2+) and P(i). The main products of pyruvate carboxylation were malate, fumarate and citrate. Pyruvate utilization, metabolite formation and incorporation of (14)C from H(14)CO(3) (-) into these metabolites in the presence and the absence of ATP were examined. The synthesis of phosphoenolpyruvate from pyruvate and bicarbonate is minimal during continued oxidation of pyruvate. Larger amounts of phosphoenolpyruvate are formed from alpha-oxoglutarate than from pyruvate. Addition of glutamate, alpha-oxoglutarate or fumarate did not appreciably increase formation of phosphoenolpyruvate when pyruvate was used as substrate. With alpha-oxoglutarate as substrate addition of fumarate resulted in increased formation of phosphoenolpyruvate, whereas addition of succinate inhibited phosphoenolpyruvate formation. In the presence of added oxaloacetate guinea-pig liver mitochondria synthesized phosphoenolpyruvate in amount sufficiently high to play an appreciable role in gluconeogenesis. 2. Addition of fatty acids of increasing carbon chain length caused a strong inhibition of pyruvate oxidation and phosphoenolpyruvate formation, and greatly promoted carbon dioxide fixation and malate, citrate and acetoacetate accumulation. The incorporation of (14)C from H(14)CO(3) (-), [1-(14)C]pyruvate and [2-(14)C]pyruvate into organic acids formed was examined. 3. It is concluded that guinea-pig liver pyruvate carboxylase contributes significantly to gluconeogenesis and that fatty acids and metabolites play an important role in its regulation.

Adenosine Triphosphate↗
PubMed1996

Measuring glycerol turnover, gluconeogenesis from glycerol, and total gluconeogenesis with [2-13C] glycerol: role of the infusion-sampling mode.

Mass isotopomer distribution analysis (MIDA) of glucose during infusion of [2-13C]glycerol is a new method for measuring total gluconeogenesis (GNG). Since this method relies on calculation of the isotopic enrichment (IE) of hepatic triose phosphates (TP), the results should be independent of the sites of tracer infusion and blood sampling. Postabsorptive and starved rats were infused with [2-13C]glycerol and sampled either in the arterial-venous (A-V) or venous-arterial (V-A) modes. Blood was also sampled from the portal vein. In both postabsorptive and starved rats, glycerol turnover rate (Rt) and the percent contribution of glycerol to total glucose production were higher in the A-V mode than in the V-A mode (P < .05). Glycerol IE in portal venous blood was intermediate between IE values observed in peripheral arterial and venous blood. Its use for calculating the contribution of glycerol to glucose production reconciled the results obtained with the two infusion-sampling modes in both postabsorptive and starved rats; this contribution was increased by starvation (P < .01). In postabsorptive rats, total GNG calculated from MIDA of glucose accounted for approximately 50% of glucose production whatever the infusion-sampling mode (A-V, 48.8% +/- 4.7%; V-A, 52.2% +/- 3.9%). This contribution increased to 90% in starved rats, again, with no difference between A-V (95.2% +/- 1.8%) and V-A (89.2% +/- 1.3%) modes. In conclusion, during infusion of [2-13C]glycerol, total GNG measured from MIDA of glucose is independent of the infusion-sampling mode, contrary to calculations of Rt and GNG from glycerol. Measurement of glycerol IE in portal venous blood reconciles the results obtained with the two modes with respect to the contribution of glycerol to GNG.

Animals↗
PubMed1976

Gluconeogenesis in infancy and childhood. I. A method for the study of the in vivo gluconeogenesis from alanine and glycerol.

The in vivo gluconeogenesis from alanine and glycerol in infants and children was studied by an isotope method, using 14C-labeled substates with subsequent separation of the radioactive compounds by thin-layer chromatography. Seven patients, aged 2 months to 2 years 11 months, with normal carbohydrate metabolism were studied. Trace amounts of [14C]alanine were injected intravenously in four fasting patients. The 14C moved quickly from alanine to lactate, with a peak activity in lactate obtained before 5 min. From 10 min on, the label disappeared rapidly from both. An equilibrium was established between alanine and lactate, displaced towards lactate. The peak activity in glucose was reached in 10-20 min, amounting to 10% of total injected activity. In one patient, who was also studied after a meal, the disappearance rate of alanine was reduced by 50%. Despite this reduction the appearance of label in lactate was increased, whereas the amount of label in glucose was much reduced. [14C]glycerol was injected intravenously in three fasting patients. In one patient, who received only a tracer dose of glycerol, 5 times more 14C appeared in glucose than in the patients studied with [14C]alanine. In two patients receiving a glycerol load together with the [14C]glycerol, the disappearance rate of glycerol was markedly reduced, as was the conversion of carbon to glucose and lactate.

Alanine↗
PubMed2001

The quantification of gluconeogenesis in healthy men by (2)H2O and [2-(13)C]glycerol yields different results: rates of gluconeogenesis in healthy men measured with (2)H2O are higher than those measured with [2-(13)C]glycerol.

The quantification of gluconeogenesis (GNG) by (2)H2O and [2-(13)C]glycerol and the mass isotopomer dilution analysis of glucose does not involve assumptions regarding the enrichment of the oxaloacetate precursor pool. To compare these two methods we measured GNG in six healthy postabsorptive males under identical, strictly standardized, eucaloric conditions, once after oral administration of (2)H2O and once during a primed continuous infusion of [2-(13)C]glycerol. Endogenous glucose production (EGP) was measured by infusion of [6,6-(2)H(2)]glucose. EGP was not different after (2)H2O administration or during [2-(13)C]glycerol infusion (12.2 +/- 0.7 vs. 11.7 +/- 0.3 micromol/kg.min). However, GNG measured after (2)H2O administration was significantly higher than that during [2-(13)C]glycerol infusion (7.4 +/- 0.7 vs. 4.9 +/- 0.6 micromol/kg.min; P = 0.03), representing approximately 60% and 41% of EGP, respectively. The (2)H2O study was repeated during primed continuous infusion of unlabeled glycerol, showing that infusion of glycerol at the rate used in the [2-(13)C]glycerol method does not affect the measurement of GNG with (2)H2O, viz. 7.4 +/- 0.7 without glycerol vs. 7.6 +/- 0.9 micromol/kg.min with glycerol, representing approximately 60% vs. 62% of EGP. In conclusion, GNG measured by (2)H(2)O yields higher results than those measured by [2-(13)C]glycerol. This discrepancy is not merely caused by infusion of glycerol per se. Rather, the discrepancy between both methods probably relates to conceptual problems in underlying assumptions in one or both methods.

Adult↗