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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The characteristics and site of inhibition of gluconeogenesis by endotoxin were investigated in liver cells isolated from control and endotoxin-treated rats. Endotoxin treatment was associated with inhibition (40-50%) of gluconeogenesis from lactate plus pyruvate over a range of concentrations of substrate and of oleate and with or without glucose or glucagon. Similar inhibition was observed with asparagine, proline, glutamine, alanine and a substrate mixture, but not with glycerol, glyceraldehyde, dihydroxyacetone or endogenous substrates. There was no change in cellular ATP content or in the rates of ketogenesis or ureogenesis from asparagine, proline or glutamine. Other effects on isotopic fluxes, metabolite contents, enzyme activities and control coefficients were consistent with the suggestion that the effects of endotoxin on gluconeogenesis are exerted at the level of phosphofructokinase-1, and not at phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate carboxylase or glucokinase.
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PMID:The characteristics and site of inhibition of gluconeogenesis in rat liver cells by bacterial endotoxin. Stimulation of phosphofructokinase-1. 295 43

Insulin/glucagon control of hepatic metabolism, i.e. a endocrine-nervous system, is one of the general systems of integration in vertebrates. In this system, substrates coming from the digestive tract or from extrahepatic metabolism are important messenger molecules. Liver uptake of insulin and glucagon mainly accounts for high metabolic clearance rates of these hormones in both ruminants and non-ruminants. Glucagon infusion into ruminants results in an increase in the net hepatic uptake of glucose precursors and gluconeogenesis. Glucagon effects have also been demonstrated in isolated hepatocytes. Glucagon, through its effect on pyruvate carboxylase (EC 6.4.1.1.) may regulate gluconeogenesis. Insulin infusion induces hypoglycaemia. As a result, glucagon secretion increases and counterregulates insulin action. However, it has been shown that hepatic gluconeogenesis decreases during euglycaemic hyperinsulin clamp, mainly due to a decrease in the hepatic supply of glucose precursors following insulin action in extrahepatic tissues. Insulin fails to elicit any significant effect in vitro. Hepatocytes exhibit insulin and glucagon receptors. The apparent characteristics of hormone binding in vitro are similar in ruminants and non-ruminants, but the characteristics of postreceptor events are unknown in the former. Glucagon, which influences hepatic glucose synthesis, may be a major hormone in ruminants.
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PMID:[Hormonal control of hepatic metabolism in ruminants]. 301 Apr 7

The first branch point in gluconeogenesis occurs at the conversion of pyruvate to oxaloacetate. To determine the amount of lactate carbon reaching glucose via the direct pyruvate carboxylase pathway versus the tricarboxylic acid cycle, adult rat hepatocytes in primary culture were incubated for 2 h with one of the following isotopic substrates: [1-14C]lactate, [U-14C]lactate, or [1,2-14C]acetate. Production of 14CO2 and [14C]glucose from each substrate was assessed. The amount of lactate carbon 2 and 3 incorporated into glucose or oxidized to CO2 was determined by subtracting values using [1-14C]lactate from those using [U-14C]lactate. After quantitation of CO2 formed from carbons 2 and 3 of lactate, the amount of these carbons incorporated into glucose via the tricarboxylic acid cycle can be determined by simple proportionality from the ratio of label incorporated into glucose or CO2 from [1,2-14C]acetate. The remaining carbons 2 and 3 of lactate incorporated into glucose are derived from the pyruvate carboxylase pathway directly. Ethanol which on oxidation provides NADH and acetate decreased lactate oxidation and enhanced the pyruvate carboxylase pathway. Glucagon increased carbon flux through both pathways but primarily through the pyruvate carboxylase pathway. In summary, a simple model is presented to examine carbon flux from lactate via the pyruvate carboxylase and tricarboxylic acid pathways during gluconeogenesis.
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PMID:Model to examine pathways of carbon flux from lactate to glucose at the first branch point in gluconeogenesis. 318 10

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.
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PMID: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. 342 47

Control properties of the gluconeogenic pathway in hepatocytes isolated from starved rats were studied in the presence of glucose. The following observations were made. (1) Glucose stimulated the rate of glucose production from 20 mM-glycerol, from a mixture of 20 mM-lactate and 2 mM-pyruvate, or from pyruvate alone; no stimulation was observed with 20 mM-alanine or 20 mM-dihydroxyacetone. Maximal stimulation was obtained between 2 and 5 mM-glucose, depending on the conditions. At concentrations above 6 mM, gluconeogenesis declined again, so that at 10 mM-glucose the glucose production rate became equal to that in its absence. (2) With glycerol, stimulation of gluconeogenesis by glucose was accompanied by oxidation of cytosolic NADH and reduction of mitochondrial NAD+ and was insensitive to the transaminase inhibitor amino-oxyacetate; this indicated that glucose accelerated the rate of transport of cytosolic reducing equivalents to the mitochondria via the glycerol 1-phosphate shuttle. (3) With lactate plus pyruvate (10:1) as substrates, stimulation of gluconeogenesis by glucose was almost additive to that obtained with glucagon. From an analysis of the effect of glucose on the curves relating gluconeogenic flux and the steady-state intracellular concentrations of gluconeogenic intermediates under various conditions, in the absence and presence of glucagon, it was concluded that addition of glucose stimulated both phosphoenolpyruvate carboxykinase and pyruvate carboxylase activity.
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PMID:Stimulation by glucose of gluconeogenesis in hepatocytes isolated from starved rats. 366 84

We have used control analysis to quantify the distribution of control in the gluconeogenic pathway in liver cells from starved rats. Lactate and pyruvate were used as gluconeogenic substrates. The flux control coefficients of the various enzymes in the gluconeogenic pathway were calculated from the elasticity coefficients of the enzymes towards their substrates and products and the fluxes through the different branches in the pathway. The elasticity coefficients were either calculated from gamma/Keq. ratios (where gamma is the mass-action ratio and Keq. is the equilibrium constant) and enzyme-kinetic data or measured experimentally. It is concluded that the gluconeogenic enzyme pyruvate carboxylase and the glycolytic enzyme pyruvate kinase play a central role in control of gluconeogenesis. If pyruvate kinase is inactive, gluconeogenic flux from lactate is largely controlled by pyruvate carboxylase. The low elasticity coefficient of pyruvate carboxylase towards its product oxaloacetate minimizes control by steps in the gluconeogenic pathway located after pyruvate carboxylase. This situation occurs when maximal gluconeogenic flux is required, i.e. in the presence of glucagon. In the absence of the hormone, when pyruvate kinase is active, control of gluconeogenesis is distributed among many steps, including pyruvate carboxylase, pyruvate kinase, fructose-1,6-bisphosphatase and also steps outside the classic gluconeogenic pathway such as the adenine-nucleotide translocator.
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PMID:Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon. 380 Aug 95

Isolated sheep hepatocytes were used to obtain estimates of kinetic parameters, identify substrate preference and interactions and study regulation of gluconeogenesis. Respective Vmax estimates for propionate, pyruvate and alanine conversion to glucose were 59.5, 12.8 and 21.5 mol glucose formed X (h X g dry weight)-1. Respective KS estimates for propionate and pyruvate were 1 mM and 18 to 40 microM. Rates of lactate utilization varied among cell preparations, possibly because of loss of lactate dehydrogenase during isolation. Dihydroxyacetone and glycerol were utilized for glucose synthesis at similar rates of 8.6 and 8.7 mumol glucose formed X (h X g dry weight)-1, respectively. Respective rates of glucose synthesis from 5 mM fructose and 10 mM galactose were 63.2 and 31.4 mumol X (h X g dry weight)-1. Maximum rates of pyruvate carboxylase and phosphoenolpyruvate carboxykinase were estimated to be 101.6 and 160.4 mumol substrate converted X (h X g dry weight)-1, respectively. Neither butyrate nor acetate accelerated gluconeogenesis from propionate while acetate increased glucose synthesis from pyruvate, presumably through activation of pyruvate carboxylase. Glucagon stimulated gluconeogenesis from propionate. Dibutyrylcyclic AMP mimicked the effect of glucagon, implying that the glucagon effect is translated via the adenyl cyclase system as in rats. The kinetic parameters established in these experiments should be useful in future experiments and in computer modeling analyses of ruminant liver and whole animal metabolism where Michaelis-Menten type equations are widely used.
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PMID:Gluconeogenesis in isolated lamb hepatocytes. 381 90

We have previously shown (Comp. Biochem. Physiol. 77B: 35-39, 1984) that a rapid postnatal increase in hepatic mitochondrial adenine nucleotide content activates pyruvate carboxylation and gluconeogenesis in the newborn rabbit. This study investigated factors limiting flux through the gluconeogenic pathway and examined the physiological stimuli responsible for the activation phenomenon. There is a 2.3-fold increase in total mitochondrial adenine nucleotides, along with a threefold increase in the matrix ATP/ADP ratio, by 2 h after birth, resulting overall in a sixfold increase in the amount of ATP/mg mitochondrial protein. Analysis of gluconeogenic intermediates, measured in freeze-clamped livers between birth and 4 h postnatal, suggests that pyruvate carboxylase controls gluconeogenic flux during this period. Newborn rabbits reared in an hypoxic environment (5% O2) exhibited decreased mitochondrial adenine nucleotide content, decreased rates of pyruvate carboxylation, and depressed blood glucose levels compared with littermates reared in room air or 95% O2. Manipulation of the insulin-to-glucagon ratio in vivo by injecting insulin at birth significantly delayed postnatal increases in the mitochondrial adenine nucleotide content and the rate of pyruvate carboxylation. Conversely, glucagon injection produced a supranormal increase in both mitochondrial adenine nucleotide content and pyruvate carboxylation. In addition, insulin injection prevented, whereas glucagon enhanced, the normal postnatal increase in tissue ATP/ADP. These results suggest that tissue oxygenation and a decreased insulin-to-glucagon ratio promote the rapid influx of adenine nucleotides from the liver cytosol into the mitochondrial matrix, thereby activating pyruvate carboxylation and gluconeogenesis during the presuckling period.
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PMID:Regulation of hepatic gluconeogenesis in newborn rabbit: controlling factors in presuckling period. 390 80

Hepatocytes were isolated from the livers of fed rats and incubated, in the presence and absence of 100 nM-glucagon, with a substrate mixture containing glucose (10 mM), fructose (4 mM), alanine (3.5 mM), acetate (1.25 mM), and ribose (1 mM). In any given incubation one substrate was labelled with 14C. Incorporation of 14C into glucose, glycogen, CO2, lactate, alanine, glutamate, lipid glycerol and fatty acids was measured after 20 and 40 min of incubation under quasi-steady-state conditions [Borowitz, Stein & Blum (1977) J. Biol. Chem. 252, 1589-1605]. These data and the measured O2 consumption were analysed with the aid of a structural metabolic model incorporating all reactions of the glycolytic, gluconeogenic, and pentose phosphate pathways, and associated mitochondrial and cytosolic reactions. A considerable excess of experimental measurements over independent flux parameters and a number of independent measurements of changes in metabolite concentrations allowed for a stringent test of the model. A satisfactory fit to the data was obtained for each condition. Significant findings included: control cells were glycogenic and glucagon-treated cells glycogenolytic during the second interval; an ordered (last in, first out) model of glycogen degradation [Devos & Hers (1979) Eur. J. Biochem. 99, 161-167] was required in order to fit the experimental data; the pentose shunt contributed approx. 15% of the carbon for gluconeogenesis in both control and glucagon-treated cells; net flux through the lower Embden-Meyerhof pathway was in the glycolytic direction except during the 20-40 min interval in glucagon-treated cells; the increased gluconeogenesis in response to glucagon was correlated with a decreased pyruvate kinase flux and lactate output; fluxes through pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase were not coordinately controlled; Krebs cycle activity did not change with glucagon treatment; flux through the malic enzyme was towards pyruvate formation except for control cells during interval II; and 'futile' cycling at each of the five substrate cycles examined (including a previously undescribed cycle at acetate/acetyl-CoA) consumed about 26% of cellular ATP production in control hepatocytes and 21% in glucagon-treated cells.
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PMID:Quantitative analysis of intermediary metabolism in hepatocytes incubated in the presence and absence of glucagon with a substrate mixture containing glucose, ribose, fructose, alanine and acetate. 391 12

The regulation of flux through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) by fatty acids and glucagon was studied in situ, in intact hepatocyte suspensions. The rate of pyruvate metabolized by carboxylation plus decarboxylation was determined from the incorporation of [1-14C]pyruvate into 14CO2 plus [14C]glucose. The flux through PDH was determined from the rate of formation of 14CO2 from [1-14C]pyruvate corrected for other decarboxylation reactions (citrate cycle, phosphoenolpyruvate carboxykinase and malic enzyme), and the flux through PC was determined by subtracting the flux through PDH from the total pyruvate metabolized. With 0.5 mM pyruvate as substrate the ratio of flux through PDH/PC was 1.9 in hepatocytes from fed rats and 1.4 in hepatocytes from 24 h-starved rats. In hepatocytes from fed rats, octanoate (0.8 mM) and palmitate (0.5 mM) increased the flux through PDH (59-76%) and PC (80-83%) without altering the PDH/PC flux ratios. Glucagon did not affect the flux through PDH but it increased the flux through PC twofold, thereby decreasing the PDH/PC flux ratio to the value of hepatocytes from starved rats. In hepatocytes from starved rats, fatty acids had similar effects on pyruvate metabolism as in hepatocytes from fed rats, however glucagon did not increase the flux through PC. 2[5(4-Chlorophenyl)pentyl]oxirane-2-carboxylate (100 microM) an inhibitor of carnitine palmitoyl transferase I, reversed the palmitate-stimulated but not the octanoate-stimulated flux through PDH, in cells from fed rats, indicating that the effects of fatty acids on PDH are secondary to the beta-oxidation of fatty acids. This inhibitor also reversed the stimulatory effect of palmitate on PC and partially inhibited the flux through PC in the presence of octanoate suggesting an effect of POCA independent of fatty acid oxidation. It is concluded that the effects of fatty acids on pyruvate metabolism are probably secondary to increased pyruvate uptake by mitochondria in exchange for acetoacetate. Glucagon favours the partitioning of pyruvate towards carboxylation, by increasing the flux through pyruvate carboxylase, without directly inhibiting the flux through PDH.
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PMID:Regulation of flux through pyruvate dehydrogenase and pyruvate carboxylase in rat hepatocytes. Effects of fatty acids and glucagon. 393 72


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