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At least 19 recordsLinked to original sources
PubMed1997

A novel assay for evaluating glycogenolysis in rat adipocytes and the inability of insulin to antagonize glycogenolysis in this cell type.

We report here on a novel procedure for measuring glycogenolysis in rat adipocytes. In this procedure, cells are incubated for 30 min at 37 degrees C with insulin or vanadate, and with [U-14C]glucose to label the glycogen pool with radioactive glucose. The cells are washed and preincubated for an additional 1 h, before being assayed. The extent of glycogenolysis is determined by the decrease in radioactivity in precipitated glycogen, which was quite substantial under experimental conditions facilitating glycogenolysis. From the assay, we determined the following. (a) Glycogenolysis is activated in rat adipocytes in response to lipolytic hormones (i.e. catecholamines and adrenocorticotropic hormone). (b) Other agents and conditions elevating intracellular adenosine 3',5'-monophosphate levels (i.e. cholera toxin, dibutyryladenosine 3',5'-monophosphate, and isobutylmethylxanthine) also activate glycogenolysis. (c) Glycogenolysis (as opposed to lipolysis) is activated at concentrations of adrenocorticotropic hormone or isoproterenol 7-11-fold lower and at adenosine 3',5'-monophosphate concentrations 7-fold lower. (d) Calyculin A, a specific inhibitor of protein phosphatase 1, activates glycogenolysis as well. Calyculin A also activates lipolysis at an equimolar potency. (e) Insulin does not antagonize glycogenolysis in rat adipocytes. In conclusion, the assay allowed us to compare glycogenolysis to lipolysis within the same cell, and to find that the sensitivity to hormones and adenosine 3',5'-monophosphate was about 1 order of magnitude higher for glycogenolysis than for lipolysis. A more striking finding was the inability of insulin to antagonize glycogenolysis in the rat adipose cell, an effect which occurs readily in liver and muscle cells via protein phosphatase 1-activating machinery. This rules out a role for adipose protein phosphatase 1 activation in the mechanism by which insulin antagonizes lipolysis and supports the contention that the insulin effect in lowering adenosine 3',5'-monophosphate levels is the central mechanism by which insulin antagonizes lipolysis.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Adrenergic regulation of glycogenolysis in isolated guinea-pig hepatocytes: evidence that beta 2-receptors mediate catecholamine stimulation of glycogenolysis.

Glycogenolysis in hepatocytes isolated from fed guinea pigs was much more enhanced by the beta-agonist, isoproterenol, than by equimolar concentrations of the alpha-agonists, phenylephrine and norepinephrine. The stimulatory effects of catecholamines occurred with the following order of potency: isoproterenol greater than epinephrine greater than norepinephrine. This order of potency is characteristic of beta 2-adrenergic receptors. That beta 2-receptors are responsible for mediating catecholamine stimulation of glycogenolysis in guinea-pig hepatocytes was further deduced from the inhibition of agonist-stimulated glycogenolysis by beta-receptor sub-type-selective antagonists. Thus, IPS 339, a beta-antagonist which has higher affinity at beta 2-sites than at beta 1-sites, was three orders of magnitude more potent in inhibiting isoproterenol-stimulated glycogenolysis than either atenolol or practolol, both of which are beta 1-selective antagonists. The beta 2-agonists zinterol and procaterol also stimulated glycogenolysis in hepatocytes and their effects were inhibited by propranolol and IPS 339, but not by practolol. Furthermore, activation of phosphorylase in these hepatocytes by isoproterenol, epinephrine, and norepinephrine also occurred with the potency order expected for beta 2-receptors. These results are in sharp contrast to those obtained with rat hepatocytes and emphasize that species differences occur in the regulation of hepatic glycogenolysis by catecholamines.

Animals↗
PubMed1985

Effect of nonsteroidal anti-inflammatory drugs on glycogenolysis in isolated hepatocytes.

E-series prostaglandins have previously been demonstrated to inhibit hormone-stimulated glycogenolysis when added to isolated hepatocytes of the rat. In the present study, the effect of nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase activity, on glycogenolysis was examined in the hepatocyte model. Ibuprofen (80 microM), indomethacin (50 microM) and meclofenamate (60 microM) all increased rates of glycogenolysis when added under basal conditions. In contrast, piroxicam (50 microM) had no effect on glycogenolysis in the hepatocyte system. Concentrations of ibuprofen below 80 microM did not significantly increase rates of glycogenolysis. Ibuprofen (80 microM) had no effect on glycogenolysis in the presence of 10(-5)M adrenaline or 5 X 10(-7)M glucagon, but did increase glycogenolytic rates in the presence of 5 X 10(-8)M glucagon. Ibuprofen-stimulated glycogenolysis was inhibited by addition of prostaglandin E2 (PGE2). Under conditions where glucagon-stimulated glycogenolysis was inhibited by exogenous PGE2, addition of ibuprofen (80 microM) increased the rate of glycogenolysis. Ibuprofen had no effect on basal or glucagon-stimulated hepatocyte adenylate cyclase activity. In conclusion, these results demonstrate that nonsteroidal anti-inflammatory drugs which are carboxylic acids can increase the rate of glycogenolysis in isolated hepatocytes. The high concentrations of drug required to stimulate glycogenolysis, the lack of effect of piroxicam, and the demonstration of stimulation by ibuprofen in the presence of exogenous PGE2 all suggest that the stimulation of glycogenolysis by ibuprofen, indomethacin and meclofenamate is independent of cyclooxygenase inhibition. These observations are consistent with reports that carboxylic acid nonsteroidal anti-inflammatory drugs can interfere with hepatic intracellular calcium handling.

Adenylyl Cyclases↗
PubMed1985

Effect of E-series prostaglandins on cyclic AMP-dependent and -independent hormone-stimulated glycogenolysis in hepatocytes.

The effect of E-series prostaglandins (PGE) on hormone-stimulated glycogenolysis was studied in isolated rat hepatocytes. As previously reported, the physiologically active analogue 16,16-dimethyl-PGE2 inhibited glucagon-stimulated glycogenolysis. This effect could be reproduced by repetitive addition of PGE2 to compensate for PGE2 catabolism. In contrast, glycogenolysis stimulated by N6,O2'-dibutyryladenosine-3',5'-cyclic monophosphate (dibutyryl-cAMP) was unaffected by either PGE2 or 16,16-dimethyl-PGE2 (rate of glycogenolysis with 0.34 microM dibutyryl-cAMP plus 1.7 microM 16,16-dimethyl-PGE2 = 99 +/- 6% of rate with 0.34 microM dibutyryl-cAMP alone; mean +/- SEM, N = 5). Similarly, glycogenolysis stimulated by 8-bromoadenosine-3',5'-cyclic monophosphate was not inhibited by PGE2 or 16,16-dimethyl-PGE2. Epinephrine-stimulated glycogenolysis was inhibited by 16,16-dimethyl-PGE2 in a dose-dependent manner. PGE inhibited the cAMP-independent stimulation of glycogenolysis resulting from phenylephrine or angiotensin II exposure (rate of glycogenolysis with 8 microM phenylephrine + 1.7 microM 16,16-dimethyl-PGE2 = 65 +/- 10% of rate with 8 microM phenylephrine alone, N = 4, P less than 0.05; 4.9 microM angiotensin II + 1.7 microM 16,16-dimethyl-PGE2 = 75 +/- 7% of rate with 4.9 microM angiotensin II alone, N = 4, P less than 0.05). Glycogenolysis stimulated by the calcium ionophore A23187 was also inhibited by PGE (rate of glycogenolysis with 0.55 micrograms/ml A23187 + 1.7 microM 16,16-dimethyl-PGE2 = 83 +/- 5% of rate with 0.55 micrograms/ml A23187 alone, N = 7, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

16,16-Dimethylprostaglandin E2↗
PubMed1999

On the inhibition of hepatic glycogenolysis by fructose. A 31P-NMR study in perfused rat liver using the fructose analogue 2,5-anhydro-D-mannitol.

Inhibition of hormone-stimulated hepatic glycogenolysis by fructose (Fru) has been attributed to accumulation of the competitive inhibitor Fru1P and/or to the associated depletion of the substrate phosphate (Pi). To evaluate the relative importance of either factor, we used the Fru analogue 2,5-anhydro-D-mannitol (aHMol). This analogue is avidly phosphorylated, traps Pi, and inhibits hormone-stimulated glycogenolysis, but it is not a gluconeogenic substrate, and hence does not confound glycogenolytic glucose production. Livers were continuously perfused with dibutyryl-cAMP (100 microM) to clamp phosphorylase in its fully activated a form. We administered aHMol (3.8 mM), and studied changes in glycogenolysis (glucose, lactate and pyruvate output) and in cytosolic Pi and phosphomonoester (PME), using in situ 31P-NMR spectroscopy (n = 4). Lobes of seven livers perfused outside the magnet were extracted for evaluation, by high-resolution 31P-NMR, of the evolution of aHMol1P and of aHMol(1,6)P2. After addition of aHMol, both glycogenolysis and the NMR Pi signal dropped precipitously, while the PME signal rose continuously and was almost entirely composed of aHMol1P. Inhibition of glycogenolysis in excess of the drop in Pi could be explained by continuing accumulation of aHMol1P. A subsequent block of mitochondrial ATP synthesis by KCN (1 mM) caused a rapid increase of Pi. Despite recovery of Pi to values exceeding control levels, glycogenolysis only recovered partially, attesting to the Pi-dependence of glycogenolysis, but also to inhibition by aHMol phosphorylation products. However, KCN resulted in conversion of the major part of aHMol1P into aHMol(1,6)P2. Residual inhibition of glycogenolysis was due to aHMol1P. Indeed, the subsequent withdrawal of aHMol caused a further gradual decrease in the proportion of aHMol1P (being converted into aHMol(1,6)P2, in the absence of de novo aHMol1P synthesis), and this resulted in a gradual de-inhibition of glycogenolysis, in the absence of marked changes in Pi. Glycogenolytic rates were consistently predicted by a model assuming non-saturated Pi kinetics and competition by aHMol1P exclusively: In conclusion, limited Pi availability and the presence of competitive inhibitors are decisive factors in the control of the in situ catalytic potential of phosphorylase a.

Animals↗
PubMed1993

Inhibition of glucagon-stimulated glycogenolysis by S-nitroso-N-acetylpenicillamine.

Rat liver is known to contain both a nitric oxide-stimulated guanylate cyclase and a cGMP-stimulated cAMP-phosphodiesterase. To evaluate the possible function of this system, the effect of the nitric oxide generating compound S-nitroso-N-acetylpenicillamine on glycogenolysis was evaluated in isolated rat hepatocytes. S-nitroso-N-acetylpenicillamine (1.0 mM) inhibited glucagon-stimulated glycogenolysis by 15%, but had no effect on basal rates of glycogenolysis. Inhibition of hepatocyte glycogenolysis by S-nitroso-N-acetylpenicillamine was associated with accumulation of cGMP (1.5 pmol/2.0 x 10(6) cells/2 min.). Exogenous 8-Br-cGMP (1.0 mM) inhibited hepatocyte glucagon-stimulated glycogenolysis by a magnitude similar to that observed with S-nitroso-N-acetylpenicillamine. S-nitroso-N-acetylpenicillamine had no effect on phenylephrine-stimulated glycogenolysis, but inhibited 8-bromo-cAMP-stimulated glycogenolysis by 15%. These observations suggest that S-nitroso-N-acetylpenicillamine inhibits cAMP-mediated stimulation of glycogenolysis at a site distal to adenylate cyclase. In summary, hepatocyte glucagon-stimulated glycogenolysis was inhibited to a small, but significant, degree by S-nitroso-N-acetylpenicillamine. This inhibition is consistent with a nitric oxide mediated stimulation of guanylate cyclase and consequent stimulation of cAMP-phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiologic conditions.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1986

Evidence for direct effect of tolbutamide on hepatic glycogenolysis induced by Ca2+-dependent hormones.

The effects of tolbutamide and glibenclamide on hepatic glycogenolysis in perfused rat liver were investigated. Tolbutamide per se did not influence glucose output from the liver, but at therapeutic concentrations (about 350 microM) it significantly inhibited the glycogenolysis induced by phenylephrine, vasopressin and angiotensin II, while glibenclamide did not. Neither tolbutamide nor glibenclamide inhibited the glycogenolysis induced by glucagon. Tolbutamide potentiated the inhibitory effect of submaximal concentrations of insulin on glycogenolysis induced by phenylephrine. This effect of tolbutamide was elicitable even in the absence of calcium in the perfusate, and was additive to that of trifluoperazine. However, tolbutamide did not potentiate the inhibitory effect of insulin on glucagon-induced glycogenolysis. Tolbutamide inhibited the glycogenolysis induced by A23187, a calcium ionophore. These results indicate that, in addition to its known effect on insulin secretion, tolbutamide has a direct effect on the liver to inhibit glycogenolysis induced by Ca2+-dependent hormones (catecholamines, vasopressin and angiotensin II) and A23187. Thus, it is likely that tolbutamide inhibits the effect of Ca2+ mobilized by Ca2+-dependent hormones to stimulate glycogenolysis.

Angiotensin II↗
PubMed1990

Structural specificity for prostaglandin effects on hepatocyte glycogenolysis.

Prostaglandins (PGs) are known to have effects on hepatic glucose metabolism. Some actions of PGs in intact liver systems may not involve PG effects directly at the level of the hepatocyte. To define the ability of structurally distinct prostaglandins to affect hepatocyte metabolism directly, the regulation of glycogenolysis was studied in hepatocytes isolated from male Sprague-Dawley rats. PGF and PGB2 inhibited glucagon-stimulated glycogenolysis in the hepatocyte system. Pinane thromboxane A2 (PTA2) and PGD2 had no effect on glucagon-stimulated glycogenolysis. Consistent with their inhibition of glucagon-stimulated glycogenolysis, PGF2 and PGF2 alpha inhibited glucagon-stimulated hepatocyte cyclic AMP accumulation. These actions of PGB2 and PGF2 alpha are identical with those previously reported for PGE2. Additionally, PGE2, PGF2 alpha and PGB2 inhibited glucagon-stimulated adenylate cyclase activity in purified hepatic plasma membranes. In contrast, PGF2 alpha, PGD2 and PTA2 were all without affect on basal rates of hepatocyte glycogenolysis or hepatocyte cyclic AMP content. PGE2 also inhibited glycogenolysis stimulated by the alpha-adrenergic agonist phenylephrine. Exogenous arachidonic acid was not able to reproduce the affects of PGE2 or PGF2 alpha on hepatocyte glycogenolysis, consistent with an extra-hepatocyte source of the prostaglandins in the intact liver. Thus PGE2 and PGF2 alpha act specifically to inhibit glucagon-stimulated adenylate cyclase activity. No prostaglandin tested was found to stimulate glycogenolysis. PGE2 and PGF2 alpha may represent intra-hepatic modulators of hepatocyte glucose metabolism.

Animals↗
PubMed1976

Hormone-stimulated glycogenolysis in isolated goldfish hepatocytes.

Hepatocytes isolated from the liver of the common goldfish Carassius auratus L. with crude bacterial collagenase maintained ATP levels for at least 2 h. Glycogenolysis was maximally activated by 1 X 10(-6) M epinephrine and 5.8 X 10(-9) M glucagon. In liver cells incubated in calcium-free buffer containing 1 mM ethylene glycol-bis-(beta-aminoethylether)-N,N'-tetraacetic acid, basal glycogenolysis was enhanced by the addition of 1-4 mM calcium but the elevation of cyclic AMP and glycogenolysis due to epinephrine was unaffected by calcium. The divalent cation ionophore A23187 did not alter basal or hormone-stimulated glycogenolysis. Isoproterenol was approximately as potent as epinephrine but phenylephrine was glycogenolytic only at very high concentrations. l-Propranolol competitively inhibited the increased glycogenolysis due to catecholamines but phentolamine was ineffective as a blocking agent. Isoproterenol and epinephrine stimulated glycogenolysis at lower concentrations than those required to elevate cyclic AMP accumulation. Phenylephrine was without effect on cyclic AMP. Propranolol competitively inhibited both epinephrine- and isoproterenol-stimulated cyclic AMP accumulation, but phentolamine did not block either response. Catecholamine-stimulated glycogenolysis in goldfish liver is apparently a beta-adrenergic effect. However, low concentrations of epinephrine enhance glycogenolysis without affecting total cyclic AMP.

Adenosine Triphosphate↗
PubMedDate not supplied

Crucial role of intracellular effectors on glycogenolysis in the isolated rat heart: potential consequences on the myocardial tolerance to ischemia.

The role played by glycogenolysis in the ischemic heart has been recently put into question because it is suspected that a slowing down of this process could be beneficial for the tolerance of the myocardium to ischemia. The role of the intracellular effectors that control the rate of glycogenolysis has therefore regained interest. We aimed to understand the role played by those intracellular effectors which are directly related to the energy balance of the heart. To this end, we review some of the previously published data on this subject and we present new data obtained from P-31 and C-13 NMR spectroscopic measurement on isolated rat heart. Two conditions of ischemia were studied: 15 min global no-flow and 25 min low-flow ischemia. The hearts were isolated either from control animals or from rats pre-treated with isoproterenol (5 mg.kg-1 b.w. i.p.) 1 h before the perfusion in order to C-13 label glycogen stores. Our main results are as follows: (1) the biochemically determined glycogenolysis rate during the early phase of ischemia (up to 10-15 min) was larger in no-flow ischemia than in low-flow conditions for both groups, (2) direct measurement of the glycogenolysis rate, as determined by C-13 NMR, after labelling of the glycogen pool in the hearts from isoproterenol-treated rats, confirms the estimations from the biochemical data, (3) glycogenolysis was slower in the hearts from pre-treated animals than in control hearts for both conditions of ischemia, (4) the total activity of glycogen phosphorylase (a + b) increased, by 50%, after 5 min no-flow ischemia, whereas it decreased by 42% after the same time of low-flow ischemia. However, the ratio phosphorylase a/a + b was not altered, whatever the conditions, (5) the concentration of inorganic phosphate (Pi) increased sharply during the first minutes of ischemia, to values above 8-10 mM, under all conditions studied. The rate of increase was larger during no-flow ischemia than during low-flow ischemia. The concentration of Pi was thereafter higher in controls than in the hearts from isoproterenol-treated animals. The calculated cytosolic concentration of free 5'AMP increased sharply at the onset on ischemia, reaching in a few minutes values above 30 microM in controls and significantly lower values around 15 microM, in the hearts from isoproterenol-treated rats. (6) The hearts from isoproterenol-treated rats displayed a reduced intracellular acidosis, when compared to controls, under both conditions of ischemia. We conclude that the intracellular effectors, mainly free AMP, play an essential role in the control of glycogenolysis via allosteric control of phosphorylase b activity. The alteration in the concentration of free Pi, the substrate of both forms of phosphorylase, can be considered as determinant in the control of the rate of glycogenolysis. The attenuation of ischemia-induced intracellular acidosis in the hearts from isoproterenol-treated rats could be a consequence of a reduced glycogenolytic rate and is likely to be related to a better resumption of the mechanical function on reperfusion.

Adenosine Triphosphate↗
PubMed1988

Prostaglandin D2 mediates the stimulation of glycogenolysis in the liver by phorbol ester.

The tumour-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), when added to the perfused liver, stimulates glycogenolysis 2-fold. This stimulation is not seen when aspirin is present in the perfusion medium. In isolated parenchymal liver cells. PMA is not able to stimulate glycogenolysis, suggesting that its effect on glycogenolysis might be indirect and depends on the presence of the non-parenchymal liver cell types. To test the possible operation of an indirect mechanism, we measured the amount of prostaglandin (PG) D2 in liver perfusates. After addition of PMA, the amount of PGD2 is doubled, in parallel with the increase in glycogenolysis. Glycogenolysis in both isolated parenchymal liver cells and perfused liver could be stimulated by the addition of PGD2. Our data indicate that stimulation of glycogenolysis in the liver by PMA may be mediated by non-parenchymal liver cells, which produce PGD2 in response to PMA. Subsequently PGD2 activates glycogenolysis in the parenchymal liver cells. The intercellular communication inside the liver in response to PMA adds a new mechanism to the complex regulation of glucose homoeostasis by the liver.

Animals↗
PubMed1992

Different preparations of zymosan induce glycogenolysis independently in the perfused rat liver. Involvement of mannose receptors, peptide-leukotrienes and prostaglandins.

Zymosan (non-boiled) induced glycogenolysis biphasically, with no lag time, in the perfused rat liver. After the zymosan was boiled, it could be separated into two fractions, both of which stimulated glycogenolysis independently. The soluble fraction of boiled zymosan (zymosan sup) showed homologous desensitization, indicating that zymosan sup-induced glycogenolysis is a receptor-mediated event. Mannan (polymannose), which is known to be a biologically active component of zymosan, induced a glycogenolytic response similar to that produced by zymosan sup, and desensitized the response to the latter. Preinfusion of platelet-activating factor (PAF, 20 nM) or isoprenaline (10 microM) did not extinguish the glycogenolytic response to zymosan sup, while the response to a secondary infusion of PAF was blocked. The glycogenolytic response to zymosan sup was completely inhibited by nordihydroguaiaretic acid (NDGA, 10 microM), a lipoxygenase inhibitor, and by ONO-1078 (100 ng/ml), a leukotriene (LT) D4 receptor antagonist. On the other hand, the glycogenolytic effect of zymosan pellet (the particulate fraction of boiled zymosan) was not affected by preinfusion of zymosan sup, and was inhibited by ibuprofen (20 microM), a cyclo-oxygenase inhibitor. Prostaglandins (PGs) detected in the perfusate were augmented with infusion of zymosan pellet. Opsonization of the zymosan pellet by serum (complement) enhanced the glycogenolytic response without a lag period, and with a concomitant enhancement of PG output. Correlations between glucose production and PGs were r = 0.832 (PGD2), r = 0.872 (PGF2 alpha), r = 0.752 (PGE2) and r = 0.349 (6-oxo-PGF1 alpha). The glycogenolytic response to non-boiled zymosan was delayed and the biphasic glycogenolytic response was not observed when mannan was infused first. NDGA mimicked the effects of the preinfusion of mannan, while ibuprofen had no effect on the non-boiled-zymosan-induced glycogenolysis. These results suggest: (1) that non-boiled zymosan stimulates glycogenolysis through a mannose receptor-dependent, but unidentified, pathway, (2) that zymosan sup induces glycogenolysis via mannose receptor activation through the production of peptide-LTs but not PAF, and (3) that zymosan pellet causes glycogenolysis through the production of prostanoids, which is enhanced in the presence of complement.

Animals↗
PubMed1992

Transient activation of hepatic glycogenolysis by thrombin in perfused rat livers.

Thrombin, a peptide with native protease activity, caused a rapid (less than 1 min) increase in glycogenolysis of about 30%, assessed from rates of production of glucose+lactate+pyruvate, and in oxygen uptake in perfused rat liver. These increases were followed by a rapid return to basal values within 5 min. The effect of thrombin on glycogenolysis was dose-dependent and was maximal at perfusate concentrations around 1 U/ml. Interestingly, the effect of thrombin on glycogenolysis could be elicited only once in any given liver. The activation of glycogenolysis by thrombin was diminished nearly 50% by prior infusion of the protease inhibitor, diisopropyl fluorophosphate (10 microM), and over 90% when thrombin was treated with diisopropyl fluorophosphate prior to infusion. The stimulation of glycogenolysis by thrombin could be detected in isolated hepatocytes or in livers stored for 24 h in cold Euro-Collins solution, a treatment which destroys endothelial cells. Further, thrombin stimulated production of prostaglandin D2 from arachidonic acid in cultured hepatic endothelial but not Kupffer cells. The effect of thrombin on carbohydrate output was also blocked by a phospholipase A2 inhibitor (quinacrine, 50 microM) and by an inhibitor of the cyclooxygenase (indomethacin, 20 microM), suggesting the involvement of cyclooxygenase in the mechanism of action of thrombin. In support of this idea, the transient kinetics of stimulation of glycogenolysis by thrombin and arachidonic acid was nearly identical to release of thromboxane B2 (80-420 pg/ml) and prostaglandin D2 (300-900 pg/ml) from the perfused liver. Further, a second addition of thrombin failed to increase thromboxane and prostaglandin D2 release as well as carbohydrate production, supporting a causal link between these phenomena. Taken together, these data support the hypothesis that thrombin interacts with receptors in the liver, possibly on endothelial cells, leading to activation of phospholipase A2 and subsequent transient production of prostaglandins and thromboxanes. These mediators subsequently interact with receptors on parenchymal cells, leading to a transient stimulation of glycogenolysis.

Animals↗
PubMed1988

Role of cyclic AMP and inorganic phosphate in the regulation of muscle glycogenolysis during exercise.

The roles of cAMP and inorganic phosphate (Pi) in the regulation of muscle glycogenolysis during exercise have been investigated in humans using the needle biopsy technique. The fraction of phosphorylase a in resting muscle was as a mean 23%, but the rate of glycogenolysis was extremely low. Epinephrine infusion increased cAMP in muscle by 3-fold and transformed 80% of phosphorylase to the a form. Despite this, the rate of glycogenolysis was only 5-10% of the maximum rate of phosphorylase a (Vmax a) determined in vitro. Isometric exercise for 25 s at 66% MVC or electrical stimulation for 50 s at 20 Hz transformed about 53% and 80% of phosphorylase in the a form. The rate of glycogenolysis ranged between 50-90 mmol.kg-1.dm.min-1 and was close to Vmax of phosphorylase a determined in vitro. No significant difference in the rate of glycogenolysis in muscle was observed after isometric exercise to fatigue without and with epinephrine infusion, respectively. Apparently the rate of glycogenolysis in muscle is not solely related to the fraction of phosphorylase in the a form. Several factors could be responsible for allosteric and/or substrate regulation. The results in the present studies can be explained on the basis of substrate regulation of phosphorylase activity, provided that Pi is present in a limiting amount at the active site of phosphorylase in muscle at rest. It is concluded that transformation of phosphorylase b to a is important but alone is not adequate for a high activity and thus for a high rate of glycogenolysis in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic AMP↗
PubMed1996

Modulation of basal hepatic glycogenolysis by nitric oxide.

We perfused livers from fed rats with a balanced salt solution containing 1 mmol/L glucose. Under these conditions a low steady rate of glycogenolysis was observed (approximately 1.7 micromol glucose equivalents/g/min; 20% of the maximal glycogenolytic activity). Nitric oxide (NO) transiently stimulated hepatic glucose production. A maximal response (on average doubling basal glucose output) was observed with 34 micromol/L NO. The same concentration of nitrite (NO2-) was ineffective. Half-maximal effects were seen at 8 to 10 micromol/L NO, irrespective of the flow direction (portocaval or retrograde). This glycogenolytic response to NO corresponded to a partial activation of phosphorylase. The NO effect was not additive to maximal stimulation of glycogenolysis (7.7 +/- 0.2 micromol hexose equivalents/g/min; n = 4) by 100 micromol/L dibutyryl cyclic adenosine monophosphate (Bt2cAMP). The requirement for activation of phosphorylase was also evidenced by the ineffectiveness of NO in phosphorylase-kinase-deficient livers of gsd/gsd rats. The NO effect was blocked by co-administration of cyclooxygenase inhibitors (50 micromol/L ibuprofen, 50 micromol/L indomethacin, or 2 mmol/L aspirin), suggesting a mediatory role of prostanoids from nonparenchymal cells. This conclusion was confirmed by the fact that NO did not activate phosphorylase in isolated hepatocytes. Moreover, NO was no longer glycogenolytic in livers perfused with Ca2+-free medium, in agreement with the known mediatory role of Ca2+ in prostanoid-mediated responses. Surprisingly, in Ca2+-free medium NO inhibited the basal glucose production. This coincided with an increased elution of cyclic guanosine monophosphate (cGMP). Inhibition of glycogenolysis by NO under these conditions was blocked by 1 mmol/L theophylline, suggestive for involvement of cGMP-stimulated cAMP phosphodiesterase. However, we could not confirm that an increase in cGMP resulted in a drop in cAMP. In conclusion, NO recruits opposing mechanisms with respect to modulation of basal hepatic glycogenolysis. In the presence of Ca2+, activation of phosphorylase with stimulation of glycogenolysis dominates. Cyclooxygenase inhibitors abolish this effect. Activation by NO of the cyclooxygenase in nonparenchymal cells is a distinct possibility. In the absence of Ca2+, inhibition of basal glycogenolysis becomes observable. It remains to be established whether this results from cGMP-mediated stimulation of hydrolysis of cAMP.

Animals↗
PubMed2001

Subnormal response of plasma glucose concentration to glucagon despite adequate glycogenolysis: the importance of kinetic measurements.

The plasma glucose concentration response to a glucagon bolus is considered an important diagnostic tool in hypoglycemia of unknown origin. The response of plasma glucose concentration to glucagon can however also be misleading in the differential diagnosis. In a 3-week-old male infant suffering recurrent severe preprandial hypoglycemia and dependent on continuous i.v. glucose infusion, extensive diagnostic screening including a liver biopsy did not lead to a diagnosis. Based on an insufficient glycemic response (twice) to a glucagon bolus, a disorder of glycogenolysis was suspected. Glucose production and gluconeogenesis were measured (glycogenolysis calculated) during diminishing i.v. glucose infusion and after a glucagon bolus. Reducing glucose infusion resulted in a steep increase in glycogenolysis and gluconeogenesis, maintaining total glucose turnover (production plus infusion) constant at +/-9 mg x kg(-1) x min(-1) (+/-60% gluconeogenesis, +/-40% glycogenolysis). Plasma glucose concentration however decreased from 4.9 mmol/l to 3.4 mmol/l. Glucagon increased glucose production by 50% but resulted in only a minor increase in glucose concentration. Conclusion. As glucose concentration depends on the balance between glucose production and utilization (uptake), facilitated glucose uptake rather than impaired glycogenolysis explains the hypoglycemic episodes in this patient. A subnormal response of plasma glucose to glucagon therefore does not necessarily imply a disturbance in glycogenolysis. In cases of hypoglycemia of unknown origin, measurement of glucose kinetics with stable isotopes is indicated.

Blood Glucose↗
PubMed1988

Regulation of immune-aggregate-stimulated hepatic glycogenolysis and vasoconstriction by vicinal dithiols.

Evidence suggesting that vicinal dithiols regulate immune-aggregate-induced vasoconstriction and glycogenolysis in the perfused rat liver was obtained. Phenylarsine oxide (PhAsO) and other tervalent organic arsenicals inhibited in a dose-dependent manner hepatic glycogenolysis, vasoconstriction, Ca2+ mobilization and the stimulated O2 consumption caused by immune-aggregate infusion. Polar tervalent and quinquivalent arsenicals were less effective than hydrophobic arsenicals. Prior infusion of Fc- but not Fab-fragments of IgG prevented partially immune-aggregate-stimulated hepatic metabolism, suggesting that immune aggregates elicit hepatic metabolic responses through Fc gamma receptors. The inhibitory action of PhAsO on immune-aggregate-stimulated hepatic glycogenolysis was unique; inhibition of glycogenolysis was not observed when phenylephrine, isoprenaline or glucagon was used as a stimulant. Although PhAsO might be expected to sequester cellular thiols, no significant change in the oxidation-reduction state of the major cellular thiol, glutathione, was found during PhAsO infusion. In addition, PhAsO exerted its effects without producing changes in hepatic adenine nucleotides and cyclic AMP. Evidence suggesting the involvement of vicinal dithiols was obtained through thiol-competition experiments using mono- and di-thiols. PhAsO inhibition of IgG-aggregate-stimulated hepatic vasoconstriction and glycogenolysis was reversed significantly by infusion of 2,3-dimercaptopropan-1-ol at 3-fold molar excess, whereas 2-mercaptoethanol at 40-fold molar excess was ineffective. The results of the present study provide evidence documenting the participation of vicinal dithiols during the coupling of hepatic immune-aggregate clearance by Kupffer cells with vasoconstriction of the hepatic vasculature (e.g. endothelial cells) and glycogenolysis (e.g. parenchymal cells).

Adenine Nucleotides↗
PubMed1982

Muscle glycogenolysis during exercise: dual control by epinephrine and contractions.

The interaction of epinephrine and contractions on muscle metabolism was studied in the isolated perfused rat hindquarter. Subtetanic contractions (180/min) through 20 min elicited glycogenolysis and increased phosphorylase a activity. In the soleus, a slow-twitch red muscle, these effects were transient, but when epinephrine at a physiological concentration (2.4 X 10(-8) M) was added to the perfusate, glycogenolysis and phosphorylase activity were sustained throughout contractions. At this high frequency of contractions, the effect of epinephrine was much smaller in the fast-twitch red fibers and not significant in the fast-twitch white fibers of the gastrocnemius muscle. However, during less frequent contractions (30/min) epinephrine increased glycogenolysis and phosphorylase a activity in fast-twitch muscle. The data suggest that epinephrine and muscle contractions exert a dual control of muscle glycogenolysis during exercise: contractions principally stimulate glycogenolysis early in exercise, and a direct effect of epinephrine on muscle is needed for continued glycogenolysis. In addition, epinephrine increased oxygen consumption and glucose uptake in both resting and electrically stimulated hindquarters and, under some conditions, it had a positive inotropic effect on contracting muscle.

Adenosine Triphosphate↗