Stimulation Of Glycogenolysis Research Articles

Role of Glucagon in The Metabolic Response

Historically, glucagon is the counter-regulatory hormone of insulin. Glucagon secretion is induced by fasting conditions or hypoglycaemia to increase glucose levels. Glucagon is the dominant product of alpha cells in the islet and was first identified in 1923 during an attempt to purify insulin, where it was identified as a contaminant hyperglycaemia factor. Further research determined that the hyperglycaemic action of glucagon is mediated by increased hepatic glycogenolysis and gluconeogenesis to increase endogenous glucose production. Insulin and glucagon as opposing hormones work together for glycaemic control. Diabetic hyperglycaemia is caused by increased impaired insulin action and inappropriately elevated glucagon levels. This review summarizes an important function of glucagon is its role as a regulator of glucose homeostasis. Increased plasma glucagon levels lead to increased hepatic glucose production. The balance between insulin and glucagon is responsible for maintaining euglycaemia conditions. In conditions of hypoglycaemia, increased glucagon secretion leads to increased hepatic glucose production through a number of cellular mechanisms including suppression of glycogenesis and glycolysis and stimulation of glycogenolysis and gluconeogenesis

OR24-4 Targeting Hyperglucagonemia Reverses Glucagon Resistance

Abstract Elevation of glucagon levels and increase in alpha-cell mass are associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications in understanding abnormal responses to hypoglycemia in diabetic patients and provide novel avenues for diabetes management. Stimulation of glucagon secretion in hypoglycemia, or by amino acids, induces hepatic glucose production via cellular mechanisms including suppression of glycogenesis and glycolysis and stimulation of glycogenolysis and gluconeogenesis. The close link between amino acids and the alpha-cell is highlighted by the liver–alpha-cell axis. This axis was identified by the major increase in alpha-cell hyperplasia and hyperglucagonemia in models of reduced glucagon action in hepatocytes genetically or pharmacologically by treatment with glucagon receptor antagonists, which was subsequently attributed to the dramatic rise in amino acids. Induction of mTORC1 by constitutive genetic deletion of TSC2 in alpha-cells (aTSC2KO) recapitulated the effects of chronic hyperaminoacidemia with increases in alpha-cell mass and chronic hyperglucagonemia indicating that mTORC1 mediates amino acids signals in alpha-cells. However, the effects of acute versus chronic induction of alpha-cell mTORC1 signaling on these outcomes have not been explored. Using mice with doxycycline induction of Rheb (activator of mTORC1 signaling) (aRhebTg) and inducible Cre-mediated deletion of the mTORC1 inhibitor, TSC2, in alpha-cells (iaTSC2KO), we showed that induction of hyperglucagonemia is associated with two phases: Acute phase characterized by impaired glucose tolerance because of increased gluconeogenesis and glucose output by the liver. And a chronic phase, characterized by normalization of glucose tolerance due to downregulation of the hepatic glucagon receptor (Gcgr), Pepck, and some genes involved in amino acid metabolism and urea production. Importantly, the consequences of chronic hyperglucagonemia were reversible after normalization of glucagon levels by turning off alpha-cell Rheb expression. These studies uncovered the acute versus chronic effects of hyperglucagonemia on glucose homeostasis and further demonstrate that glucagon resistance is a reversible process. These observations provide insight into the impact of glucagon in the pathogenesis of hyperglycemia and the physiological effects of administration of dual GLP1/Glucagon receptor agonists. Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.

Contribution of Adenosine in the Physiological Changes and Injuries Secondary to Exposure to Extreme Oxygen Pressure in Healthy Subjects

Climbers and aviators are exposed to severe hypoxia at high altitudes, whereas divers are exposed to hyperoxia at depth. The aim of this study was to report changes in the adenosinergic system induced by exposure to extreme oxygen partial pressures. At high altitudes, the increased adenosine concentration contributes to brain protection against hypoxia through various mechanisms such as stimulation of glycogenolysis for ATP production, reduction in neuronal energy requirements, enhancement in 2,3-bisphosphoglycerate production, and increase in cerebral blood flow secondary to vasodilation of cerebral arteries. In the context of mountain illness, the increased level of A2AR expression leads to glial dysfunction through neuroinflammation and is involved in the pathogenesis of neurological disorders. Nonetheless, a high level of adenosine concentration can protect against high-altitude pulmonary edema via a decrease in pulmonary arterial pressure. The adenosinergic system is also involved in the acclimatization phenomenon induced by prolonged exposure to altitude hypoxia. During hyperoxic exposure, decreased extracellular adenosine and low A2A receptor expression contribute to vasoconstriction. The resulting decrease in cerebral blood flow is considered a preventive phenomenon against cerebral oxygen toxicity through the decrease in oxygen delivery to the brain. With regard to lung oxygen toxicity, hyperoxia leads to an increase in extracellular adenosine, which acts to preserve pulmonary barrier function. Changes in the adenosinergic system induced by exposure to extreme oxygen partial pressures frequently have a benefit in decreasing the risk of adverse effects.

Glucagon regulates lipolysis and fatty acid oxidation through inositol triphosphate receptor1 in the liver.

Glucagon promotes hepatic glucose production, lipolysis and amino acid catabolism. Inhibition of glucagon activity, or glucagon resistance, not only lowers blood glucose levels, but also induces non-alcoholic fatty liver disease and hyperaminoacidemia.

Analysis of Direct Effects of the CB1 Receptor Antagonist Rimonabant on Fatty Acid Oxidation and Glycogenolysis in Liver and Muscle Cells in vitro.

Recent pharmacological findings regarding rimonabant, an anorectic and cannabinoid type 1 receptor (CB1R) antagonist, strongly suggest that some of its effects on the metabolic parameters and energy balance in rats are not related to the centrally mediated reduction in caloric intake. Instead, they may be associated with acute induction of glycogenolysis in the liver, in combination with transient increase in glucose oxidation and persistent increase in fat oxidation. It is possible that rimonabant produced direct short- or long-term stimulatory effect on these processes in primary and cultured rat cells. Rimonabant slightly stimulated β-oxidation of long-chain fatty acids in cultured rat myocytes overexpressing glucose transporter isoform 4, as well as activated phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK) in primary rat hepatocytes upon long-term incubation. However, short-term action of rimonabant failed to stimulate β-oxidation in myocytes, myotubes, and hepatocytes, as well as to upregulate AMPK phosphorylation, glycogenolysis, and cAMP levels in hepatocytes. As a consequence, the acute effects of rimonabant on hepatic glycogen content (reduction) and total energy expenditure (increase) in rats fed with a standard diet cannot be explained by direct stimulation of glycogenolysis and fatty acid oxidation in muscles and liver. Rather, these effects seem to be centrally mediated.

A New Activator of Hepatocyte CaMKII in Fasting and Type 2 Diabetes.

Positive regulation of hepatic glucose production (HGP) and stimulation of glycogenolysis during fasting are critical processes to prevent hypoglycemia. A key hormone that carries out this function is glucagon, which is secreted by pancreatic α-cells in response to fasting and acts on its receptor on hepatocytes to promote HGP and glycogenolysis (1). However, as often happens, processes that are critical in physiology can promote disease processes in nonphysiological settings. As such, glucagon-induced HGP is a major contributor to excessive HGP and hyperglycemia in obesity and type 2 diabetes (T2D) (2). In this issue of Diabetes , Wang et al. (3) provide evidence that another circulating factor that is increased in fasting and obesity/T2D—prostaglandin F2α (PGF2α)—also promotes HGP in both fasting and obese, insulin-resistant mice. Previous work has elucidated a number of pathways through which activation of the hepatocyte glucagon receptor (GcgR), which is a G-protein–coupled receptor (GPCR), promotes HGP and glycogenolysis in both fasting and obesity. Specifically, adenylyl cyclase/cyclic AMP-mediated protein kinase A (PKA) activation by G proteins of the GcgR controls the transcriptional regulation of HGP and glycogenolysis through at least three distinct but complementary processes (Fig. 1): phosphorylation of CREB, which results in recruitment of its coactivators, CBP and p300; deactivation of a kinase called SIK2; and activation of inositol 3-phosphate receptors (IP3Rs), leading to release of endoplasmic reticulum calcium into the cytosol and subsequent activation of the phosphatase calcineurin and the kinase Ca2+/calmodulin-activated protein kinase IIγ …

Effect of fipronil on energy metabolism in the perfused rat liver

Fipronil is an insecticide used to control pests in animals and plants that can causes hepatotoxicity in animals and humans, and it is hepatically metabolized to fipronil sulfone by cytochrome P-450. The present study aimed to characterize the effects of fipronil (10–50μM) on energy metabolism in isolated perfused rat livers. In fed animals, there was increased glucose and lactate release from glycogen catabolism, indicating the stimulation of glycogenolysis and glycolysis. In the livers of fasted animals, fipronil inhibited glucose and urea production from exogenous l-alanine, whereas ammonia and lactate production were increased. In addition, fipronil at 50μM concentration inhibited the oxygen uptake and increased the cytosolic NADH/NAD+ ratio under glycolytic conditions. The metabolic alterations were found both in livers from normal or proadifen-pretreated rats revealing that fipronil and its reactive metabolites contributed for the observed activity. The effects on oxygen uptake indicated that the possible mechanism of toxicity of fipronil involves impairment on mitochondrial respiratory activity, and therefore, interference with energy metabolism. The inhibitory effects on oxygen uptake observed at the highest concentration of 50μM was abolished by pretreatment of the rats with proadifen indicating that the metabolites of fipronil, including fipronil sulfone, acted predominantly as inhibitors of respiratory chain. The hepatoxicity of both the parent compound and its reactive metabolites was corroborated by the increase in the activity of lactate dehydrogenase in the effluent perfusate in livers from normal or proadifen-pretreated rats.

Basic Mechanism Leading to Stimulation of Glycogenolysis by Isoproterenol, EGF, Elevated Extracellular K+ Concentrations, or GABA

Glycogenolysis, in brain parenchyma an astrocyte-specific process, has changed from being envisaged as an emergency procedure to playing central roles during brain response to whisker stimulation, memory formation, astrocytic K(+) uptake and stimulated release of ATP. It is activated by several transmitters and by even very small increases in extracellular K(+) concentration, and to be critically dependent upon an increase in free cytosolic Ca(2+) concentration ([Ca(2+)]i), whereas cAMP plays only a facilitatory role together with increased [Ca(2+)]i. Detailed knowledge about the signaling pathways eliciting glycogenolysis is therefore of interest and was investigated in the present study in well differentiated cultures of mouse astrocytes. The β-adrenergic agonist isoproterenol stimulated glycogenolysis by a β1-adrenergic effect, which initiated a pathway in which cAMP/protein kinase A activated a Gi/Gs shift, leading to Ca(2+)-activated glycogenolysis. Inhibition of this pathway downstream of cAMP but upstream of the Gi/Gs shift abolished the glycogenolysis. However, inhibitors operating downstream of the Ca(2+)-sensitive step, but preventing transactivation-mediated epidermal growth factor (EGF) receptor stimulation, a later step in the activated pathway, also caused inhibition of glycogenolysis. For this reason the effect of EGF was investigated and it was found to be glycogenolytic. Large increases in extracellular K(+) activated glycogenolysis by a nifedipine-inhibited L-channel opening allowing influx of Ca(2+), known to be glycogenolysis-dependent. Small increases (addition of 5mMKCl) caused a smaller effect by a similarly glycogenolysis-reliant opening of an IP3 receptor-dependent ouabain signaling pathway. The same pathway could be activated by GABA (also in brain slices) due to its depolarizing effect in astrocytes.

Purinergic Effects of a Hydroalcoholic Agaricus brasiliensis (A. blazei) Extract on Liver Functions

The effects of a hydroalcoholic extract of Agaricus brasiliensis (A. blazei) on functional parameters in the perfused rat liver were examined with emphasis on its content of nucleotides and nucleosides. Several nucleosides and nucleotides were identified in the A. brasiliensis extract, which was active on several liver functions. A significant part of the effects is the result of the purinergic action of nucleosides and nucleotides: pressure increment, glycogenolysis stimulation, transient inhibition of oxygen consumption, and redox state changes. Other phenomena such as the stimulation of gluconeogenesis, ureogenesis, and oxygen consumption are more likely consequences of the metabolic transformation of substrates contained within the extract, especially amino acids. It seems apparent that consumption of A. brasiliensis represents not only the ingestion of metabolic precursors but also the ingestion of substances that, even at low concentrations, can exert important signaling functions in the liver as well as in the organism as a whole.

The Structure Of Phosphorylase Kinase Holoenzyme At Subnanometer Resolution, Location Of The Catalytic Subunit And The Substrate Glycogen Phosphorylase

Phosphorylase kinase (PhK) coordinates hormonal and neuronal signals to initiate the breakdown of glycogen. The enzyme catalyzes the phosphorylation of inactive glycogen phosphorylase b (GPb), resulting in the formation of active glycogen phosphorylase a (GPa) and the stimulation of glycogenolysis. PhK is one of the largest of the protein kinases (MW 1.3 x 106) and contains four copies of four subunits: α,β,γ and δ. Here we present a 9.9Å resolution structure of PhK determined by electron cryo-microscopy single-particle reconstruction. The enzyme has a butterfly-like shape comprised of two lobes with 222 symmetry. This 3D structure has allowed us to dock the catalytic γ domain, whose crystal structure is known, to the PhK holoenzyme at a location that is towards the ends of the lobes. The kinase domain is not involved in homo-dimer interactions. We have also determined the structure of PhK decorated with GPb at 18-Å resolution, which shows GPb located at the end of the lobes. Comparison of PhK/GPb complex with the volume of density for the GPb dimer derived from the X-ray model indicates that only one subunit of GPb is localized. Careful examination of the electron microscope images revealed a mixture of large and small PhK particles. In addition to the large particles described above we have determined the reduced size particles at 9.8Å resolution. This structure was consistent with a proteolysed activated form of PhK that had lost the α subunit and possibly the γ subunit.

Imaging the tissue distribution of glucose in livers using a PARACEST sensor

Noninvasive imaging of glucose in tissues could provide important insights about glucose gradients in tissue, the origins of gluconeogenesis, or perhaps differences in tissue glucose utilization in vivo. Direct spectral detection of glucose in vivo by (1)H NMR is complicated by interfering signals from other metabolites and the much larger water signal. One potential way to overcome these problems is to use an exogenous glucose sensor that reports glucose concentrations indirectly through the water signal by chemical exchange saturation transfer (CEST). Such a method is demonstrated here in mouse liver perfused with a Eu(3+)-based glucose sensor containing two phenylboronate moieties as the recognition site. Activation of the sensor by applying a frequency-selective presaturation pulse at 42 ppm resulted in a 17% decrease in water signal in livers perfused with 10 mM sensor and 10 mM glucose compared with livers with the same amount of sensor but without glucose. It was shown that livers perfused with 5 mM sensor but no glucose can detect glucose exported from hepatocytes after hormonal stimulation of glycogenolysis. CEST images of livers perfused in the magnet responded to changes in glucose concentrations demonstrating that the method has potential for imaging the tissue distribution of glucose in vivo.

Effect of short-time malathion administration on glucose homeostasis in Wistar rat

The main objective of this study is to investigate the 24 h kinetic effect of acute administration of malathion, an organophosphorus insecticide, on glucose homeostasis in adult rats. A single dose of malathion (400 mg/kg, 1/5 of LD 50) was administered orally to rats, blood glucose was measured, liver and pancreas were removed to determine the level of hepatic glycogen, the activity of pancreatic acetylcholinesterase and butyrylcholinesterase, as well as the level of TBARs. Blood glucose increased in rats treated with a single dose of malathion. This effect was observed in the first hours of treatment, reached a 2.2 fold peak after 2 h, and then decreased after 4 h, followed by a decrease in the level of hepatic glycogen. The storage of glycogen starts from 6 to 12 h of administration. A decrease in cholinesterase activities was noted. The level of TBARs increased considerably in liver and pancreas. Results of this study can be explain by a stimulation of glycogenolysis and gluconeogenesis by liver, with a temporarily loss of endocrine functions of pancreas leading to hyperglycemia.

Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site

The bioactivity in hepatocytes of glycogen phosphorylase inhibitors that bind to the active site, the allosteric activator site and the indole carboxamide site has been described. However, the pharmacological potential of the purine nucleoside inhibitor site has remained unexplored. We report the chemical synthesis and bioactivity in hepatocytes of four new olefin derivatives of flavopiridol (1–4) that bind to the purine site. Flavopiridol and 1–4 counteracted the activation of phosphorylase in hepatocytes caused by AICAR (5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside), which is metabolised to an AMP analogue. Unlike an indole carboxamide inhibitor, the analogues 1 and 4 suppressed the basal rate of glycogenolysis in hepatocytes by allosteric inhibition rather than by inactivation of phosphorylase, and accordingly caused negligible stimulation of glycogen synthesis. However, they counteracted the stimulation of glycogenolysis by dibutyryl cAMP by both allosteric inhibition and inactivation of phosphorylase. Cumulatively, the results show key differences between purine site and indole carboxamide site inhibitors in terms of (i) relative roles of dephosphorylation of phosphorylase-a as compared with allosteric inhibition, (ii) counteraction of the efficacy of the inhibitors on glycogenolysis by dibutyryl-cAMP and (iii) stimulation of glycogen synthesis.

Liver parenchyma heterogeneity in the response to extracellular NAD+

The perfused rat liver responds intensely to NAD+ infusion (20-100 microM). Increases in portal perfusion pressure and glycogenolysis and transient inhibition of oxygen consumption are some of the effects that were observed. The aim of the present work was to investigate the distribution of the response to extracellular NAD+ along the hepatic acinus. The bivascularly perfused rat liver was used. Various combinations of perfusion directions (antegrade and retrograde) and infusion routes (portal vein, hepatic vein and hepatic artery) were used in order to supply NAD+ to different regions of the liver parenchyma, also taking advantage of the fact that its extracellular transformation generates steep concentration gradients. Oxygen uptake was stimulated by NAD+ in retrograde perfusion (irrespective of the infusion route) and transiently inhibited in antegrade perfusion. This indicates that the signal causing oxygen uptake inhibition is generated in the periportal area. The signal responsible for oxygen uptake stimulation is homogenously distributed. Stimulation of glucose release was more intense when NAD+ was infused into the portal vein or into the hepatic artery, indicating that stimulation of glycogenolysis predominates in the periportal area. The increases in perfusion pressure were more pronounced when the periportal area was supplied with NAD+ suggesting that the vasoconstrictive elements responding to NAD+ predominate in this region. The response to extracellular NAD+ is thus unequally distributed in the liver. As a paracrine agent, NAD+ is likely to be released locally. It can be concluded that its effects will be different depending on the area where it is released.

Effects of the Kielmeyera coriacea extract on energy metabolism in the rat liver

Kielmeyera coriacea Mart is a medicinal plant of the Clusiacea (Guttiferae) family used by the native population of Brazil in the treatment of several tropical diseases such as malaria, schistosomiasis, leishmaniasis, and fungal or bacterial infections. Kielmeyera coriacea is also effective as an antidepressant drug. Extracts of the plant are rich in xanthones. Compounds of this class have been reported to inhibit mitochondrial energy metabolism. For this reason the action of the Kielmeyera coriacea extract on hepatic energy metabolism was investigated in the present work, using isolated rat liver mitochondria and the perfused rat liver. In perfused livers the extract (20–80 μg/ml) caused stimulation of oxygen consumption, inhibition of gluconeogenesis and stimulation of glycogenolysis and glycolysis. In isolated mitochondria the Kielmeyera coriacea extract (5–20 μg/ml) stimulated state IV respiration, reduced the ADP/O ratio and decreased the respiratory coefficient. The activities of succinate-oxidase, NADH-oxidase, NADH dehydrogenase and succinate dehydrogenase were inhibited. The ATPase of intact mitochondria was stimulated and the ATPase of uncoupled mitochondria was inhibited. The results of this investigation suggest that the Kielmeyera coriacea extract impairs the hepatic energy metabolism by acting as mitochondrial uncoupler and inhibitor of enzymatic activities linked to the respiratory chain. The impairment of mitochondrial energy metabolism could lead to adverse metabolic effects by the use of the crude extract, but it could equally be the basis of its antiprotozoan and antifungal effects.

Importance of glutamate‐generating metabolic pathways for memory consolidation in chicks

Glutamatergic and noradrenergic stimulation is essential for formation of memory of single-trial discriminative avoidance of colored beads in the 1-day-old chick. Transmitter glutamate is released soon after training and again before memory consolidation 30 min after training. Memory consolidation is abolished by posttraining injection of iodoacetate, which inhibits glycolysis and thus not only energy metabolism but also pyruvate carboxylase-dependent glucose conversion to glutamate, needed for consolidation; a similar effect is evoked by the antagonists propranolol acting at beta(2)-adrenoceptors or SR59230A acting at beta(3)-adrenoceptors. This paper shows that the effect of these inhibitors can be overcome by central injection of glutamine, providing an alternate source of transmitter glutamate and compensating for the inhibition of glycolysis by iodoacetate or the blockade of adrenergic stimulation of glycogenolysis by propranolol or of glucose uptake by SR59230A. Conversely, inhibition of memory consolidation by methionine sulfoximine (MSO), an inhibitor of glutamine synthetase and thus of the glutamate-glutamine cycle, essential for neuronal reaccumulation of previously released transmitter glutamate, could be challenged by noradrenaline, stimulating glucose uptake and glycogenolysis and providing glutamate synthesis from glucose to compensate for the lack of return of previously released glutamate. Also, administration of either glutamine or noradrenaline could prevent the spontaneous decay of labile memory 30 min after training on a weakened stimulus, suggesting that direct supply of glutamate from glucose may secure sufficient supplies of transmitter glutamate for release prior to memory consolidation at 30 min.

Zonation of the metabolic action of vasopressin in the bivascularly perfused rat liver

Predominance of the vasopressin binding capacity in the hepatic perivenous area leads to the hypothesis that the metabolic effects of the hormone should also be more pronounced in this area. Until now this question has been approached solely by experiments with isolated hepatocytes where an apparent absence of metabolic zonation was found. We have reexamined this question using the bivascularly perfused liver. In this system periportal cells can be reached in a selective manner with substrates and effectors via the hepatic artery when retrograde perfusion (hepatic vein → portal vein) is done. The action of vasopressin (1–10 nM) on glycogenolysis, initial calcium efflux, glycolysis and oxygen uptake were measured. The results revealed that the action of vasopressin in the liver is heterogeneously distributed. Glycogenolysis stimulation and initial calcium efflux were predominant in the perivenous area, irrespective of the vasopressin concentration. Oxygen uptake was stimulated in the perivenous area; in the periportal area it ranged from inhibition at low vasopressin concentrations to stimulation at high ones. Lactate production was generally greater in the perivenous zone, whereas the opposite occurred with pyruvate production. Analysis of these and other results suggests that at least three factors are contributing to the heterogenic response of the liver parenchyma to vasopressin: a) receptor density, which tends to favour the perivenous zone; b) cell-to-cell interactions, which tend to favour situations where the perivenous zone is amply supplied with vasopressin; and c) the different response capacities of perivenous and periportal cells.

Introduction

RESEARCH IN THE last 20 years has addressed the negative effects of angiotensin II and the advantages of its inhibition on renal and cardiovascular diseases, including hypertension. However, why should natural selection over billions of years have led to the production of an hormone with so potentially harmful effects? Angiotensins are the products of a series of proteolytic reactions, starting with the cleavage of angiotensinogen by renin. Of these peptides, angiotensin II is the one with the broadest range of activities and the highest potency in the cardiovascular system. Most of the rapid actions of angiotensin II can be viewed as a concerted response that supports the circulation when it is challenged by shrinkage of intravascular volume. Form such standpoint it can be as vital in today’s threatening situations, for instance, after a car accident, like it was the reaction of our old Ancestors (and sometimes of ourselves nowadays) when faced with a lion. Those pressor actions include vasoconstriction to reduce the capacity of the vascular tree, increased aldosterone secretion to retain salt, increased thirst and release of antidiuretic hormone to conserve water, increased strength of myocardial contraction to maintain cardiac output, and potentiation of sympathetic nervous system activity to synergize with the vasoconstrictor and inotropic actions of angiotensin. Platelet agglutination might also be considered a volume-conserving response to hemorrhage, and the effect of angiotensin II on the gut would reduce intestinal volume loss. Other acute effects of the angiotensin such as stimulation of glycogenolysis could also be framed into a stress reaction aimed to rapidly increase the blood glucose in the circulation.

Action of quercetin on glycogen catabolism in the rat liver

1. The influence of quercetin on glycogen catabolism and related parameters was investigated in the isolated perfused rat liver and subcellular systems. 2. Quercetin stimulated glycogenolysis (glucose release). This effect was already evident at a concentration of 50 µ M maximal at 300 µ M and declined at higher concentrations. Quercetin also stimulated oxygen consumption, with a similar concentration dependence. 3. Lactate production from endogenous glycogen (glycolysis) was diminished by quercetin without significant changes in pyruvate production. 4. Quercetin did not inhibit glucose transport into cells but decreased intracellular sequestration of [5- 3 H]glucose under conditions of net glucose release. 5. In isolated mitochondria, quercetin diminished the energy transduction efficiency. It also inhibited several enzymatic activities, e.g. the K + -ATPase/Na + -ATPase of plasma membrane vesicles and the glucose 6-phosphatase of isolated microsomes. 6. No significant changes of the cellular contents of AMP, ADP and ATP were found. The cellular content of glucose 6-phosphate, however, was increased (3.12-fold). 7. Some of the effects of quercetin (glycogenolysis stimulation) can be attributed to its action on mitochondrial energy metabolism, as, for example, uncoupling of oxidative phosphorylation. However, the multiplicity of the effects on several enzymatic systems certainly produces an intricate interplay that also generates complex and apparently contradictory effects.

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