Key Enzymes Of Glycogen Metabolism Research Articles

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden invitro and invivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

Anti-diabetic potential of Psidium guajava leaf in streptozotocin induced diabetic rats

BackgroundPsidium guajava is a medicinal plant with antidiabetic properties and can be found growing in tropical and sub-tropical countries around the world. PurposeThe aim of the present study was to investigate the anti-diabetic potential of Psidium guajava leaf in streptozotocin-induced diabetic rats, with particular focus on key enzymes of glycogen metabolism in skeletal muscle. Study designThe study design involved preparation of an aqueous Psidium guajava leaf extract; investigation of its effect on muscle glycogen synthase and phosphorylase activities and possible protective effect on pancreas in streptozotocin induced diabetic male Sprague-Dawley rats and phytochemical study of the extract to identify further compounds with anti-diabetic potential. MethodDiabetes was induced in male Sprague-Dawley rats with a single intraperitoneal injection of 40 mg/kg streptozotocin. Normal and diabetic animals were treated with 400 mg/kg body weight of Psidium guajava leaves aqueous extract for a period of 14 days. ResultsThe treatment of diabetic animals with the Psidium guajava extract ameliorated damage to the pancreatic islets and enhanced lowering of blood glucose following a glucose load. Diabetes significantly decreased (P < 0.05) glycogen synthase activity by 31% compared to normal animals this being associated with a decrease in enzyme expression. Psidium guajava treatment returned the enzyme activity to near normal levels. In diabetic animals, glycogen phosphorylase activity was elevated but not significantly (P > 0.5) and treatment of both diabetic and normal animals with the extract reduced activity of the enzyme. The Psidium guajava extract also reduced glycogen phosphorylase expression in diabetic animals. Skeletal muscle glycogen content reduced by diabetes was increased as a result of treatment of diabetic animals with the Psidium guajava extract. Phytochemical analysis of the aqueous extract of Psidium guajava using Gas Chromatography-Mass Spectroscopy indicated the presence of triterpenes and phenolic compounds and we also report what we believe are three new compounds. ConclusionThe results from this study suggest that the antidiabetic effects of Psidium guajava may be due to modulation of glycogen metabolism mediated by phenolic compounds and triterpenes present in the extract.

Astrocytic glycogen mobilization participates in salvianolic acid B-mediated neuroprotection against reperfusion injury after ischemic stroke

Astrocytic glycogen serves as an important glucose reserve, and its degradation provides extra support for neighboring neurons during energy deficiency. Salvianolic acid B (SAB) exerts a neuroprotective effect on reperfusion insult after cerebrovascular occlusion, but the effect of SAB on astrocytic glycogen and its relationship with neuroprotection are not completely understood. Here, we knocked down astrocyte-specific glycogen phosphorylase (GP, the rate-limiting enzyme in glycogenolysis) in vitro and in vivo and investigated the changes in key enzymes in glycogen metabolism by performing immunoblotting in vitro and immunofluorescence in vivo. Neurobehavioral and morphological assessments were conducted to uncover the outcomes during brain reperfusion. SAB accelerated astrocytic glycogenolysis by upregulating GP activity but not GP expression after reperfusion. Suppression of astrocytic glycogenolysis weakened SAB-mediated neuroprotection against the reperfusion insult. In addition, activation of glycogenolysis by SAB contributed to the survival of astrocytes and surrounding neurons by increasing antioxidant levels in astrocytes. Our data reveal that astrocytic GP represents an important metabolic target in SAB-induced protection against brain damage after cerebrovascular recanalization.

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin-like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin-1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin-proteasome and autophagocytosis systems and protein chaperones. The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.

The Motor Neuron-Like Cell Line NSC-34 and Its Parent Cell Line N18TG2 Have Glycogen that is Degraded Under Cellular Stress

Brain glycogen has a long and versatile history: Primarily regarded as an evolutionary remnant, it was then thought of as an unspecific emergency fuel store. A dynamic role for glycogen in normal brain function has been proposed later but exclusively attributed to astrocytes, its main storage site. Neuronal glycogen had long been neglected, but came into focus when sensitive technical methods allowed quantification of glycogen at low concentration range and the detection of glycogen metabolizing enzymes in cells and cell lysates. Recently, an active role of neuronal glycogen and even its contribution to neuronal survival could be demonstrated. We used the neuronal cell lines NSC-34 and N18TG2 and could demonstrate that they express the key-enzymes of glycogen metabolism, glycogen phosphorylase and glycogen synthase and contain glycogen which is mobilized on glucose deprivation and elevated potassium concentrations, but not by hormones stimulating cAMP formation. Conditions of metabolic stress, namely hypoxia, oxidative stress and pH lowering, induce glycogen degradation. Our studies revealed that glycogen can contribute to the energy supply of neuronal cell lines in situations of metabolic stress. These findings shed new light on the so far neglected role of neuronal glycogen. The key-enzyme in glycogen degradation is glycogen phosphorylase. Neurons express only the brain isoform of the enzyme that is supposed to be activated primarily by the allosteric activator AMP and less by covalent phosphorylation via the cAMP cascade. Our results indicate that neuronal glycogen is not degraded upon hormone action but by factors lowering the energy charge of the cells directly.

Metabolic Features of Mouse and Human Retinas: Rods versus Cones, Macula versus Periphery, Retina versus RPE.

SummaryPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle, and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine, and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

General anesthesia severely affects the metabolites in the brain. Glycogen, principally stored in astrocytes and providing the short-term delivery of substrates to neurons, has been implicated as an affected molecule. However, whether glycogen plays a pivotal role in modulating anesthesia–arousal remains unclear. Here, we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions. Glycogen synthase (GS) and glycogen phosphorylase (GP), key enzymes of glycogen metabolism, showed increased activity after isoflurane exposure. Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), a GP antagonist, we found a prolonged time of emergence from anesthesia and an enhanced δ frequency in the EEG (electroencephalogram). In addition, augmented expression of glycogenolysis genes in glycogen phosphorylase, brain (Pygb) knock-in (PygbH11/H11) mice resulted in delayed induction of anesthesia, a shortened emergence time, and a lower ratio of EEG-δ. Our findings revealed a role of brain glycogen in regulating anesthesia–arousal, providing a potential target for modulating anesthesia.

Parallel comparative proteomics and phosphoproteomics reveal that cattle myostatin regulates phosphorylation of key enzymes in glycogen metabolism and glycolysis pathway.

MSTN-encoded myostatin is a negative regulator of skeletal muscle development. Here, we utilized the gluteus tissues from MSTN gene editing and wild type Luxi beef cattle which are native breed of cattle in China, performed tandem mass tag (TMT) -based comparative proteomics and phosphoproteomics analyses to investigate the regulatory mechanism of MSTN related to cellular metabolism and signaling pathway in muscle development. Out of 1,315 proteins, 69 differentially expressed proteins (DEPs) were found in global proteomics analysis. Meanwhile, 149 differentially changed phosphopeptides corresponding to 76 unique phosphorylated proteins (DEPPs) were detected from 2,600 identified phosphopeptides in 702 phosphorylated proteins. Bioinformatics analyses suggested that majority of DEPs and DEPPs were closely related to glycolysis, glycogenolysis, and muscle contractile fibre processes. The global discovery results were validated by Multiple Reaction Monitoring (MRM)-based targeted peptide quantitation analysis, western blotting, and muscle glycogen content measurement. Our data revealed that increase in abundance of key enzymes and phosphorylation on their regulatory sites appears responsible for the enhanced glycogenolysis and glycolysis in MSTN−/−. The elevated glycogenolysis was assocaited with an enhanced phosphorylation of Ser1018 in PHKA1, and Ser641/Ser645 in GYS1, which were regulated by upstream phosphorylated AKT-GSK3β pathway and highly consistent with the lower glycogen content in gluteus of MSTN−/−. Collectively, this study provides new insights into the regulatory mechanisms of MSTN involved in energy metabolism and muscle growth.

Glycogen synthase kinase 3 in Wnt signaling pathway and cancer.

Glycogen synthase kinase 3 (GSK-3) was first discovered in 1980 as one of the key enzymes of glycogen metabolism. Since then, GSK-3 has been revealed as one of the master regulators of a diverse range of signaling pathways, including those activated by Wnts, participating in the regulation of numerous cellular functions, suggesting that its activity is tightly regulated. Numerous studies have pointed to an association of GSK-3 dysregulation with the onset and progression of human diseases, including diabetes mellitus, obesity, inflammation, neurological illnesses, and cancer. Therefore, GSK-3 is recognized as an attractive therapeutic target in multiple disorders. However, the great number of substrates that are phosphorylated by GSK-3 has raised the question of whether this limits its feasibility as a therapeutic target because of the potential disruption of many cellular processes and also by the fear that inhibition of GSK-3 may stimulate or aid in malignant transformation, as GSK-3 can phosphorylate pro-oncogenic factors. This mini review focuses on the role played by GSK-3 in Wnt signaling pathway and cancer using as model colon cancer.

Selective photoregulation of the activity of glycogen synthase and glycogen phosphorylase, two key enzymes in glycogen metabolism.

Glycogen is a polymer of α-1,4- and α-1,6-linked glucose units that provides a readily available source of energy in living organisms. Glycogen synthase (GS) and glycogen phosphorylase (GP) are the two enzymes that control, respectively, the synthesis and degradation of this polysaccharide and constitute adequate pharmacological targets to modulate cellular glycogen levels, by means of inhibition of their catalytic activity. Here we report on the synthesis and biological evaluation of a selective inhibitor that consists of an azobenzene moiety glycosidically linked to the anomeric carbon of a glucose molecule. In the ground state, the more stable (E)-isomer of the azobenzene glucoside had a slight inhibitory effect on rat muscle GP (RMGP, IC50 = 4.9 mM) and Escherichia coli GS (EcGS, IC50 = 1.6 mM). After irradiation and subsequent conversion to the (Z)-form, the inhibitory potency of the azobenzene glucoside did not significantly change for RMGP (IC50 = 2.4 mM), while its effect on EcGS increased 50-fold (IC50 = 32 μM). Sucrose synthase 4 from potatoes, a glycosyltransferase that does not operate on glycogen, was only slightly inhibited by the (E)-isomer (IC50 = 0.73 mM). These findings could be rationalized on the basis of kinetic and computer-aided docking analysis, which indicated that both isomers of the azobenzene glucoside mimic the EcGS acceptor substrate and exert their inhibitory effect by binding to the glycogen subsite in the active center of the enzyme. The ability to selectively photoregulate the catalytic activity of key enzymes of glycogen metabolism may represent a new approach for the treatment of glycogen metabolism disorders.

Axonal and dendritic localization of mRNAs for glycogen-metabolizing enzymes in cultured rodent neurons.

BackgroundLocalization of mRNAs encoding cytoskeletal or signaling proteins to neuronal processes is known to contribute to axon growth, synaptic differentiation and plasticity. In addition, a still increasing spectrum of mRNAs has been demonstrated to be localized under different conditions and developing stages thus reflecting a highly regulated mechanism and a role of mRNA localization in a broad range of cellular processes.ResultsApplying fluorescence in-situ-hybridization with specific riboprobes on cultured neurons and nervous tissue sections, we investigated whether the mRNAs for two metabolic enzymes, namely glycogen synthase (GS) and glycogen phosphorylase (GP), the key enzymes of glycogen metabolism, may also be targeted to neuronal processes. If it were so, this might contribute to clarify the so far enigmatic role of neuronal glycogen. We found that the mRNAs for both enzymes are localized to axonal and dendritic processes in cultured lumbar spinal motoneurons, but not in cultured trigeminal neurons. In cultured cortical neurons which do not store glycogen but nevertheless express glycogen synthase, the GS mRNA is also subject to axonal and dendritic localization. In spinal motoneurons and trigeminal neurons in situ, however, the mRNAs could only be demonstrated in the neuronal somata but not in the nerves.ConclusionsWe could demonstrate that the mRNAs for major enzymes of neural energy metabolism can be localized to neuronal processes. The heterogeneous pattern of mRNA localization in different culture types and developmental stages stresses that mRNA localization is a versatile mechanism for the fine-tuning of cellular events. Our findings suggest that mRNA localization for enzymes of glycogen metabolism could allow adaptation to spatial and temporal energy demands in neuronal events like growth, repair and synaptic transmission.

Glycogen storage in the human retinal pigment epithelium: a comparative study of diabetic and non-diabetic donors

Liver and muscle glycogen content is reduced in diabetic patients but there is no information on the effect of diabetes on the glycogen content in the retinal pigment epithelium (RPE). The main aim of the study was to compare the glycogen content in the RPE between diabetic and non-diabetic human donors. Glycogen synthase (GS) and glycogen phosphorylase (GP), the key enzymes of glycogen metabolism, as well as their isoforms, were also assessed. For this purpose, 44 human postmortem eye cups were included (22 from 11 type 2 diabetic and 22 from 11 non-diabetic donors matched by age). Human RPE cells cultured in normoglycemic and hyperglycemic conditions were also analyzed. Glycogen content as well as the mRNA, protein content and enzyme activity of GS and GP were determined. In addition, GS and GP isoforms were characterized. In the RPE from diabetic donors, as well as in RPE cells grown in hyperglycemic conditions, the glycogen content was increased. The increase in glycogen content was associated with an increase in GS without changes in GP levels. In RPE form human donors, the muscle GS isoform but not the liver GS isoform was detected. Regarding GP, the muscle and brain isoform of GP but not the liver GP isoform were detected. We conclude that glycogen storage is increased in the RPE of diabetic patients, and it is associated with an increase in GS activity. Further studies aimed at determining the role of glycogen deposits in the pathogenesis of diabetic retinopathy are warranted.

PReS-FINAL-2262: Arthritis in a patient with type 1 glycogen storage disease

Glycogen storage diseases, the commonest of which is Von Gierke disease, are characterized by excessive deposit of glycogen in liver and muscle owing to the lack of key enzymes in glycogen metabolism.

Tu1996 Glycogen Metabolism Defects Produce Gastrointestinal Myopathy With Polyglucosan Bodies

INTRODUCTION The intestine is a significant site of gluconeogenesis, with high expression of glucose 6 phosphatase. Abnormal forms of glycogen, including polyglucosan bodies, occur in the muscularis propria in a subset of patients with gastrointestinal motility disorders. Little is known, however, of the distribution of glycogen metabolic enzymes and related proteins in normal gastrointestinal tract, or effects of deficiencies of these proteins on the bowel. METHODS Key enzymes in glycogen metabolism, including glycogen synthase (GS), glycogen branching enzyme (GBE), malin and laforin were examined in stomach, ileum and colon of two mouse strains and in normal human bowel using immunohistochemistry with semiquantitiative analysis of epithelium, muscle, submucosal and myenteric plexus, validated by western blotting and positive and negative controls. The pathological effects of GBE, laforin and malin gene knockout on mouse gastrointestinal tract were also studied. RESULTS GS was present at high levels in the smooth muscle of muscularis propria, GBE in the majority of large ganglion cells of the submucosal and myenteric plexuses, and laforin and malin in submucosal ganglia. Analysis of human bowel showed no significant regional differences in the distribution of GBE, laforin and malin, GS was more prominent in the muscularis propria of the small intestine, compared with stomach and colon. GBE knockout produced a progressive severe myopathy with numerous polyglucosan bodies and vacuolation. Polyglucosan bodies were also present in both laforin and malin knockout models, but with a less severe phenotype than that seen in the GBE knockout, and were not seen in controls. CONCLUSION The distribution of glycogen metabolic proteins in the bowel wall of mouse and man shows a specific neuromuscular distribution for each pathway component. Defects in glycogen metabolism in mouse knockout models reproduce histological features of polyglucosan body myopathy in human digestive motility disorders.

Tu1997 A Novel In Vivo Method to Measure Gastrointestinal Transit in Mice

INTRODUCTION The intestine is a significant site of gluconeogenesis, with high expression of glucose 6 phosphatase. Abnormal forms of glycogen, including polyglucosan bodies, occur in the muscularis propria in a subset of patients with gastrointestinal motility disorders. Little is known, however, of the distribution of glycogen metabolic enzymes and related proteins in normal gastrointestinal tract, or effects of deficiencies of these proteins on the bowel. METHODS Key enzymes in glycogen metabolism, including glycogen synthase (GS), glycogen branching enzyme (GBE), malin and laforin were examined in stomach, ileum and colon of two mouse strains and in normal human bowel using immunohistochemistry with semiquantitiative analysis of epithelium, muscle, submucosal and myenteric plexus, validated by western blotting and positive and negative controls. The pathological effects of GBE, laforin and malin gene knockout on mouse gastrointestinal tract were also studied. RESULTS GS was present at high levels in the smooth muscle of muscularis propria, GBE in the majority of large ganglion cells of the submucosal and myenteric plexuses, and laforin and malin in submucosal ganglia. Analysis of human bowel showed no significant regional differences in the distribution of GBE, laforin and malin, GS was more prominent in the muscularis propria of the small intestine, compared with stomach and colon. GBE knockout produced a progressive severe myopathy with numerous polyglucosan bodies and vacuolation. Polyglucosan bodies were also present in both laforin and malin knockout models, but with a less severe phenotype than that seen in the GBE knockout, and were not seen in controls. CONCLUSION The distribution of glycogen metabolic proteins in the bowel wall of mouse and man shows a specific neuromuscular distribution for each pathway component. Defects in glycogen metabolism in mouse knockout models reproduce histological features of polyglucosan body myopathy in human digestive motility disorders.

Control of carbohydrate metabolism in an anoxia‐tolerant nervous system

Anoxia-tolerant animal models are crucial to understand protective mechanisms during low oxygen excursions. As glycogen is the main fermentable fuel supporting energy production during oxygen tension reduction, understanding glycogen metabolism can provide important insights about processes involved in anoxia survival. In this report we studied carbohydrate metabolism regulation in the central nervous system (CNS) of an anoxia-tolerant land snail during experimental anoxia exposure and subsequent reoxygenation. Glucose uptake, glycogen synthesis from glucose, and the key enzymes of glycogen metabolism, glycogen synthase (GS) and glycogen phosphorylase (GP), were analyzed. When exposed to anoxia, the nervous ganglia of the snail achieved a sustained glucose uptake and glycogen synthesis levels, which seems important to maintain neural homeostasis. However, the activities of GS and GP were reduced, indicating a possible metabolic depression in the CNS. During the aerobic recovery period, the enzyme activities returned to basal values. The possible strategies used by Megalobulimus abbreviatus CNS to survive anoxia are discussed.

Two independent effects of cortisol on chicken liver.

Activities of two key enzymes of glycogen metabolism have been measured after an acute administration of cortisol to 3d-old chickens. Glycogen synthase activity is enhanced 2-3 hours after a cortisol injection, and this activation is blocked by use of protein synthesis inhibitors. Glycogen phosphorylase activity is enhanced at an early stage, and this effect is not suppressed by protein synthesis inhibitors. Liver cAMP levels are not increased concomitantly with this early activation of glycogen phosphorylase; indeed they are depleted. These results point to the existence of an effect of cortisol previous to and independent of its nuclear interaction, and not mediated by an activation of the membrane adenylate cyclase.

Seasonal variation of the glycogen enzyme activity in diploid and triploid Pacific oyster gonad during sexual maturation

The glycogen content and the activities of two key enzymes in glycogen metabolism, glycogen phosphorylase and glycogen synthetase, in the gonad of diploid and triploid Pacific oysters (Crassostrea gigas) were compared during maturation. The glycogen content in the gonad of diploids decreased with gametogenesis (by 85.7%), but the glycogen content in the gonad of triploids did not vary significantly. Activity of glycogen phosphorylase (GP) in the gonad of diploids decreased with gametogenesis (by 55.5%), while GP activity of triploids did not vary significantly during maturation. Activity of glycogen synthetase (GS) in the gonad of diploids increased slightly with gametogenesis, reaching a peak in June. Activity of GS declined sharply from June to July, which might be due to gonad spawning. GS activity of triploid oysters in spawning time (July and August) was significantly higher than that in other months, which might be explained with a ‘compensating’ mechanism for the higher glycogen content in triploids.

Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

Glycogen-targeting subunits of protein phosphatase-1 (PP-1) are scaffolding proteins that facilitate the regulation of key enzymes of glycogen metabolism by PP-1. In the current study, we have tested the effects of hepatic expression of GMDeltaC, a truncated version of the muscle-targeting subunit isoform, in rats rendered insulin-deficient via injection of a single moderate dose of streptozotocin (STZ). Three key findings emerged. First, GMDeltaC expression in liver was sufficient to fully normalize blood glucose levels (from 335 +/- 31 mg/dl prior to viral injection to 109 +/- 28 mg/dl 6 days after injection) and liver glycogen content in STZ-injected rats. Second, this normalization occurred despite very low levels of liver glucokinase expression in the insulin-deficient STZ-injected rats. Finally, the hyperphagia induced by STZ injection was completely reversed by GMDeltaC expression in liver. In contrast to these findings with GMDeltaC, overexpression of another targeting subunit, GL, in STZ-injected rats caused a large increase in liver glycogen stores but only a transient decrease in food intake and blood glucose levels. The surprising demonstration of a glucose-lowering effect of GMDeltaC in the background of depressed hepatic glucokinase expression suggests that controlled stimulation of liver glycogen storage may be an effective mechanism for improving glucose homeostasis, even when normal pathways of glucose disposal are impaired.

Control of glycogen deposition

Traditionally, glycogen synthase (GS) has been considered to catalyze the key step of glycogen synthesis and to exercise most of the control over this metabolic pathway. However, recent advances have shown that other factors must be considered. Moreover, the control of glycogen deposition does not follow identical mechanisms in muscle and liver. Glucose must be phosphorylated to promote activation of GS. Glucose-6-phosphate (Glc-6-P) binds to GS, causing the allosteric activation of the enzyme probably through a conformational rearrangement that simultaneously converts it into a better substrate for protein phosphatases, which can then lead to the covalent activation of GS. The potency of Glc-6-P for activation of liver GS is determined by its source, since Glc-6-P arising from the catalytic action of glucokinase (GK) is much more effective in mediating the activation of the enzyme than the same metabolite produced by hexokinase I (HK I). As a result, hepatic glycogen deposition from glucose is subject to a system of control in which the ‘controller’, GS, is in turn controlled by GK. In contrast, in skeletal muscle, the control of glycogen synthesis is shared between glucose transport and GS. The characteristics of the two pairs of isoenzymes, liver GS/GK and muscle GS/HK I, and the relationships that they establish are tailored to suit specific metabolic roles of the tissues in which they are expressed. The key enzymes in glycogen metabolism change their intracellular localization in response to glucose. The changes in the intracellular distribution of liver GS and GK triggered by glucose correlate with stimulation of glycogen synthesis. The translocation of GS, which constitutes an additional mechanism of control, causes the orderly deposition of hepatic glycogen and probably represents a functional advantage in the metabolism of the polysaccharide.