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PubMed1981

Effects of glucagon on hepatic glycogen and smooth endoplasmic reticulum.

The action of glucagon on hepatic glycogen and smooth endoplasmic reticulum (SER) was studied in samples of liver taken sequentially from anesthetized rats. The physiological state of each animal was assessed by continuously monitoring aortic blood pressure and blood lactatepyruvate ratios. High hepatic glycogen levels were established by using 10--12 hr fasted control-fed rats infused continuously with glucose. In rats receiving glucose only, hepatic glycogen levels remained above 5.0% during the 4-hr period of glucose administration. Centrilobular hepatocytes displayed an abundance of glycogen which often appeared dispersed with elements of SER between the glycogen particles. Periportal cells had dense clumps of glycogen with few vesicles of SER restricted to the periphery of the glycogen masses. The addition of glucagon to the glucose infusate caused a marked stimulation of glycogenolysis. In these rats, the hepatic glycogen level (X +/- SE) was 6.74 +/- .15% 1 hr after glucose and declined after initiation of glucagon infusion as follows: 5.86 +/- .29% (15 min), 4.89 +/- .26% (1 hr), 2.16 +/- .40% (2 hr), and 1.66 +/- .29% (3 hr). The fine structure of hepatocytes showed a dramatic response to the administration of glucagon. The glycogen regions of the cells were noticeably decreased in size and number of glycogen granules 3 hr after initiation of glucagon infusion, and SER was abundant in both periportal and centrilobular hepatocytes. The interpretation offered is that glucagon induces the formation of new SER membranes which participate in glycogen breakdown and/or glucose release from hepatocytes.

Animals↗
PubMed1991

Biochemical and ultrastructural study of glycogen in cultured astrocytes submitted to the convulsant methionine sulfoximine.

The convulsant methionine sulfoximine is a potent glycogenic agent in the central nervous system of rodents in vivo. This investigation was undertaken to look for the basic mechanism underlying this property. Astrocytes were cultivated from newborn rat neopallium and glycogen was studied by both biochemical and ultrastructural methods. When the astrocytes were incubated in a medium containing 5.55 mM glucose, methionine sulfoximine (0.55 mM) induced a significant increase in their glycogen content. Glucose content did not change in astrocytes, but it diminished in the medium in all cases. When the decrease in glucose level in the medium was limited, the same glycogenic effects of methionine sulfoximine were observed, but the glycogen contents were higher. The augmentation of the concentration of the convulsant enhanced its glycogenic effect, but this was not directly dose dependent. When the flat and polygonal astrocytes were transformed into process-bearing astrocytes by dibutyryl cyclic AMP methionine sulfoximine always induced an increase in glycogen content. In this case, the values of glycogen contents were lower. In electron microscopy, no glycogen particles were present in the astrocytes even after methionine sulfoximine treatment, contrary to the case in vivo. These results show that the convulsant does not need the presence of neuronal cells to induce glycogen accumulation and that astrocytes may be the direct cell targets. The apparent discrepancy between the biochemical and ultrastructural data is probably due to the relatively low concentration of glycogen in cultured astrocytes.

Animals↗
PubMed1977

Glycogen and other soluble glucans from chytridiomycete and oomycete species.

Dry weight, protein, lipid, and glycogen were determined at various times during cultivation of the Chytridiomycetes, Rhizophydium sphaerotheca and Monoblepharella elongata. M. elongata had relatively stable levels of glycogen, but, in R. sphaerotheca, glycogen levels showed significant changes, particularly in older cultures in which a depletion of glycogen was accompanied by a marked thickening of the cell walls. Glycogen was a significant cellular constituent in both chytridiomycete species. In R. sphaerotheca and M. elongata, respectively, glycogen accounted for as much as 6% and 8.1% of the dry weight. In purified glycogens of both species, only alpha-1,4- and alpha-1,6-linked glucosyl residues were detected and the absorbance spectra of I2-complexes were similar to those of other well characterized glycogens. Purified Rhizophydium glycogen had a beta-amylolysis limit of 43%, and a CL of approximately 12. For the Monoblepharella polysaccharide, the respective values were 45% and 11. In extracts of the Oomycetes, Pythium debaryanum, Mindeniella spinospora, and Apodachlya sp., only beta-1,3- and beta-1,6-linked glucosyl residues were detected. These glucans were not iodophilic nor were they sensitive to alpha-amylase and beta-amylase. The properties of the oomycete polysaccharides suggested that they were similar to the mycolaminarans of Phytophthora spp. Although both investigated chytridiomycete species produced glycogen with typical properties, glycogen was apparently absent in the investigated Oomycetes.

Fungal Proteins↗
PubMed1977

Intranuclear synthesized and native glycogen particles in human gastric cancer: ultrastructure and histochemistry.

Ultrastructural and histochemical studies on human gastric cancer cells disclosed the presence of native and synthesized glycogen particles. The glycogen particles were investigated in the histochemical synthesis of glycogen particles from glucose 1-phosphate by the phosphorylase-branching glycosyltransferase system and non-incubated native glycogen in human gastric adenocarcinoma tubulare. It was observed that focal synthesis localized inthe intracytoplasmic matrix and intranucleus. Intranuclear synthesized glycogen appeared as a rosette form ranging from 1100 to 1300 A in diameter and free particles ranging from 325 to 900 A in diagmeter. The synthesis of glycogen appeared in the nucleus as well as in the cytoplasm of the human gastric cancer cells, and the synthesized glycogen was observed as a group of particles. Newly formed glycogen particles appeared occasionally in the interchromatin area as a large macromolecular structure of rosette form. Native glycogen appeared as a free-particle (250-333 A, medium =300 A) and aggregated rosette from (694-1050 A, medium=917 A) in the autophagosome of gastric cancer cells. There was not, however, a native glycogen particle in the nuclei of gastric cancer cells. Under certain conditons the nuclei of gastric cancer cells can acquire the capacity to synthesize glycogen.

Adenocarcinoma↗
PubMedDate not supplied

Loss of glycogen during preconditioning is not a prerequisite for protection of the rabbit heart.

Depletion of glycogen has been proposed as the mechanism of protection from ischemic preconditioning. The hypothesis was tested by seeing whether pharmacological manipulation of preconditioning causes parallel changes in cardiac glycogen content. Five groups of isolated rabbit hearts were studied. Group 1 experienced 30 min of ischemia only. Group 2 (PC) was preconditioned with 5 min of global ischemia followed by 10 min of reperfusion. Group 3 was preconditioned with 5 min exposure to 400 nM bradykinin followed by a 10 min washout period. Group 4 experienced exposure to 10 microM adenosine followed by a 10 min washout period, and the fifth group was also preconditioned with 5 min ischemia and 10 min reperfusion but 100 microM 8-(p-sulfophenyl)theophylline (SPT), which blocks adenosine receptors, was included in the buffer to block preconditioning's protection. Transmural biopsies were taken before treatment, just prior to the 30 min period of global ischemia, and after 30 min of global ischemia. Glycogen in the samples was digested with amyloglucosidase and the resulting glucose was assayed. Baseline glycogen averaged 17.3 +/- 0.6 mumol glucose/g wet weight. After preconditioning glycogen decreased to 13.3 +/- 1.3 mumol glucose/g wet weight (p < 0.005 vs. baseline). Glycogen was similarly depleted after pharmacological preconditioning with adenosine (14.0 +/- 1.0 mumol glucose/g wet weight, p < 0.05 vs. baseline) suggesting a correlation. However, when preconditioning was performed in the presence of SPT, which blocks protection, glycogen was also depleted by the same amount (13.3 +/- 0.7 mumol glucose/g wet weight, p = ns vs. PC). Bradykinin, which also mimics preconditioning, caused no depletion of glycogen (16.3 +/- 0.8 mumol glucose/g wet weight, p = ns vs. baseline). Because preconditioning with bradykinin did not deplete glycogen and because glycogen continued to be low when protection from preconditioning was blocked with SPT, we conclude that loss of glycogen per se does not cause the protection of preconditioning.

Adenosine↗
PubMed2002

Molecular and biochemical characterization of the Neurospora crassa glycogen synthase encoded by the gsn cDNA.

Glycogen synthases catalyze the transfer of a glucosyl moiety from a nucleotide phosphosugar to a nascent glycogen chain via an alpha1-->4 linkage. Although many genes coding for glycogen synthases have been described, the enzymes from rabbit and yeast are the best characterized. The fungus Neurospora crassa accumulates glycogen during exponential growth, and mobilizes it at the onset of stationary phase, or when placed at high temperature or starved for carbon. Through a PCR methodology, the gsn cDNA coding for the N. crassa glycogen synthase was isolated, and the amino acid sequence of the protein was deduced. The product of the cDNA seems to be the only glycogen synthase present in N. crassa. Characterization of the gsn cDNA revealed that it codes for a 706-amino acids protein, which is very similar to mammalian and yeast glycogen synthases. Gene expression increased during exponential growth, reaching its maximal level at the end of the exponential growth phase, which is consistent with the pattern of glycogen synthase activity and glycogen level. Expression of the gsn is highly regulated at the transcriptional level. Under culture conditions that induce heat shock, conidiation, and carbon starvation, expression of the gsn gene was decreased, and glycogen synthase activity and glycogen content behaved similarly.

Amino Acid Sequence↗
PubMed1987

Characterization of GSK-M, a glycogen synthase kinase from rat skeletal muscle.

A form of glycogen synthase kinase designated GSK-M3 was purified 4000-fold from rat skeletal muscle by phosphocellulose, Affi-Gel blue, Sephacryl S-300 and carboxymethyl-Sephadex column chromatography. Separation of GSK-M from the catalytic subunit of the cAMP-dependent protein kinase was facilitated by converting the catalytic subunit to the holoenzyme form by addition of the regulatory subunit prior to the gel filtration step. GSK-M had an apparent Mr 62,000 (based on gel filtration), an apparent Km of 11 microM for ATP, and an apparent Km of 4 microM for rat skeletal muscle glycogen synthase. The kinase had very little activity with 0.2 mM GTP as the phosphate donor. Kinase activity was not affected by the addition of cyclic nucleotides, EGTA, heparin, glucose 6-P, glycogen, or the heat-stable inhibitor of cAMP-dependent protein kinase. Phosphorylation of glycogen synthase from rat skeletal muscle by GSK-M reduced the activity ratio (activity in the absence of Glc-6-P/activity in the presence of Glc-6-P X 100) from 90 to 25% when approximately 1.2 mol of phosphate was incorporated per mole of glycogen synthase subunit. Phosphopeptide maps of glycogen synthase obtained after digestion with CNBr or trypsin showed that this kinase phosphorylated glycogen synthase in serine residues found in the peptides containing the sites known as site 2, which is located in the N-terminal CNBr peptide, and site 3, which is located in the C-terminal CNBr peptide of glycogen synthase. In addition to phosphorylating glycogen synthase, GSK-M phosphorylated inhibitor 2 and activated ATP-Mg-dependent protein phosphatase. Activation of the protein phosphatase by GSK-M was dependent on ATP and was virtually absent when ATP was replaced with GTP. GSK-M had minimal activity toward phosphorylase b, casein, phosvitin, and mixed histones. These data indicate that GSK-M, a major form of glycogen synthase kinase from rat skeletal muscle, differs from the known glycogen synthase kinases isolated from rabbit skeletal muscle.

Animals↗
PubMed1983

Schistosoma mansoni, S. japonicum, S. haematobium: glycogen content and glucose uptake in parasites from fasted and control hosts.

The glycogen content of male and female Schistosoma mansoni has been measured in flukes from normally fed hosts and those from fasted hosts. In infections from both the mouse and the hamster, a significant reduction in schistosomal glycogen of males is seen hours after food is withdrawn from the host. Reductions in protein content of the schistosomes were only observed in hamster infections fasted at least 72 hr. The livers of infected mice not only decrease in size during fasting, but there is a concomitant reduction in glycogen per unit wet weight. Comparisons of glycogen:protein ratios of mansonian males, females, and host livers indicate that the fasting-induced loss of liver glycogen is also observed in the male schistosome, but not the female. Studies of both S. mansoni and S. haematobium pairs from fed hosts suggest that the ratio of glycogen:protein contents in the male schistosome correlates with the glycogen:protein ratio of the female partner. Measurements of glucose uptake in vitro suggest that greater uptake rates may be observed in flukes perfused from fasted hosts. In S. japonicum from infected mice, a reduction in male glycogen was also detected as early as after a 6-hr fasting period, but changes in the females were not significant. Unmated male S. japonicum also exhibit a reduction in glycogen levels after fasting, but the quantity of worm glycogen present in these males remains higher than comparable mated males. In mice entrained to a regulated pattern of available food, fluctuations in glycogen content of the male schistosomes were observed, but in the female partners fluctuations were of a smaller magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Direct effects of the hyperglycemic factor of the freshwater snail Lymnaea stagnalis on isolated glycogen cells.

In the freshwater pulmonate snail Lymnaea stagnalis special cells, the glycogen cells (GC) are present for the storage of glycogen reserves. These cells occur in large numbers in the anterior mantle region. In a previous paper in vitro experiments with intact anterior mantle tissue indicated that a hyperglycemic factor is released from the central nervous system (CNS) which stimulates glycogen mobilization in mantle tissue (M. A. Hemminga, J. J. Maaskant, W. Koomen, and J. Joosse (1985). Neuroendocrine control of glycogen mobilization in the freshwater snail Lymnaea stagnalis. Gen. Comp. Endocrinol. 57, 117-123). In the present study the question of whether this factor affects glycogen metabolism of GC isolated from mantle tissue was investigated. It is reported that in high-K+ Ringers the CNS is stimulated to release a factor which, in a dose-dependent way, inhibits glycogen synthesis in isolated GC (measured as a decreased incorporation of [14C]glucose into glycogen). Simultaneous with this glycogen synthesis-inhibiting effect, stimulation of glycogen degradation is found (measured as a decreased retention of prelabeled glycogen). It is concluded that (1) the factor released by the CNS having these effects on isolated GC is the same as the hyperglycemic factor which was reported to stimulate glycogen mobilization in intact mantle tissue, and (2) GC after isolation from mantle tissue have retained their ability to respond to this factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Observations on the role of smooth endoplasmic reticulumin glucocorticoid-induced hepatic glycogen deposition.

We have studied by quantitative electron microscopy the relationship of specific hepatic cellular organelles to glycogen synthesis using dexamethasone, a potent synthetic glucocorticoid, to induce glycogen deposition in livers of adrenalectomized rats. Chemical and ultrastructural glycogen determinations revealed that the livers of fasted adrenalectomized rats had very low glycogen levels. Dexamethasone caused a time-related increase in hepatic glycogen which was the result of increases in the number of hepatocytes depositing glycogen and the amount of glycogen in each cell. The surface density of smooth endoplasmic reticulum (SER) in centrilobular and periportal hepatocytes also increased after treatment with dexamethasone; this increase preceded glycogen deposition. The newly deposited glycogen was spatially associated with membranes of SER, and a continued increase in SER surface density was correlated temporally with the increasing glycogen volume density. In both centrilobular and periportal hepatocytes, the surface density of rough endoplasmic reticulum (RER) initially decreased after dexamethasone administration but later increased. These data support the hypothesis that dexamethasone-induced enhancement of SER is functionally associated with the increase in glycogen, and that although the initial increase in SER may occur through transformation of RER to SER, later increases in SER require synthesis of new membranes.

Adrenalectomy↗
PubMed1984

Calcium control of glycogen synthase activities in mouse diaphragms, rat adipocytes and rat hepatocytes.

The following article provides evidence that cellular calcium controls the activity of glycogen synthase in all three major glycogen storage tissues; muscle, fat, and liver. Depletion of cellular calcium resulted in a moderate increase of glycogen synthase %I activities in intact mouse diaphragms, in isolated rat adipocytes, and in rat hepatocytes. The increase in %I activity of glycogen synthase was more pronounced when the uridine di-phosphoglucose concentration in the glycogen synthase assay was lowered from 4.4 mM to 0.2 mM. Calcium depletion resulted in an approximately two-fold decrease in the Ka values for glucose-6-phosphate in all three tissues. The activities of glycogen synthase also correlated well with the content of cell-associated calcium in rat hepatocytes. The glucose-6-phosphate independent activities of glycogen synthase in extracts of calcium-replete and calcium-depleted tissue approached the same value following the exposure to crude phosphoprotein phosphatase. The activities of glycogen phosphorylase decreased in calcium-depleted tissues and cells. Insulin stimulated the activity of glycogen synthase in muscle and fat in the absence of added sugar and in the absence of extracellular calcium. It is concluded that glycogen synthase is under the control of calcium in the three main glycogen storage tissues. The actions of calcium are probably mediated through the actions of calcium-sensitive protein kinase(s).

Adipose Tissue↗
PubMed2004

Inhibition of glycogen breakdown by imino sugars in vitro and in vivo.

The imino sugar N-butyldeoxynojirimycin (NB-DNJ) is a glucose analogue which inhibits the glycoprotein N-glycan processing enzymes alpha-glucosidases I and II and the ceramide glucosyltransferase that catalyses the first step of glycosphingolipid biosynthesis. This and other N-alkylated DNJ compounds have the potential to inhibit other glucosidase, including acid alpha-glucosidase and alpha-1,6-glucosidase, enzymes involved in glycogen breakdown. We have investigated the effect of NB-DNJ and N-nonyldeoxynojirimycin (NN-DNJ) on glycogen catabolism. Both NB-DNJ and NN-DNJ were potent inhibitors of acid alpha-glucosidase and alpha-1,6-glucosidase in vitro. NB-DNJ and NN-DNJ inhibited liver glycogen breakdown in vivo in fasting mice. Inhibition of glycogen catabolism occurred in the cytosol and lysosomes. The liver glycogen breakdown inhibition was only induced at high doses of NB-DNJ, whereas NN-DNJ caused glycogen accumulation at lower doses. The in vivo effect of NB-DNJ on liver glycogen was transient as there was no inhibition of breakdown after 90 days of treatment. The inhibition by NN-DNJ, was more pronounced, reached a plateau at 50 days and then remained unchanged. Increased glycogen was also observed in skeletal muscle in NB-DNJ- and NN-DNJ-treated mice. Since the effects on glycogen metabolism by NB-DNJ are transient and only occur at high concentrations, it is not predicted that glycogen breakdown will be impaired in patients receiving NB-DNJ therapy. NN-DNJ is the prototype of long alkyl chain derivatives of DNJ that are entering pre-clinical development as potential hepatitis B/hepatitis C (HBV/HCV) therapeutics. Depending on the dose of these compounds used, there is the potential for glycogen catabolism to be partially impaired in experimental animals and man.

1-Deoxynojirimycin↗
PubMed2005

Effect of diet supplementation with glutamine, dihydroxyacetone, and leucine on food intake, weight gain, and postprandial glycogen metabolism of rats.

OBJECTIVE: We tested the hypothesis that increasing the rate of postprandial hepatic glycogen synthesis would decrease food intake and growth rate in normal rats. METHODS: Diets supplemented with glutamine, glutamine plus dihydroxyacetone, and glutamine plus dihydroxyacetone plus leucine were administered to male Sprague-Dawley rats for 1 wk. These are combinations that have been shown to stimulate hepatic glycogen synthesis in vitro. Food intake and body weight were monitored throughout the experiment. At the end of the feeding period, rats were fed a test meal and injected with 3H2O to measure in vivo rates of glycogen and lipid synthesis. Positional analysis of the 3H incorporated into glycogen was used to determine the proportion of glycogen synthesized via pyruvate. Final levels of plasma glucose and triacylglycerol and hepatic glycogen were also measured. RESULTS: Dietary glutamine increased hepatic glycogen synthesis. Addition of dihydroxyacetone, with or without additional leucine, caused an additional increase in hepatic glycogen synthesis and increased the proportion of glycogen synthesized via pyruvate. Lipogenesis was not altered in the liver or adipose tissue. None of the dietary treatments had any effect on food intake, but the diets that contained dihydroxyacetone decreased the rate of weight gain. CONCLUSIONS: Increasing glycogen synthesis had no effect on food intake. Increasing the proportion of glycogen synthesized by the indirect pathway through pyruvate was associated with a decrease in weight gain.

Animals↗
PubMed1999

Slowed glycogen utilization enhances exercise endurance in patients with heart failure.

OBJECTIVES: The objective of the study was to investigate the impact of alteration of glycogen stores and metabolism on exercise performance in patients with heart failure. BACKGROUND: In normal subjects, muscle glycogen depletion results in increased exertional fatigue and reduced endurance. Skeletal muscle biopsies have revealed reduced glycogen content in patients with congestive heart failure (CHF). Whether glycogen depletion contributes to reduced endurance and abnormal ventilation in these patients is unknown. METHODS: Bicycle exercise tests with measurement of respiratory gases were performed following dietary manipulations to induce glycogen depletion (60% protein, 40% fat) and slow glycogen utilization (60% carbohydrate, 30% fat, 10% protein) in 13 patients with CHF (left ventricular ejection fraction 22+/-6%; age 48+/-9 years) and 7 control subjects (age 45+/-5 years). Maximal exercise, exercise at 75% of peak workload until exhaustion and 1-min cycles of supramaximal exercise at 133% of peak were performed on three occasions over a two-week period. RESULTS: Significant changes in resting respiratory quotients (RQs) in normal (Baseline: 0.78+/-0.03; Depleted: 0.69+/-0.05) and CHF subjects (Baseline: 0.84+/-0.05; Depleted: 0.72+/-0.05) were observed (both p<0.05). Peak Vo2 (oxygen consumption) in both groups was unchanged. The ventilatory response to exercise was analyzed by correlating CO2 production (V(CO2)) to minute ventilation (VE) in each test. The slopes of these correlations were not affected in either group. With glycogen depletion, exercise endurance was reduced from 17 to 6.1 min (57+/-19%) in normal subjects versus a reduction of 9.4 to 8.1 min (11+/-19%) in patients (p<0.05). With slowed glycogen use, CHF patients increased exercise endurance from 9.4 to 16.5 min (65%) versus 17 to 20.6 min (18%) in normal subjects (p<0.05). CONCLUSIONS: Glycogen depletion minimally affects maximal exercise performance, endurance or ventilation in CHF patients, whereas slowed glycogen utilization markedly enhances exercise endurance. Therapeutic interventions that increase or slow use of glycogen stores may have clinical benefit.

Adult↗
PubMed1984

Carbon-13 nuclear magnetic resonance studies of myocardial glycogen metabolism in live guinea pigs.

Myocardial glycogen metabolism was studied in live guinea pigs by 13C NMR at 20.19 MHz. Open-chest surgery was used to expose the heart, which was then positioned within a solenoidal radio frequency coil for NMR measurements. The time course of myocardial glycogen synthesis during 1-h infusions of 0.5 g of D-[1-13C]glucose (and insulin) into the jugular vein was investigated. The possible turnover of the 13C-labeled glycogen was also studied in vivo by following the labeled glucose infusion with a similar infusion of unlabeled glucose. The degree of 13C enrichment of the C-1 glycogen carbons during these infusions was measured in heart extracts by 1H NMR at 360 MHz. High-quality proton-decoupled 13C NMR spectra of the labeled C-1 carbons of myocardial glycogen in vivo were obtained in 1 min of data accumulation. This time resolution allowed measurement of the time course of glycogenolysis of the 13C-labeled glycogen during anoxia by 13C NMR in vivo. With the solenoidal coil used for 13C NMR, the spin-lattice relaxation time of the labeled C-1 carbons of myocardial glycogen could be measured in vivo. For a comparison, spin-lattice relaxation times of heart glycogen were measured in vitro at 90.55 MHz. Natural abundance 13C NMR studies of the quantitative hydrolysis of extracted heart glycogen in vitro at 90.55 MHz showed that virtually all the carbons in heart glycogen contribute to the 13C NMR signals. The same result was obtained in 13C NMR studies of glycogen hydrolysis in excised guinea pig heart.

Animals↗
PubMed1989

Ordered synthesis and mobilization of glycogen in the perfused heart.

The molecular order of synthesis and mobilization of glycogen in the perfused heart was studied by 13C NMR. By varying the glucose isotopomer ([1-13C]glucose or [2-13C]glucose) supplied to the heart, glycogen synthesized at different times during the perfusion was labeled at different carbon sites. Subsequently, the in situ mobilization of glycogen during ischemia was observed by detection of labeled lactate derived from glycolysis of the glucosyl monomers. When [1-13C]glucose was given initially in the perfusion and [2-13C]glucose was given second, [2-13C]lactate was detected first during ischemia and [3-13C]lactate second. This result, and the equivalent result when the glucose labels were given in the reverse order, demonstrates that glycogen synthesis and mobilization are ordered in the heart, where glycogen is found morphologically only as beta particles. Previous studies of glycogen synthesis and mobilization in liver and adipocytes [Devos, P., & Hers, H.-G. (1979) Eur. J. Biochem. 99, 161-167; Devos, P., & Hers, H.-G. (1980) Biochem. Biophys. Res. Commun. 95, 1031-1036] have suggested that the organization of beta particles into alpha particles was partially responsible for ordered synthesis and mobilization. The observations reported here for cardiac glycogen suggest that another mechanism is responsible. In addition to examining the ordered synthesis and mobilization of cardiac glycogen, we have selectively monitored the NMR properties of 13C-labeled glycogen synthesized early in the perfusion during further glycogen synthesis from a second, differently labeled substrate. During synthesis from the second labeled glucose monomer, the glycogen resonance from the first label decreased in integrated intensity and increased in line width.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Inhibition of autophagic proteolysis by inhibitors of phosphoinositide 3-kinase can interfere with the regulation of glycogen synthesis in isolated hepatocytes.

Amino acid-induced cell swelling stimulates conversion of glucose into glycogen in isolated hepatocytes. Activation of glycogen synthase (GS) phosphatase, caused by the fall in intracellular chloride accompanying regulatory volume decrease, and activation of phosphoinositide 3-kinase (PI 3-kinase), induced by cell swelling, have been proposed as underlying mechanisms. Because PI 3-kinase controls autophagic proteolysis, we examined the possibility that PI 3-kinase inhibitors interfere with glycogen production due to their anti-proteolytic action. The PI 3-kinase inhibitor wortmannin inhibited endogenous proteolysis, the production of glycogen from glucose and the activity of active (dephosphorylated) GS (GS a ) in the absence of added amino acids. The stimulation by amino acids of glycogen production and of GS a was only slightly affected by wortmannin. These effects of wortmannin could be mimicked by proteinase inhibitors. A combination of leucine, phenylalanine and tyrosine, which we showed previously to stimulate PI 3-kinase-dependent phosphorylation of ribosomal protein S6, did not stimulate glycogen production from glucose. In contrast with wortmannin, LY294002, another PI 3-kinase inhibitor, strongly inhibited both glycogen synthesis and GS a activity, irrespective of the presence of amino acids. Inhibition of glycogen synthesis by LY294002 could be ascribed in part to increased glycogenolysis and glycolysis. It is concluded that, in hepatocytes, activation of PI 3-kinase may not be responsible for the stimulation of glycogen synthesis by amino acids; LY294002 inhibits glycogen synthesis and stimulates glycogen breakdown by a mechanism that is unrelated to its action as an inhibitor of PI 3-kinase.

Adenosine Triphosphate↗
PubMed2004

Hyperglycemia and inhibition of glycogen synthase in streptozotocin-treated mice: role of O-linked N-acetylglucosamine.

Glycogen synthase is post-translationally modified by both phosphate and O-linked N-acetylglucosamine (O-GlcNAc). In 3T3-L1 adipocytes exposed to high concentrations of glucose, O-GlcNAc contributes to insulin resistance of glycogen synthase. We sought to determine whether O-GlcNAc also regulates glycogen synthase in vivo. Glycogen synthase activity in fat pad extracts was inhibited in streptozotocin (STZ)-treated diabetic mice. The half-maximal activation concentration for glucose 6-phosphate (A(0.5)) was increased to 830 +/- 120 microm compared with 240 +/- 20 microm in control mice (C, p < 0.01), while the basal glycogen synthase activity (%I-form) was decreased to 2.4 +/- 1.4% compared with 10.1 +/- 1.8% in controls (p < 0.01). Glycogen synthase activity remained inhibited after compensatory insulin treatment. After insulin treatment kinetic parameters of glycogen synthase were more closely correlated with blood glucose (A(0.5), r(2) = 0.70; %I-form, r(2) = 0.59) than insulin levels (A(0.5), r(2) = 0.04; %I-form, r(2) = 0.09). Hyperglycemia also resulted in an increase in the level of O-GlcNAc on glycogen synthase (16.1 +/- 1.8 compared with 7.0 +/- 0.9 arbitrary intensity units for controls, p < 0.01), even though the level of phosphorylation was identical in diabetic and control mice either with (STZ: 2.9 +/- 1.0 and C: 3.2 +/- 0.8) or without (STZ: 12.2 +/- 2.8 and C: 13.8 +/- 3.0 arbitrary intensity units) insulin treatment. In all mice the percent activation of glycogen synthase that could be achieved in vitro by recombinant protein phosphatase 1 (230 +/- 30%) was significantly greater in the presence of beta-d-N-acetylglucosaminidase (410 +/- 60%, p < 0.01). This synergistic stimulation of glycogen synthase due to codigestion by protein phosphatase 1 and beta-d-N-acetylglucosaminidase was more pronounced in STZ-diabetic mice (310 +/- 70%) compared with control mice (100 +/- 10%, p < 0.05). The findings demonstrate that O-GlcNAc has a role in the regulation of glycogen synthase both in normoglycemia and diabetes.

Adipose Tissue↗