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PubMedDate not supplied

[Glycogen content in the placenta of rats in experimental diabetes].

Glycogen was determined histochemically and biochemically in the placenta of female rats with alloxan diabetes induced in sexually immature animals, including the placenta of rats treated with sulfamides before the occurrence of pregnancy. Histochemical studies were carried out on 18, and biochemical on 38 Wistar rats. Glycogen content in the mature placenta before labour was greater in animals with manifest alloxan diabetes than in healthy rats. This increase of glycogen granules took place on account of their increase both in the glycogen cells, and, extracellularly, in the spongious zone. A significant increase of glycogen content in the placenta in manifest and latent diabetes was also demonstrated by biochemical methods; as to "prediabetic" rats--elevation of glycogen content in their placenta was insignificant in comparison with control. In diabetes compensated with sulfamides glycogen content in glycogen cells changed differently: there was a disappearance of extracellular glycogen from the spongious zone, and numerous glycogen granules (determined in healthy rats and in those with alloxan diabetes in insignificant amount) appeared in the labyrinth.

Alloxan↗

PubMed1982

Cyclic AMP-dependent and cyclic AMP-independent antagonism of insulin activation of cardiac glycogen synthase.

The hormonal regulation of glycogen synthase has been studied with isolated perfused hearts that were depleted of 85% of their endogenous glycogen. Glycogen depletion alone promoted a 3-fold activation of glycogen synthase and magnified by 3-fold the response to insulin. Glycogen depletion also facilitated the detection of epinephrine-promoted glycogen synthase inactivation. Hormonal effects on glycogen synthase have been correlated with changes in phosphorylase, phosphorylase kinase, and tissue cAMP levels. Insulin activation of glycogen synthase was observed within 90 s of hormone addition and was maximal by 4 min. A half-maximum effect was obtained at an insulin concentration of 100 microunits/ml. Insulin-dependent activation is reversed by beta-adrenergic agonists, alpha-adrenergic agonists, and glucagon. Each promote the same degree of inactivation and the maximum extent of inactivation produced by each is independent of whether or not the tissue has been stimulated with insulin. beta-Adrenergic agonists and glucagon act via cAMP, alpha-agonists most likely act via intracellular Ca2+ translocation, and insulin action would appear to be independent of either cAMP or Ca2+. The action of epinephrine on cardiac glycogen synthase is mediated by interaction with both alpha- and beta-receptors. As indicated by dose-response curves, receptor occupancy of each occurs to an almost equal extent at suboptimal epinephrine concentrations. Regulation of cardiac glycogen synthase by epinephrine thus is mediated by two second messenger systems which converge to produce the end physiological response.

Animals↗

PubMed1976

Studies on the alpha-adrenergic activation of hepatic glucose output. I. Studies on the alpha-adrenergic activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase in isolated rat liver parenchymal cells.

Epinephrine and the alpha-adrenergic agonist phenylephrine activated phosphorylase, glycogenolysis, and gluconeogenesis from lactate in a dose-dependent manner in isolated rat liver parenchymal cells. The half-maximally active dose of epinephrine was 10-7 M and of phenylephrine was 10(-6) M. These effects were blocked by alpha-adrenergic antagonists including phenoxybenzamine, but were largely unaffected by beta-adrenergic antagonists including propranolol. Epinephrine caused a transient 2-fold elevation of adenosine 3':5'-monophosphate (cAMP) which was abolished by propranolol and other beta blockers, but was unaffected by phenoxybenzamine and other alpha blockers. Phenoxybenzamine and propranolol were shown to be specific for their respective adrenergic receptors and to not affect the actions of glucagon or exogenous cAMP. Neither epinephrine (10-7 M), phenylephrine (10-5 M), nor glucagon (10-7 M) inactivated glycogen synthase in liver cells from fed rats. When the glycogen synthase activity ratio (-glucose 6-phosphate/+ glucose 6-phosphate) was increased from 0.09 to 0.66 by preincubation of such cells with 40 mM glucose, these agents substantially inactivated the enzyme. Incubation of hepatocytes from fed rats resulted in glycogen depletion which was correlated with an increase in the glycogen synthase activity ratio and a decrease in phosphorylase alpha activity. In hepatocytes from fasted animals, the glycogen synthase activity ratio was 0.32 +/- 0.03, and epinephrine, glucagon, and phenylephrine were able to lower this significantly. The effects of epinephrine and phenylephrine on the enzyme were blocked by phenoxybenzamine, but were largely unaffected by propranolol. Maximal phosphorylase activation in hepatocytes from fasted rats incubated with 10(-5) M phenylephrine preceded the maximal inactivation of glycogen synthase. Addition of glucose rapidly reduced, in a dose-dependent manner, both basal and phenylephrine-elevated phosphorylase alpha activity in hepatocytes prepared from fasted rats. Glucose also increased the glycogen synthase activity ratio, but this effect lagged behind the change in phosphorylase. Phenylephrine (10-5 M) and glucagon (5 x 10(-10) M) decreased by one-half the fall in phosphoryalse alpha activity seen with 10 mM glucose and markedly suppressed the elevation of glycogen synthase activity. The following conclusions are drawn from these findings. (a) The effects of epinephrine and phenylephrine on carbohydrate metabolism in rat liver parenchymal cells are mediated predominantly by alpha-adrenergic receptors. (b) Stimulation of these receptors by epinephrine or phenylephrine results in activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase by mechanisms not involving an increase in cellular cAMP. (c) Activation of beta-adrenergic receptors by epinephrine leads to the accumulation of cAMP, but this is associated with minimal activation of phosphorylase or inactivation of glycogen synthase...

Adrenergic alpha-Agonists↗

PubMed1996

[The glycogen-forming function of the hepatocytes during the regeneration of the cirrhotic rat liver after a partial hepatectomy].

The paper deals with a cytofluorimetric study of the content of glycogen and its fractions as well as with a microbiochemical study of glucose-6-phosphatase, glycogen phosphorylase, and glycogen synthase activities in the rat liver parenchyma cells in norm, in the course of cirrhosis development, and at various time intervals after the end of the carbon tetrachloride (CCl4) poisoning and after a partial hepatectomy (PH). Serial liver biopsies were obtained from each animal prior to CCl4 action (control), 6 months after a chronic intoxication with CCl4 inducing liver cirrhosis, and then 3 and 6 months after the end of CCl4 poisoning of rats, and after the cirrhotic liver PH. It has been shown that the total glycogen content in the cirrhotic liver hepatocytes increases by 1.4-1.5 times, compared with control, however, it returns to the norm 6 months after the PH. The glycogen labile fraction (LF), that accounts for 85% of the total glycogen, amounted to 65% in liver cirrhosis. The most striking changes in liver cirrhosis occurred in the glycogen stable fraction (SF) which rose by 3.9 times in the cirrhotic liver. The LF/SF ratio returned to the norm 6 months after the PH. The activity of glucose-6-phosphatase fell by 2.7 times in the liver cirrhosis; its activity after the PH initially increased, then decreased again to reach 6 months after the PH the same level as in the cirrhotic liver before the PH. The activities of glycogen phosphorylase and glycogen synthase returned to the normal level 6 months after the PH. The results of the current study make it possible to conclude that the PH of the cirrhotic liver facilitates only a partial restoration of the glycogen forming function of hepatocytes.

Animals↗

PubMed2005

Glycogen metabolism in rat ependymal primary cultures: regulation by serotonin.

Ependymal primary cultures are a model for studying ependymal energy metabolism. Intracellular glycogen is built up in the cultures dependent on culture age and the presence of glucose and glutamate. This energy store is mobilized upon glucose withdrawal, stimulation with isoproterenol, forskolin or serotonin and after uncoupling of oxidative phosphorylation from ATP production. Serotonin regulates ependymal glycogen metabolism predominantly via 5-HT receptor (5-HTR) 7, which elicits an increase in the level of ependymal cyclic AMP. Although the most abundant mRNAs for serotonin receptors are those of 5-HTR 2B and 5-HTR 3A, ependymal cells in primary culture do not respond to serotonin with an increase in their concentration of cytosolic calcium ions. The mRNAs of 5-HTRs 1A, 6, 1B, 5B, 7, 1/2C and 5A are also detectable in order of decreasing abundance. The mRNAs for 5-HTRs 1D, 1F, 3B and 4 are absent from the cultured cells. The ability of serotonin to mobilize ependymal glycogen depends on the culture age and the time allowed for glycogen buildup. During glycogen buildup time, glutamate is consumed by the cells. An increased ability of 5-HT to mobilize ependymal glycogen stores is noticed after the depletion of glutamate from the glycogen buildup medium. In ependymal primary cultures, cilia are colocalized with glycogen phosphorylase isozyme BB, while the MM isoform is not expressed. It is known from the literature that an increase in the concentration of cytosolic cAMP in ependymal cells leads to a decrease in ciliary beat frequency. Therefore, the present data point towards a function for ependymal glycogen other than supplying energy for the movement of cilia.

Animals↗

PubMed2002

Hepatic and skeletal muscle glycogen metabolism in rats with short-term cholestasis.

BACKGROUND/AIMS: To study the effect of short-term cholestasis on glycogen metabolism. METHODS: Rats were bile duct ligated (BDL) for 4 or 8 days and compared to sham-operated control rats pair-fed to BDL (pair-fed CON) or fed ad libitum (ad libitum-fed CON). RESULTS: Four days after surgery, the hepatic glycogen content was 21.6+/-7.6 mg/g in BDL, 21.2+/-8.5 mg/g in pair-fed CON and 72.9+/-7.7 mg/g in ad libitum-fed CON, respectively. Eight days after surgery, the hepatic glycogen content was reduced in BDL as compared to pair-fed (31.2+/-8.9 vs. 59.1+/-5.4 mg/g) or ad libitum-fed CON (58.3+/-4.7 mg/g). Similar findings were obtained with the glycogen content expressed per ml hepatocytes or per liver. Histological analysis of BDL livers showed that most hepatocytes were affected. As compared to CON, activities and mRNA levels of glycogen synthase and phosphorylase were reduced in BDL, whereas plasma glucagon and endotoxin levels were increased at both time points. In contrast to liver, skeletal muscle glycogen metabolism remained unaffected. CONCLUSIONS: While reduced intake of food explains the decrease in the hepatic glycogen stores in BDL and pair-fed CON 4 days after surgery, reduced glycogen synthesis, possibly related to endotoxinemia, is the most probable cause of the decrease in the hepatic glycogen content in BDL 8 days after surgery.

Acute Disease↗

PubMed2006

High glycogen levels in the hippocampus of patients with epilepsy.

During intense cerebral activation approximately half of the glucose plus lactate taken up by the human brain is not oxidized and could replenish glycogen deposits, but the human brain glycogen concentration is unknown. In patients with temporal lobe epilepsy, undergoing curative surgery, brain biopsies were obtained from pathologic hippocampus (n=19) and from apparently 'normal' cortical grey and white matter. We determined the in vivo brain glycogen level and the activity of glycogen phosphorylase and synthase. Regional differences in glycogen concentration were examined similarly in healthy pigs (n=5). In the patients, the glycogen concentration in 'normal' grey and white matter was 5 to 6 mmol/L, but much higher in the hippocampus, 13.1+/-4.3 mmol/L (mean+/-s.d.; P<0.001); the activities of glycogen phosphorylase and synthase displayed the same pattern. In normal hippocampus from pigs, glycogen was similarly higher than in grey and white matter. Consequently, in human grey and white matter and, particularly, in the hippocampus of patients with temporal lope epilepsy, glycogen constitutes a large, active energy reserve, which may be of importance for energy provision during sustained synaptic activity as epileptic seizures.

Adult↗

PubMed2026

Application of 13C MRS demonstrates carbohydrate feeding spares muscle but not liver glycogen utilization during high-intensity interval exercise.

We examined liver and muscle glycogen utilization during high-intensity interval cycling, and the impact of carbohydrate (CHO) feeding, using noninvasive 13C magnetic resonance spectroscopy (MRS). Following 24 h of standardized dietary intake, nine male cyclists completed 8 × 5-min intervals (1-min recovery), ingesting either placebo (PLA), 60 g maltodextrin (CHO), or 60 g maltodextrin plus caffeine, taurine, l-theanine, l-citrulline, and citicoline (CHO+) in a randomized crossover design. 13C MRS and 1H imaging were performed pre- and postexercise to determine liver and muscle glycogen and liver volume, respectively. Liver glycogen utilization was not significantly different between trials (P = 0.101) despite lower postexercise plasma glucagon concentrations in CHO and CHO+ (P = 0.001). In contrast, muscle glycogen utilization was significantly lower (∼40%) with CHO feeding compared with PLA (P = 0.006), yet this sparing effect was not evident with CHO+ (P = 0.073) in accordance with a higher mean power output during the late intervals (+2.8%, P = 0.046). Plasma glucose was comparable between trials (P = 0.175), whereas plasma lactate was higher in CHO+ versus CHO (P = 0.003), alongside lower blood bicarbonate (P = 0.005), base excess (P < 0.001), and total CO2 (P = 0.004). These findings demonstrate preferential use of skeletal muscle glycogen during high-intensity interval training (HIIT), which is attenuated under conditions of CHO feeding. This sparing effect is, however, not evident with the coingestion of a caffeine-containing multi-ingredient blend, potentially due to an increased capacity to sustain higher power outputs resulting in greater glycogen utilization.NEW & NOTEWORTHY Using 13C MRS, we provide data demonstrating preferential use of skeletal muscle glycogen during HIIT. Furthermore, data show muscle glycogen utilization is attenuated with CHO feeding, yet sparing is not evident when coingesting a caffeine-containing formulation, potentially reflecting increased capacity to perform more total work rather than a direct metabolic effect of caffeine. In contrast, liver glycogen utilization was not significantly different with CHO feeding despite a modest reduction of ∼5 g versus placebo.

Male↗

PubMed1985

Excess purine degradation in exercising muscles of patients with glycogen storage disease types V and VII.

To investigate purine catabolism in exercising muscles of patients with muscle glycogen storage disease, we performed ischemic forearm exercise tests and quantitated metabolites appearing in cubital venous blood. Two patients with glycogen storage disease type V and three with glycogen storage disease type VII participated in this study. Basal lactate concentrations lowered in every patient with glycogen storage disease type V or type VII. Two patients with glycogen storage disease type VII, who had markedly elevated concentrations of serum uric acid (14.3 and 11.9 mg/dl, respectively), showed high basal concentrations of ammonia (118 and 79 mumol/liter, respectively; 23 +/- 4 mumol/liter in healthy controls) and of hypoxanthine (23.4 and 20.4 mumol/liter, respectively; 2.0 +/- 0.4 mumol/liter in healthy controls). Other patients showed near normal measurements of these metabolites. After forearm exercise, ammonia, inosine, and hypoxanthine levels increased greatly in every patient studied, in contrast with the lack of increase in lactate levels. The incremental area under the concentration curves for venous ammonia was 13-fold greater in the glycogen storage disease group than in controls (1,120 +/- 182 vs. 83 +/- 26 mumol X min/liter). The incremental areas of inosine and hypoxanthine were also greater in the glycogen storage disease group (29.2 +/- 7.2 vs. 0.4 +/- 0.1 and 134.6 +/- 23.1 vs. 14.9 +/- 3.2 mumol X min/liter, respectively). The incremental areas of ammonia in controls and in glycogen storage disease patients strongly correlated with those of hypoxanthine (r = 0.984, n = 11, P less than 0.005). These findings indicated that excess purine degradation occurred in the exercising muscles of patients with glycogen storage disease types V and VII, and suggested that the ATP pool in the exercising muscles may be deranged because of defective glycogenolysis or glycolysis.

Adult↗

PubMed2000

Glycogen synthase sensitivity to insulin and glucose-6-phosphate is mediated by both NH2- and COOH-terminal phosphorylation sites.

In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase. To study the mechanism of regulation of glycogen synthase by insulin and glucose-6-phosphate, we generated stable Rat-1 fibroblast clones expressing rabbit muscle glycogen synthase with Ser-->Ala substitutions at key phosphorylation sites. We found that 1) elimination of the phosphorylation of either NH2- or COOH-terminal sites did not abolish insulin stimulation of glycogen synthase; 2) mutations at both Ser-7 and Ser-640 were necessary to bypass insulin activation; 3) mutation at Ser-7, coupled with the disruption of the motif for recognition by glycogen synthase kinase-3 (GSK-3), did not eliminate the insulin effect; and 4) mutation of either Ser-7 or Ser-640 increased the sensitivity of glycogen synthase to glucose 6-phosphate >10-fold. We conclude that Ser-7 and Ser-640 are both involved in mediating the response of glycogen synthase to insulin and activation by glucose 6-phosphate. In Rat-1 fibroblasts, GSK-3 action is not essential for glycogen synthase activation by insulin, and GSK-3-independent mechanisms also operate.

Alanine↗

PubMedDate not supplied

Insulin-stimulated glycogen synthesis in cultured hepatoma cells: differential effects of inhibitors of insulin signaling molecules.

In rat HTC hepatoma cells overexpressing human insulin receptors, insulin stimulated glycogen synthesis by 55-70%. To study postreceptor signaling events leading to insulin-stimulated glycogen synthesis in these cells, we have employed pathway-specific chemical inhibitors such as LY294002, rapamycin and PD98059 to inhibit phosphatidylinositol-3-kinase (PI3K), p70 ribosomal S6 kinase and mitogen-activated protein kinase (MAPK) kinase/MAPK, respectively. LY294002 (50 microM) completely abolished insulin-stimulated glycogen synthesis whereas rapamycin (2-20 nM) partially inhibited it. Neither LY294002 nor rapamycin significantly affected the basal glycogen synthesis. However, PD98059 (100 microM) significantly inhibited the basal glycogen synthesis without affecting insulin-stimulated glycogen synthesis. In these cells, insulin at 100 nM decreased glycogen synthase kinase 3 alpha (GSK3 alpha) activity by 30-35%. LY294002, but neither rapamycin nor PD98059, abolished insulin-induced inactivation of GSK3 alpha. These data suggest that insulin-stimulated glycogen synthesis in rat HTC hepatoma cells is mediated mainly by PI3K-dependent mechanism. In these cells, inactivation of GSK3 alpha, downstream of PI3K, may play a role in insulin-stimulated glycogen synthesis.

Amino Acid Sequence↗

PubMed1985

Mapping increased glycogen phosphorylase activity in dorsal root ganglia and in the spinal cord following peripheral stimuli.

A histochemical technique has been used to map the distribution and the relative proportion of the active and inactive form of the enzyme glycogen phosphorylase in the primary afferent cell bodies of lumbar dorsal root ganglia and within the lumbar spinal cord of the rat. The glycogen phosphorylase was found to be present in large and small diameter primary afferent cell bodies and in the grey matter of the spinal cord, except in lamina 2. Most of the glycogen phosphorylase in control rats was in the inactive form. Peripheral innocuous mechanical and thermal stimuli failed to alter the activity of glycogen phosphorylase in the lumbar spinal cord, but noxious mechanical, chemical, and thermal stimuli when applied to the hindlimb of decerebrate rats increased the enzyme activity in the ipsilateral dorsal horn within 10 minutes. The number of primary afferent cell bodies with active glycogen phosphorylase also increased. These changes are likely to be due to the conversion of the inactive "b" form of the enzyme to the active "a" form under the influence of a calcium or cyclic AMP activated phosphorylase b kinase. Pentobarbitone anaesthesia diminished but did not completely suppress the noxious stimulus-evoked glycogen phosphorylase activity changes. Graded electrical stimulation of the sciatic nerve was performed to simulate the effects of the peripheral noxious stimuli in a controlled fashion. Stimulation at a strength that activated only large myelinated afferents produced no greater effect on the distribution of the active form of the enzyme in the dorsal horn than that produced by exposure of the nerve, but stimulation of the thin myelinated A-delta afferents and unmyelinated C-fibres produced a widespread increase in glycogen phosphorylase activity in the spinal cord and in the L4 dorsal root ganglion. The increased activity could be detected after stimulation for as short a period of time as 5 minutes. The mechanisms underlying the stimulus-evoked increase in glycogen phosphorylase activity in the spinal cord and dorsal root ganglia are not yet known, nor have we positively established which elements in the spinal cord, neurones, or glia are responsible for the changes in the glycogen phosphorylase activity. Nevertheless, it is clear that the neural activity generated by certain types of high threshold input is associated with the activation of glycogen phosphorylase, and this may be a useful tool for studying the spatial distribution of some activity-related changes in the nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2002

Glucose and glycogen catabolism in perfused livers of Walker-256 tumor-bearing rats and the response to hormones.

The alterations in hepatic glucose and glycogen catabolism were evaluated in rats bearing the Walker-256 tumor. Food intake was monitored concomitantly with measurements of the in vivo hepatic glycogen levels. Glycogenolysis, glycolysis and oxygen uptake were measured in the isolated perfused liver. The hepatic glucose phosphorylating capacity was measured in the high-speed supernatant fraction of liver homogenates. Food intake was 21.4% reduced in tumor-bearing rats; the glycogen levels were decreased by 63.6%. Initial basal rates of glucose release (glycogenolysis) and lactate+pyruvate production from endogenous glycogen (glycolysis) in the perfused liver were not changed by the tumor-bearing state, resulting in a higher relative rate of glycogen breakdown (% of glycogen degradation per unit time). In absolute terms stimulation of glycogen mobilization by glucagon or norepinephrine was smaller in the tumor-bearing state. The percentage of extra glycogen degradation per unit time caused by both hormones, however, was practically the same in the control and in the tumor-bearing state. The hepatic glucose phosphorylating capacity was reduced from 3.92+/-0.39 nmolmin(-1)(mgprotein)(-1) in normal rats to 2.61+/-0.23 nmolmin(-1)(mgprotein)(-1) in livers from tumor-bearing rats. Glycolysis from exogenous glucose (20 mM) in perfused livers was diminished from 0.136+/-0.023 &mgr;molmin(-1)(gliver)(-1) in normal rats to 0.046+/-0.008 &mgr;molmin(-1)(gliver)(-1) in tumor-bearing rats. It can be concluded that livers from rats bearing the Walker-256 tumor are less able to transform glucose and accumulate glycogen while possessing a greater tendency of releasing glucose from the glycogen stores.

Journal Article↗

PubMed1997

Expression of glycogen phosphorylase isozymes in developing rat lung.

Glycogen accumulates to significant levels in epithelial cells of the developing respiratory tract. Mobilization of glycogen stores is regulated differentially along the respiratory epithelium such that glycogenolysis in the alveolar epithelium (the site of surfactant synthesis) precedes that in the bronchial and bronchiolar epithelium. The initial step in glycogen degradation is catalyzed by glycogen phosphorylase, which exists as three genetically distinct isozymes referred to as muscle, liver, and brain isoforms. The goal of this study was to characterize the temporal and spatial expression of each of the glycogen phosphorylase isozymes in developing lung to determine which isoform(s) was associated with glycogen mobilization in the fetal type II epithelial cell. RNA levels encoding glycogen phosphorylase were assessed by ribonuclease protection assay using isoform-specific antisense probes. RNAs encoding the brain and liver isozymes were detected in isolated day 20 fetal type II epithelial cells and at lower levels in adult type II cells. The muscle isoform RNA was barely detectable in fetal type II cells and was undetectable in adult type II cells. Expression of brain and liver isoform RNAs was higher in whole fetal lung than in fetal type II cells. Consistent with this result, in situ hybridization studies demonstrated widespread expression of the brain and liver isoforms in developing lung tissues; in contrast, expression of the muscle isoform was restricted to the pulmonary vein. Glycogen phosphorylase enzyme activity corresponding to the brain isoform was clearly detected in isolated fetal type II cells; however, the majority of enzyme activity migrated as two bands with distinct electrophoretic mobilities that may have been the result of isoform heterodimerization. Collectively, these results suggest that the brain and liver isoforms of glycogen phosphorylase may be involved in mobilization of type II cell glycogen during late fetal lung development.

Animals↗

PubMed2005

Insulin induces a positive relationship between the rates of ATP and glycogen changes in isolated rat liver in presence of glucose; a 31P and 13C NMR study.

BACKGROUND: There is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is also a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle. However, little is known about its effects in the liver. Since there is a theoretical relationship between glycogen metabolism and energy status, a simultaneous and continuous investigation of hepatic ATP and glycogen content was performed in intact and isolated perfused liver by 31P and 13C nuclear magnetic resonance (NMR) The hepatic rates of ATP and glycogen changes were evaluated with different concentrations of insulin and glucose during continuous and short-term supply. RESULTS: Liver from rats fed ad libitum were perfused with Krebs-Henseleit Buffer (KHB)(controls) or KHB containing 6 mM glucose, 30 mM glucose, insulin alone, insulin + 6 mM glucose, insulin + 30 mM glucose. In the control, glycogenolysis occurred at a rate of -0.53 +/- 0.021 % x min(-1) and ATP content decreased at a rate of -0.28 +/- 0.029 % x min(-1). In the absence of insulin, there was a close proportional relationship between the glycogen flux and the glucose concentration, whereas ATP rates never varied. With insulin + glucose, both glycogen and ATP rates were strongly related to the glucose concentration; the magnitude of net glycogen flux was linearly correlated to the magnitude of net ATP flux: flux(glycogen) = 72.543(fluxATP) + 172.08, R2 = 0.98. CONCLUSION: Only the co-infusion of 30 mM glucose and insulin led to (i) a net glycogen synthesis, (ii) the maintenance of the hepatic ATP content, and a strong positive correlation between their net fluxes. This has never previously been reported. The specific effect of insulin on ATP change is likely related to a rapid stimulation of the hepatic mitochondrial oxidative phosphorylation. We propose that variations in the correlation between rates of ATP and glycogen changes could be a probe for insulin resistance due to the action of substrates, drugs or pathologic situations. Consequently, any work evaluating insulin resistance on isolated organs or in vivo should determine both ATP and glycogen fluxes.

Journal Article↗

PubMed2006

The experimental type 2 diabetes therapy glycogen phosphorylase inhibition can impair aerobic muscle function during prolonged contraction.

Glycogen phosphorylase inhibition represents a promising strategy to suppress inappropriate hepatic glucose output, while muscle glycogen is a major source of fuel during contraction. Glycogen phosphorylase inhibitors (GPi) currently being investigated for the treatment of type 2 diabetes do not demonstrate hepatic versus muscle glycogen phosphorylase isoform selectivity and may therefore impair patient aerobic exercise capabilities. Skeletal muscle energy metabolism and function are not impaired by GPi during high-intensity contraction in rat skeletal muscle; however, it is unknown whether glycogen phosphorylase inhibitors would impair function during prolonged lower-intensity contraction. Utilizing a novel red cell-perfused rodent gastrocnemius-plantaris-soleus system, muscle was pretreated for 60 min with either 3 micromol/l free drug GPi (n=8) or vehicle control (n=7). During 60 min of aerobic contraction, GPi treatment resulted in approximately 35% greater fatigue. Muscle glycogen phosphorylase a form (P<0.01) and maximal activity (P<0.01) were reduced in the GPi group, and postcontraction glycogen (121.8 +/- 16.1 vs. 168.3 +/- 8.5 mmol/kg dry muscle, P<0.05) was greater. Furthermore, lower muscle lactate efflux and glucose uptake (P<0.01), yet higher muscle Vo(2), support the conclusion that carbohydrate utilization was impaired during contraction. Our data provide new confirmation that muscle glycogen plays an essential role during submaximal contraction. Given the critical role of exercise prescription in the treatment of type 2 diabetes, it will be important to monitor endurance capacity during the clinical evaluation of nonselective GPi. Alternatively, greater effort should be devoted toward the discovery of hepatic-selective GPi, hepatic-specific drug delivery strategies, and/or alternative strategies for controlling excess hepatic glucose production in type 2 diabetes.

Animals↗

PubMed2000

Stimulation of glycogen synthesis by insulin requires S6 kinase and phosphatidylinositol-3-kinase in HTC-IR cells.

In order to study the role of phosphatidylinositol-3-kinase (PI3K), PKB, FRAP, S6 kinase, and MAP kinase in insulin-stimulated glycogen synthesis, we used a specific inhibitor of PI3K, LY294002, the immunosuppressant inhibitor of FRAP, rapamycin, and the inhibitor of MAPK kinase (MEK)/MAPK, PD98059, in rat HTC hepatoma cells overexpressing human insulin receptors. The PI3K inhibitor LY294002 completely blocks insulin-stimulated glycogen synthesis by inhibiting glycogen synthase, PKB (Akt-1), and FRAP (RAFT) autophosphorylation, as well as p70 S6 kinase activation, whereas insulin receptor substrates tyrosine phosphorylation and MEK activity were not affected. However, rapamycin only partially blocks insulin-stimulated glycogen synthesis by partial inhibition of glycogen synthase, whereas it completely blocks S6 kinase activation and FRAP autophosphorylation, but does not affect either PKB autophosphorylation, MEK activity, or insulin receptor tyrosine phosphorylation. Insulin-stimulated glycogen synthesis and glycogen synthase were not affected by the MEK/MAPK inhibitor PD98059. These data suggest that the PI3K, and not the MAPK pathway plays an important role in the insulin-stimulated glycogen synthesis in the hepatocyte, partly mediated by FRAP and S6 kinase activation. However, the inhibition of FRAP and S6 kinase activation is not sufficient to block insulin-stimulated glycogen synthesis, suggesting an important role of a branching pathway upstream of S6 kinase and downstream of PI3K, which is probably mediated by PKB in the signaling of the insulin receptor in hepatoma HTC cells.

Animals↗

PubMed1998

Interleukin 1beta and interleukin 6, but not tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes.

Recent evidence indicates that inflammatory cytokines are involved in changes of blood glucose concentrations and hepatic glucose metabolism in infectious diseases, including sepsis. However, little is known regarding how cytokines interact with glucoregulatory hormones such as insulin. The objective of the present study is to investigate if and how cytokines influence insulin-stimulated glycogen metabolism in the liver. Interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) markedly inhibited the increase of glycogen deposition stimulated by insulin in primary rat hepatocyte cultures; however, tumor necrosis factor alpha had no effect. Labeling experiments revealed that both cytokines counteracted insulin action by decreasing [14C]-glucose incorporation into glycogen and by increasing [14C]-glycogen degradation. Furthermore, it was discovered that IL-1beta and IL-6 inhibited glycogen synthase activity and, in contrast, accelerated glycogen phosphorylase activity. In experiments with kinase inhibitors, serine/threonine kinase inhibitor K252a blocked IL-1beta- and IL-6-induced inhibitions of glycogen deposition, as well as glycogen synthase activity, whereas another kinase inhibitor staurosporine blocked only IL-6-induced inhibition. Tyrosine kinase inhibitor herbimycin A blocked only IL-1beta-induced inhibition. These results indicate that IL-1beta and IL-6 regulate insulin-stimulated glycogen synthesis through different pathways involving protein phosphorylation in hepatocytes. They may mediate the change of hepatic glucose metabolism under pathological and even physiological conditions by modifying insulin action in vivo.

Animals↗