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PubMed2004

Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity.

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these mutants to co-distribute with the androgen receptor in the cell nucleus, also that both glycogen synthase kinase-3beta and androgen receptor proteins can be found in cell nuclei of prostate cancer tissue samples. Because glycogen synthase kinase-3 beta activity is suppressed after the enzyme is phosphorylated by protein kinase B/Akt and Akt activity frequently increases during the progression of prostate cancer, nullification of the glycogen synthase kinase-3 beta-mediated suppression of androgen receptor activity by Akt likely contributes to prostate cancer progression.

Androgen Receptor Antagonists↗

PubMed1999

Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice.

To determine the role of GLUT4 on postexercise glucose transport and glycogen resynthesis in skeletal muscle, GLUT4-deficient and wild-type mice were studied after a 3 h swim exercise. In wild-type mice, insulin and swimming each increased 2-deoxyglucose uptake by twofold in extensor digitorum longus muscle. In contrast, insulin did not increase 2-deoxyglucose glucose uptake in muscle from GLUT4-null mice. Swimming increased glucose transport twofold in muscle from fed GLUT4-null mice, with no effect noted in fasted GLUT4-null mice. This exercise-associated 2-deoxyglucose glucose uptake was not accompanied by increased cell surface GLUT1 content. Glucose transport in GLUT4-null muscle was increased 1.6-fold over basal levels after electrical stimulation. Contraction-induced glucose transport activity was fourfold greater in wild-type vs. GLUT4-null muscle. Glycogen content in gastrocnemius muscle was similar between wild-type and GLUT4-null mice and was reduced approximately 50% after exercise. After 5 h carbohydrate refeeding, muscle glycogen content was fully restored in wild-type, with no change in GLUT4-null mice. After 24 h carbohydrate refeeding, muscle glycogen in GLUT4-null mice was restored to fed levels. In conclusion, GLUT4 is the major transporter responsible for exercise-induced glucose transport. Also, postexercise glycogen resynthesis in muscle was greatly delayed; unlike wild-type mice, glycogen supercompensation was not found. GLUT4 it is not essential for glycogen repletion since muscle glycogen levels in previously exercised GLUT4-null mice were totally restored after 24 h carbohydrate refeeding.-Ryder, J. W., Kawano, Y., Galuska, D., Fahlman, R., Wallberg-Henriksson, H., Charron, M. J., Zierath, J. R. Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice.

Animals↗

PubMed1983

On the mechanism by which glucocorticoids cause the activation of glycogen synthase in mouse and rat livers.

The administration of glucocorticoids to mice caused within 3 h an inactivation of glycogen phosphorylase and activation of glycogen synthase in their livers. In a Sephadex filtrate of liver extract, as well as in a purified glycogen fraction obtained from treated mice, but not in the same preparations obtained from control mice, glycogen synthase was activated without previous inactivation of phosphorylase. The initial rate of synthase activation in a Sephadex filtrate was proportional to the rate of glycogen synthesis in vivo in the same animal. When the glycogen fraction was isolated in the presence of soluble starch, it could be separated from phosphorylase, phosphorylase phosphatase and synthase phosphatase. When added to a control Sephadex filtrate, this purified glycogen fraction obtained from prednisolone-treated mice relieved synthase phosphatase from inhibition by phosphorylase a, indicating that it contained a transferable 'deinhibiting factor'. This deinhibiting factor appears to be a protein and was further purified by alkyl-Sepharose or DEAE-cellulose chromatography. Another modification introduced by treatment with prednisolone was that phosphorylase phosphatase was 1.5-2-fold more active than in the liver of control mice. This property however did not correlate with the rate of glycogen synthesis in vivo. Administration of actinomycin D prevented the expression of the glucocorticoid effects on the rate of glycogen synthesis in vivo and on the protein phosphatases in vitro. The deinhibition of synthase phosphatase was also observed in isolated rat hepatocytes incubated in the presence of glucocorticoids, but in these preparations synthase was not activated.

Animals↗

PubMed1991

The molecular mechanism by which adrenalin inhibits glycogen synthesis.

Improved methodology was used to establish that the phosphorylation of a serine located 10 residues from the N-terminus of glycogen synthase (N10) increases from 0.12 mol.mol-1 to 0.54 mol.mol-1 in vivo in response to adrenalin. The only 'N10 kinase' detected in muscle extracts was casein kinase-1 (CK1), although its activity was unaffected by injection of adrenalin in vivo or by incubation with cyclic-AMP-dependent protein kinase and MgATP in vitro. Prior phosphorylation of the serine residue N7 by phosphorylase kinase increased sixfold the rate of phosphorylation of glycogen synthase by CK1, and altered the specificity of CK1 so that it phosphorylated the serine residue N10 specifically. Stoichiometric phosphorylation of N7 decreased the activity ratio (+/- glucose 6-phosphate) of glycogen synthase from 0.80 to 0.45, and subsequent phosphorylation of N10 to 0.8 mol.mol-1 produced a further decrease to 0.17, demonstrating that N10 phosphorylation inhibits glycogen synthase. The major 'N10 phosphatase' in skeletal muscle extracts was identified as the glycogen-associated form of protein phosphatase-1 (PP1G), accounting for approximately 75% of the N10 phosphatase activity in the extracts and about 90% of the activity in isolated glycogen particles. Phosphorylation of N10, after prior phosphorylation of N7, decreased the rate of dephosphorylation of N7. These results, in conjunction with previous findings, establish that adrenalin inhibits glycogen synthase by increasing the phosphorylation of N7, N10 and three further serines located 30, 34 and 38 residues from the start of the C-terminal CNBr peptide (termed the region C30-C38). They also indicate that increased phosphorylation of N10, the region C30-C38, and perhaps N7, is initiated through the inhibition of PP1G by adrenalin, which results from phosphorylation of its glycogen-targetting subunit by cyclic-AMP-dependent protein kinase [Hubbard, M.J. & Cohen, P. (1989) Eur. J. Biochem. 186, 711-716]. The conclusion that direct phosphorylation of glycogen synthase by cyclic-AMP-dependent protein kinase makes little contribution to inhibition by adrenalin, is at variance with the teachings of the major textbooks of biochemistry.

Animals↗

PubMed1996

Direct activating effects of dexamethasone on glycogen metabolizing enzymes in primary cultured rat hepatocytes.

The direct effects of dexamethasone on glycogen synthase and phosphorylase and glycogen content have been investigated in primary cultured rat hepatocytes. Dexamethasone induced the transient translocation of glycogen synthase from the soluble to the 10000xg pelletable fraction and the activation of this enzyme, although more significant, longer-standing activation was achieved in the pelletable fraction. Neither total glycogen synthase content nor glycogen synthase mRNA levels were modified. Dexamethasone also caused the sustained activation (up to 6h) of glycogen phosphorylase, which was not accompanied by an increase in its mRNA level. Glycogen cell content and the incorporation of (14C) glucose into glycogen decreased after dexamethasone treatment. The data show that dexamethasone, unlike other glycogenolytic hormones, at concentrations of 10 nM or higher, stimulate hepatocyte glycogenolysis without inducing the inverse coupling of synthase and phosphorylase. The co-existence of active forms of both glycogen synthase and phosphorylase promoted by dexamethasone leads to a situation that is analogous to that of the fasted liver.

Animals↗

PubMed1989

Glycogen metabolism and post-exercise ketosis in carbohydrate-restricted trained and untrained rats.

Liver and muscle glycogen, and blood 3-hydroxybutyrate concentrations were studied during and for 2 h after treadmill running for 1 h, in 144 carbohydrate-starved trained and untrained rats. The resting liver glycogen concentration of the trained animals was 227 +/- 8 (mean +/- S.E.M.) mumol glucosyl units/g wet mass, compared with 162 +/- 12 mumol/g in the untrained animals. The muscle glycogen levels were 42 +/- 1 and 28 +/- 1 mumol/g respectively. Exercise reduced muscle and liver glycogen concentrations by approximately the same absolute amounts in both animal groups, leaving the trained rats with nearly 3 times as much residual glycogen as the untrained animals. There was very little resynthesis of muscle glycogen recovery, but the trained animals replenished approximately 43% of the liver glycogen used during exercise. The blood 3-hydroxybutyrate concentrations were negatively correlated with the simultaneous liver glycogen concentration of our experimental animals (r = -0.55; P less than 0.001). It is concluded that trained animals primarily owe their resistance to post-exercise ketosis to their large stores of glycogen.

3-Hydroxybutyric Acid↗

PubMed2001

Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase PP1G/RGL.

The regulatory-targeting subunit (RGL), also called GM) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/RGL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of RGL. To investigate the function of the phosphatase, RGL knockout mice were generated. Animals lacking RGL show no obvious defects. The RGL protein is absent from the skeletal and cardiac muscle of null mutants and present at approximately 50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by approximately 50% in the RGL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant RGL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by approximately 90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and RGL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that RGL is genetically linked to glycogen metabolism, since its loss decreases PP1 and basal GS activities and glycogen accumulation. However, PP1G/RGL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.

Animals↗

PubMed2003

Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage.

Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 +/- 20.5 micromol/g glycogen compared with 17.7 +/- 2.6 micromol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 +/- 0.3 and 3.9 +/- 0.6 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) and postcontraction (7.9 +/- 0.4 and 7.0 +/- 0.4 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [14C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship.

Adaptation, Physiological↗

PubMed1976

Response of mouse liver glycogen cycle enzymes to endotoxin treatment.

The present study was undertaken to characterize endotoxin-induced changes in carbohydrate metabolism and more specifically, to determine the contribution of glycogenolysis to the loss of liver glycogen. Female ICR mice, fasted overnight, were injected with a median lethal dose (LD50, 9 mg/kg) of endotoxin extracted from Salmonella typhimurium strain SR-11. Glycogen synthase and glycogen phosphorylase activities were measured at 0.5 and 6 h after treatment. Endotoxin treatment did not alter total glycogen synthase activity, but the amount of enzyme present in the active form was significantly lower in endotoxic mice. There was no significant increase in glycogen phosphorylase activity in endotoxin-treated mice. Glycogen phosphorylase was activated to the same extent in control and endotoxic mice by decapitation or intravenous epinephrine (25 or 1 mug/kg). The results of this study indicate no significant increase in glycogen phosphorylase activity in endotoxic mice, contraindicating enhanced glycogenolysis as a mechanism for depletion of carbohydrate following endotoxin injection. Altered activation of glycogen synthase, however, may contribute to the loss of glycogen during endotoxemia.

Animals↗

PubMed1975

Glycogen replenishment following exercise: effects of denervation and tenotomy.

To examine the role of the nervous system in the rapid replenishment of muscle glycogen that occurs after exhaustive exercise, glycogen stores and glycogen synthetase activity of normal gastrocnemius muscles of untrained and trained guinea pigs were compared to glycogen and synthetase activity of trained gastrocnemius muscles that were denervated or tenotomized immediately after exhaustive exercise and then allowed to recover for 48 h. The trained tenotomized muscles, but not the denervated muscles, had significantly (P smaller than 0.05) less glycogen than the trained normal muscles. These results suggest that neither nerve impulse conduction nor tropic substances contained in neural tissue proximal to the site of denervation mediate glycogen replenishment after exercise. The active, glucose 6-phosphate independent (I) form of glycogen synthetase activity was reduced by both denervation and tenotomy at 48 h after exercise with no significant (P greater than 0.05) differences detected for the total of I and D (glucose 6-phosphate dependent) synthetase activity. Synthetase I relative to total synthetase activity was similar in trained and untrained normal muscles, both of which had significantly (P smaller than 0.05) greater relative I activities than denervated or tenotomized muscles. These synthetase data show that elevated glycogen stores following recovery from exercise may be observed in the absence of increased levels of glycogen synthetase activity.

Achilles Tendon↗

PubMed1987

Effects of glucose or fructose feeding on glycogen repletion in muscle and liver after exercise or fasting.

In athletics, muscle and liver glycogen content is critical to endurance. This study compared the effectiveness of glucose and fructose feeding on restoring glycogen content after glycogen was decreased by exercise (90-min swim) or fasting (24 h). After 2 h of recovery from either exercise or fasting there was no measurable glycogen repletion in red vastus lateralis muscle in response to fructose. In contrast, glucose feeding induced a similar and significant carbohydrate storage after both depletion treatments (8.44 mumol X g-1 X 2 h-1). In the liver, following 2 h of recovery, the rates of glycogen storage were similar after either glucose or fructose ingestion, but fasting caused a greater rate of repletion (83 mumol X g-1 X 2 h-1) than exercise (50 mumol X g-1 X 2 h-1). After 4 h of recovery fructose-fed exercised animals had the highest glycogen concentration (165 mumol X g-1) followed by the glucose-fed exercised group (119 mumol X g-1). These values were 50 and 36%, respectively, of that measured in the normal-fed liver (327 mumol X g-1). In contrast, liver glycogen values in the fasted group decreased between the 2nd and 4th hour of recovery in response to both feeding regimens. From these results we conclude that fructose is a poor nutritional precursor for rapid glycogen restoration in muscle after exercise, but that both glucose and fructose promote rapid accumulation of glycogen in the liver.

Animals↗

PubMed2001

A defect in glycogen synthesis characterizes insulin resistance in hypertensive patients with type 2 diabetes.

A subgroup of patients with type 2 diabetes shows a clustering of abnormalities such as peripheral insulin resistance, hypertension, and microalbuminuria. To evaluate whether these traits reflect intrinsic disorders of cell function rather than in vivo environmental effects, we studied a group of 7 nondiabetic hypertensive subjects with an altered albumin excretion rate (AER) (HyMA+) and 3 groups of patients with type 2 diabetes: 7 with normal blood pressure and normal AER (DH-MA-), 7 with high blood pressure and normal AER (DH+MA-), and 7 with both high blood pressure and altered AER (DH+MA+). Glucose disposal was measured during an hyperinsulinemic clamp (40 mU. m(2)(-1). min(-1)) with primed deuterated [6.6 (2)H(2)] glucose infusion. In the same subjects, a skin biopsy was performed and the following parameters were investigated: glucose transport (as determined by [(3)H]2-deoxyglucose uptake); glycogen synthase activity (as determined by [(14)C] glucose incorporation from UDP-[U-(14)C] glucose into glycogen); glycogen phosphorylase activity (as measured by the incorporation of [U-(14)C]glucose 1-phosphate into glycogen); and total glycogen content. In vivo glucose disposal was significantly reduced in DH+MA- and DH+MA+, with respect to DH-MA-, HyMA+, and controls. Insulin-stimulated glucose transport was similar in the 3 groups of patients with diabetes. A significant reduction of intracellular glycogen content was observed in DH+MA- and DH+MA+ compared with DH-MA- in both basal and insulin-stimulated conditions, probably because of a major impairment of glycogen synthase activity. Glycogen phosphorylase activity did not show differences between the groups. These results suggest that (1) the combination of type 2 diabetes with hypertension and altered AER is associated with impaired insulin sensitivity, and (2) intrinsic, possibly genetic, factors may account for increased peripheral insulin resistance in hypertensive microalbuminuric patients with type 2 diabetes, pointing to the reduction of glycogen synthase activity as a shared common defect.

Albuminuria↗

PubMed2005

Failure to repeatedly supercompensate muscle glycogen stores in highly trained men.

PURPOSE: It is not known whether it is possible to repeatedly supercompensate muscle glycogen stores after exhaustive exercise bouts undertaken within several days. METHODS: We evaluated the effect of repeated exercise-diet manipulation on muscle glycogen and triacylglycerol (IMTG) metabolism and exercise capacity in six well-trained subjects who completed an intermittent, exhaustive cycling protocol (EX) on three occasions separated by 48 h (i.e., days 1, 3, and 5) in a 5-d period. Twenty-four hours before day 1, subjects consumed a moderate (6 g.kg)-carbohydrate (CHO) diet, followed by 5 d of a high (12 g.kg.d)-CHO diet. Muscle biopsies were taken at rest, immediately post-EX on days 1, 3, and 5, and after 3 h of recovery on days 1 and 3. RESULTS: Compared with day 1, resting muscle [glycogen] was elevated on day 3 but not day 5 (435+/-57 vs 713+/-60 vs 409+/-40 mmol.kg, P<0.001). [IMTG] was reduced by 28% (P<0.05) after EX on day 1, but post-EX levels on days 3 and 5 were similar to rest. EX was enhanced on days 3 and 5 compared with day 1 (31.9+/-2.5 and 35.4+/-3.8 vs 24.1+/-1.4 kJ.kg, P<0.05). Glycogen synthase activity at rest and immediately post-EX was similar between trials. Additionally, the rates of muscle glycogen accumulation were similar during the 3-h recovery period on days 1 and 3. CONCLUSION: We show that well-trained men cannot repeatedly supercompensate muscle [glycogen] after glycogen-depleting exercise and 2 d of a high-CHO diet, suggesting that the mechanisms responsible for glycogen accumulation are attenuated as a consequence of successive days of glycogen-depleting exercise.

Adult↗

PubMed1975

Hormonal regulation of glycogen metabolism in human fetal liver. I. Normal development and effects of dibutyryl cyclic AMP, glucagon, and insulin in liver explants.

Glycogen accumulates in human fetal liver beginning at the eighth week of gestation. A parallel increase in total glycogen synthase activity is found, although the I-form activity remains low and constant throughout the first two thirds of gestation. Total phosphorylase activity increases slightly during this period, with the proportion in the active form amounting to about one half of the total throughout. After an initial rapid decline, the glycogen concentration in explants of human fetal liver remained constant for twenty to forty hours at about 20 per cent of the in vivo level. Incubation with glucagon, cyclic AMP (adenosine 3',5'-monophosphate) or its dibutyryl derivative markedly reduced tissue glycogen concentrations while insulin brought about a small increase. The effect of maximal doses of dibutyryl cyclic AMP and glucagon were the same, and the combination of agents produced no further effect. The response to dibutyryl cyclic AMP was apparent by one hour and maximal by three to six hours, whereas the response to insulin required about six hours to be detected, and it continued for at least eighteen hours. Insulin antagonized the glycogenolytic effect of low doses of glucagon or theophylline but was without significant effect in the presence of high glucagon concentrations. Glucagon stimulated cyclic AMP output from explants, and this effect was further augmented by theophylline. Insultin had no consistent effect on cyclic AMP output in either the presence or the absence of glucagon or theophylline. Incubation with dibutyryl cyclic AMP resulted in a decrease of glycogen synthase I-form activity, while insulin tended to increase this enzyme activity. In neither circumstance was the proportion of active phosphorylase altered. These results suggest that the regulation of glycogen levels in human fetal liver by cyclic AMP, glucagon, and insulin may entail alterations in the activity of glycogen synthase activity without necessitating alterations in phosphorylase activity. Cyclic AMP or glucagon was capable of depleting tissue glycogen stores in tissue from fetuses of six weeks' gestation. Insulin increased tissue glycogen concentrations in tissue from fetuses of seven or more weeks.

Bucladesine↗

PubMed2002

Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats.

Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 +/- 2% (P < 0.001) and 26 +/- 4% (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia in diabetic rats by 6.0 +/- 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with type 2 diabetes.

Animals↗

PubMed1985

Interactions between insulin and alpha 1-adrenergic agents in the regulation of glycogen metabolism in isolated hepatocytes.

Addition of insulin to liver cells from fed rats incubated in the absence of other hormones resulted in a 2-fold increase in glycogen synthase activity. This direct effect of insulin has been characterized and compared with the antagonism by insulin of alpha 1-adrenergic effects on glycogen metabolism. The activation of glycogen synthase by insulin developed slowly (20-25 min) and was most effective when the enzyme was partially preactivated by glucose. With glucose concentrations above 15 mM the effects of insulin and glucose were additive. In contrast to glucose, which caused inverse changes in phosphorylase and glycogen synthase activity, insulin activated glycogen synthase without affecting phosphorylase a. Treatment of hepatocytes with phenylephrine led to an activation of phosphorylase and inactivation of glycogen synthase, which could be partially blocked by insulin. This antagonistic effect of insulin was rapid (complete within 5 min of insulin addition) and showed an identical time course for both enzymes. The activation of glycogen synthase by insulin and inactivation by phenylephrine both resulted principally from alterations in the Vmax. Insulin added alone did not alter the basal cytosolic free Ca2+ concentration, which was 160 nM as measured with Quin 2 as an intracellular Ca2+ indicator. Both the magnitude and the initial rate of cytosolic free Ca2+ increase induced by phenylephrine were reduced by about 50% in cells pretreated with insulin. It is concluded that the direct activation of glycogen synthase by insulin is mediated by a glycogen synthase-specific kinase or phosphatase, whereas insulin antagonizes the effects of alpha 1-agonists by interfering with their ability to elevate cytosolic free Ca2+.

Adrenergic alpha-Agonists↗

PubMed1984

Insulin regulation of glycogen synthase phosphatase in primary cultures of hepatocytes.

Activation of glycogen synthase in the perfused rat liver is defective in severely diabetic rats. In the present study, activation of glycogen synthase by glucose and increased incorporation of [14C]glucose into glycogen by insulin are defective in hepatocytes isolated from alloxan diabetic rats. Acute activation of glycogen synthase in hepatocytes isolated from diabetic rats was restored by treatment of the rats with insulin in vivo. Restoration of synthase activation was not achieved by incubation of hepatocytes in the presence of insulin in vitro for up to 12 h. When isolated hepatocytes from diabetic rats were placed in primary culture in a serum-free defined medium over a 3-day period, glycogen synthesis was partially restored by cortisol and triiodothyronine and dramatically increased by insulin. Concomitant with restoration of [14C]glycogen synthesis was an insulin-mediated increase in glycogen synthase I and synthase phosphatase activity. Restoration of regulation of glycogen synthesis in primary cultures of hepatocytes from diabetic rats by insulin required the presence of cortisol and triiodothyronine. Primary cultures of hepatocytes from normal rats did not require triiodothyronine for insulin to effect glycogenesis over a 3-day period. These data demonstrate that insulin acts in a chronic manner in concert with other hormones to control synthase phosphatase activity, an effect which may be influencing acute control of hepatic glycogen synthesis.

Animals↗

PubMed1983

Glycogen metabolism in phosphorus-depleted rats.

Glycogen content as well as the enzymes of glycogenolysis and glycogen synthesis were examined in myocardium, skeletal muscle, liver and kidneys of rats with dietary phosphorus deprivation. Myocardial glycogen content was decreased and this was accompanied by activation of the enzymes of glycogenolysis and inhibition of the enzymes of glycogen synthesis. Beta blockade (nadolol) abolished the effect of phosphorus depletion (PD) on myocardial glycogen metabolism, documenting that the effect of PD is mediated, at least in part, by increased sympathetic activity. Furthermore, administration of insulin caused a marked increase of glycogen content in the heart of both control and phosphorus-depleted (PD) animals. There was no change of glycogen content or the activities of enzymes of glycogen metabolism in skeletal muscle or kidney, but a decrease of glycogen content of the liver was observed in PD animals.

Adrenergic beta-Antagonists↗