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The nucleotide sequence of a cDNA coding for rat liver glycogen phosphorylase has been determined. The 2715 base pairs of the cDNA are sufficient to encode the total protein as determined by comparison with the liver type of glycogen phosphorylase of man. Human and rat liver glycogen phosphorylase showed 86% homology at the DNA level whereas the deduced amino acid sequence has 93.5% identity.
Palmityl-CoA inhibits free liver glycogen synthase; the concentration required for half-maximum inhibition is 3 to 4 micrometer. Almost complete inhibition was observed at 50 micrometer. Palmityl-CoA inhibition is associated with dissociation of the tetrameric enzyme into monomers, and binding of palmityl-CoA to the monomers. Glycogen-bound enzyme is also inhibited by palmityl-CoA, resulting in dissociation of the enzyme into monomers and concomitant release of the enzyme from the primer glycogen. Palmityl-CoA inhibition of the enzyme is partially reversed by the glycogen synthase activator, glucose-6-P, whereas sodium lauryl sulfate-inhibited enzyme is not reactivated by glucose-6-P. Sodium lauryl sulfate inhibition results in the dissociation of the tetramer into the monomers. Bovine serum albumin and cyclodextrin can prevent palmityl-CoA inhibition only when they are added prior to palmityl-CoA addition. The possible physiological role of palmityl-CoA in glucose homeostasis is discussed.
The mechanism of liver glycogen synthesis after refeeding has been investigated in diabetic rats, diabetic insulin-treated rats, and in control rats fasted for 48 h. The accumulation of liver glycogen was the same in diabetic rats and in control rats after 2 h of feeding, but did not proceed any further in the diabetic group during the next 2 h. Insulin-treated diabetic rats synthesized five times more hepatic glycogen than the control rats after 1 h of refeeding, but the amount accumulated at the end of the refeeding period was the same. Feeding resulted in a transient activation of glycogen synthase in untreated as well as in treated diabetic rats. In control rats, however, glycogen synthase was already partially in the active form before access to food, and the onset of glycogen synthesis occurred without further activation of the enzyme. A transient inactivation of phosphorylase was observed in all groups during the meal, but was very slight in the untreated diabetic rats in which phosphorylase a values were already reduced before the access to food. Peripheral glycemia was markedly increased upon refeeding in treated and untreated diabetic rats, but remained normal in control rats. Peripheral insulinemia was increased by feeding in the control rats and remained low in the diabetic rats and high in the insulin-treated diabetic rats. The results indicate that, in normal controls in contrast to diabetic rats, synthase activation is not a prerequisite for the initiation of glycogen synthesis after a meal; phosphorylase inactivation may be of major importance in normal controls, but also appears to play a role in the diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of chronic treatment with metformin (320 mg/kg/day) on plasma glucose and insulin as well as liver glycogen synthase activity and hepatic glycogen content was studied in obese hyperinsulinemic Zucker rats. Metformin significantly reduced both plasma glucose (by 10%) and insulin levels (by 39%) at fasting but had no effect on hepatic glycogen content or on the basal activity of liver glycogen synthase.
We analyzed the biochemical mechanisms involved in the liver glycogen repletion upon refeeding for 360 min in 48 and 96 h-fasted rats. In 48 h-fasted rats, the glycogen synthesis involved a rapid and further sustained induction of glucokinase (GK) (increased twice from 90 min) and a rapid but transient activation of glycogen synthase a (GSa) (maximal increase by 150% at 90 min). It did not involve the inhibition of glycogen phosphorylase a (GPa). In 96 h-fasted rats, the glycogen repletion did not involve the induction of GK for the first 180 min of refeeding. It involved a slow activation of GSa (maximal 150% increase at 180 min) and a rapid inhibition of GPa (significant from 90 min, maximal 50% inhibition by 180 min). In both groups of rats, there was a progressive inhibition of the glucose-6 phosphatase (Glc6Pase) activity (maximal suppression by 30% in both groups at 360 min). These results highlighted a key role for the inhibition of Glc6Pase activity in the liver glycogen repletion upon refeeding.
The effects of Eimeria maxima or restricted pair-feeding on weight gain, plasma concentrations of protein, glucose, free fatty acids (FFA) and uric acid and liver glycogen were compared in immature fowl. Food intake/kg body weight and weight gain decreased during the acute phase of infection (days 5-7) while weight loss was prolonged for an extra day compared with pair-fed birds. During recovery, food intake/kg body weight of infected birds was greater than that of non-infected controls but there was no evidence for an increase in growth rate compared with controls when body weight was considered. Growth rate of pair-fed birds was greater than that of infected birds during recovery, indicating their better use of ingested food. Liver glycogen and plasma protein concentration were decreased during the acute phase of infection but the concentrations of plasma glucose, free fatty acid (FFA) and uric acid were not affected. In pair-fed birds liver glycogen was depleted, concentrations of plasma glucose and uric acid decreased and FFA increased, and these changes persisted for the remainder of the experiment. The findings are similar to those in birds whose food has been withheld and were probably due to the pattern of food intake imposed by the experimental protocol. It is concluded that the metabolic differences between infected and pair-fed birds are of doubtful significance.
In Wistar rats after swimming for 3 h, the glycogen level remained low in the liver during a period of 7 h. When sucrose was administered immediately after exercise, the liver glycogen content increased rapidly. From the 3rd to the 5th postexercise hour a secondary reduction was observed in hepatic glycogen. Sucrose administration inhibited the reduction of the blood glucose concentration which increased during exercise. However, 7 h after exercise, a slight hypoglycemia occurred in sucrose-treated rats. Administration of sucrose as a bolus immediately after exercise does not ensure a complete refilling of the hepatic glycogen store.
To determine the effect of maternal exercise on fetal liver glycogen content, fed and fasted rats that were pregnant for 20.5 or 21.5 days were run on a rodent treadmill for 60 min at 12 m/min with a 0% grade or 16 m/min up a 10% grade. The rats were anesthetized by intravenous injection of pentobarbital sodium, and fetal and maternal liver and plasma samples were collected and frozen. Fetal liver glycogenolysis did not occur as a result of maternal exercise. Fetal blood levels of lactate increased 22-60%, but glucose, plasma glucagon, and insulin were unchanged during maternal exercise. Maternal liver glycogen decreased as a result of exercise in all groups of rats except the fasted 20.5-day-pregnant group. Plasma free fatty acids increased in all groups and blood lactate increased in fed (20.5 days) and fasted (21.5 days) pregnant rats. Maternal glucose, glucagon, and insulin values remained constant during exercise. The fetus appears to be well-protected from metabolic stress during moderate-intensity maternal exercise.
Maternal hypothyroidism impairs fetal growth in the rat, but the mechanisms by which this occurs are unknown. Since the fetus derives its glucose supply from the mother, and maternal thyroidectomy may disturb maternal and placental glucose metabolism, we postulated that maternal and/or placental glucose metabolic compromise may contribute to fetal growth retardation in hypothyroid dams. Feto-placental growth, tissue glycogen stores and glucose levels in sera and amniotic fluid were determined in rat dams partially thyroidectomized (TX) before pregnancy and in euthyroid controls. Fetal body weight at 16, 19 and 21 days gestation (d.g.) was related to pre-mating maternal serum total thyroxine (TT(4)) levels; permanent fetal growth retardation occurred in severely (TX(s); pre-mating maternal serum TT(4)<or=16.19 nM) - but not in moderately (TX(m)) - hypothyroid dams. In TX(s) dams, glycogen concentration was elevated in maternal liver and in the fetal side of the placenta at 16 and 19 d.g., and in the maternal side of the placenta at 19 and 21 d.g., despite maternal euglycemia. In contrast, fetal liver glycogen concentration was deficient in TX(m) dams at 19 d.g. and in TX(s) dams at 19 and 21 d.g., and fetal hypoglycemia occurred in TX(s) dams at 21 d.g. Multiple regression analyses indicate that these fetal deficits are strongly associated with the retardation in fetal growth, while the elevated maternal liver and placental glycogen concentrations have no impact on fetal growth near term. The mechanisms by which severe maternal hypothyroidism permanently retards rat fetal growth remain to be determined.
1. The changes in liver glycogen concentration in normal, adrenalectomized and hypophysectomized foetal lambs have been examined during the last third of gestation using a biopsy technique to remove one or more samples of liver from the same foetus at different gestational ages. 2. The rate of glycogen deposition increased sharply from about 130 days' gestation in normal lamb foetuses whereas after hypophysectomy or adrenalectomy liver glycogen concentrations remained low even when gestation was prolonged. 3. I.V. infusions of cortisol (4-10 mg/day) for 52 hr resulted in four- to fivefold increases in liver glycogen in all three groups of foetuses. The level of glycogen in the liver appeared to be related to log plasma corticosteroid concentration in all foetuses whether they had received cortisol infusions or not. 4. Little or no change occurred in glycogen concentration in other foetal tissues apart from a decrease in the glycogen levels in peri-renal fat of adrenalectomized and hypophysectomized foetuses after cortisol infusion. There were also no detectable changes in foetal plasma lactate, urea or alpha amino nitrogen following the cortisol infusions. Foetal plasma glucose values rose slightly but this change was significant only in the adrenalectomized group. 5. The 52 hr cortisol infusions to the foetus resulted in a slight but significant fall in maternal plasma progesterone in the last few hours of the infusion period.
Hepatic glucose production is increased in people with type 2 diabetes. Glucose released from storage in liver glycogen by phosphorylase accounts for approximately 50% of the glucose produced after an overnight fast. Therefore, understanding how glycogenolysis in the liver is regulated is of great importance. Toward this goal, we have determined the kinetic characteristics of recombinant human liver glycogen phosphorylase a (HLGPa) (active form) and compared them with those of the purified rat enzyme (RLGPa). The Michaelis-Menten constant (K(m)) of HLGPa for P(i), 5 mM, was about fivefold greater than the K(m) of RLGPa. Two P(i) (substrate) concentrations were used (1 and 5 mM) to cover the physiological range for P(i). Other effectors were added at estimated intracellular concentrations. When added individually, AMP stimulated, whereas ADP, ATP and glucose inhibited, activity. These results were similar to those of the RLGPa. However, glucose inhibition was about twofold more potent with the human enzyme. UDP-glucose, glucose 6-phosphate, and fructose 1-phosphate were only minor inhibitors of both enzymes. We reported previously that when all known effectors were present in combination at physiological concentrations, the net effect was no change in RLGPa activity. However, the same combination reduced HLGPa activity, and the inhibition was glucose dependent. We conclude that a combination of the known effectors of phosphorylase a activity, when present at estimated intracellular concentrations, is inhibitory. Of these effectors, only glucose changes greatly in vivo. Thus it may be the major regulator of HLGPa activity.
To quantify the extent to which exogenous glucose is used directly or indirectly for hepatic glycogen synthesis, fasted rats were given [U-14C,3-3H] glucose intragastrically, intravenously, or as a component of a solid diet eaten ad libitum. In all cases liver glycogen was deposited at high linear rates over a 3-h period. Portal vein glucose levels seldom exceeded 8 mM. At a time when the specific activities of 3H and 14C in circulating glucose were identical with those in the administered material their values in newly synthesized glycogen were reduced by 72-88% and 50-65%, respectively. An intragastric load of unlabeled glucose sufficient to suppress completely hepatic glucose output greatly stimulated the incorporation of intravenously infused [14C]bicarbonate, [14C]lactate, [14C]alanine, and [14C] glutamine into liver glycogen. Using an improved assay the ability of liver homogenates to phosphorylate glucose at concentrations of 5-10 mM was found to be far short of what would be needed if glucose were used directly to support hepatic glycogen synthesis in vivo. These data support the notion that in the rat a major fraction of liver glycogen deposited in response to exogenous carbohydrate is formed by a pathway involving glucose leads to C3 unit leads to glycogen, although the site of the initial steps in the sequence is not yet known. The limited capacity of the liver to utilize intact glucose for glycogen synthesis might reside in its limited capacity to phosphorylate the sugar at physiological concentrations.
The concentrations of total serum proteins, total lipids, glucose, and liver glycogen were determined in normal as well as Eimeria-infected palm doves. A highly significant increase in total serum protein concentration was observed in infected birds as compared with that seen in noninfected doves. There was an increase in total serum lipids subsequent to infection, but this was only significant in females. No significant increase in serum glucose concentration was observed in infected male or female birds. However, an insignificant decrease in the liver glycogen level of both male and female infected doves was observed.
Liver glycogen content decreased in golden hamsters experimentally infected with plerocercoids of Spirometra erinacei. The activity of glycogen synthase a decreased significantly in infected animals, whereas that of glycogen phosphorylase a was not significantly affected. These observations suggest that changes in glycogen content were not attributable to increased glycogenolysis, but rather resulted from suppressed glycogenesis. Plasma immunoreactive insulin (IRI) concentrations in infected animals were slightly lower than those in controls, but the differences were not statistically significant. Plasma glucagon concentrations were significantly higher in infected animals. These results suggest that the suppression of glycogen synthase activity in S. erinacei-infected hamsters was attributable to enhanced levels of glucagon and that enhanced secretion of glucagon was caused by parasite-induced hypoglycemia.
1. Levels of glycogen and fat in the liver showed a diurnal difference, being higher at dusk than at dawn during the post- and premigratory periods. 2. Fat level increased by at least more than double from its lowest in the postmigratory period (August) to highest towards migration time (21-30 April) at both dawn as well as dusk. 3. With the steady increase in liver fat, there was a gradual decrease in liver glycogen up to about the middle of April and a slight increase thereafter. 4. RQ values obtained for liver and pectoralis muscle slices in vitro at postmigration (August) indicated lipid utilization. Those for the premigratory period indicated hyperlipogenesis, while towards migration time the values denoted carbohydrate catabolism and sparing of lipid.
To analyse the importance of the ventromedial hypothalamic nucleus (VMH) for the circadian regulation of the carbohydrate metabolism rats were investigated after bilateral cervical sympathetic ganglionectomy (SCGx) 30 d earlier and exposure to cold (10 degrees C) 72 h earlier. In order to assess the circadian rhythms of nuclear volume oscillations of the VMH, blood glucose, and liver glycogen 4 times a day (light-dark cycle: 14L:10D, light on 05.00 h) rats were sacrificed at midlight and middark as well as 1 h after the onset of the light and dark periods. The circadian curves were calculated in a model-free way by the procedures of locally adjusted polynomial approximation. Ganglion removal and exposure to cold resulted in an increase of blood sugar and of nuclear volume of the VMH, but only of its lateral part. The liver glycogen decreased. Additionally, both the coordination between the circadian curves of the nuclear volume and of the blood glucose as well as of the inverse curves of the liver glycogen was destroyed after SCGx. These results are in agreement with the conviction that the enhanced blood glucose activates the VMH. The augmentation of blood glucose was discussed in connection with influences of the likewise increased thyrotropin-releasing hormone and thyrotropin on the increased plasma levels of catecholamines, with secondary increased plasma levels of glucagon as well as decreased insulin levels after SCGx and exposure to cold. The sympathetic denervation of the pineal gland (SCGx) produced the mentioned desynchronization of the curves. At the present we are not able to explain the approximate restitution of the circadian rhythms after additional exposure to cold.
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The effect of hepatocellular trauma due to bile reflux and endotoxaemia on liver glycogen metabolism was studied in guineapigs with common bile duct obstruction. Considerable drops in basal glycogen levels of hepatocytes from bile duct ligated (BDL) animals were recorded in comparison with the sham operated (SHAM) ones. However, the regurgitation of bile did not affect the basal blood glucose concentrations of BDL guineapigs. The circulating glucose was consumed, mainly reflecting the level of energy requirement of the peripheral tissues in the endotoxaemic SHAM pair-fed animals and the BDL group. The hepatic glycogen stores failed to prevent the SHAM group from becoming hypoglycaemic at the end of the eighth hour after endotoxin administration. Enhancement in glucose consumption and diminished liver glycogen indicated the necessity of glucose intake in the early phase of extrahepatic bile duct obstruction. It was concluded that both endogenous and exogenous glucose have limited value in improving energy metabolism in lethal endotoxaemia following bile duct obstruction.