Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

Glucagon and epinephrine promote the inactivation of basal glycogen synthase in hepatocytes isolated from fed rats. However, this effect is only observable when the activation state of glycogen synthase is measured using the low glucose-6-P/high glucose-6-P activity ratio assay. This inactivation is the consequence of an increase in the kinetic parameters (S0.5 for UDP-glucose and M0.5 for glucose-6-P) of the enzyme. Therefore, this work demonstrates these hormones are also able to control glycogen synthase from fed animals.
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PMID:Inactivation of basal glycogen synthase by glucagon and epinephrine in hepatocytes from fed rats. 308 99

Vanadate inactivated rat hepatocyte glycogen synthase and activated glycogen phosphorylase in a dose- and time-dependent manner. These effects were observed in hepatocytes from both fasted as well as fed rats. When rat hepatocytes were preincubated with [32P]phosphate and then with vanadate, and the 32P-labeled glycogen synthase was specifically immunoprecipitated, it was observed that vanadate stimulated the phosphorylation of the 88,000-dalton subunit of glycogen synthase. All of the phosphate was located in the same two CNBr fragments of the enzyme which are phosphorylated by glucagon and other glycogenolytic hormones. In cells incubated in a calcium-depleted medium, vanadate was still able to inactivate glycogen synthase but its effects on phosphorylase were essentially lost. These results demonstrate that, in the hepatocyte, vanadate exerts opposite effects than in the adipocyte and skeletal muscle, where vanadate has an insulin-like action.
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PMID:Glycogenolytic, noninsulin-like effects of vanadate on rat hepatocyte glycogen synthase and phosphorylase. 309 39

We have examined in fasted rats the effects of graded doses of intravenous fructose (50 to 500 mg/kg) in order to determine potential mechanisms by which different concentrations of fructose reaching the liver may modify the activity of glycogen synthase (and phosphorylase). With increasing fructose doses the % synthase I increased threefold to a maximum at a dose of 125 mg/kg and then decreased progressively after higher fructose doses were given. The % phosphorylase a decreased by 30% to a minimum at a dose of 125 mg/kg but increased with higher doses to 370% of the control values. Both the % synthase I and the % phosphorylase a were elevated above the control values at fructose doses of 175 to 225 mg/kg. The increase in % synthase I after low doses of fructose occurred with a significant increase in glucose-6-P but no significant change in hepatic fructose, glucose, UDPglucose, ATP/Mg++, Pi, cAMP, plasma insulin, or glucagon concentrations. The reciprocal decrease in % synthase I and increase in % phosphorylase a occurred despite increases in glucose and glucose-6-P, at fructose doses resulting in no change in ATP/Mg++, Pi or cAMP, and only a small increase (0.39 mmol/L) in the fructose-1-P concentration. We propose that activation of synthase phosphatase by a rise in the glucose-6-P concentration is responsible for the increase in % synthase I after low doses of fructose. The mechanism by which higher fructose doses overcome the expected activation of synthase phosphatase by glucose and glucose-6-P and a decreased ATP/Mg++ ratio is uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of graded intravenous doses of fructose on glycogen synthase in the liver of fasted rats. 310 29

Glutamine stimulated glycogen synthesis and lactate production in hepatocytes from overnight-fasted normal and diabetic rats. The effect, which was half-maximal with about 3 mM-glutamine, depended on glucose concentration and was maximal below 10 mM-glucose. beta-2-Aminobicyclo[2.2.1.]heptane-2-carboxylic acid, an analogue of leucine, stimulated glutaminase flux, but inhibited the stimulation of glycogen synthesis by glutamine. Various purine analogues and inhibitors of purine synthesis were found to inhibit glycogen synthesis from glucose, but they did not abolish the stimulatory effect of glutamine on glycogen synthesis. The correlation between the rate of glycogen synthesis and synthase activity suggested that the stimulation of glycogen synthesis by glutamine depended solely on the activation of glycogen synthase. This activation of synthase was not due to a change in total synthase, nor was it caused by a faster inactivation of glycogen phosphorylase, as was the case after glucose. It could, however, result from a stimulation of synthase phosphatase, since, after the addition of 1 nM-glucagon or 10 nM-vasopressin, glutamine did not interfere with the inactivation of synthase, but did promote its subsequent re-activation. Glutamine was also found to inhibit ketone-body production and to stimulate lipogenesis.
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PMID:Stimulation of glycogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes. 312 12

The regulation of glycogen synthase by Ca2+-mobilizing hormones was studied by using rat liver parenchymal cells in primary culture. Long-term exposure of hepatocytes to 4 beta-phorbol 12-myristate 13-acetate (TPA) resulted in a decrease in vasopressin or ATP inhibition of glycogen synthesis and glycogen synthase activity, without any change in the activation of glycogen phosphorylase. In contrast, treatment with TPA did not diminish the effects of glucagon, isoprenaline or A23187 on glycogen synthase or phosphorylase. TPA treatment for 18 h did not change specific [3H]vasopressin binding, but abolished protein kinase C activity in a concentration-dependent manner. The effects of TPA to decrease protein kinase C activity and to reverse the inactivation of glycogen synthase by vasopressin were well correlated and were mimicked by mezerein, but not by 4 alpha-phorbol. However, 1 microM-TPA totally inhibited protein kinase C activity, but reversed only 60% of the vasopressin effect on glycogen synthase. It is therefore concluded that Ca2+-mobilizing hormones inhibit glycogen synthase partly, but not wholly, through a mechanism involving protein kinase C.
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PMID:The role of protein kinase C in the inactivation of hepatic glycogen synthase by calcium-mobilizing agonists. 313 12

The glycogen synthase-mediated reaction is rate-limiting for glycogen synthesis in the liver. Glycogen synthase has been purified essentially to homogeneity and has been shown to be a dimer composed of identical subunits. It is regulated by a phosphorylation-dephosphorylation mechanism, catalyzed by kinases and a phosphatase. The subunits of synthase D, the most phosphorylated form, each contain approximately 17 phosphates. The subunits of synthase I, the least phosphorylated form, each contain 14 phosphates. Thus, during the transition between these two forms, a net of three phosphoryl groups is added or removed. In synthase D, six of the phosphates are alkali-labile. In synthase I, three of the phosphates are alkali-labile. Therefore, all of the phosphorylation sites important in the interconversion of these two forms are alkali-labile (attached to serine or threonine residues). In short-term experiments using isolated hepatocytes, [32P]phosphate was only incorporated into the alkali-labile sites and the phosphate in these sites was shown to turn over rapidly. Glucose addition, which is known to reduce the proportion of synthase in the D form when assayed kinetically, also reduced the [32P]phosphate content. Glucagon addition, which increases the proportion of synthase in the D form, increased it. These changes do not appear to be site-specific. Ingestion or administration of fructose, or galactose, as well as glucose, result in a shift in synthase equilibrium in favor of the less phosphorylated forms. Possible mechanisms by which synthase phosphatase activity may be increased after ingestion of glucose or fructose, and thus shift the equilibrium in favor of the less phosphorylated forms, are discussed. The mechanism by which galactose may stimulate the phosphatase reaction is completely unknown.
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PMID:Regulation of glycogen synthesis in the liver. 314 65

The liver is innervated by sympathetic and parasympathetic nerves. The effects and mechanisms of actions of hepatic nerves were studied in the isolated rat, guinea pig and Tupaia liver perfused in a non-recirculating manner either via the portal vein or via both the hepatic artery and the portal vein. The arterial plexus was stimulated at the common hepatic artery, the portal plexus at the mesenteric vein or both plexus jointly at the artery and the portal vein in the liver hilus (1-20 Hz, 2 ms, 20 V, 0.5-5 min). Upon nerve stimulation sympathetic effects clearly predominated; parasympathetic actions could only be demonstrated in the presence of alpha- and beta-antagonists. Sympathetic stimulation increased glucose output, shifted lactate uptake to output, decreased ketone body, urea and glutamine formation as well as ammonia uptake, lowered oxygen uptake, reduced perfusion flow combined with an intrahepatic redistribution and perfusate mobilization, and caused an overflow of noradrenaline into the hepatic vein. All effects were mediated predominantly via alpha-receptors; they were dependent on extracellular calcium. Some effects were modulated by hormones: the glucagon-mediated increase of glucose output was further enhanced but that of lactate uptake was decreased by nerve stimulation; in the presence of insulin glucose output was increased only slightly. Parasympathetic stimulation had no effect on basal metabolism or hemodynamics. Yet, it antagonized the glucagon-stimulated glucose release and enhanced the slight, insulin-dependent increase of glucose utilization. The sympathetic nerves may act directly at the parenchymal cells or indirectly via an overflow of neurotransmitter from the vasculature or via hemodynamic changes. Experiments with the vessel relaxant sodium nitroprusside and with retrograde perfusion indicate that neither hemodynamic alterations nor noradrenaline overflow from the vasculature play a major role in the sympathetic alterations in glucose and lactate metabolism; rather the nerves appear to act directly within the parenchyma. Comparative studies with rat, guinea pig and tupaia livers corroborate the view that the sympathetic nerves act in the rat via contacts to only a few periportal hepatocytes with signal propagation through gap junctions, while they act in the guinea pig and tupaia via contacts to almost all parenchymal cells. Sympathetic nerve stimulation caused an increase in the activity of glycogen phosphorylase and a decrease of glycogen synthase; it left the activity of pyruvate kinase and the levels of fructose 2.6-bisphosphate and cyclic AMP unaltered.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Regulation of liver metabolism and hemodynamics by the hepatic nerves]. 359 Sep 3

In the isolated rat liver perfused as usual via the portal vein, joint electrical stimulation of the nerve fibers around the artery and the portal vein in the liver hilus increased glucose output, shifted lactate uptake to output, decreased urea and glutamine formation as well as ammonia uptake, reduced ketone body production, lowered oxygen uptake and reduced perfusion flow simultaneously changing the intrahepatic flow distribution; it was accompanied by an overflow of noradrenaline into the hepatic vein. All effects were mediated predominantly via alpha-receptors; they were dependent on extracellular calcium. In livers perfused both via the artery and the portal vein, separate stimulation of the plexus at the common hepatic artery or at the portal vein caused similar effects on glucose and lactate balance and on perfusion flow. Arterial stimulation caused the higher metabolic responses and alterations not only in arterial but also 'transhepaticly' in portal flow, and conversely, portal flow elicited the smaller metabolic responses and alterations in both portal and 'transhepaticly' arterial flow. If sympathetic nerve actions were blocked using alpha- and beta-antagonists, the resulting parasympathetic stimulation increased glucose uptake in the presence of insulin and antagonized the glucagon stimulated glucose release, both alone and more strongly in the presence of insulin. The sympathetic nerves may act directly at the parenchymal cells or indirectly via an overflow of neurotransmitter from the vasculature into the sinusoids or via hemodynamic changes. Experiments with the smooth muscle relaxant sodium nitroprusside and with retrograde flow indicate that neither hemodynamic changes nor noradrenaline overflow from the vasculature can play a major role in the mechanism of action of sympathetic liver nerves on glucose and lactate metabolism. Comparative studies with perfused livers of rats, guinea pigs and tupaias are in line with the view that in the rat the sympathetic nerves act via contacts with only a few periportal hepatocytes, from where the signal is propagated through gap junctions, while in guinea pig and tupaia the nerves act via contacts with almost all parenchymal cells. Sympathetic nerve stimulation of the perfused rat liver caused an increase in the activity of glycogen phosphorylase and a decrease of glycogen synthase, but left the activity of pyruvate kinase unaltered; fructose 2,6-bisphosphate and cAMP were only slightly enhanced.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of liver metabolism by the hepatic nerves. 367 10

Insulin resistance has been measured in man by nonsteady state tracer methodology. Increase in overall glucose utilization and suppression of glucose production was measured when hyperglycemia was achieved either by infusing glucagon or glucose. With the first method, insulin resistance was assessed in obese man and in lean hypertriglyceridemic patients. With the second method, insulin resistance was assessed in lean mild type II diabetics. These methodologies can only assess deficiences in overall glucose utilization and glucose production, but cannot delineate the defect in glucose uptake by the liver. However, if a given metabolic event is essentially characteristic of only one organ, metabolic abnormalities specific to that organ can be detected in vivo provided there is a probe specific to that metabolic pathway. Therefore, in lean mild type II diabetics the liver glucose futile cycle was assessed by a double tracer method. Previously it was shown that liver glucose futile cycling is increased in diabetic dogs. In healthy control subjects in basal state and during glucose infusion, the futile cycle could not be detected, but it represented a major part of glucose metabolism in liver of type II diabetics. It appears, therefore, that most of the glucose taken up by the liver during the glucose challenge in diabetics reenters the blood stream without being oxidized or polymerized. On the basis of these studies, it was concluded that excessive hyperglycemia in the diabetics during glucose infusion is due to a decrease in irreversible glucose uptake (impaired phosphorylation and futile cycling) and to a decrease in suppression of glucose production. The relative contribution of the liver and periphery to hyperglycemia seems to be almost equivalent. The mechanism behind the increased glucose cycle activity is not clear. It may be due to a relative decrease of glycogen synthase or increase in glucose-6-phosphatase or both. These observations in mild lean type II diabetics may have implications also in some other types of diabetes, since we have observed that futile cycling is even more marked in obese type II diabetics and that it could account in part for the diabetogenic effect of growth hormone in acromegalics.
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PMID:New probes to study insulin resistance in men; futile cycle and glucose turnover. 389 64


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