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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Birth in most mammalian species represents an abrupt change from a high-carbohydrate and low-fat diet to a high-fat and low-carbohydrate diet. Gluconeogenesis is absent from the liver of the fetus of well-fed mothers, but can be induced prematurely by prolonged fasting of the mother. Gluconeogenesis increases rapidly in the liver of newborn mammals in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this pathway. The rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of liver PEPCK induction. When liver PEPCK has reached its adult value, i.e. 24 h after birth, other factors are involved in the regulation of hepatic gluconeogenesis. In order to maintain a high gluconeogenic rate, the newborn liver must be supplied with sufficient amount of gluconeogenic substrates and free fatty acids. An active hepatic fatty acid oxidation is necessary to support hepatic gluconeogenesis by providing essential cofactors such as acetyl CoA and NADH. The relevance of animal studies for the understanding of neonatal glucose homeostasis in man is discussed.
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PMID:[Hormonal control of the development of hepatic gluconeogenesis in the neonate]. 305 68

The induction of phosphoenolpyruvate carboxykinase (PEPCK) by glucagon was studied in primary rat hepatocyte cultures by determining the time course of the sequential events, increases in the enzyme's mRNA abundance, synthesis rate, amount and activity, and by investigating the antagonistic action of insulin on the induction by glucagon. 1. The mRNA of PEPCK was induced maximally 2-3 h after addition of 10 nM glucagon, as detected by Northern-blot analysis after hybridization with a biotinylated antisense RNA of PEPCK. 2. The synthesis rate of PEPCK increased maximally 2-3 h after application of glucagon as revealed by pansorbin-linked immunoprecipitation of [35S]methionine-labelled PEPCK. 3. The enzyme amount and activity was maximally induced 4 h after glucagon application. 4. The mRNA of PEPCK was half-maximally induced by 0.1 nM and maximally by 1 nM and 10 nM glucagon. The half-maximal induction by 0.1 nM glucagon was antagonized almost totally, and the maximal induction by 1 nM glucagon partially, while the maximal induction by 10 nM glucagon remained unaffected by 10 nM insulin. The results show that in cultured rat hepatocytes physiological concentrations of glucagon stimulated the induction of PEPCK by an increase in mRNA, that the glucagon-dependent increase in mRNA and enzyme-synthesis rate occurred in parallel and preceded the increase of enzyme amount and activity by 1-1.5 h, and that physiological levels of insulin antagonized the induction by glucagon in the physiological concentration range, with glucagon being the dominant hormone.
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PMID:Regulation of the expression of the phosphoenolpyruvate carboxykinase gene in cultured rat hepatocytes by glucagon and insulin. 306 15

The effects of glucagon and the alpha-adrenergic agonist, phenylephrine, on the rate of 14CO2 production and gluconeogenesis from [1-14C]lactate and [1-14C]pyruvate were investigated in isolated perfused livers of 24-h-fasted rats. Both glucagon and phenylephrine stimulated the rate of 14CO2 production from [1-14C]lactate but not from [1-14C]pyruvate. Neither glucagon nor phenylephrine affected the activation state of the pyruvate dehydrogenase complex in perfused livers derived from 24-h-fasted rats. 3-Mercaptopicolinate, an inhibitor of the phosphoenolpyruvate carboxykinase reaction, inhibited the rates of 14CO2 production and glucose production from [1-14C]lactate by 50% and 100%, respectively. Furthermore, 3-mercaptopicolinate blocked the glucagon- and phenylephrine-stimulated 14CO2 production from [1-14C]lactate. Additionally, measurements of the specific radioactivity of glucose synthesized from [1-14C]lactate, [1-14C]pyruvate and [2-14C]pyruvate indicated that the 14C-labeled carboxyl groups of oxaloacetate synthesized from 1-14C-labeled precursors were completely randomized and pyruvate----oxaloacetate----pyruvate substrate cycle activity was minimal. The present study also demonstrates that glucagon and phenylephrine stimulation of the rate of 14CO2 production from [1-14C]lactate is a result of increased metabolic flux through the phosphoenolpyruvate carboxykinase reaction, and phenylephrine-stimulated gluconeogenesis from pyruvate is regulated at step(s) between phosphoenolpyruvate and glucose.
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PMID:Regulation of gluconeogenesis from pyruvate and lactate in the isolated perfused rat liver. 309 74

Induction of cytosolic aspartate aminotransferase (cAspAT) was observed in rat liver on administration of a high-protein diet, or glucagon and during fasting. The enzyme activity in the liver of rats given 80% protein diet or glucagon injection during starvation increased to 2- to 2.4-fold that in the liver of rats maintained on 20% protein diet, with about 2-fold increases in the levels of hybridizable cAspAT mRNA, measured by blot analysis using the cloned rat cAspAT cDNA as a probe. No increase in the enzyme was detected in kidney, heart, brain, or skeletal muscle. The activity of mitochondrial aspartate aminotransferase (mAspAT) did not increase. Induction of cAspAT was observed when glucose metabolism tended toward gluconeogenesis. The physiological function of the induction of cAspAT is considered to be to increase the supply of oxaloacetate as a substrate for cytosolic phosphoenolpyruvate carboxykinase (PEPCK) [EC 4.1.1.32] for gluconeogenesis.
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PMID:Rat cytosolic aspartate aminotransferase: regulation of its mRNA and contribution to gluconeogenesis. 318 50

Energy intake, weight gain, carcass composition, plasma hormones and fuels, hepatic metabolites and the activities of phosphoenolpyruvate carboxykinase (PEPCK), malic enzyme, and glucose 6-phosphate dehydrogenase (G6P-DH) were examined in adult rats during a 44-day period of low fat, high carbohydrate (LF) feeding or of consumption of one or two high (70% metabolizable energy) fat diets composed of 63% (metabolizable energy) long-chain (LCT) or medium-chain (MCT) triglycerides. Energy intake was similar in the LCT and MCT groups but was less than that of LF group. The weight gain of rats fed MCT diet was 30% less than that of rats fed LF or LCT diets. Energy retention was less when the diet provided MCT than LCT or LF, and that resulted in a 60% decrease in the daily lipids deposition. Plasma glucose, free fatty acids, glycerol, and insulin/glucagon ratio were similar in the three groups. Blood ketone body (KB) concentrations in rats fed the high fat diets were extremely elevated, particularly in the MCT group, but declined throughout the experiment and by the 44th day hyperketonemia decreased by 50% but remained higher than in the LF diet. The blood beta-hydroxybutyrate/acetoacetate (B/A) ratio remained slightly elevated in rats fed the high fat diets. Similar changes were observed in liver KB concentration and in the B/A ratio. Liver lactate/pyruvate ratio elevated in the LCT and MCT groups at the initiation of the diets decreased by 50% at the end of the experiment. The consumption of high fat diets led to a 1.5-fold increase in liver PEPCK activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolic effects induced by long-term feeding of medium-chain triglycerides in the rat. 329 41

We rendered pregnant rats chronically hyperinsulinemic to determine the effect of reduced maternal metabolic fuel availability on fetal growth and development. We implanted osmotically driven insulin loaded minipumps on day 14 (term 21.5 days) in pregnant rats. This significantly increased maternal plasma concentrations of insulin and reduced glucose from day 15 until term. From day 17 until birth, fetal growth was significantly less for hyperinsulinemic mothers (term birth weight 4.53 +/- 0.07 versus 5.64 +/- 0.06 g, p less than 0.001). In fetuses of hyperinsulinemic mothers plasma glucose and insulin concentrations were significantly reduced while glucagon concentrations were increased. Total plasma amino acids were significantly reduced in maternal rats and their fetuses from days 17 to 19 while arteriovenous blood gas tensions and pH did not differ between fetuses of hyperinsulinemic and control mothers. Small for gestational age newborn pups of hyperinsulinemic mothers were hypoglycemic for the first 240 min of life as a result of limited hepatic glycogen stores and a delay in the normally expected induction of hepatic cytosolic phosphoenolpyruvate carboxykinase. This occurred despite significant increases in neonatal plasma glucagon concentrations. These data indicate that limitation of maternal glucose and amino acids with normal placental gaseous exchange retards fetal growth, limits hepatic glycogen deposition, and delays neonatal phosphoenolpyruvate carboxykinase induction. Limited fetal insulin secretion resulting from diminished maternal fuel availability may have also been a factor in retarding growth. The delay in phosphoenolpyruvate carboxykinase induction despite enhanced glucagon secretion during fetal and neonatal life suggests a specific "resistance" to this hormone in the rat growth retarded by limited metabolic fuel availability.
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PMID:Limited maternal fuel availability due to hyperinsulinemia retards fetal growth and development in the rat. 331 55

In primary cultures of rat hepatocytes the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was studied in the presence of putative local hormone and substrate modulators which form clear concentration gradients during liver passage such as adenosine, ketone bodies and ammonia. 1) Adenosine inhibited the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 50 and 200 microM up to 4 h after glucagon application; AMP had similar, adenine, inosine and guanosine had no effect. Adenosine was almost totally metabolized by the liver cells during the first 4 h of the induction period. The inhibitory action of adenosine was also observed using dibutyryl-cAMP or 8-bromo-cAMP as inducer; it could not be prevented by the adenosine receptor antagonist caffeine nor could it be mimicked by the selective adenosine receptor agonist N6-(phenylisopropyl)adenosine. 2) Acetoacetate suppressed the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 5 and 20mM during the first 4 h after glucagon addition. beta-Hydroxybutyrate showed no effect. Neither starting with acetoacetate nor with beta-hydroxybutyrate did the cell cultures establish the thermodynamic equilibrium between the two compounds. 3) Ammonia did not affect induction of phosphoenolpyruvate carboxykinase at concentrations up to 2mM. Ammonia was converted to urea within the first 4 h; yet it remained at clearly hyperphysiological concentrations in the medium during that period. It is concluded that the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was modulated by the local hormone adenosine via a mechanism not involving adenylate cyclase and by acetoacetate via an unknown mechanism. The inhibitory action of adenosine may, that of acetoacetate can hardly be physiologically relevant.
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PMID:Modulation of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase by adenosine, but not ketone bodies or ammonia in rat hepatocyte cultures. Possible significance for the zonal heterogeneity of liver parenchyma. 344 1

We measured several growth stimulating variables in growth retarded (small-for-gestational-age [SGA]) rat fetuses on days 18, 19, 20, and 21 of their 21.5-day gestation. Bilateral maternal uterine artery ligation on day 18 was used to retard fetal growth, and fetuses of sham and nonoperated (normal) mothers served as controls. SGA fetuses had the lowest body and placental weights, while sham fetuses had intermediate weights from days 19 to 21. Similarly, SGA fetuses had the most profound alterations in arteriovenous PO2, PCO2, and pH, while sham fetuses had significant but less severe alterations. Fetal plasma concentrations and fetal/maternal ratios of glucose were significantly diminished in SGA fetuses on days 18 and 19; sham fetuses had intermediate values on day 19. Plasma concentrations and fetal/maternal ratios of leucine, isoleucine, and valine, but not the other amino acids, were significantly diminished in SGA fetuses on days 18, 19, and 20. Plasma insulin concentrations were significantly diminished in SGA fetuses on days 19 and 20, and hepatic concentrations of glycogen were significantly diminished on all days. Despite significantly elevated plasma glucagon concentrations in SGA fetuses, hepatic cytosolic phosphoenolpyruvate carboxykinase (PEPCK) activity was not elevated. These data indicate that bilateral uterine artery ligation retards fetal growth in the rat by altering gas exchange and limiting fuel availability. The limited insulin in SGA fetuses might further have retarded growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat. 353 62

Birth in most mammalian species represents an abrupt change from a high-carbohydrate and low-fat diet to a high-fat and low-carbohydrate diet. Gluconeogenesis is absent from the liver of the fetus of well fed mothers, but can be induced prematurely by prolonged fasting of the mother. Gluconeogenesis increases rapidly in the liver of newborn mammals in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this pathway. The rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of liver PEPCK induction. When liver PEPCK has reached its adult value, i.e. 24 h after birth, other factors are involved in the regulation of hepatic gluconeogensis. In order to maintain a high gluconeogenic rate, the newborn liver must be supplied with sufficient amount of gluconeogenic substrates and free fatty acids. An active hepatic fatty acid oxidation is necessary to support hepatic gluconeogenesis by providing essential cofactors such as acetyl CoA and NADH. The relevance of animal studies for the understanding of neonatal glucose homeostasis in man is discussed.
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PMID:Gluconeogenesis in late fetal and early neonatal life. 354 66

Control properties of the gluconeogenic pathway in hepatocytes isolated from starved rats were studied in the presence of glucose. The following observations were made. (1) Glucose stimulated the rate of glucose production from 20 mM-glycerol, from a mixture of 20 mM-lactate and 2 mM-pyruvate, or from pyruvate alone; no stimulation was observed with 20 mM-alanine or 20 mM-dihydroxyacetone. Maximal stimulation was obtained between 2 and 5 mM-glucose, depending on the conditions. At concentrations above 6 mM, gluconeogenesis declined again, so that at 10 mM-glucose the glucose production rate became equal to that in its absence. (2) With glycerol, stimulation of gluconeogenesis by glucose was accompanied by oxidation of cytosolic NADH and reduction of mitochondrial NAD+ and was insensitive to the transaminase inhibitor amino-oxyacetate; this indicated that glucose accelerated the rate of transport of cytosolic reducing equivalents to the mitochondria via the glycerol 1-phosphate shuttle. (3) With lactate plus pyruvate (10:1) as substrates, stimulation of gluconeogenesis by glucose was almost additive to that obtained with glucagon. From an analysis of the effect of glucose on the curves relating gluconeogenic flux and the steady-state intracellular concentrations of gluconeogenic intermediates under various conditions, in the absence and presence of glucagon, it was concluded that addition of glucose stimulated both phosphoenolpyruvate carboxykinase and pyruvate carboxylase activity.
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PMID:Stimulation by glucose of gluconeogenesis in hepatocytes isolated from starved rats. 366 84


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