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)

Isolated rat liver cells maintained in suspension culture for 4 to 5 h synthesize the gluconeogenic cytosolic enzyme phosphoenolpyruvate carboxykinase at a rate approximately 5-fold lower than the in vivo hepatic rate. Glucagon rapidly re-induces phosphoenolpyruvate carboxykinase synthesis in such cells. The rate of enzyme synthesis doubles in 40 min and plateaus at a level 6- to 13-fold higher than in control cells 120 min after glucagon addition at maximal concentration. Consistent with the presumed role of cyclic AMP as a mediator of enzyme induction, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, added simultaneously with glucagon, shifts the hormone dose-response curve 2 log units to the left. Moreover, cyclic AMP supplied exogenously to the cells mimics the inductive effect of glucagon. Total cellular RNA isolated from hepatocytes induced by glucagon contains an increased level of mRNA coding for phosphoenolpyruvate carboxykinase, as determined by translational assay. The kinetics and extent of the rise in mRNA level are adequate to explain the stimulation of enzyme synthesis. Although glucagon on its own induces a build-up of phosphoenolpyruvate carboxykinase mRNA and a commensurate stimulation of enzyme synthesis, the glucagon induction is very markedly amplified when the cells are first preincubated with dexamethasone. The glucocorticoid by itself, however, does not have any substantial effect on the level of phosphoenolpyruvate carboxykinase mRNA or on the rate of enzyme synthesis. Its role can therefore be characterized as permissive.
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PMID:Regulation of phosphoenolpyruvate carboxykinase (GTP) synthesis in rat liver cells. Rapid induction of specific mRNA by glucagon or cyclic AMP and permissive effect of dexamethasone. 629 90

Administration of low levels of lead (0.001, 0.005 and 0.025 micrograms/g/day p.o.) to neonate rats from age three days to eight weeks failed to alter the activities of hepatic glucose-6-phosphatase, fructose-1,6-diphosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase, the four key gluconeogenic enzymes. Administration of lead at a higher dose (0.1 micrograms/g/day p.o.) was also observed to produce no alterations in enzyme activity at eight weeks. However, the higher dose did enhance the activities of fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase at age six weeks. Plasma insulin and glucagon were not significantly altered by up to 0.025 micrograms/g exposure to lead until eight weeks of age, although levels of these hormones appear to be slightly dose-responsive tending towards elevated glucagon and decreased insulin levels with increasing lead dosage. At 0.1 micrograms/g/day glucagon was significantly increased at eight weeks. Blood glucose and hepatic glycogen remained unaltered. Blood, hepatic and pancreatic lead levels were unchanged by treatment with lead up to 0.025 micrograms/g/day to eight weeks of age, but there was evidence of lead accumulation in pancreatic tissue whereas levels of the metal in the liver paralleled those in the blood. Significant increases were observed with 0.1 micrograms/g/day lead at six and eight weeks in blood and pancreas. Data are presented which suggest that six week old animals are more influenced by subacute lead exposure than are the eight week old animals, as reflected in some alteration of gluconeogenic enzyme activity in younger rats.
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PMID:Effects of subacute low level lead exposure on glucose homeostasis. 630 42

Insulin causes a 7-10-fold decrease of both the mRNA that codes for rat hepatic phosphoenolpyruvate carboxykinase (mRNAPEPCK) and of PEPCK synthesis, provided the animals are made diabetic and fed chow. mRNAPEPCK, measured either by in vitro translation or cDNA hybridization, decreases with a half-time of 30-60 min after insulin treatment. This coordinant decrease, which approximates the half-life of mRNAPEPCK measured in a variety of situations, suggests that insulin acts by decreasing mRNAPEPCK production, and that the hormone does not alter the activity of a fixed amount of this RNA, or enhance its degradation. Glucagon results in a ninefold induction of mRNAPEPCK. Half-maximal induction occurs with doses between 20-75 micrograms/100 g body wt and occurs within 30-45 min. Maximal induction requires 150 micrograms/100 g body wt and occurs about 80 min after a single glucagon injection. N6,O2'-dibutyryl cAMP and a cAMP analogue that is not metabolized, 8-(4-chlorophenyl-thio)cAMP, induce mRNAPEPCK as effectively as glucagon and with similar kinetics. Since sodium butyrate, adenosine, and dibutyryl cGMP are ineffective inducers, cAMP appears to be the active agent in the hepatocyte.
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PMID:Insulin and glucagon regulate cytosolic phosphoenolpyruvate carboxykinase (GTP) mRNA in rat liver. 632 36

Continuous glucose infusion was used to induce mild hyperglycemia in unrestrained pregnant rats during the last three days of pregnancy. Control rats were infused with distilled water. Compared with the controls, fetuses from glucose-infused rats showed higher plasma glucose levels, increased plasma insulin and lower plasma glucagon concentrations. Pregnancy prolonged until day 23.5 resulted in a sharp decrease in plasma insulin concentrations and a dramatic increase in plasma glucagon concentrations. In 23.5-day old fetuses from both groups, plasma insulin concentration rose when phentolamine was injected but not when propanolol was injected. Plasma glucagon concentration in 23.5-day old fetuses from glucose-infused rats dropped with propanolol injection. In fetuses from control rats, liver phosphoenolpyruvate activity increased markedly and liver glycogen stores decreased sharply. In fetuses from glucose-infused rats, liver phosphoenolpyruvate carboxykinase activity rose and glycogen content decreased, but to a lesser degree. Moreover, in postmature fetuses from glucose-infused rats, elevated plasma glucose and insulin concentrations were related to increased body weight and total carcass fat. Concurrently, the rate of lipogenesis in the carcass of these fetuses (estimated from the incorporation of 3H from 3H2O into fatty acids) was significantly increased.
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PMID:[Maternal hyperglycemia and fetal development in the rat: effects of a continuous glucose perfusion in the rat at the end of gestation]. 634 25

In hepatocytes precultured for 24 h with dexamethasone glucagon increased phosphoenolpyruvate carboxykinase activity 3-4-fold with a half maximal activity increase at 30 pM. The half maximal effective glucagon concentration was enhanced 10-fold to 300 pM when insulin was added simultaneously. The glucagon-insulin antagonism was maximally expressed when glucagon was present at low physiological concentrations. At equimolar doses it was only in the concentration range around 0.1 nM that glucagon and insulin became powerful antagonists; at higher levels glucagon was the dominant hormone. In hepatocytes not pretreated with dexamethasone glucagon still enhanced phosphoenolpyruvate carboxykinase activity, but the half maximal effective dose raised more than 30-fold to 1 nM. The degree of stimulation, however, remained essentially unchanged. Thus dexamethasone shifted the glucagon sensitivity of the cells into the physiological concentration range; it exerted a half maximal effect at 10 nM. Dexamethasone was not required for the enzyme induction proper if the cells had been pretreated with the glucocorticoid. The amount of the glucagon-stimulated enzyme induction was dependent on the time period of cell pretreatment with dexamethasone. Glucagon enhanced enzyme activity to the same constant suboptimal level irrespective of whether cells had been pretreated with glucocorticoid for 1 or for 14 h. If cells were pretreated for more than 15 h, glucagon linearly increased enzyme activity further until the maximal value was reached after 24 h pretreatment. The glucagon-insulin antagonism and the glucagon-glucocorticoid synergism were observed at physiological hormone concentrations indicating that the interaction should be effective also in vivo. Dexamethasone does not seem to be generally permissive for the inducing action of glucagon, but rather sensitizes the cell towards lower physiological hormone concentrations.
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PMID:The glucagon-insulin antagonism and glucagon-dexamethasone synergism in the induction of phosphoenolpyruvate carboxykinase in cultured rat hepatocytes. 636 20

Chronic fetal hyperinsulinemia, similar to that found in human infants of diabetic mothers, was produced in fetal rhesus monkeys during the latter third of gestation. Fetal plasma glucose and amino acid concentrations were found to be inversely logarithmically correlated with plasma insulin concentration. Fetal plasma glucagon concentrations were suppressed by hyperinsulinemia. Fetal plasma erythropoietin concentrations were increased by hyperinsulinemia in a dose/response manner. The activity of the hepatic gluconeogenic enzymes glucose-6-phosphatase and total phosphoenolpyruvate carboxykinase were reduced by hyperinsulinemia. Fatty acid synthase complex activity was, in contrast, increased by hyperinsulinemia while citrate cleavage enzyme and glucose-6-phosphate dehydrogenase were only increased when supraphysiologic hyperinsulinemia was produced. This model provides an opportunity to study the metabolic effects of hyperinsulinemia separate from those of hyperglycemia on the primate fetus, making it a useful model for the study of fetal pathologic conditions in diabetic pregnancies.
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PMID:Chronic hyperinsulinemia in the fetal rhesus monkey: effects of physiologic hyperinsulinemia on fetal substrates, hormones, and hepatic enzymes. 638 23

(1) Activation of rat liver mitochondrial functions following glucagon treatment was demonstrated in mitochondria that had not been isolated by the conventional technique of differential centrifugation and washing in sucrose solutions. Crude liver homogenates in 0.3 M-sucrose or 0.15 M-KCl prepared from rats treated with glucagon showed stimulation of State-3 and uncoupled respiration, carboxylation of pyruvate, and citrulline synthesis comparable with those previously reported in isolated mitochondria. (2) During the isolation procedure of mitochondria the hormonal stimulations of pyruvate carboxylation and citrulline formation were shown not to be enhanced by sequential washing. (3) Mitochondria isolated from glucagon-treated rats by differential centrifugation and washing in 0.3 M-mannitol/1 mM-EGTA, pH 7.0, exhibited a mean rate of citrulline synthesis that was greater than twice that of the control. Liver homogenates prepared in 0.3 M-sucrose or 0.3 M-mannitol showed identical rates of State-3 respiration and percentage stimulations of respiration by glucagon treatment. (4) Addition of glucagon led to a rapid accumulation of malate and aspartate and decreased the amounts of glutamate and citrate in isolated hepatocytes incubated with L-lactate. When gluconeogenesis was inhibited at the phosphoenolpyruvate carboxykinase (EC 4.1.1.32) reaction these phenomena were accentuated, lending support to the interpretation that they are the direct result of stimulation of carboxylation and oxidation reactions in the mitochondria. These results do not support the proposal [Siess, Fahimi & Wieland (1981) Hoppe-Seyler's Z. Physiol. Chem. 362. 1643-1651] that the mitochondrial effects of glucagon treatment result from a stabilization of mitochondria to detrimental effects of sucrose during their isolation. (5) The mean hormonal stimulation of pyruvate carboxylation in mitochondria isolated in 0.3 M-sucrose was shown to be approx. 2.5-fold when assayed either at 37 degrees C or 25 degrees C. In contrast, on the basis of similar experiments, Siess et al. (1981) concluded that the effects of glucagon on hepatic mitochondria are not characteristic of a true hormonal stimulation. Our data indicate this conclusion to be unjustified.
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PMID:Stimulation of mitochondrial functions by glucagon treatment. Evidence that effects are not artifacts of mitochondrial isolation. 640 79

A method is described for measuring rates of mitochondrial pyruvate carboxylation in hepatocytes treated with the polyene antibiotic, filipin, to render the plasma membrane permeable to substrates. With this approach it was possible to demonstrate that treatment of cells with glucagon or catecholamines results in a stimulation of mitochondrial CO2 fixation measured in situ comparable with that observed in the isolated mitochondria, in terms of time of onset of the response, hormone selectivity and sensitivity. In addition, angiotensin II and vasopressin were shown to enhance the activity of pyruvate carboxylase in both the intact mitochondria and filipin-treated cells, thus strengthening the postulate that this site is a major locus of hormone action in the control of gluconeogenesis. Addition of 3-mercaptopicolinic acid, to inhibit gluconeogenesis at the level of phosphoenolpyruvate carboxykinase, had no significant effect on the stimulation of pyruvate carboxylation by adrenaline, suggesting that the effect of the hormone at this site is independent of changes in activity of other enzymes further on in the pathway. The data presented preclude the possibility that acute effects of hormones on mitochondrial metabolism are solely artifacts of the preparation procedure.
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PMID:Hormonal stimulation of mitochondrial pyruvate carboxylation in filipin-treated hepatocytes. 641 Oct 66

Glucagon induced a rapid (within 3 min) increase in glucose radioactivity and a decrease in the labeling of ketone bodies when isolated hepatocytes were incubated in the presence of [1-14C]palmitate. Simultaneously, the hormone induced a decrease in the levels of pyruvate and Krebs cycle intermediates and an increase in the level of phosphoenolpyruvate (PEP). The glucagon-induced increase in glucose radioactivity was much larger than the simultaneous decrease in lactate labeling. A comparison of the incorporation of labeled carbon from [1-14C]palmitate and [U-14C]palmitate into glucose and CO2 indicates a selective stimulatory action of glucagon on the flux through the phosphoenolpyruvate carboxykinase (PEPCK) reaction.
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PMID:The effect of glucagon on the carbon flux from palmitate into glucose, lactate and ketone bodies, studied with isolated hepatocytes. 646 42

Acute hormonal effects on the synthesis rate of the cytosolic form of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP), were investigated using rat hepatocytes maintained in short-term suspension culture. Cells were pulse-labeled with [3H]leucine or [35S]methionine and the rate of synthesis of phosphoenolpyruvate carboxykinase was estimated after immunoprecipitation of cell extracts with specific antibodies or following high-resolution two-dimensional gel electrophoresis of cell proteins. Total RNA was also extracted from cultured cells and subsequently translated in a wheat germ cell-free protein-synthesis system, in order to quantify the level of functional mRNA coding for phosphoenolpyruvate carboxykinase. Glucagon, the single most effective inducer, causes a 15--20-fold increase in the level of specific mRNA in 2 h, accompanied by a similar increase in enzyme synthesis rate. The extent of induction is further amplified about threefold when dexamethasone is added to the culture medium. The synergistic action of dexamethasone does not require pre-exposure of the cells to the glucocorticoid, but on the contrary occurs without lag upon simultaneous addition of glucagon and dexamethasone. The induction of phosphoenolpyruvate carboxykinase mRNA by glucagon is markedly depressed in hepatocytes inhibited for protein synthesis by cycloheximide. Cycloheximide-inhibited cells, however, display a considerable induction of the message after joint stimulation with dexamethasone and glucagon. Thus, the synergistic action of dexamethasone does not require concomitant protein synthesis. These data provide indirect evidence for a primary effect of the glucocorticoids on the expression of the phosphoenolpyruvate carboxykinase gene. Besides glucagon and dexamethasone, the thyroid hormones are shown to influence the rate of phosphoenolpyruvate carboxykinase synthesis in isolated liver cells. The stimulatory effect of 3,5,3'-triiodothyronine (T3) is best demonstrated as a twofold increase in relative rate of enzyme synthesis in cells supplied with T3 plus glucagon, as compared to cells challenged with glucagon alone. The effect of T3 relies on a pretranslational mechanism, as shown by a commensurate increase in functional mRNA coding for phosphoenolpyruvate carboxykinase. Dose-response experiments with T3 as well as dexamethasone demonstrate effects at very low hormone levels, consistent with a role for these hormones as physiological modulators of phosphoenolpyruvate carboxykinase expression.
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PMID:Effects of glucagon, dexamethasone and triiodothyronine on phosphoenolpyruvate carboxykinase (GTP) synthesis and mRNA level in rat liver cells. 651 Apr 13


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