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)

Cyclic AMP plays a major, if not primary, role in the regulation of hepatic gluconeogenesis. The cyclic nucleotide acts on two levels. First, cAMP levels determine the phosphorylation state of key regulatory enzymes including pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Regulation of cAMP levels by glucagon, insulin, and catecholamines accounts in large part for minute-to-minute hormonal control of pathway flux in fed animals and during the transition from fed to starved; second, cAMP plays a key role in regulation of gene transcription of phosphoenolpyruvate carboxykinase, pyruvate kinase, glucokinase, and probably 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Cyclic AMP acts to induce synthesis of mRNA for phosphoenolpyruvate carboxykinase and probably fructose 1, 6-bisphosphatase while it suppresses transcription of the genes for pyruvate kinase and glucokinase. Its role in the regulation of gene transcription of the bifunctional enzyme and 6-phosphofructo 1-kinase remains to be defined. Insulin is the most important hormone for restraining the level of cAMP. Insulin acts to oppose the acute actions of cAMP on enzyme phosphorylation, presumably by activating a phosphodiesterase and thereby lowering cAMP levels. Insulin also opposes the action of hormones (alpha-adrenergic agonists, angiotensin, vasopressin) that act in liver via cAMP-independent phosphorylation. However, in the systems in which this has been studied, the cAMP-independent effects on gluconeogenic/glycolytic pathway flux are small in comparison to cAMP-dependent regulation. Insulin also opposes the action of cAMP on gene transcription by an as yet unknown mechanism. This effect does not appear to involve changes in the level of cAMP because the hormone also acts in cultured cells when added alone or in the presence of dexamethasone. The ability of insulin to lower hepatic cAMP levels and to modulate gene expression are important because restoration of acute regulatory hormone responsiveness to starved or diabetic animals could not occur if insulin were unable to lower cAMP levels and be the dominant factor in modulating the gene expression of these key regulatory enzymes. Clearly, the hepatic gluconeogenic/glycolytic pathway undergoes a complex but extremely well-integrated regulation by hormones that accounts in large part for the major role the organ plays in the control of glucose homeostasis.
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PMID:The role of cyclic AMP in rapid and long-term regulation of gluconeogenesis and glycolysis. 285 23

The regulation of synthesis of the gluconeogenic cytosolic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and of tyrosine aminotransferase (TAT) by glucagon and glucocorticoid hormones was studied in hepatocytes maintained in suspension culture for 7 h. Specific antibodies were used to measure relative rates of enzyme synthesis after pulse-labelling of the cells with [3H]leucine or [35S]methionine. Concomitantly, amounts of mRNA were quantified after translation in vitro in a reticulocyte lysate and specific immunoprecipitation of the proteins. Glucagon stimulated the rate of synthesis of PEPCK by 4-6-fold and that of TAT by 6-8-fold in 2h. In contrast, dexamethasone had little effect on PEPCK synthesis, whereas it increased TAT synthesis by 5-9-fold. When used in combination, the two hormones displayed additive effects on TAT synthesis, whereas the glucocorticoid hormone strongly potentiated stimulation of PEPCK synthesis by glucagon. In every instance, changes in rates of synthesis of the two enzymes were totally accounted for by increases in amounts of the corresponding functional mRNA, suggesting a pretranslational site of action for both glucagon and dexamethasone.
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PMID:Pretranslational regulation of tyrosine aminotransferase and phosphoenolpyruvate carboxykinase (GTP) synthesis by glucagon and dexamethasone in adult rat hepatocytes. 285 99

The capacity for gluconeogenesis in the isolated amphibian retina was found to be approx. 70-fold greater with lactate than with glutamate as the gluconeogenic precursor, 1426 versus 21 pmol of glucose incorporated into glycogen/h per mg of protein. It was also found that 11-15% of the glucosyl units in glycogen are derived from C3 metabolites of the glycolytic pathway, suggesting that lactate is recycled within the retina. In concert with these metabolic observations, a full complement of the gluconeogenic enzymes was detected in retinal homogenates. These included: glucose-6-phosphatase, fructose-1,6-bisphosphatase, acetyl-CoA-dependent pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Agents that regulate the rate of gluconeogenesis in hepatic tissue were tested on the retina. At concentrations of glutamate and lactate that are presumed to be relevant physiologically, it was found that vasoactive intestinal peptide, ionophore A23187 and elevated [K+] each enhanced the rate of gluconeogenesis in Ringer containing 50 microM-glutamate, whereas in Ringer containing 8.5 mM-lactate these agents inhibited the rate of gluconeogenesis. Further, it was found that the classic gluconeogenic hormone glucagon inhibited gluconeogenesis in both glutamate- and lactate-containing Ringer. Retinal energy metabolism was found to be altered in lactate-containing Ringer, in that lactate production was suppressed completely. In addition, glycogen metabolism appeared to be dependent on increased cytosolic Ca2+ and was insensitive to increased retinal cyclic AMP.
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PMID:Gluconeogenesis in the amphibian retina. Lactate is preferred to glutamate as the gluconeogenic precursor. 290 49

The characteristics and site of inhibition of gluconeogenesis by endotoxin were investigated in liver cells isolated from control and endotoxin-treated rats. Endotoxin treatment was associated with inhibition (40-50%) of gluconeogenesis from lactate plus pyruvate over a range of concentrations of substrate and of oleate and with or without glucose or glucagon. Similar inhibition was observed with asparagine, proline, glutamine, alanine and a substrate mixture, but not with glycerol, glyceraldehyde, dihydroxyacetone or endogenous substrates. There was no change in cellular ATP content or in the rates of ketogenesis or ureogenesis from asparagine, proline or glutamine. Other effects on isotopic fluxes, metabolite contents, enzyme activities and control coefficients were consistent with the suggestion that the effects of endotoxin on gluconeogenesis are exerted at the level of phosphofructokinase-1, and not at phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate carboxylase or glucokinase.
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PMID:The characteristics and site of inhibition of gluconeogenesis in rat liver cells by bacterial endotoxin. Stimulation of phosphofructokinase-1. 295 43

In chickens, the liver functions in gluconeogenesis to recycle lactate carbon (Cori cycle) and the kidney is the major organ for net gluconeogenesis from substrates such as pyruvate and amino acids. This is markedly different from mammalian systems where the liver is the primary gluconeogenic organ. The limited ability of chicken hepatocytes to synthesize glucose is explained, at least in part, by the observation that phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) in these cells is located exclusively in the mitochondria. The kidney possesses a cytosolic form of this enzyme that adapts to dietary and acid-base stimuli. The relative abundance of mRNA coding for the cytosolic enzyme has been detected by using a specific cDNA probe. Starvation increases the level of this mRNA in chicken kidney and also results in the appearance of the message in chicken liver. Isolated hepatocytes have been used to determine which hormones regulate expression of the hepatic gene. Incubations with glucagon, epinephrine, norepinephrine, dexamethasone, or dibutyryl cyclic AMP increase the relative abundance of the message in liver cells isolated from fed chickens. Despite considerable levels of this mRNA in the liver of starved chickens, functional cytosolic enzyme activity is not detected. This indicates some form of posttranscriptional regulation. The studies summarized illustrate the usefulness of isolated hepatocytes and recombinant DNA probes in the study of hormonal regulation of hepatic gene expression.
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PMID:Gluconeogenesis in the chicken: regulation of phosphoenolpyruvate carboxykinase gene expression. 298 55

The activities and zonal distribution of key enzymes of carbohydrate metabolism were studied in livers of diabetic rats. 48 h after alloxan treatment the following alterations were observed, intermediate values being reached after 24 h: Blood glucose, acetoacetate and beta-hydroxybutyrate were increased to more than 500%; liver glycogen was reduced to about 10%. Portal vein insulin was reduced to below 10%, portal glucagon was increased to almost 200%. The glucogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were enhanced to 320% and 150%, respectively. The glycolytic enzymes glucokinase and pyruvate kinase L (differentiated from the M2 isoenzyme with a specific anti-L-antibody) were lowered to 50% and 75%, respectively. The citrate cycle enzyme succinate dehydrogenase remained unchanged. The normal periportal to perivenous gradient of phosphoenolpyruvate carboxykinase of about 3:1, as measured in microdissected tissue samples, was enhanced to about 4:1 with activities elevated to 230% and 190%, respectively, in the two zones. The normal periportal to perivenous gradient of pyruvate kinase L of about 1:1.7, as determined with the microdissection technique, was reduced to about 1:1.4 with levels lowered to 55% and 45%, respectively, in the two zones. The even zonal distribution of pyruvate kinase M2 remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolic zonation in liver of diabetic rats. Zonal distribution of phosphoenolpyruvate carboxykinase, pyruvate kinase, glucose-6-phosphatase and succinate dehydrogenase. 298 84

The effects of stress (diethyl ether anaesthesia for 4-8 min, or intravenous injection of 0.05 ml of a dimethyl sulphoxide/water mixture) and of a scald injury given under ether anaesthesia on hepatic PEPCK (phosphoenolpyruvate carboxykinase, EC 4.1.1.32) were studied in the post-absorptive rat. Injury raised PEPCK activity by about 70% in 2 h and by over 100% in 4 h, over three times as fast as in animals that had only been handled (controls). The two stresses, both of types commonly imposed in animal experiments, had almost as much effect as injury for the first 2 h, although much less thereafter. The roles of sympathetic stimulation and corticosterone in mediating these rises were studied by using alpha beta-blockers and trilostane respectively as inhibitors. (Trilostane only decreased corticosterone concentrations to a little above control values.) The ether-induced increase was somewhat decreased by alpha beta-blockade, but was only eliminated by combined alpha beta-blockade and trilostane. After injury, however, PEPCK synthesis was unaffected by either alpha beta-blockade or trilostane, although it was decreased by their combined action; and it seems that either corticosterone or sympathetic stimulation was sufficient to stimulate PEPCK synthesis maximally. Stimulation by corticosterone was much greater than reported previously by others, for reasons that are discussed. Sympathetic stimulation may have been mediated by glucagon and cyclic AMP, since injury raised portal glucagon concentrations, and stress and injury raised those of hepatic cyclic AMP. PEPCK synthesis was, however, stimulated despite increases in portal insulin concentration, and was not related to the [insulin]/[glucagon] ratio. Thus stress and injury over-rode normal control mechanisms.
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PMID:The effects of stress and injury on the activity of phosphoenolpyruvate carboxykinase in the liver of the rat. 300 59

Plasma insulin, glucagon, glucose, free fatty acids and glycerol, hepatic cyclic AMP and glycogen, and liver phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase (FBPase), glucose 6-phosphatase (G6Pase) and alanine amino transferase (AAT) activities were examined in adult rats during the first 24 h of either starvation or consumption of a high protein, carbohydrate-free (HP) diet. Under both nutritional conditions, plasma insulin fell within 12 h and remained constant thereafter. Glucagon increased 12 h after the start of the experiment and peaked between 18-24 h. The insulin: glucagon ratio was lower during the last 12 h of the experiment. In both experimental groups, liver cyclic AMP increased progressively and peaked between 15-24 h, but it increase was higher on HP diet than on starvation. Whereas plasma glucose remained low on starvation for 24 h, it returned to normal on consumption of the HP diet. In both groups, liver glycogen fell within 12 h and remained low until the end of experiment. FBPase, G6Pase and AAT did not change on starvation, while they increased toward the end of 1 d HP consumption. During starvation or consumption of the HP diet, PEPCK increased progressively and peaked between 15-24 h, but the increase was greater with the HP diet than with starvation. These findings suggest that in the first 24 hours, the adaptative response of hepatic gluconeogenesis is higher with a HP diet than upon starvation.
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PMID:Comparison between starvation and consumption of a high protein diet: plasma insulin and glucagon and hepatic activities of gluconeogenic enzymes during the first 24 hours. 300 46

Activities (mumol X min-1 X g liver) and zonal distributions of key enzymes of carbohydrate metabolism were studied in livers of streptozotocin-diabetic rats and compared to the values in alloxan-diabetes. Streptozotocin led to a non-ketotic diabetes with blood glucose being increased by more than fivefold but ketone bodies being in the normal range, while alloxan produced a ketotic diabetes with blood glucose, acetoacetate and beta-hydroxybutyrate being elevated by more than fivefold. Portal insulin was decreased to about 20% in streptozotocin- and more drastically to about 7% in alloxan-diabetes. Conversely, portal glucagon was increased in the two states to about 250% and 180%, respectively. The glucogenic key enzyme phosphoenolpyruvate carboxykinase (PEPCK) was enhanced in streptozotocin- and alloxan-diabetes to over 300%, while the glycolytic pyruvate kinase L (PKL) was lowered to 65% and 80%, respectively. The normal periportal to perivenous gradient of PEPCK of about 3:1, as measured in microdissected tissue samples, was maintained with elevated activities in the two zones. The normal periportal to perivenous gradient of PKL of 1:1.7 was diminished with lowered activities in the two zones. The glucogenic glucose-6-phosphatase (G6Pase) was increased in streptozotocin- and alloxan-diabetes to 130% and 140%, respectively, while the glucose utilizing glucokinase (GK) was decreased to 60% and 50%, respectively. The normal periportal to perivenous gradient of G6Pase, demonstrated histochemically, remained unaffected. Carnitine palmitoyltransferase (CPT) was increased to over 190% and acetyl-CoA carboxylase (ACC) was decreased to 60% in streptozotocin, non-ketotic diabetes, while the two enzymes were altered more drastically to 400% and 50%, respectively, in alloxan, ketotic diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gluconeogenic-glycolytic capacities and metabolic zonation in liver of rats with streptozotocin, non-ketotic as compared to alloxan, ketotic diabetes. 302 62

A technique has been devised to attach adult rat hepatocytes to collagen-coated dextran microcarriers. Cells were cultured serum-free for 2 d and their viability, enzyme activities, glucose metabolism, and hormone responsiveness were compared to data obtained from conventional dish cell culture. The two different culture methods showed no difference in cell viability and morphology. Microcarrier-cultured cells exhibited hormone responsiveness comparable to dish cultures; glycolysis could be activated three-fold by the sole addition of insulin, and gluconeogenesis was increased by 40 to 50% by glucagon. During the 48-h culture glucokinase and phosphoenolpyruvate carboxykinase activities declined at a similar rate in both culture systems. Long-term culture with 0.1 microM insulin prevented the decrease of glucokinase activity. Insulin responsiveness (activation of glycolysis) was still pronounced after 48 h in culture. The microcarrier technique establishes a new in vitro liver system in which acute and long-term hormonal actions can be investigated using the technical advantages of a suspension culture.
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PMID:Adult rat hepatocyte microcarrier culture. Comparison to the conventional dish culture system. 305 97


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