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)

Hepatic glucose production is stimulated in vitro twice as effectively by pulsatile as by continuous glucagon, given equivalent time-averaged doses. Efficacy studies of pulsatile insulin have yielded conflicting results. In the rat hepatoma cell line H-4-II-E-C3, insulin rapidly (t1/2 15 min) inhibits transcription of the gene and lowers mRNA levels for the gluconeogenic enzyme. PEPCK via a receptor-mediated process. We attached H-4-II-E-C3 cells to Cytodex-3 microcarriers and used a perifusion column system to test whether pulsatile insulin is more or less effective than equivalent time-averaged doses of continuous insulin. PEPCK transcription was induced by inclusion of cAMP analogue 8-(4-chlorophenyl-thio)-cAMP (0.1 mM) and dexamethasone (0.5 microM) in the perifusion medium. Three columns were exposed either to continuous, pulsatile, or no insulin. After 3 h, total nucleic acid was extracted, and mRNA(PEPCK) was measured with a sensitive-solution hybridization assay. Continuous insulin inhibited PEPCK expression in a dose-dependent fashion with EC50 1 x 10(-11) M. Equivalent time-averaged amounts of insulin delivered as pulses achieved significant inhibition but less effectively than continuous insulin. The apparent EC50 for pulsatile insulin increased from 2 x 10(-11) M to 5 x 10(-11) M as the oscillatory period was raised from 5 to 20 min, respectively. These observations suggest that insulin-mediated inhibition of PEPCK gene transcription is diminished by a pulsatile mode of administration in marked contrast to the pulse enhancement demonstrated for glucagon-mediated hepatic glucose production.
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PMID:Insulin pulses less effective than continuous insulin in inhibiting PEPCK mRNA levels stimulated by cAMP and dexamethasone in perifused hepatoma cells. 165 Mar 13

Several hormones, including insulin, glucagon, and glucocorticoids, regulate the expression of the rate-limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase [GTP: oxaloacetate carboxy-lyase (transphosphorylating); EC 4.1.1.32; PEPCK] in liver. In this report we demonstrate that retinoic acid (RA) also regulates PEPCK expression by inducing a 3-fold increase in the rate of transcription of the PEPCK gene. A RA response element located between -468 and -431 in the PEPCK promoter mediates a 7-fold increase in expression of a chimeric construct containing the basal PEPCK promoter ligated to the chloramphenicol acetyltransferase reporter gene. This element confers RA responsiveness through the heterologous thymidine kinase promoter and functions relatively independent of position and orientation. An 18-base-pair core sequence (-451 to -434) (i) mediates an effect of RA on PEPCK gene expression and contains motifs found in two other RA response elements; (ii) corresponds to AF1, an accessory factor element that is an integral component of the complex glucocorticoid response unit in the PEPCK gene promoter; (iii) is in a region involved in the developmental expression of the PEPCK gene; and (iv) shows homology to elements involved in the tissue-specific regulation of genes, including the hepatic apolipoprotein genes and the alpha 1-antitrypsin gene.
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PMID:A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene. 184 96

Transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) from the rat is acutely regulated by a number of hormones, including glucagon (acting via cAMP), glucocorticoids, and insulin. In this study we demonstrate by DNase I footprinting that a region of the PEPCK promoter, extending from -460 to +73, contained eight protein binding domains. Two nuclear proteins protected adjacent sites from -121 to -99 and -96 to -77, which have been previously shown to be involved in maintaining the level of basal gene transcription and conferring cAMP responsiveness, respectively. Oligonucleotide competition studies suggested that the protein(s) binding to the cAMP-responsive element (CRE) occupies a second site at -147 to -130, which has a high degree of sequence homology to the CRE, and also binds to two other elements that show partial sequence homologies. The protein(s) which bound to these four elements copurified through oligonucleotide affinity chromatography, suggesting that the PEPCK promoter has four binding sites for the CRE-binding protein(s). Potential tissue-specific elements in the PEPCK promoter were identified by footprinting with nuclear extracts prepared from rat liver, kidney, brain, and spleen. The multiple protein-binding sites in this promoter-regulatory region reflect the complex transcriptional regulation that is characteristic of this gene.
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PMID:Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. 254 17

In summary, the surges of glucagon and epinephrine at birth, coupled with the fall in insulin secretion, are in accord with appropriate receptor changes, as well as genetic ontogenic patterns of enzyme development. Enzyme activities are further stimulated by the hormonal changes at birth; phosphorylase is activated by glucagon and epinephrine, while PEPCK is activated by glucagon and its expression is facilitated by the fall in insulin. In concert, these changes permit rapid activation of catabolic processes and the mobilization and utilization of endogenous fuel stores. Glucose homeostasis is maintained by glycogenolysis and gluconeogenesis supported by the appropriate enzyme inductions. The free fatty acids released, via lipolysis, also serve to sustain gluconeogenesis, since hepatic fatty acid oxidation is necessary for gluconeogenesis by providing the essential cofactors. This framework permits a rational interpretation of the mechanisms underlying the remarkable transition from intrauterine dependence on maternal glucose to extrauterine autonomy of newborn energy integration. This framework can also explain several causes of neonatal hypoglycemia and act as a base for future investigations.
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PMID:Carbohydrate metabolism. 283 6

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

We have determined that one reason for diminished PEPCK activity during endotoxemia is the inhibition of glucocorticoid action in hepatic cells. Since glucocorticoid and glucagon hormones act cooperatively to regulate the expression of PEPCK mRNA, we examined whether endotoxin also inhibits the action of glucagon to induce this enzyme. Treated mice were injected intraperitoneally with endotoxin and glucose after a 24 hr fast and given ad libitum access to food and water. Control mice received the same amount of glucose and access to food and water. All mice were given intravenous injections of glucagon for 3 consecutive hours before euthanasia. Blood was analyzed for glucose concentrations, and the liver was assayed for PEPCK activity. Refeeding control mice after a 24 hr fast increased plasma glucose levels to 173 +/- 14 mg/dL and decreased PEPCK activity to 20.6 +/- 2.0 units/mg liver. Subsequent administration of exogenous glucagon further increased plasma glucose to 224 +/- 17 mg/dL and hepatic PEPCK to 31.4 +/- 1.4 units/mg liver. Refeeding endotoxin-treated mice after a 24 hr fast slightly increased plasma glucose levels to 75 +/- 4 mg/dL but had no effect on PEPCK activity. Subsequent glucagon administration had no effect on plasma glucose levels (75 +/- 1.0 mg/dL) or hepatic PEPCK activities (18.8 +/- 5.0 units/mg liver). Therefore, glucagon action to increase liver PEPCK activity and plasma glucose levels was inhibited in endotoxin-treated mice.
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PMID:Failure of glucagon to induce hepatic phosphoenolpyruvate carboxykinase in endotoxic shock. 320 22

The mechanisms of the responses of an enzyme to different hormones and metabolites or several enzymes to a single hormone are surprisingly varied. There is neither an operon for lipogenic enzymes nor a common step at which hormones and metabolites coordinately regulate the expression of lipogenic genes. In bacteria, coordinated expression of several enzymes in a single metabolic pathway often is achieved by organizing the genes into operons. An operon is a group of genes linked together in a linear fashion and producing a polycistronic mRNA. Trans-acting factors regulate the transcription of these genes by interacting with promoter/regulatory sequences in the 5'-flanking region of the most 5'-ward of the genes. In vertebrate animals, however, coordinated control of gene transcription is not achieved by linking the individual genes, but by putting in the 5'-flanking regions of these genes a regulatory sequence that interacts with common trans-acting factors. Genes controlled by different hormones are expected to have regulatory elements for each hormone. The presence of glucocorticoid and cyclic AMP regulatory elements at the 5'-end of the PEPCK gene is consistent with this notion. Transcription is not the only step at which hormones and metabolites control the pathways for gene expression. The levels of the mRNAs for L-PK, ME, S11, and S14 are increased by T3 at post-transcriptional steps. Glucagon also regulates the accumulation of ME mRNA post-transcriptionally. Neither the mechanism nor the sequence organization of regulatory elements is known for post-transcriptional control of gene expression. In the case of PEPCK and HMG-CoA reductase, the next steps will be to determine more precisely the sequences in the 5'-region that mediate hormone sensitivity and feedback inhibition, respectively, and whether trans-acting factors are involved. For the other genes discussed, identification of the regulated step must precede identification of sequences that confer hormone or metabolite-sensitive regulation on a specific gene. In general, it is probable that the hybrid gene approach, so successful for PEPCK and HMG-CoA reductase, also will be effective in defining cis-acting hormone- or metabolite-regulatory elements in other genes. These techniques should be applicable to both transcriptional and post-transcriptional mechanisms. Our long-term objective is to understand the molecular basis of each event that intervenes between the binding of hormone or metabolite to its appropriate receptor and altered enzyme level.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dietary regulation of gene expression: enzymes involved in carbohydrate and lipid metabolism. 330 Jul 31

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

Phloridzin, an inhibitor of renal sugar transport, produces an important loss of glucose in urine of treated animals. In order to reduce severely the maternal glucose supply to the fetuses in short-term experiments, we have combined phloridzin administration to pregnant rats with 18 h starvation. Fetuses from starved phloridzin-treated mothers were compared with fetuses from starved mothers. Combined treatment markedly decreases fetal blood glucose concentration (-36%) and fetal liver glycogen stores (-76%). These changes are associated with a decrease in plasma insulin (-25%), a rise in plasma glucagon (+120%) and a marked increase of hepatic PEPCK activity (+400%). It appears from these results that phloridzin treatment for a short duration is able to induce glycogenolysis and the premature appearance of PEPCK in the liver of rat fetuses.
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PMID:Fetal metabolic response to phloridzin-induced hypoglycemia in pregnant rats. 699 14

It is becoming increasingly apparent that interleukin-1 (IL-1) acts systemically and centrally to play an important role in regulating the hormonal and metabolic response to stress, infection, and trauma. The aim of this study was to observe the peripheral metabolic and endocrine responses to 15, 25, and 50 ng intracerebroventricular (i.c.v.) recombinant IL-1 beta in awake, freely moving rats over a 6-hour period. The rate and duration of elevation of temperature and plasma corticosterone and glucose were dose-dependent and did not return to control levels until 6 or more hours later. Hepatic glycogen content 6 h after i.c.v. IL-1 was 58, 52 and 78% of control after 15, 25, and 50 ng, respectively. The plasma insulin response to elevated plasma glucose in rats treated with 15 ng was absent in those treated with 25 and 50 ng. Responses of plasma glucagon to each dose of IL-1 were not significantly different from control responses. PEPCK enzyme activity was diminished to 60, 66, and 81% of control after 15, 25, and 50 ng IL-1, respectively. No changes of body temperature or plasma corticosterone were observed when 25 or 50 ng IL-1 were injected intravenously. These results are strong evidence that central actions of IL-1 significantly affect peripheral glycemia via classical hepatic and endocrine adjustments.
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PMID:Peripheral endocrine and metabolic responses to centrally administered interleukin-1. 796 79


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