UNIPROT:P01275 - FACTA Search

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

1. In rat isolated islets of Langerhans the selective beta 2-adrenoceptor agonist, clenbuterol (1 to 20 microM), significantly increased the level of adenosine 3':5'-cyclic monophosphate (cyclic AMP) within 2 min of incubation. 2. The cyclic AMP response to clenbuterol was inhibited in the presence of the selective beta 2 adrenoceptor antagonist, ICI 118551 (0.1 or 10 microM) but remained unchanged when the beta 1-antagonist, atenolol (0.1 microM) was administered. 3. Despite causing an elevation in cyclic AMP, clenbuterol (up to 20 microM) failed to influence insulin secretion at any glucose concentration tested, even in the presence of a phosphodiesterase inhibitor. 4. By contrast, clenbuterol elicited a dose-dependent rise in the rate of glucagon secretion; the maximal agonist-induced increase in secretion was two fold, a response equivalent to that observed with 20 mM L-arginine. 5. ICI 118551 significantly inhibited the rise in glucagon secretion induced by clenbuterol (up to 20 microM). 6. The results indicate that the rat islet A cell population is equipped with functional beta 2-adrenoceptors which influence glucagon secretion via the second messenger cyclic AMP, but that the B cells are deficient in functional beta-receptors.
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PMID:Selective stimulation of glucagon secretion by beta 2-adrenoceptors in isolated islets of Langerhans of the rat. 171 26

Using experimentally derived data for the activities and kinetic constants of hepatocyte cyclic AMP phosphodiesterase isoenzymes together with the derived changes in adenylate cyclase activity, due to stimulation and subsequent desensitization by glucagon, a computer model was established to simulate hepatocyte cyclic AMP metabolism. The established ability of glucagon to activate the 'dense-vesicle' cyclic AMP phosphodiesterase by eliciting its cyclic AMP-dependent phosphorylation was shown on the model to be capable of eliciting a profound reduction in the glucagon-stimulated increase in intracellular cyclic AMP. This was consistent with experimentally derived observations using the compound ICI 118233 which was used to inactivate the 'dense-vesicle' enzyme selectively. The non-hydrolysable adenosine agonist N6 (phenylisopropyl)-adenosine (PIA), which prevents glucagon pre-treatment of hepatocytes blocking the ability of insulin to stimulate the peripheral plasma membrane cyclic AMP phosphodiesterase, is shown here to accentuate the ability of insulin to decrease glucagon-elevated intracellular cyclic AMP concentrations. This effect was obliterated using the compound ICI 63197, a selective inhibitor of the peripheral plasma membrane phosphodiesterase. Computer modelling studies, taking into account experimentally derived actions in insulin in activating the peripheral plasma membrane phosphodiesterase, confirmed the potential of this enzyme to decrease intracellular cyclic AMP concentrations. Modelling of the putative effect of an insulin 'mediator' in activating the two cyclic GMP-stimulated cyclic AMP phosphodiesterase isoenzymes was shown to elicit a decrease in intracellular cyclic AMP concentrations which was comparable to that caused by insulin's action on intact hepatocytes. The relative contribution of each phosphodiesterase form to the metabolism of hepatocyte intracellular cyclic AMP, together with an assessment of the potential effect of inhibition and activation of specific species, was evaluated using the computer model. These experimental and stimulation studies indicate that alterations in the phosphodiesterase activity of the 'dense-vesicle' enzyme, the peripheral plasma membrane enzyme, the cyclic GMP-stimulated cyclic AMP isoforms and the IBMX-insensitive PDE-MQ-II can elicit profound effects upon hepatocyte intracellular cyclic AMP concentrations.
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PMID:The use of selective inhibitors and computer modelling to evaluate the role of specific high affinity cyclic AMP phosphodiesterases in the hormonal regulation of hepatocyte intracellular cyclic AMP concentrations. 217 3

The effect of glucagon was studied on the isolated gastric fundus from immature rats in comparison with histamine. Glucagon (10(-7) -3 X 10(-6) M) caused a concentration-dependent increase in acid output, being approximately 25 fold more potent than histamine (ED50 values were 6.38 X 10(-7) M and 2.42 X 10(-5) M for glucagon and histamine, respectively). These compounds, however, did not differ in regard to the maximum response. The stimulatory effect of glucagon was not enhanced by pretreatment with 3 X 10(-8) M forskolin or 10(-7) M ICI 63197, a phosphodiesterase (PD) inhibitor. Conversely, both forskolin and ICI 63197 shifted to the left the concentration-response curve to histamine. The increase in acid secretion by glucagon was reduced by PGE1 (10(-5) M) and PGE2 (10(-5) M) but only PGE2 inhibited the response to histamine. From these data it can be concluded that glucagon stimulated acid production in the stomach from immature rats, and this effect does not seem to involve the same adenylate cyclase activated by histamine.
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PMID:Effect of glucagon on gastric acid secretion by the isolated fundus from immature rats. 283 65

The relationship of hepatic ornithine decarboxylase (ODC) activity to cyclic AMP levels and nutritional status was studied in the pre-weanling rat. Previous studies demonstrated that 2 hr without food causes a loss of hepatic ODC induction after glucagon or catecholamine injection. Isoproterenol or glucagon administration produced increased hepatic cyclic AMP and tyrosine aminotransferase activity which were not prevented by nutritional deprivation. Blockade of hepatic beta 2 receptors by the selective antagonist ICI 118,551 prevented increased cAMP levels and ODC activity after isoproterenol administration. Blockade of beta 1 receptors by atenolol did not prevent increased cAMP levels or ODC induction by isoproterenol although it did block activation of cardiac ODC. The phosphodiesterase inhibitor RO20-1724 increased hepatic cAMP levels as well as ODC and TAT activities, although the increase in ODC activity was attenuated by nutritional deprivation. RO20-1724 also potentiated the induction of hepatic ODC after glucagon or isoproterenol administration. Administration of 8-bromo cAMP elevated hepatic ODC activity regardless of nutritional status but also elevated serum levels of growth hormone and corticosterone. Hepatic ODC induction by glucagon or beta 2 agonists can be dissociated from changes in cAMP levels during nutritional deprivation.
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PMID:Hepatic cyclic AMP generation and ornithine decarboxylase induction by glucagon and beta adrenergic agonists. 286 May 51

Species differences concerning the effects of alpha- and beta-receptor stimulation on glucagon release and carbohydrate metabolism have been reported. The aim of the present study was to investigate how the subtypes of alpha- and beta-receptors regulate the plasma levels of glucagon, insulin, glucose and free fatty acids in fasted rabbits. Epinephrine-induced 1) hyperglucagonaemia, 2) hypoinsulinaemia and 3) hyperglycaemia were significantly inhibited by alpha-2 receptor blockade (yohimbine), and not influenced by alpha-1 receptor blockade (prazosin). Isoproterenol-induced 1) hyperglucagonaemia was not affected by beta-1 or beta-2 receptor blockade, 2) hyperinsulinaemia was inhibited by a lower dose of beta-2 (ICI 118.551) than beta-1 receptor blockade (metoprolol), 3) hyperglycaemia was inhibited by beta-2 receptor blockade and 4) increases in the plasma levels of free fatty acids were blocked by beta-1 receptor blockade. It is concluded that in fasted rabbits: 1) plasma levels of glucagon are mainly increased by alpha-2 receptor stimulation, 2) plasma levels of insulin are decreased by alpha-2 receptor stimulation, and increased more by beta-2 than by beta-1 receptor stimulation, 3) plasma levels of glucose are increased by alpha-2 and beta-2 receptor stimulation and 4) the plasma levels of free fatty acids are increased by beta-1 receptor stimulation.
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PMID:Adrenergic effects on plasma levels of glucagon, insulin, glucose and free fatty acids in rabbits--influences of selective blocking drugs. 614 41

To evaluate the hypothesis that lactate supply is essential to maintain euglycemia during iron deficiency, female Sprague-Dawley rats were assigned to iron-sufficient (50 mg Fe2+/kg diet, +Fe), or iron-deficient (15 mg Fe2+/kg diet, -Fe) dietary groups and were injected with a specific beta 2-adrenergic inhibitor, ICI 118,551 (1.0 mg/kg body wt). Rats were studied at rest or after 30 min of running at 13.4 m/min 0% grade. Dietary iron deficiency decreased hemoglobin concentration 38%, but resting arterial concentrations of glucose ([Glc]), lactate ([La]), or alanine ([Ala]) were unaffected. Administration of ICI 118,551 (beta 2-blockade) decreased [La] and [Glc] 52 and 32% in resting -Fe rats, respectively. beta 2-Blockade attenuated the exercise-induced rise in [La] and decreased [Glc] 31% in exercising -Fe rats. [Ala] were unaffected by iron deficiency or exercise but decreased 24 and 18% because of beta 2-blockade in resting and exercising +Fe rats. Iron deficiency depleted resting liver glycogen concentration 45%, with no additional effect of exercise or beta 2-blockade. beta-Blockade decreased arterial insulin and increased arterial glucagon concentrations in resting -Fe and +Fe rats. During exercise glucagon concentration increased significantly more in -Fe than +Fe rats. Decreased arterial [La] with a corresponding decrease in arterial [Glc] in response to beta 2-blockade support the contention that lactate supply is critical to maintenance of euglycemia in -Fe rats at rest and during exercise.
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PMID:Lactate is essential for maintenance of euglycemia in iron-deficient rats at rest and during exercise. 809 76

Primary cultures of rat hepatocytes were used to study the combined effects of insulin and dexamethasone on cyclic AMP phosphodiesterase 3 (PDE 3) and glycogen metabolism. PDE activity was measured in extracts obtained by hypotonic shock treatment of the particulate fraction from cultured hepatocytes. PDE 3 was identified by inhibition with ICI 118233, Western blotting, immunoprecipitation of the activity with the use of a new PDE 3B-specific anti-peptide antibody and stimulation of the activity after adding insulin, glucagon and okadaic acid to the culture medium. Specific PDE inhibitors were always used to identify the measured PDE activities. Hypotonic extracts contained 30% PDE 3 and 50% PDE 4. Both PDE types show a nearly constant level during cultivation up to 48 h. Long-term exposure of dexamethasone alone has no effect on PDE 3 activity, whereas, in combination with insulin, the insulin stimulation of PDE 3 activity was found to be increased between 48 and 72 h of cultivation. Additionally, db-cAMP was able to stimulate PDE 3. A possible effect of insulin or db-cAMP on PDE 3B expression could not be found. On the other hand, activation of PDE 3B after 48 h of culturing decreased rapidly after removal of insulin or db-cAMP from the culture medium. Insulin-stimulated incorporation of 14C-glucose into glycogen was inhibited by PDE 3- and PDE 4-specific inhibitors as well as by the unspecific PDE inhibitor IMBX. Inhibitions by PDE 3- and PDE 4-specific inhibitors were found to be additive and reached the same extent as with IMBX. Summarising our results, we can conclude that PDE 3 and PDE 4 effectively control the hepatic glycogen metabolism. Insulin effects on PDE activity and glycogen metabolism require the presence of dexamethasone. Insulin-stimulated PDE seems to play an important role in realising insulin effects on hepatic glycogen metabolism.
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PMID:Combined effects of insulin and dexamethasone on cyclic AMP phosphodiesterase 3 and glycogen metabolism in cultured rat hepatocytes. 979 44

67% of total cAMP phosphodiesterase activity (PDE) in cultured rat hepatocytes could be detected in the cytosol, 15% in plasma membrane, 15% in 'dense vesicle,' and 3% in endoplasmatic reticulum fractions. Up to 84% of the PDE activity of the cytosol is represented by the rolipram-sensitive PDE 4. ICI 118233-inhibited PDE 3 was found predominantly in membranes. We were able to show that dexamethasone acts on the PDE 4 in cytosolic and plasma membrane fractions whereas glucagon effected the PDE 4 of the cytosol and the PDE 3 in 'dense vesicle' membranes. Primary culture of hepatocytes was used to study long-term effects of dexamethasone and glucagon on PDE 4 activity. Addition of dexamethasone (0.1 microM) at the beginning of cultivation leads to a decrease of total PDE 4 activity whereas after 24 h precultivation no dexamethasone effect could be observed. Glucagon effects on PDE 4 were investigated in 20 h precultured hepatocytes. Maximal stimulation was achieved after 2 h of exposure. PDE 4 subtypes A, B , D and, to a lesser degree, subtype C could be detected by RT-PCR analysis. The results of semiquantitative RT-PCR show that the presence of dexamethasone during the first 24 h of cultivation reduced selectively the transcription of PDE 4D, whereas glucagon was without any effect. Also the translation of PDE 4D was reduced as shown in the Western blot. We would like to discuss the way that dexamethasone influences PDE 4D expression-most likely in combination with other factors such as cytokines--during the time of cell plating, whereas glucagon actions are part of metabolic regulations via phosphorylation reactions.
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PMID:Effects of dexamethosone and glucagon after long-term exposure on cyclic AMP phosphodiesterase 4 in cultured rat hepatocytes. 1053 Aug 77

The biochemical properties of an in vivo hormonally regulated low Km cAMP phosphodiesterase (PDE) activity associated with a liver Golgi-endosomal (GE) fraction have been characterized. DEAE-Sephacel chromatography of a GE fraction solubilized by a lysosomal extract resulted in the sequential elution of three peaks of activity (numbered I, II, and III), while ion-exchange HPLC resolved five peaks of activity (numbered 1, 2, 3, 4, and 5). Based on the sensitivity of the eluted activity to cGMP and selected phosphodiesterase inhibitors, two phosphodiesterase isoforms were resolved: a cGMP-stimulated and EHNA-inhibited PDE2, eluted in DEAE-Sephacel peak I and HPLC peak 2 and a cGMP-, a cilostamide-, and ICI 118233-inhibited PDE3, eluted in DEAE-Sephacel peak III and HPLC peaks 3, 4, and 5. GE fractions isolated after acute treatments with insulin, tetraiodoglucagon, and growth hormone displayed an increase in phosphodiesterase activity relative to saline-injected controls, as did GE fractions from genetically obese and hyperinsulinemic rats relative to lean littermates. In all experimental rats, an increase in PDE3 activity associated with DEAE-Sephacel peak III and HPLC peaks 4 and 5 was observed relative to control animals. Furthermore, in genetically obese Zucker rats, an increase in the sensitivity of PDE activity to cilostamide and in the amount of PDE activity immunoprecipitated by an antibody to adipose tissue PDE3 was observed relative to lean littermates. These results extend earlier studies on isolated hepatocytes and show that liver PDE3 is the main if not sole PDE isoform activated by insulin, glucagon, and growth hormone in vivo.
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PMID:Characterization of an in vivo hormonally regulated phosphodiesterase 3 (PDE3) associated with a liver Golgi-endosomal fraction. 1136 77

Glucose homeostasis in blood is mainly maintained by insulin released from beta-cells and glucagon released from alpha-cells, both integrated within the pancreatic islet of Langerhans. The secretory processes in both types of cells are triggered by a rise in intracellular calcium concentration ([Ca2+](i)). In this study, rapid effects of the natural hormone E2 on [Ca2+](i) were studied in both types of cells within intact islets using laser scanning confocal microscopy. alpha- And beta-cells showed opposite [Ca2+](i) responses when stimulated with physiological concentrations of 17beta-E2. Although the estrogen produced an increase in the frequency of glucose-induced [Ca2+](i) oscillations in insulin-releasing beta-cells, it prevented the low glucose-induced [Ca2+](i) oscillations in glucagon-releasing alpha-cells. The effects of 17beta-E2 on alpha-cells were mimicked by the cGMP permeable analog 8bromo-cGMP and blocked by the cGMP-dependent protein kinase (PKG) inhibitor KT5823. Evidence indicated that these were membrane actions mediated by a nonclassical ER. Both effects were rapid in onset and were reproduced by 17beta-E2 linked to horseradish peroxidase, a cell-impermeable molecule. Furthermore, these actions were not blocked by the specific ER blocker ICI 182,780. Competition studies performed with 17beta-E2 linked to horseradish peroxidase binding in alpha-cells supported the idea that the membrane receptor involved is neither ERalpha nor ERbeta. Additionally, the binding site was shared by the neurotransmitters epinephrine, norepinephrine, and dopamine and had the same pharmacological profile as the receptor previously described for beta-cells. Therefore, rapid estrogen actions in islet cells are initiated by a nonclassical estrogen membrane receptor.
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PMID:A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. 1187 8

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