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)

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

Ingestion of caffeine has been reported to enhance performance during prolonged endurance exercise. This effect on performance has been attributed to a caffeine-induced enhancement of lipid oxidation, thereby sparing muscle glycogen. The purpose of this experiment was to determine the effect of caffeine on the rate of liver glycogenolysis during exercise. Adult male rats were given an intravenous injection of caffeine (5 mg X kg-1) or of 0.9% NaCl. One h later they were run on a motor driven treadmill at 28 m X min-1 up a 15% grade for 45 or 90 min. Liver and muscles were frozen, and blood was collected for analysis. No significant differences were found between caffeine- and saline-injected rats in liver or muscle glycogen, plasma free fatty acid, insulin, glucagon, blood glucose, or blood glycerol. Liver adenosine 3',5'-cyclic monophosphate was essentially the same in caffeine- and saline-injected rats after 90 min of exercise. In a separate study, injection of 5 or 25 mg caffeine per kg body weight immediately prior to a 60-min bout of exercise had no effect on the rate of liver muscle glycogenolysis or on any of the hormones and metabolites studied. We conclude that in the rat, blood levels of caffeine in the range of 3.7 to 29 micrograms X ml-1 have no effect on liver adenosine 3',5'-cyclic monophosphate or the rate of liver glycogenolysis during prolonged treadmill running.
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PMID:Effect of intravenous caffeine on liver glycogenolysis during prolonged exercise. 370 46

A possible role for adenylcyclase in insulin secretion was investigated. Isoproterenol, a predominantly beta-adrenergic agent, when mixed with an alpha-adrenergic blocking agent (phenoxybenzamine), stimulated insulin secretion from pieces of the rat's pancreas in vitro. Theophylline, caffeine, 3'5'-cyclic AMP, glucagon, adrenocorticotropin (ACTH), and thyrotropin (TSH), all of which are thought to act through the adenylcyclase systems in the liver and adipose tissue, also stimulated insulin secretion in vitro; oxytocin and vasopressin, which do not stimulate lipolysis in adipose tissue, were inactive. In all cases, stimulation of insulin secretion could not be detected when glucose was absent or present in only low concentrations (less than 100 mg/100 ml) and was maximal at high levels of glucose (300 mg/100 ml). When pancreatic tissue was obtained from normoglycemic rats and contained no detectable glycogen in the Islets, the stimulant effects of glucose and of theophylline were reduced or abolished by mannoheptulose and 2-deoxyglucose. When tissue was derived from rats infused for 8-10 hr with glucose and contained glycogen, theophylline, even in the absence of glucose, stimulated secretion and this effect was reduced by 2-deoxyglucose but not by mannoheptulose. It is suggested that the beta-cell contains an adenylcyclase system through which phosphorylase and possibly phosphofructokinase could be activated; and that insulin secretion could depend upon and be regulated by hormones and other substances which influence the rate at which glycolysis proceeds within the beta-cell.
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PMID:A possible role for the adenylcyclase system in insulin secretion. 429 54

1. Protein kinase activity was measured in islets of Langerhans that had been incubated in the presence of agents known to affect insulin release. 2. Glucagon, theophylline, caffeine and 3-isobutyl-1-methylxanthine, agents that raise cyclic AMP concentrations in islet cells and stimulate insulin release, increased protein kinase activity. Adrenaline and diazoxide, agents that decrease cyclic AMP concentrations and inhibit insulin secretion, decreased the activity. 3. The increase in protein kinase activity produced by different concentrations of 3-isobutyl-1-methylxanthine was apparently related to the increase in intracellular concentrations of cyclic AMP. 4. The sulphonylureas, tolbutamide and glibenclamide, agents that increase insulin release, also increased the protein kinase activity; however, leucine, arginine and xylitol, which also stimulate insulin release, were without effect on the kinase activity. 5. Increasing the glucose concentration of the incubation medium from 2 to 20mm had no effect on protein kinase activity. Further, the ability of 3-isobutyl-1-methylxanthine to increase the protein kinase activity was not affected by the glucose concentration of the incubation medium. 6. These results suggest that agents which affect insulin secretion by altering cyclic AMP concentrations may exert their effects on hormone release by altering the activity of a cyclic AMP-dependent protein kinase in islet cells.
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PMID:The mode of action of adenosine 3':5'-cyclic monophosphate in mammalian islets of Langerhans. Effects of insulin secretagogues on islet-cell protein kinase activity. 435 86

1. Rates of insulin release, glucose utilization (measured as [(3)H]water formation from [5-(3)H]glucose) and glucose oxidation (measured as (14)CO(2) formation from [1-(14)C]- or [6-(14)C]-glucose) were determined in mouse pancreatic islets incubated in vitro, and were used to estimate the rate of oxidation of glucose by the pentose cycle pathway under various conditions. Rates of oxidation of [U-(14)C]ribose and [U-(14)C]xylitol were also measured. 2. Insulin secretion was stimulated fivefold when the medium glucose concentration was raised from 3.3 to 16.7mm in the absence of caffeine; in the presence of caffeine (5mm) a similar increase in glucose concentration evoked a much larger (30-fold) increase in insulin release. Glucose utilization was also increased severalfold as the intracellular glucose concentration was raised over this range, particularly between 5 and 11mm, but the rate of oxidation of glucose via the pentose cycle was not increased. 3. Glucosamine (20mm) inhibited glucose-stimulated insulin release and glucose utilization but not glucose metabolism via the pentose cycle. No evidence was obtained for any selective effect on the metabolism of glucose via the pentose cycle of tolbutamide, glibenclamide, dibutyryl 3':5'-cyclic AMP, glucagon, caffeine, theophylline, ouabain, adrenaline, colchicine, mannoheptulose or iodoacetamide. Phenazine methosulphate (5mum) increased pentose-cycle flux but inhibited glucose-stimulated insulin release. 4. No formation of (14)CO(2) from [U-(14)C]ribose could be detected: [U-(14)C]xylitol gave rise to small amounts of (14)CO(2). Ribose and xylitol had no effect on the rate of oxidation of glucose; ribitol and xylitol had no effect on the rate of glucose utilization. Ribose, ribitol and xylitol did not stimulate insulin release under conditions in which glucose produced a large stimulation. 5. It is concluded that in normal mouse islets glucose metabolism via the pentose cycle does not play a primary role in insulin-secretory responses.
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PMID:The pentose cycle and insulin release in mouse pancreatic islets. 456 19

This chapter has covered a wide range of different actions of methylxanthines. They are able to slightly reduce the tone of the lower esophageal sphincter. This is of little concern in the normal individual, but in patients with a reduced initial tone it might lead to heartburn. Coffee intake has been associated with gastritis, but the role of methylxanthines in this effect is obscure. High doses of methylxanthines are also known to be emetic. Practically every function in the intestine can be influenced by high doses of methylxanthines, but the mechanisms involved and the biological significance remain largely obscure. Although in vitro studies with high doses of methylxanthines have demonstrated effects on secretion from salivary glands and exocrine pancreas, there is little evidence that this is clinically important in man. There is also small effects on insulin, glucagon, and TSH secretion. There is a consistent effect on fatty acid mobilization from adipose tissue, which may be of importance, eg, by improving physical performance and by increasing the overall metabolic rate. There is also some evidence for long-term effects on fat depots. By contrast, the effects on carbohydrate metabolism are much less prominent and reproducible, and may to some extent be secondary to altered lipid metabolism. Despite more than a century of effort to elucidate the actions of methylxanthines in man, one of the major conclusions to be drawn is that there is a need for further studies. In view of the newer ideas about the mechanism of action of caffeine and other methylxanthines, careful studies, especially of long-term effects of methylxanthines on several aspects of gastrointestinal function, on calcium homeostasis, on body composition, and on physical performance, would be desirable.
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PMID:Gastrointestinal and metabolic effects of methylxanthines. 608 44

Ligation of the anterior descending coronary artery two-thirds from its origin in the pig was found to precipitate ventricular arrhythmias and fibrillation, starting approximately 20 min post-ligation, which were associated with regional accumulation of myocardial cAMP in the ischaemic area. When the arrhythmias stopped, cyclic AMP levels in the ischaemic zone were decreased. Arrhythmias could then be induced by subepicardial infusion (10 microliter/min) close to the visible edge of ischaemia of cAMP analogues [N6-monobutyryl cAMP, N6,O2'-dibutyryl cAMP (5.10(-2) M each)] or agents which increase the myocardial contents of cAMP. These agents were: isoproterenol (10(-6) M), noradrenaline, adrenaline (10(-5) M each), glucagon, histamine (10(-3) M each), theophylline and caffeine (5.10(-2) M each). Also active were dopamine (10(-3) M), ouabain (10(-5) M) and aconitine (10(-6) M). The arrhythmias induced by infusion of catecholamines were dependent on Ca2+ and were abolished by beta-adrenoceptor blocking agents (pindolol, 10(-6) M) and calcium antagonists (isoptin, D 600, 10(-4) M each). Infusion of 150 mM sodium chloride or 100 mM sodium butyrate did not precipitate arrhythmias. It is concluded that myocardial cAMP may play an important role in the genesis of ventricular arrhythmias in the ischaemic heart, probably by augmenting the slow calcium inward current.
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PMID:Cyclic AMP mediated arrhythmias induced in the ischaemic pig heart. 611 88

A comparative study on the insulinotropic effect of xylitol and glucose was undertaken using isolated rat islets of Langerhans. Xylitol and glucose showed equal insulinotropic effects when compared at equivalent dose levels. Xylitol-induced insulin release was not inhibited by either mannoheptulose or 2-deoxy-D-glucose whereas glucose-induced insulin release was significantly inhibited. Glucagon, caffeine and cyclic-AMP enhanced the insulinotropic effect of glucose and leucine significantly, but insulin release in response to xylitol was not affected. Arginine did not potentiate the insulin releasing effect of xylitol though leucine showed an additive effect. These findings suggest that the mode of action of xylitol may be different from that of glucose.
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PMID:Studies on xylitol-induced insulin secretion in vitro. 638 93

Insulin release from pancreata of human fetuses aged 4 to 9 months and from adult pancreata were studied in monolayer cell culture by static incubation and perifusion technique. Fetal pancreata at the midterm of gestation (4 to 6 months) showed no response of insulin release to glucose. In a case of 9 months-old fetus, in which a small but significant increase of insulin release was observed with glucose (300 mg/ml). Tolbutamide (100 microgram/ml) had no effect on insulin release from all the pancreata of fetuses tested. Caffeine (5 and 10 mM), a phosphodiesterase inhibitor, potentiated insulin release by itself and also induced the glucose-stimulated insulin release from the fetal pancreata in the dose related manner. Glucagon (2 microgram/ml), L-isoproterenol (2 microgram/ml), L-arginine (10 mM) and L-leucine (10 mM) failed to induce any increase of insulin release from fetal pancreata. In the presence of caffeine, the significant increase of insulin release from fetal pancreata was observed with L-leucine, but not with L-arginine. There was no evidence of the maturation of B-cells during the culture periods (4 to 8 days), probably lacking the key steps of stimulus-secretion couplings in relation to adenylate cyclase-cyclic AMP system. By contrast, glucose (100 and 300 mg/100 ml), tolbutamide (100 microgram/ml), L-arginine (10 mM) and caffeine (5 mM) caused a significant increase of insulin release from adult pancreata. Thus, the development of human pancreatic B-cells seems to depend substantially on gestational age, being ready to equip most machinary of insulin release before delivery.
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PMID:Monolayer culture of human fetal and adult pancreas. Static and dynamic studies of insulin release in vitro. 699 62

The effects of two calcium channel blockers, nifedipine and nicardipine, on glucagon-stimulated glycogenolysis in primary cultures of rat hepatocytes were examined in vitro. When nifedipine and nicardipine (10(-7)-10(-6) M) were added to the incubation mixture with various concentrations of glucagon (10(-10)-10(-6) M), these dihydropyridine calcium channel blockers significantly potentiated the glycogenolytic action of glucagon by increasing intracellular cAMP levels. 1-Methyl-3-isobutylxanthine (IBMX), caffeine and papaverine, which is known to inhibit cAMP phosphodiesterase, also potentiated the stimulatory effect of glucagon on the glycogenolysis in a dose-dependent manner. Parallel to the potentiation of glycogenolysis, IBMX also increased the glucagon-stimulated intracellular cAMP levels in a dose-dependent manner. These results suggest that the mechanism of potentiation of the glucagon-stimulated glycogenolysis by nifedipine and nicardipine is related to the known inhibition of cAMP phosphodiesterase by these agents.
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PMID:Nifedipine and nicardipine potentiate glucagon-stimulated glycogenolysis in primary cultures of rat hepatocytes. 750 85


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