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)

Endocrine L-cells of the distal intestine synthesize both peptide YY (PYY) and proglucagon-derived peptides (PGDPs), whose release has been reported to be either parallel or selective. Here we compare the release mechanisms of PYY, glucagon-like peptide-1 (GLP-1), and oxyntomodulin-like immunoreactivity (OLI) in vivo. Anaesthetized rats were intraduodenally (ID) given either a mixed semi-liquid meal or oleic acid, or they received oleic acid or short chain fatty acids (SCFA) intracolonically (IC). The ID meal released the three peptides with a similar time-course (peak at 30 min); ID oleic acid produced a progressive release of PYY and OLI, while GLP-1 release was less. IC oleic acid or SCFA released smaller (but significant) amounts of PYY but no OLI or GLP-1. Hexamethonium inhibited most of the response to the ID meal and ID oleic acid, but did not change the PYY response to IC oleic acid. NG-nitro-l-arginine methyl ester (l-NAME, a nitric oxide synthase inhibitor) inhibited meal-induced PYY release and left OLI and GLP-1 unaffected. BW10 (a gastrin-releasing peptide antagonist) had no effect on the meal-induced release of either peptide. These results suggest a parallel initial release of PYY, OLI and GLP-1 after the ID meal, or oleic acid, by an indirect mechanism triggered in the proximal bowel, using nicotinic synapses, and involving nitric oxide release for PYY and an unknown mediator for PGDPs. For PYY there is a later phase of peptide release, probably induced by direct contact between nutrients and colonic L-cells.
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PMID:Comparison of the postprandial release of peptide YY and proglucagon-derived peptides in the rat. 1039 59

We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N(G)-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0.05 or 0.5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucose-stimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucose-induced insulin release and (45)Ca(2+) efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in (45)Ca(2+) efflux. In islets depolarized with 30 mM K(+) in the presence of the K(+)(ATP) channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucose-stimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca(2+) fluxes and is exerted mainly independently of membrane depolarization events.
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PMID:Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice. 1049 5

The role of nitric oxide (NO) in mediating pancreatic endocrine responses to moderate hypoglycaemia has been investigated in conscious unrestrained calves. The synthesis of endogenous NO was inhibited by the administration of N-nitro-L-arginine methyl ester (L-NAME; 100 mg kg-1 I.A.), while sodium nitroprusside was infused continuously (2-4 microg min-1 kg-1 I.V.) to mimic the tonic production of NO. This effectively abolished the rise in plasma pancreatic polypeptide (PP) concentration during moderate hypoglycaemia (0.7 nmol kg-1 insulin I.V.) and significantly reduced the response to more intense hypoglycaemia (2.0 nmol kg-1 insulin I. V.). In contrast, the glucagon response was not significantly affected in either group, although consistently higher plasma glucagon values were obtained in response to the higher dose of insulin following the administration of L-NAME. It is concluded that, in the absence of L-NAME, production of NO contributes to the PP response, but not the glucagon response to hypoglycaemia in this species under physiological conditions.
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PMID:The role of nitric oxide in mediating pancreatic endocrine responses to insulin-induced hypoglycaemia in the conscious calf. 1056 7

Islet production of nitric oxide (NO) and CO in relation to islet hormone secretion was investigated in mice given the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in their drinking water. In these mice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and immunoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in L-NAME-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after L-NAME drinking. Glucagon secretion was increased in vitro. Control islets incubated with different NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimulated insulin release also from islets of L-NAME-drinking mice. In contrast, glucagon release was suppressed. In islets from L-NAME-drinking mice, cyclic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusion, chronic NOS blockade evoked iNOS-derived NO production in pancreatic islets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the islet cAMP and HO-CO systems.
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PMID:Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release. 1089 28

Despite the suppression of glucagon release, an adaptive response aimed at maintaining vasodilatation after octreotide treatment may exist in portal hypertension. The present study was undertaken to evaluate the possible interaction between endothelium and non-endothelium-derived vasodilators after 1-wk octreotide administration in cirrhotic rats. Rats were allocated to receive either vehicle or octreotide (30 or 100 microg/kg every 12 h subcutaneously). Hemodynamic values, plasma glucagon levels, endothelium-related vasodilatory activities, and aortic endothelial nitric oxide synthase (eNOS) expression were determined after treatment. Octreotide administration decreased plasma glucagon and increased serum 6-keto-PGF(1 alpha) and NOx levels without affecting the hemodynamic values. In cirrhotic rats receiving octreotide, there was a blunt response to either L-NAME or indomethacin administration alone, but this blunt pressor response disappeared after simultaneous administration of the two drugs. Additionally, an increased aortic eNOS expression was observed in cirrhotic rats receiving 1-wk octreotide. It is concluded that 1-wk octreotide treatment did not correct the hemodynamic derangement in cirrhotic rats. The enhanced endothelium-related vasodilatory activity was noted after octreotide treatment that overcame the octreotide-induced hemodynamic effects in portal hypertension.
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PMID:Adaptive vasodilatory response after octreotide treatment. 1140 62

We have examined the expression and activity of inducible nitric oxide synthase (iNOS) and the activity of neuronal constitutive NOS (ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/protein kinase A (cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation (20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction in ncNOS activity and increased insulin release. The GLP-1-induced suppression of glucose-stimulated iNOS activity and expression and its stimulation of insulin release is, at least in part, PKA dependent, since the PKA inhibitor H-89 reverses the effects of GLP-1. These observations have been confirmed by confocal microscopy showing the glucose-stimulated expression of iNOS, its suppression by GLP-1 and its reversion by H-89 in beta-cells. We have also found that the NO scavenger cPTIO and the NOS inhibitor L-NAME potentiate the insulin response to glucose, again suggesting that NO is a negative modulator of glucose-stimulated insulin release. We conclude that the induction of iNOS and the increase in ncNOS activity caused by glucose in rat islets is suppressed by the cyclic AMP/PKA system. The inhibition of iNOS expression by the GLP-1/cyclic AMP/PKA pathway might possibly be of therapeutic potential in NO-mediated beta-cell dysfunction and destruction.
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PMID:Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway. 1555 23

The primary aims of this study were to evaluate the effects of the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) on gastric emptying (GE) of, and the blood pressure (BP), glycemic, insulin, and incretin responses to, oral glucose in older subjects. Eight healthy subjects (4 males and 4 females, aged 70.9 +/- 1.3 yr) were studied on two separate days, in double-blind, randomized order. Subjects received an intravenous infusion of either l-NAME (180 mug.kg(-1).h(-1)) or saline (0.9%) at a rate of 3 ml/min for 150 min. Thirty minutes after the commencement of the infusion (0 min), subjects consumed a 300-ml drink containing 50 g glucose labeled with 20 MBq (99m)Tc-sulfur colloid, while sitting in front of a gamma camera. GE, BP (systolic and diastolic), heart rate (HR), blood glucose, plasma insulin, and incretin hormones, glucose-dependant insulinotropic-polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), were measured. l-NAME had no effect on GE, GIP, and GLP-1. Between -30 and 0 min l-NAME had no effect on BP or HR. After the drink (0-60 min), systolic and diastolic BP fell (P < 0.05) and HR increased (P < 0.01) during saline; these effects were attenuated (P < 0.001) by l-NAME. Blood glucose levels between 90 and 150 min were higher (P < 0.001) and plasma insulin were between 15 and 150 min less (P < 0.001) after l-NAME. The fall in BP, increase in HR, and stimulation of insulin secretion by oral glucose in older subjects were mediated by NO mechanisms by an effect unrelated to GE or changes in incretin hormones.
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PMID:Role of nitric oxide mechanisms in gastric emptying of, and the blood pressure and glycemic responses to, oral glucose in healthy older subjects. 1569 67

In view of our previous data, showing that ghrelin and nitric oxide (NO) display apparently parallel effects on insulin secretion (inhibitory) and glucagon secretion (stimulatory), we have now investigated the effect of ghrelin on islet hormone secretion in relation to its effect on NO synthase (NOS) isoenzymes in isolated rat pancreatic islets. Dose-response studies revealed that ghrelin at concentrations of 0.01-1 micromol l-1 inhibited insulin secretion stimulated by 8.3 mmol l-1 glucose, while ghrelin at concentrations lower than the physiological range (0.01 pmol l-1 to 1 nmol l-1) were without effect. In contrast, glucagon secretion was stimulated by 1.0 nmol l-1 to 1 micromol l-1 ghrelin. These effects of ghrelin on insulin and glucagon secretion were accompanied by increased NO production through activation of neuronal constitutive NOS (ncNOS). Ghrelin had no appreciable effect on the activity of inducible NOS (iNOS) in the islets. Addition of an NO scavenger (cPTIO) or the NOS inhibitor L-NAME to the incubation medium prevented the effects of ghrelin on hormone secretion from isolated islets. The present results confirm our previous data showing that ghrelin inhibits insulin and stimulates glucagon secretion from pancreatic islets of the mouse and we now show similar effects in rat islets. The effects of ghrelin were accompanied by an increased rate of NO production. Conceivably, ncNOS activation partly accounts for to the inhibitory effect of ghrelin on insulin secretion and the stimulatory effect of ghrelin on glucagon secretion.
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PMID:Ghrelin activates neuronal constitutive nitric oxide synthase in pancreatic islet cells while inhibiting insulin release and stimulating glucagon release. 1572 87

The aim of this study was to investigate the effects of intracerebroventricularly injected glucagon-like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and to elucidate the mechanisms involved. Absolute ethanol was administered through an orogastric cannula 5 min before GLP-1 (1 microg/10 microl) injection. One hour later, the rats were decapitated, their stomachs were removed and scored for mucosal damage. GLP-1 inhibited the ethanol-induced gastric mucosal damage by 92%. Centrally injected atropine sulphate, a muscarinic receptor antagonist (5 microg/10 microl), prevented the gastroprotective effect of GLP-1, while mecamylamine, a nicotinic receptor antagonist (25 microg/10 microl), was ineffective. Peripherally injected atropine methyl nitrate (1 mg/kg) did not change the effect of GLP-1, but mecamylamine (5 mg/kg) blocked it. Cysteamine, a somatostatin depletor (280 mg/kg, s.c.), did not affect the protective activity of GLP-1, while inhibition of nitric oxide (NO) synthesis by L-NAME (3 mg/kg, i.v.) significantly abolished the protective effect of GLP-1 on ethanol-induced gastric mucosal lesions. We conclude that central muscarinic and peripheral nicotinic cholinergic receptors and NO, but not somatostatin, contribute to the protective effect of intracerebroventricularly injected GLP-1 on ethanol-induced gastric mucosal damage.
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PMID:Investigation of the mechanisms involved in the central effects of glucagon-like peptide-1 on ethanol-induced gastric mucosal lesions. 1572 88

It has been shown that glucagon like peptide-1 (GLP-1) acts on the central nervous system (CNS), in addition to its peripheral actions. Central administration of glucagon like peptide-1 (GLP-1) delays liquid gastric emptying via non-adrenergic, non-cholinergic neurons in rats. However, it remains unclear how central GLP-1 delays solid gastric emptying in rats. GLP-1 receptors at the CNS mediates the endocrine and anxiety responses to psychogenic and interoceptive stress. Corticotropin-releasing factor (CRF) is also known as a stress-related peptide, which delays gastric emptying of liquid and solid food via the autonomic nervous system. We have recently showed that central CRF delays solid gastric emptying via sympathetic pathways in rats. However, it remains unknown how central GLP-1 and CRF interact in mediating the inhibitory effect on solid gastric emptying. After a 24 h-fasting, GLP-1 was administered by intracisternal (ic)-injection immediately after the solid meal ingestion. Ninety minutes after the peptide injection, gastric contents were measured. Ic-injection of GLP-1 (30-3000 pmol) dose-dependently inhibited solid gastric emptying. Ic-injection of GLP-1 (3000 pmol)-induced delay of gastric emptying was partially antagonized by celiac ganglionectomy but not by atropine or N(G)-nitro-l-arginine methyl ester (L-NAME). Ic-injection of a CRF antagonist, astressin (2.8 nmol), partially antagonized GLP-1-induced delay of solid gastric emptying. These results indicate that central CRF and peripheral sympathetic pathway are, at least in part, involved in mediating central GLP-1-induced delay of solid gastric emptying in rats.
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PMID:Central glucagon like peptide-1 delays solid gastric emptying via central CRF and peripheral sympathetic pathway in rats. 1688

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