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

Nitric oxide (NO) produced by islet constitutive NO synthase (cNOS) is a putative modulator of islet hormone secretion. We show here for the first time that the release of insulin induced by L-arginine or L-homoarginine is inhibited and that of glucagon stimulated in parallel with the rate of islet NO production. It was found that L-homoarginine was approximately 25-30% less potent than L-arginine as an insulin secretagogue but equally potent as a glucagon secretagogue. Biochemical determination of islet cNOS activity revealed that the NO production with L-homoarginine as substrate was only approximately 40% of that of L-arginine. Selective inhibition of islet cNOS potentiated insulin release during amino acid stimulation. Moreover, inhibition of cNOS suppressed glucagon release, more so with L-arginine than with L-homoarginine as secretagogue, reflecting the relative rates of their NO production. In K+-depolarized islets, inhibition of cNOS enhanced the insulin response to L-arginine by 50% and that to L-homoarginine by 23%, largely corresponding to their relative NO production. The intracellular NO donor hydroxylamine dose dependently inhibited insulin but increased glucagon secretion in K+-depolarized and amino acid-stimulated islets. We conclude that both amino acids have a dual action on insulin release, since their stimulatory effects are reduced in parallel with the rates of their NO production. Furthermore, the greater NO production induced by L-arginine relative to L-homoarginine corresponds to NO-mediated increases in glucagon release. These NO effects are mainly exerted independently of membrane depolarization events.
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PMID:Arginine-induced insulin release is decreased and glucagon increased in parallel with islet NO production. 972 18

We examined the relation between the islet NO system and islet hormone secretion induced by either the non-glucose nutrient alpha-ketoisocaproic acid (KIC) or, in some experiments, glucose. KIC dose dependently stimulated insulin but inhibited glucagon secretion. In a medium devoid of any nutrient, the NO synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) induced an increase in basal insulin release but a decrease in glucagon release. These effects were evident also in K+-depolarised islets. KIC-induced insulin release was increased by L-NAME. This increase was abolished in K+-depolarised islets. In contrast, glucose- induced insulin release was potentiated by L-NAME after K+ depolarisation. The intracellular NO donor hydroxylamine dose dependently inhibited KIC-stimulated insulin release and reversed KIC-induced suppression of glucagon release. Our data suggest that islet hormone secretion in a medium devoid of nutrients is greatly affected by the islet NO system, whereas KIC-induced secretion is little affected. Glucose-induced insulin release, however, is accompanied by increased NOS activity, the NOS-activating signal being derived from the glycolytic-pentose shunt part of glucose metabolism. The observed NO effects on islet hormone release can proceed independently of membrane-depolarisation events.
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PMID:Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses. 979 46

We have investigated the putative role of nitric oxide (NO) as a modular of islet hormone release, when stimulated by the muscarinic receptor agonist phospholipase C activator, carbachol, with special regard to whether the IP3-Ca2+ or the diacylglycerol-protein kinase C messenger systems might be involved. It was observed that the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methylester (L-NAME) markedly potentiated insulin release and modestly inhibited glucagon release induced by carbachol. Similarly, insulin release induced by the phorbol ester TPA (protein kinase C activator) was markedly potentiated. Glucagon release, however, was unaffected. Dynamic perifusion experiments with 45C2+ -loaded islets revealed that the inhibitory action of L-NAME on carbachol-stimulated NO-production was reflected in a rapid and sustained increase in insulin secretion above carbachol controls, whereas the 45Ca2+ -efflux pattern was similar in both groups with the exception of a slight elevation of 45C2+ in the L-NAME-carbachol group during the latter part of the perifusion. No difference in either insulin release or 45Ca2+ -efflux pattern between the carbachol group and L-NAME-carbachol group was seen in another series of experiments with identical design but performed in the absence of extracellular Ca2+. However, it should be noted that in the absence of extracellular Ca2+ both 45Ca2+ -efflux and, especially, insulin release were greatly reduced in comparison with experiments in normal Ca2+. Further, in the presence of diazoxide, a potent K+ ATP-channel opener, plus a depolarizing concentration of K+ the NOS-inhibitor L-NAME still markedly potentiated carbachol-induced insulin release and inhibited glucagon release. The enantiomer D-NAME, which is devoid of NOS-inhibitory properties, did not affect carbachol-induced hormone release. TPA-induced hormone release in depolarized islets was not affected by either L-NAME or D-NAME. The pharmacological intracellular NO donor hydroxylamine dose-dependently inhibited insulin release stimulated by TPA. Furthermore, a series of perifusion experiments revealed that hydroxylamine greatly inhibited carbachol-induced insulin release without affecting the 45Ca2+ -efflux pattern. In summary, our results suggest that the inhibitory effect of NO on carbachol-induced insulin release is not to any significant extent exerted on the IP3-Ca2+ messenger system but rather through S-nitrosylation of critical thiol-residues in protein kinase C and/or other secretion-regulatory thiol groups. In contrast, the stimulating action of NO on carbachol-induced glucagon release was, at least partially, connected to the IP3-Ca2+ messenger system. The main effects of NO on both insulin and glucagon release induced by carbachol were apparently exerted independently of membrane depolarization events.
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PMID:Evidence for nitric oxide mediated effects on islet hormone secretory phospholipase C signal transduction mechanisms. 987 33

Diabetes is associated with endothelial dysfunction and increased risk of hypertension, cardiovascular disease, and renal complications. Earlier studies have revealed that hyperglycemia impairs nitric oxide (NO) production and diabetes causes endothelial dysfunction in humans and experimental animals. This study was designed to test the effects of altered concentrations of glucose, insulin, and glucagon, the principal variables in types I and II diabetes, on NO production and endothelial NO synthase (eNOS) expression in cultured human coronary endothelial cells. Cultured endothelial cells were incubated in the presence of glucose at either normal (5.6 mM) or high (25 mM) concentrations for 7 days. The rates of basal and bradykinin-stimulated NO production (nitrate + nitrite) and eNOS protein expression (Western blot) were then determined at the basal condition and in the presence of insulin (10(-8) and 10(-7) M), glucagon (10(-8) and 10(-7) M), or both. Incubation with a high-glucose concentration for 7 days significantly downregulated, whereas insulin significantly upregulated, basal and bradykinin-stimulated NO production and eNOS expression in cultured endothelial cells. The stimulatory action of insulin was mitigated by high-glucose concentration and abolished by cotreatment of cells with glucagon. Thus hyperglycemia, insulinopenia, and hyperglucagonemia, which frequently coexist in diabetes, can work in concert to suppress NO production by human coronary artery endothelial cells.
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PMID:Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. 1089 17

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

It has been reported that nitric oxide (NO) is a positive modulator of glucagon release. The involvement of cyclic guanosine 3',5'-monophosphate (cGMP) in NO-induced glucagon secretion and the possible role of NO in glucagon release induced by l-arginine were investigated in mouse clonal alpha-cell line clone 6 (alpha TC6) cells, which predominantly secrete glucagon. NOC12, an NO donor, elicited an increase in glucagon release from alpha Tc6 cells in perifusion and static incubation. An inhibitor of cGMP-dependent protein kinase inhibited NOC12-induced glucagon release. NOC12 (1 mmol/L) also increased the cellular level of cGMP. In addition, a permeable cGMP agonist increased glucagon release. l-arginine (15 mmol/L) increased perifusate concentrations of glucagon and nitrite in alpha Tc6 cells, which were inhibited by N(G)-nitro-L-arginine methyl ester. NO synthase (NOS) activity was shown in alpha Tc6 cells by l-citrulline formation assay. Our present findings suggest that NO plays a stimulating role in glucagon release from the alpha cells, and that a cGMP-dependent pathway is involved in NO action. These findings also provide further evidence that l-arginine might play a stimulating role in regulating glucagon secretion, at least partly, through generation of NO in the islets.
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PMID:Involvement of cyclic guanosine 3',5'-monophosphate in nitric oxide-induced glucagon secretion from pancreatic alpha cells. 1139 48

This study examined the effect of nitric oxide (NO) on the cytosolic free Ca(2+) concentration ([Ca(2+)](c)) of alpha-cells isolated from rat pancreatic islets. When extracellular glucose was reduced from 7 to 0 mM, about half of the alpha-cells displayed [Ca(2+)](c) oscillations. Nicardipine, a Ca(2+) channel blocker, terminated the oscillations, while thapsigargine, an inhibitor of Ca(2+)-ATPase on the endoplasmic reticulum, did not affect them, suggesting that the [Ca(2+)](c) oscillations were produced by periodic Ca(2+) influx via L-type voltage-operated Ca(2+) channels. NOC 7, an NO donor, did not cause any changes in [Ca(2+)](c) at 7 mM glucose, but reduced [Ca(2+)](c) or terminated [Ca(2+)](c) oscillations at 0 or 2.8 mM glucose. A similar inhibitory effect on [Ca(2+)](c) of alpha-cells was caused by 8-bromo-cGMP. When the [Ca(2+)](c) of alpha-cells was elevated by L-arginine in the presence of N(omega)-nitro-L-arginine, an NO synthase inhibitor, the subsequent application of NOC 7 and 8-bromo-cGMP reduced [Ca(2+)](c). As there is a direct relationship between [Ca(2+)](c) and glucagon release, these results suggest that the NO-cGMP system in rat pancreatic islets reduces glucagon release by suppressing [Ca(2+)](c) responses in alpha-cells.
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PMID:Inhibition by nitric oxide of Ca(2+) responses in rat pancreatic alpha-cells. 1202 Jul 50

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

Glucagon and alpha-adrenergic-induced glycogenolysis is realized via the agonist/adenylyl cyclase/cAMP/protein kinase signaling pathway or via the activation of phosphorylase kinase by the mobilized calcium that supports the inhibition of glycogen synthase, respectively. The role of nitric oxide (NO) in this process has not been extensively studied. The present work was directed to the question whether NO is produced during glucagon-induced glycogenolysis in rat hepatocyte in a similar way like alpha-adrenoceptor stimulation. Glycogen-rich hepatocyte cultures were used. NO production (NO(2)(-)) was assessed under the influence of glucagon, dibutyryl cyclic AMP (db-cAMP), forskolin, the nitric oxide synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine, and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). Inducible NOS (iNOS) mRNA was examined by reverse transcription-polymerase chain reaction. Glycogenolysis was followed up by estimation of medium glucose levels. The amount of glucose and NO(2)(-) released by glycogen-rich hepatocytes was increased as a result of glucagon, db-cAMP, forskolin and SNAP treatments. iNOS gene expression was upregulated by glucagon. Glycogenolysis that occurs through glucagon receptor stimulation involves NO production downstream of transduction pathways through an isoform of NO synthase. The present and previous studies document possible involvement of NO signaling in glycogenolytic response to glucagon and adrenergic agonists in hepatocytes.
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PMID:Glucose release as a response to glucagon in rat hepatocyte culture: involvement of NO signaling. 1770 67

Nitric oxide (NO) is known as an orexigenic factor in the brain of mammals and mediates the feeding-stimulatory effect of other factors such as neuropeptide Y (NPY). In neonatal chicks, however, we recently reported that NO might have an anorexigenic effect and suggested that the feeding-regulatory mechanism in chicks might be different from that in mammals regarding NO. In the present study, we investigated the involvement of NO in the effect of other orexigenic and anorexigenic factors in neonatal chicks. Intracerebroventricular co-injection of N(G)-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, did not affect NPY- and prolactin-releasing peptide-induced feeding behavior. On the other hand, the co-injection of l-NAME significantly attenuated the anorexigenic effect of corticotropin-releasing hormone (CRH). The anorexigenic effects of glucagon-like peptide-1, alpha-melanocyte-stimulating hormone and ghrelin were not affected by the l-NAME treatment. These results suggest that NO might mediate the anorexigenic effect of CRH in the brain of neonatal chicks.
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PMID:Nitric oxide synthase inhibitor attenuates the anorexigenic effect of corticotropin-releasing hormone in neonatal chicks. 1828 Jul 62


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