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

Effects of phospholipase A2 inhibitor, cyclooxygenase inhibitor and lipoxygenase inhibitor on glucagon secretion induced by the alpha 2-adrenergic agonist clonidine were studied in the isolated perfused rat pancreas. The phospholipase A2 inhibitor mepacrine at 25 and 50 mumol/l significantly inhibited glucagon secretion induced by 0.1 mumol/l clonidine (P less than 0.01, respectively), whereas 5 mumol/l mepacrine did not affect clonidine-induced glucagon secretion. Also, both 100 mumol/l acetylsalicylic acid (cyclooxygenase inhibitor) and 100 mumol/l caffeic acid (lipoxygenase inhibitor) significantly inhibited clonidine-induced glucagon secretion (P less than 0.01, respectively), whereas neither 10 mumol/l acetylsalicylic acid nor 10 mumol/l caffeic acid affected clonidine-induced glucagon secretion. None of the drugs at the tested concentrations affected insulin secretion at a glucose concentration of 5.5 mmol/l. These results suggest that not only cyclooxygenase metabolites but also lipoxygenase metabolites are involved in the stimulation of glucagon secretion mediated through the alpha 2-adrenergic receptors in perfused rat pancreas.
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PMID:Arachidonic acid metabolites and alpha 2-adrenoceptor-mediated glucagon secretion in rats. 133 Apr 64

Arachidonic acid metabolites are involved in a wide spectrum of hepatobiliary physiologic functions and disease. Prostanoids alter hepatic bile flow. Prostaglandins with a C9 ketooxygen stimulate a bicarbonate-rich choleresis and those with a C9 hydroxyloxygen produce a chloride-rich choleresis. Prostaglandin F2 alpha stimulates the release of the potent choleretic glucagon and the stimulatory effect of prostaglandin F2 alpha on bile flow is inhibited by cyclooxygenase inhibitors, suggesting that prostaglandins play a role in the release of choleretic hormones as well as in their action. Prostanoids are involved in gallbladder contraction and water absorption. Prostaglandins produce gallbladder contraction in various species and cause gallbladder relaxation in other species. Prostaglandins also may be mediators of cholecystokinetic hormone action; however, cyclooxygenase inhibitors do not inhibit the effect of cholecystokinetic hormones in all species. Prostanoids alter the normal process of water absorption by gallbladder mucosa and induce net water secretion. The inflamed gallbladder secretes rather than absorbs fluid. The demonstration that prostaglandin E2 inhibits gallbladder fluid absorption has led to subsequent studies that demonstrated that the secretion of fluid into the inflamed gallbladder lumen may be mediated by prostanoids. In cholecystitis, the prostanoids may mediate the distention produced by mucosal fluid secretion and the contraction of the diseased gallbladder. The inflammatory changes produced in various experimental models of cholecystitis can be prevented by cyclooxygenase inhibitors. Cyclooxygenase inhibitors decrease gallbladder prostaglandin formation and are effective in producing relief of the symptoms of gallbladder disease. In experimental cholesterol gallstone formation, prostaglandins are involved in the production of mucin, which acts as a nidus for stone formation, and cyclooxygenase inhibitors prevent the formation of experimental cholesterol gallstones. Prostaglandins have been shown to be cytoprotective in various types of experimental hepatic injury and leukotrienes have been shown to be injurious to hepatocytes and biliary tract tissues. Specific prostanoids and lipoxygenase inhibitors may be valuable in treating patients with various acute hepatic inflammatory disease processes. Continued evaluation of the role of arachidonic acid metabolites in hepatobiliary physiology and disease may lead to important new therapeutic modalities.
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PMID:Arachidonic acid metabolites in hepatobiliary physiology and disease. 266 54

Although the cyclo-oxygenase pathway of arachidonic acid (AA) metabolism inhibits glucose-stimulated insulin release through synthesis of prostaglandins, very little attention has been given to the effects of lipoxygenase pathway products on beta cell function. We have examined the effects of two structurally-dissimilar lipoxygenase inhibitors on insulin release from monolayer-cultured rat islet cells. Both nordihydroguaiaretic acid (NDGA, 20-50 microM) and BW755c (100-250 microM) caused a dose-responsive inhibition of glucose-induced insulin release. This inhibitory effect occurred despite concomitant inhibition of prostaglandin E synthesis. Lipoxygenase inhibitors also impeded cyclic AMP accumulation. Insulin and cyclic AMP release induced by glucagon were also blunted. These studies suggest the hypothesis that AA released in or near the beta cell is metabolized to lipoxygenase product(s) which have feed-forward properties important to glucose- and glucagon-stimulated cyclic nucleotide accumulation and insulin release.
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PMID:A role for the lipoxygenase pathway of arachidonic acid metabolism in glucose- and glucagon-induced insulin secretion. 629 51

We and others had observed that drugs that inhibit the lipoxygenase enzymes inhibit insulin release. The aim of the study was to search for evidence that, among the products of lipoxygenase-activated metabolism of arachidonic acid, leukotrienes (LTs) promote insulin release. Synthetic LTB4, LTC4, LTD4, and LTE4 were administered over 1-min periods to the isolated, perfused rat pancreas in the presence of 5.6 mM glucose. Perfusion effluent levels of insulin and glucagon were measured by radioimmunoassay. LTB4 and LTC4 and, to a lesser extent, LTE4 and LTD4 stimulated insulin release in a dose-related manner, in the concentration range of 10(-11) to 10(-7) M. Only 10(-7) M LTC4 stimulated glucagon release. We conclude that (i) among the arachidonic acid metabolites, LTs are involved in the modulation of secretion of pancreatic islet hormones and (ii) LTs preferentially promote insulin release.
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PMID:Leukotrienes stimulate insulin release from the rat pancreas. 632 12

Metabolism of arachidonic acid (AA) via the cyclooxygenase pathway reduces glucose-stimulated insulin release. However, metabolism of AA by the lipoxygenase pathway and the consequent effects on insulin secretion have not been simultaneously assessed in the endocrine islet. Both dispersed endocrine cell-enriched pancreatic cells of the neonatal rat, as well as intact islets of the adult rat, metabolized [(3)H]AA not only to cyclooxygenase products (prostaglandins E(2), F(2alpha), and prostacyclin) but also to the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). 12-HETE was identified by coelution with authentic tritiated or unlabeled 12-HETE using four high performance liquid chromatographic systems under eight mobile-phase conditions and its identity was confirmed by gas chromatography/mass spectrometry using selected ion monitoring. The predominant effect of exogenous AA (5 mug/ml) was to stimulate insulin release from pancreatic cells grown in monolayer. This effect was concentration- and time-dependent, and reversible. The effect of AA upon insulin release was potentiated by a cyclooxygenase inhibitor (indomethacin) and was prevented by either of two lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid [ETYA] and BW755c). In addition, glucose, as well as two structurally dissimilar agents (the calcium ionophore A23187 and bradykinin), which activate phospholipase(s) and thereby release endogenous AA in several cell systems, also stimulated insulin secretion. The effects of glucose, glucagon, bradykinin and high concentrations of A23187 (5 mug/ml) to augment insulin release were blocked or considerably reduced by lipoxygenase inhibitors. However, a lower concentration of the ionophore (0.25 mug/ml), which did not appear to activate phospholipase, was resistant to blockade. Exogenous 12-HETE (up to 2,000 ng/ml) did not alter glucose-induced insulin release. However, the labile intermediate 12-hydroperoxy-ETE increased insulin release. Furthermore, diethylmaleate (which binds intracellular glutathione and thereby impedes conversion of the lipoxygenase intermediates hydroperoxy-ETE and leukotriene A(4) to HETE and leukotriene C(4), respectively) potentiated the effect of glucose and of exogenous AA. Finally, 5,6-epoxy, 8,11,14-eicosatrienoic acid (a relatively stable epoxide analogue of leukotriene A(4)) as well as two other epoxy-analogues, potentiated glucose-induced insulin release. We conclude that dual pathways of AA metabolism exist in islet endocrine cells and have opposing regulatory effects on the beta cell-an inhibitory cyclooxygenase cascade and a stimulatory lipoxygenase cascade. Labile products of the latter pathway may play a pivotal role in stimulus-secretion coupling in the islet.
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PMID:Lipoxygenase pathway in islet endocrine cells. Oxidative metabolism of arachidonic acid promotes insulin release. 640 44

Hyperglycemic diabetics are prone to unusual or especially severe infections; at the cellular level, diabetic polymorphonuclear leukocytes (PMNs) show defects in several antimicrobial functions. However, the basis for these defects is unknown, and they may not be fully ascribable to hyperglycemia, hypoinsulinemia or acidosis alone. Recently, it has been shown that several important PMN functions may be mediated (at least in part) by metabolites of arachidonic acid synthesized via the lipoxygenase pathway, especially arachidonate hydroperoxides and leukotriene (LT) B4. We speculate that synthesis of these mediators may be deficient in severely hyperglycemic diabetics (fasting plasma glucose greater than 250-300 mg/dl) due to deficiencies of substrate (arachidonic acid) synthesis and release. Such defects might be expected since, in animal studies, severe insulin lack and glucagon excess inhibit the desaturation of precursor fatty acids to arachidonic acid. On the other hand, whereas low levels of lipid peroxides or their derivatives may be required in certain cells for normal function, excessive levels of such compounds also are detrimental to cellular function and could play a role as well in the complications of milder or partially treated diabetics who manifest high basal insulin levels. For example, cells which may be particularly sensitive to an excess of peroxides include islet beta cells, PMNs and possibly vascular endothelial cells (all of which appear to be deficient in glutathione peroxidase). These observations suggest a role for accumulation of lipid peroxides in the impaired insulin secretion, defective PMN function and possibly endothelial death and increased vascular (retinal, endothelial, and renal) permeability of some milder diabetics. The available data are compatible with the speculation that in partially treated or lesser degrees of hyperglycemia, increased arachidonate synthesis and excessive lipid peroxidation may be present. Although it remains to be established that all of the results from experimentally-induced diabetics can be extrapolated to humans, these findings suggest that the cell damage attendant upon peroxide generation might be susceptible to prophylactic treatment with anti-oxidants such as alpha-tocopherol or ascorbic acid. In the more severe or later stages of hyperglycemia, a deficiency of lipoxygenase-derived products may supervene; dietary modifications designed to increase essential fatty acid availability might present a unique ancillary therapeutic approach at this stage of diabetes.
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PMID:Altered arachidonic acid synthesis and lipid peroxidation in diabetes mellitus: possible roles in leukocyte dysfunction and other cellular defects. 642 13

Enhancement of arachidonic acid metabolism results in increased insulin secretion. To determine which pathways of arachidonic acid metabolism were involved in this stimulation, we studied the effects of various inhibitors of arachidonate metabolism on arginine-induced insulin and glucagon secretion in the isolated, perfused rat pancreas. The release of PGE2 from the pancreas was monitored to document the efficacy of the inhibitory drugs. p-Bromophenacyl bromide, a phospholipase A2 inhibitor, diminished PGE2 release and significantly inhibited both the early and late phases of insulin and glucagon release in response to arginine. Flurbiprofen, a specific cyclooxygenase inhibitor, decreased the early phase of insulin release and inhibited both phases of arginine-stimulated glucagon secretion; these decreases were concurrent with a large inhibition of PGE2 release. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, at a dose of 10(-5) M did not affect PGE2 release, inhibited the early phase of insulin release, and did not modify glucagon secretion. The combination of flurbiprofen and nordihydroguaiaretic acid, although the most potent in inhibiting PGE2, lowered only the early phase of insulin and had no effect on glucagon secretion. We conclude that: (1) endogenous cyclooxygenase-derived metabolites of arachidonic acid promote insulin and glucagon release, (2) endogenous lipoxygenase products preferentially stimulate insulin release, and (3) phospholipase A2 activity has an intrinsic modulatory effect on insulin and glucagon secretion.
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PMID:Possible role of endogenous arachidonic acid metabolites in stimulated release of insulin and glucagon from the isolated, perfused rat pancreas. 643 60

Rat pancreatic islets incubated in nutrient medium were used to study the role of endogenous arachidonic acid metabolism in pancreatic hormone secretion. Both glucose and fetal calf serum stimulated radioimmunoassayable PGE2 production and insulin secretion from islets. These effects were abolished by the phospholipase inhibitor p-bromophenacyl bromide or by concurrent inhibition of cyclooxygenase and lipoxygenase by flurbiprofen plus nordihydroguaiaretic acid (NDGA), respectively. Bromophenacyl bromide also inhibited glucagon secretion. When used alone, flurbiprofen caused a significant enhancement of glucose-induced insulin secretion that was attributed to reactive stimulation of lipoxygenase-product formation rather than to selective cyclooxygenase inhibition. NDGA given alone in the presence of stimulatory concentrations of glucose suppressed the normal eight-fold rise in insulin secretion, but caused a marked enhancement in glucagon secretion that could be overcome by simultaneous inclusion of flurbiprofen. We concluded that: (1) Increased metabolism of arachidonic acid in pancreatic islets amplifies the secretion of insulin and glucagon. (2) The lipoxygenase as well as the cyclooxygenase pathways of arachidonate metabolism participate in the amplification of insulin secretion. (3) The observations made in this study are inconclusive with respect to the involvement of the lipoxygenase and cyclooxygenase pathways in glucagon secretion; an inhibitory role for lipoxygenase pathway products is suggested.
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PMID:Role of arachidonate lipoxygenase and cyclooxygenase products in insulin and glucagon secretion from rat pancreatic islets. 643 99

In this study the possible role of Na+ influx, arachidonate mediators and alpha-subunit phosphorylation in the stimulatory response of hepatic Na+/K(+)-ATPase to glucagon was examined. Glucagon stimulation of ouabain-sensitive 86Rb+ uptake in freshly isolated rat hepatocytes reached maximal levels in less than 1 min after hormone addition and was half-maximal (EC50) at a concentration of 2.4( +/- 1.3) x 10(-10) M. Analysis of the K(+)-dependence of this response indicates an effect on the apparent Vmax. for K+ with no significant change in the apparent kappa 0.5. Unlike monensin, glucagon stimulation of Na+/K(+)-ATPase-mediated transport activity was not associated with an increase in 22Na+ influx. This indicates that the stimulation of Na+/K(+)-ATPase by glucagon is not secondary to an increase in Na+ influx. A role for arachidonate mediators in this effect also appears unlikely because neither basal nor glucagon-stimulated ouabain-sensitive 86Rb+ uptake was significantly affected by supramaximal concentrations of cyclo-oxygenase, lipoxygenase, cytochrome p-450 or phospholipase A2 inhibitors. To study the possible role of protein kinase-mediated phosphorylation in the stimulation of ouabain-sensitive 86Rb uptake, hepatocytes were metabolically radiolabelled with [32P]P(i), Glucagon stimulated incorporation of 32P into a 95 kDa phosphoprotein that comigrates with Na+/K(+)-ATPase alpha-subunit immunoreactivity in two-dimensional gel electrophoresis. The alpha-subunit could be immunoprecipitated from detergent-solubilized particulate fractions of hepatocytes using an anti-(rat kidney Na+/K(+)-ATPase) serum. When hepatocytes were metabolically radiolabelled with [32P]P(i), the immunoprecipitated alpha-subunit contained 32P. Glucagon increased the incorporation of 32P into the immunoprecipitated subunit by 197 +/- 21% (n = 6). Similar results were observed with a rabbit anti-peptide serum ('anti-LEAVE' serum) prepared against an amino acid sequence in the alpha-subunit. The EC50 for glucagon-stimulated phosphorylation of the alpha-subunit (approximately 1 x 10(-10) M) was very close to that for glucagon stimulation of ouabain-sensitive 86Rb+ uptake. In conclusion, it appears that glucagon stimulation of hepatic Na+/K(+)-ATPase-mediated transport activity is not secondary to increases in Na+ influx or changes in the levels of an arachidonate mediator. The data provide support for the hypothesis that glucagon stimulation of Na(+)-pump activity in hepatocytes may be related to protein kinase-mediated changes in the phosphorylation state of the alpha-subunit.
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PMID:Glucagon stimulation of hepatic Na(+)-pump activity and alpha-subunit phosphorylation in rat hepatocytes. 861 Nov 84

Recent studies have shown that glucagon is processed by cardiac cells into its COOH-terminal (19-29) fragment, mini-glucagon, and that this metabolite is an essential component of the contractile positive inotropic effect of glucagon (Sauvadet, A., Rohn, T., Pecker, F. and Pavoine, C. (1996) Circ. Res. 78, 102-109). We now show that mini-glucagon triggers arachidonic acid (AA) release from [3H]AA-loaded embryonic chick ventricular myocytes via the activation of a phospholipase A2 sensitive to submicromolar Ca2+ concentrations. The phospholipase A2 inhibitor, AACOCF3, prevented mini-glucagon-induced [45Ca2+] accumulation into the sarcoplasmic reticulum, but inhibitors of lipoxygenase, cyclooxygenase, or epoxygenase pathways were ineffective. AA applied exogenously, at 0. 3 microM, reproduced the effects of mini-glucagon on Ca2+ homeostasis and contraction. Thus AA: (i) caused [45Ca2+] accumulation into a sarcoplasmic reticulum compartment sensitive to caffeine; 2) potentiated caffeine-induced Ca2+ mobilization from cells loaded with Fura-2; 3) acted synergistically with glucagon or cAMP to increase both the amplitude of Ca2+ transients and contraction of electrically stimulated cells. AA action was dose-dependent and specific since it was mimicked by its non-hydrolyzable analog 5,8,11,14-eicosatetraynoic acid but not reproduced by other lipids such as, arachidic acid, linolenic acid, cis-5,8,11,14,17-eicosapentaenoic acid, cis-4,7,10,13,16, 19-docosahexaenoic acid, or arachidonyl-CoA, even in the micromolar range. We conclude that AA drives mini-glucagon action in the heart and that the positive inotropic effect of glucagon on heart contraction relies on both second messengers, cAMP and AA.
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PMID:Arachidonic acid drives mini-glucagon action in cardiac cells. 913 91


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