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)

Tumor necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6) are central mediators of the inflammatory response. We investigated the modulation of these cytokines by hormones in vitro. Murine adherent peritoneal exudate cells (PEC) were exposed to various concentrations of hormones followed by lipopolysaccharide (LPS, 10 micrograms/ml). TNF, IL-1 and IL-6 production were assessed by bioassays, enzyme-linked immunosorbent assays (ELISA) or Western blot, and specific RNA transcripts by Northern blot. Hydrocortisone in concentrations as low as 10 ng/ml had dramatic inhibitory effects on supernatant levels of TNF and IL-1 and on TNF, IL-1 and IL-6 transcript number. Supernatant levels of IL-6 were only slightly diminished by hydrocortisone. Adrenocorticotrophic hormone (ACTH) and insulin increased supernatant levels of TNF bioactivity in response to LPS, while each decreased available TNF-alpha gene transcripts. Thus TNF protein production was affected at a post-transcriptional level. ACTH and insulin increased supernatant levels of IL-6 produced in response to LPS without altering available transcripts. Corticotrophin-releasing factor (CRF), epinephrine and glucagon had no effect on supernatant levels of cytokine. Thus, physiological and pharmacological concentrations of hydrocortisone had dramatic inhibitory effects on the supernatant levels of TNF and IL-1, and on the number of available TNF, IL-1 and IL-6 transcripts in PEC exposed to LPS, but had minimal effects on supernatant levels of IL-6 bioactivity. This hydrocortisone action may be a specific negative feedback system for IL-1 and TNF, with relative sparing of IL-6.
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PMID:Hormonal regulation of inflammatory cell cytokine transcript and bioactivity production in response to endotoxin. 131 63

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.
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PMID:Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. 250 83

Alterations of the specific enzymes located in the cell membranes might promote changes of the cyclic nucleotides ratio which is regulatory in growth stimulation of hepatocytes. Bacterial toxins, hormones and drugs affecting cyclic nucleotides system can interfere with this process in liver diseases. The Authors have determined hepatic cAMP concentrations by means of cAMP radioimmunoassay, in vivo, in rats treated with cholera toxin (CT), E. coli endotoxin (LPS) and glucagon. CT (0.15 mg i.v./rat/4th hr) and glucagon (0.8 mg/i.v./10') (significantly p less than 0.01) increase liver cAMP from 1.72 n mol/g wet wt (controls) to 2.62 and 4.13 n mol/g wet/wt respectively. Serum transaminases levels were unmodified. LPS (1.5 mg/hg/i.v./3th hr) significantly (p less than 0.01) raises serum transaminase activity while liver cAMP was not affected. Kinetics study however show that LPS, at lower dosage (0.5 mg/hg i.v.) enhances liver cAMP before cytotoxicity is observed.
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PMID:Bacterial toxins and glucagon in liver cAMP regulation: a physiopathological role in liver diseases? 626 94

The control of metallothionein (MT) synthesis was investigated in freshly prepared rat hepatocytes in experiments of short-term duration. Viability and metabolic function were maintained in incubations of 6-h duration. MT synthesis was measurable in hepatocytes from fed rats at Zn concentrations down to 1 microM. Zn and dexamethasone induced concentration-dependent increases in the synthesis of MT with maximal increases above the 5-h control of 3.2- and 2.5-fold, respectively. Zn induction of MT was first measurable at 2 h and was inhibited by actinomycin C. Although initial (0 h) MT concentrations in hepatocytes from fasted rats were double those from fed rats, after 6-h incubation in the presence of 50 microM Zn, the fasted rat hepatocytes showed only half the MT concentrations of the fed rat hepatocytes. Glucagon and interleukin-6 (IL-6) were less effective inducers and increased MT synthesis by 28 and 17%, respectively. IL-6 (100 U/mL) was found to have an additive effect on MT synthesis above that of Zn alone (1-50 microM) or Zn plus dexamethasone (1 microM). A supernatant from LPS-stimulated macrophages increased MT synthesis by 40%. The basal MT synthesis was not increased by either tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1). All incubations were carried out in the presence of RPMI 1640 medium with Hepes (20 mM), bicarbonate (24 mM), and fatty acid-free albumin (FAFA; 0.5% w/v). MT synthesis was also seen using Krebs bicarbonate buffer with glucose (10 mM), Hepes (20 mM), and FAFA (0.5% w/v), and although the level of MT synthesis was less than in RPMI, the increases in concentrations of MT at 5 h were 225, 139, 36 and 20% for Zn, dexamethasone, glucagon, and control, respectively. It is concluded that MT synthesis occurs in freshly prepared hepatocytes and that these cells are responsive to some of the established inducers of MT. This system enables the study of MT synthesis in individual rats in various metabolic and pathological states.
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PMID:Metallothionein induction in freshly isolated rat hepatocytes. 768 80

The objective of the present studies was to determine whether the existence of functional glucagon receptors could be established on lympoid cells. The glucagon receptor, which positively regulates adenylate cyclase, is a member of the superfamily of seven transmembrane domain G-protein coupled receptors. Previously reported specific binding with [125I]-glucagon to a variety of lymphoid and myeloid cell preparations suggests that glucagon receptors are expressed within the immune system. In the present study, Northern analysis of polyA RNA isolated from primary mouse and rat derived lymphoid tissues and lymphoid cell lines EL-4.IL-2, Jurkat E6-1, CH12LX, and BCL1-3B3 cells were probed with a 32P-labeled human hepatic glucagon receptor. Mouse spleen and thymus, rat spleen, and the B cell line, CH12LX, all possessed a single 1.5 kb fragment (BCL1-3B3, 1.4 kb) which hybridized to the glucagon receptor cDNA probe, as compared to mouse liver which exhibited a 2.8 kb fragment. EL-4.IL-2 and Jurkat E6-1 cells possessed a 3.7 kb fragment with an additional 2.75 kb band present in Jurkat E6-1 cells. Treatment of mouse splenocytes and T- and B-lymphoma cells with glucagon (0 - 100 nM) produced a dose-dependent enhancement in intracellular cAMP which was maximal at 5 min post treatment followed by a gradual decline. Direct addition of glucagon to spleen cell cultures over a broad concentration range produced no effect on either lymphoproliferation following stimulation with anti-CD3 mAb, or LPS nor on the antibody forming cell (AFC) response to sRBC. Conversely, glucagon effectively reversed the suppression of the sRBC AFC response produced by delta9-tetrahydocannabinol (delta9-THC), and partially reversed the suppression produced by 2',3'-dideoxyadenosine, both of which are potent inhibitors of adenylate cyclase. These studies confirm the expression of functional glucagon receptors on lymphoid cells.
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PMID:Expression of functional glucagon receptors on lymphoid cells. 863 21

This study tested the hypothesis that systemic stressors in rats activate glucagon-like peptide-1 (GLP-1)-immunoreactive neurons in the caudal brain stem, including those that project to the paraventricular nucleus of the hypothalamus (PVN). Neural tracer was microinjected into the PVN to retrogradely label brain stem neurons. Seven to ten days later, rats were injected with lithium chloride (LiCl; 50 mg/kg). Additional non-tracer-injected rats were treated with lipopolysaccharide (LPS; 100 microgram/kg) or CCK (100 microgram/kg) or were allowed to consume a very large meal. Rats were killed 90-120 min after drug treatment or 30 min after the meal. Brains were processed for immunocytochemical localization of c-Fos (a marker of neuronal activation), GLP-1, and, when appropriate, neural tracer. The majority of GLP-1 neurons were activated to express c-Fos after LiCl, LPS, or CCK treatment, including (in LiCl-treated rats) those projecting to the PVN. In contrast, GLP-1 neurons rarely expressed c-Fos after ingestion of a large meal, despite prominent activation of other brain stem neurons. These results suggest that GLP-1 neurons are uniquely activated in situations of interoceptive stress, and may participate in adaptive hypothalamic stress responses.
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PMID:Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. 1044 67

The mechanisms responsible for the glycemic changes associated with endotoxic shock are not fully understood, but are known to involve the ability of the liver to produce glucose. The purpose of the present study was to determine whether endotoxin (LPS) influences the expression and activity of glucose-6-phosphatase (Glu-6-Pase) during the early hyperglycemic phase and the later hypoglycemic phase. Rats were injected with a relatively large dose of LPS (20 mg/kg) or saline (control), and sacrificed at 1 or 5 h post-injection. Both the plasma glucose concentration and glucose production were elevated 1 h post-LPS (2-fold) and both decreased at 5 h postinjection (50%). Compared to time-matched control values, hepatic glucose-6-phosphate and fructose-6-phosphate levels were significantly decreased at both 1 and 5 h. Hepatic Glu-6-Pase activity and mRNA levels were moderately increased, 1 h after injection of LPS. At 5 h, an 88% decrease in mRNA abundance for Glu-6-Pase was associated with a 30% decrease in activity of this enzyme. Plasma insulin concentrations were not different 1 h after LPS and were elevated 2-fold from control values at 5 h. Circulating levels of glucagon and corticosterone were elevated at both time points following LPS. Our data indicate that the LPS-induced hypoglycemia and reduction in hepatic glucose production were accompanied by a depression in Glu-6-Pase activity and gene expression.
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PMID:Endotoxin-induced alterations in hepatic glucose-6-phosphatase activity and gene expression. 1044 5

Lipopolysaccharide (LPS; a model of systemic bacterial infection) causes fever and activates glucagon-like peptide-1 (GLP-1) neurons in the caudal brainstem. The present study examined whether central GLP-1 receptor signaling plays a functional role in LPS-induced fever. Adult male Sprague-Dawley rats were injected i.p. with LPS (0 or 100 microg/kg), then were infused intracerebroventricularly with GLP-1 receptor antagonist (0 or 10 microg) delivered 2.5 h after injection of LPS or vehicle. Core body temperature was measured at 30-min intervals for 6.5 h after LPS treatment. Consistent with previous reports, body temperature was significantly elevated within 90 min and remained elevated for the remainder of the monitoring period. The pyrogenic effect of LPS was amplified in rats that received central infusion of GLP-1 receptor antagonist, although the antagonist by itself did not alter body temperature. These findings suggest that endogenous GLP-1 acts at central receptors to limit the fever response in rats after i.p. administration of LPS.
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PMID:Antagonism of central glucagon-like peptide-1 receptors enhances lipopolysaccharide-induced fever. 1118 34

Four multiparous lactating cows (175 to 220 d in milk [DIM]) were used in a 4 x 4 Latin square design to assess the effects of four doses (0.0, 0.5, 1.0, and 1.5 microg/kg of body weight) of lipopolysaccharide (LPS; Escherichia coli 0111:B4) on performance and plasma metabolite and hormone concentrations. In addition, effects of immune activation on in vitro hepatic metabolic capacity were evaluated in 12 multiparous lactating cows (150 to 220 DIM) infused with 0 (n = 6), 1.0 (n = 4) or 2.0 (n = 2) microg of LPS/kg. Milk production and DMI decreased linearly with LPS dose for 24 h after LPS infusion. Overall mean plasma tumor necrosis factor-alpha, insulin, glucagon, and cortisol concentrations increased linearly with LPS dose, and plasma beta-hydroxybutyrate decreased linearly by dose after LPS infusion. Infusion of LPS decreased the insulin:glucagon molar ratio, but did not affect plasma concentrations of growth hormone, insulin-like growth factor-1, leptin, or L-(+)-lactate. Plasma concentrations of glucose tended to increase initially and subsequently decrease, and there was a quadratic tendency for increased plasma nonesterified fatty acid concentrations after LPS administration. In vitro hepatic capacity for conversion of [1-(14)C]L-(+)-lactate and [1-(14)C]palmitate, but not [1-(14)C]propionate or [1-(14)C]L-alanine, to CO2 increased after LPS administration. Hepatic capacity to convert [1-(14)C]propionate to glucose tended to increase, but neither esterification nor the conversion of palmitate to acid soluble products was altered by LPS. The LPS infusion resulted in significant changes of endocrine mediators responsible for regulation of energy metabolism of lactating cows and tended to alter subsequent in vitro hepatic metabolic capacity.
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PMID:Effect of lipopolysaccharide on indices of peripheral and hepatic metabolism in lactating cows. 1467 74

The central glucagon-like peptide-1 (GLP-1) system has been implicated in the control of feeding behavior. Here we explore GLP-1 mediation of the anorexic response to administration of systemic LPS and address the relative importance of caudal brain stem and forebrain GLP-1 receptor (GLP-1-R) for the mediation of the response. Fourth-intracerebroventricular delivery of the GLP-1-R antagonist exendin-(9-39) (10 microg) did not itself affect food intake in the 24 h after injection but significantly attenuated the otherwise robust (approximately 60%) reduction in food intake obtained after LPS (100 microg/kg) treatment. This result highlights a role for caudal brain stem GLP-1-R in the mediation of LPS anorexia but does not rule out the possibility that forebrain receptors also contribute to the response. Forebrain contribution was addressed by delivery of the GLP-1-R antagonist to the third ventricle with the caudal flow of cerebrospinal fluid blocked by occlusion of the cerebral aqueduct. Exendin-(9-39) delivery thus limited to forebrain did not attenuate the anorexic response to LPS. These data suggest that LPS anorexia is mediated, in part, by release of the native peptide acting on GLP-1-R within the caudal brain stem.
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PMID:Attenuation of lipopolysaccharide anorexia by antagonism of caudal brain stem but not forebrain GLP-1-R. 1547 2


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