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)

Prostaglandins, released from Kupffer cells, have been shown to mediate the increase in hepatic glycogenolysis by various stimuli such as zymosan, endotoxin, immune complexes, and anaphylotoxin C3a involving prostaglandin (PG) receptors coupled to phospholipase C via a G(0) protein. PGs also decreased glucagon-stimulated glycogenolysis in hepatocytes by a different signal chain involving PGE2 receptors coupled to adenylate cyclase via a Gi protein (EP3 receptors). The source of the prostaglandins for this latter glucagon-antagonistic action is so far unknown. This study provides evidence that Kupffer cells may be one source: in Kupffer cells, maintained in primary culture for 72 hours, glucagon (0.1 to 10 nmol/L) increased PGE2, PGF2 alpha, and PGD2 synthesis rapidly and transiently. Maximal prostaglandin concentrations were reached after 5 minutes. Glucagon (1 nmol/L) elevated the cyclic adenosine monophosphate (cAMP) and inositol triphosphate (InsP3) levels in Kupffer cells about fivefold and twofold, respectively. The increase in glycogen phosphorylase activity elicited by 1 nmol/L glucagon was about twice as large in monocultures of hepatocytes than in cocultures of hepatocytes and Kupffer cells with the same hepatocyte density. Treatment of cocultures with 500 mumol/L acetylsalicylic acid (ASA) to irreversibly inhibit cyclooxygenase (PGH-synthase) 30 minutes before addition of glucagon abolished this difference. These data support the hypothesis that PGs produced by Kupffer cells in response to glucagon might participate in a feedback loop inhibiting glucagon-stimulated glycogenolysis in hepatocytes.
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PMID:Feedback-inhibition of glucagon-stimulated glycogenolysis in hepatocyte/Kupffer cell cocultures by glucagon-elicited prostaglandin production in Kupffer cells. 759 Jun 78

Rats fed ad libitum were given insulin alone (4 U/kg), glucagon alone (25 micrograms/kg), or insulin and glucagon sequentially. Phosphorylase a and synthase R activities, hepatic glycogen, uridine diphosphoglucose, inorganic phosphate (Pi), and plasma glucose, lactate, glucagon, and insulin concentrations were determined over the subsequent 40 min. In separate animals, muscle extraction of 2-deoxy-D-[3H]glucose also was determined. After glucagon administration, glycogen phosphorylase a and plasma glucose were increased within 5 min. However, the glycogen concentration did not decrease for 20 min. Glucagon administration to rats pretreated with insulin stimulated a similar increase in phosphorylase a activity. Again, glycogen was not degraded for 20 min. After insulin only, glycogen concentration remained unchanged. Plasma glucose decreased as expected. In each group, muscle extraction of 2-deoxy-D-[3H]glucose increased compared with the controls (P < 0.05). In summary, glucagon and/or insulin administration did not stimulate significant glycogen degradation for 20 min, even though phosphorylase was activated. The mechanism remains to be determined.
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PMID:Effects of glucagon with or without insulin administration on liver glycogen metabolism. 914 96

In organ cultures of liver tissue from the axolotl, Ambystoma mexicanum, 1 nmol/l arginine vasotocin (AVT) increased tissue cyclic AMP (cAMP) concentration, activated glycogen phosphorylase, and caused glycogen breakdown and glucose release. Addition of 10 nmol/l insulin had no effect on any of these parameters. Addition of glucagon together with AVT caused a further increase in tissue cAMP but not in glucose release. Ten nanomoles per liter of insulin added to the cultures 5 min before 1 nmol/liter AVT inhibited all the above actions of AVT. This inhibitory action of insulin was not apparent in the presence of the cAMP phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), which indicates that insulin activates cAMP phosphodiesterase and so reduces the concentration of cAMP in the tissue. This cannot occur in the presence of IBMX. These findings confirm previous reports that AVT causes hepatic glycogenolysis in the axolotl via an increase in tissue cAMP level.
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PMID:Insulin counters the glycogenolytic effect of arginine vasotocin in liver pieces from the axolotl, Ambystoma mexicanum, cultured in vitro. 768 Oct 19

We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m2) during physiological hyperinsulinemia (280 +/- 25 pmol/l) compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 +/- 2.72 mumol.kg-1.min-1, P < 0.01), glucose uptake was approximately 49% lower (21.20 +/- 3.55 mumol.kg-1.min-1, P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by Km decline by approximately 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by approximately 40% (P = 0.0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.
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PMID:Counterregulation of hypoglycemia. Skeletal muscle glycogen metabolism during three hours of physiological hyperinsulinemia in humans. 769 11

An immortalized cell line, called P9, was derived from hepatocytes by transfection with SV40 DNA. These cells expressed enzyme activities characteristic of hepatocytes, namely glucose-6-phosphatase, glycogen phosphorylase, bilirubin glucuronyltransferase and both glucagon- and prostaglandin E1 (PGE1)-stimulated adenylate cyclase activities, albeit at decreased levels compared with native hepatocytes. Levels of the G-protein subunits alpha-Gi-2, alpha-Gi-3, G beta and the 'long' form of alpha-G2 (45 kDa) were approximately 4-fold higher relative to native hepatocytes, whereas those of the 'short' form of alpha-G2 (42 kDa) were lower by approximately 40%. Associated with this were marked alterations in the guanine nucleotide regulation of adenylate cyclase. Receptor-mediated stimulation, achieved by either PGE1 or glucagon, was apparent in P9 cells, although the latter was only evident upon amplification with forskolin. Glucagon-stimulated cyclic AMP accumulation in P9 cells did not exhibit desensitization, as in hepatocytes, nor was the phosphorylation of alpha-Gi-2 evident. Culture of P9 cells with insulin led to a dose-dependent decrease (EC50 0.2 +/- 0.1 nM) in the ability of PGE1 to stimulate adenylate cyclase activity, with the maximum effect attained after approximately 6 h. A comparable attenuation of stimulation was seen for glucagon- and guanine-nucleotide-stimulated adenylate cyclase activities. In cells cultured with insulin, lower levels of GTP were required to stimulate adenylate cyclase, ADP-ribosylation of the 45 kDa form of alpha-Gs with cholera toxin was attenuated, and the expression of both alpha Gi-2 and alpha-Gi-3 was increased. It is suggested that the expression of alpha-Gi-2 and alpha-Gi-3 may be directly regulated by the action of insulin in hepatocytes and P9 cells.
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PMID:Analysis of the adenylate cyclase signalling system, and alterations induced by culture with insulin, in a novel SV40-DNA-immortalized hepatocyte cell line (P9 cells). 801 Sep 67

In cultured rat hepatocytes the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK) is known to be induced by glucagon via an elevation of cAMP. Prostaglandin E2 has been shown to antagonize the glucagon-activated cAMP formation, glycogen phosphorylase activity and glucose output in hepatocytes. It was the purpose of the current investigation to study the potential of PGE2 to inhibit the glucagon-induced expression of PCK on the level of mRNA and enzyme activity. PCK mRNA and enzyme activity were increased by 0.1 nM glucagon to a maximum after 2 h and 4 h, respectively. This increase was completely inhibited if 10 microM PGE2 was added concomitantly with glucagon. This inhibition by PGE2 of glucagon-induced PCK activity was abolished by pertussis toxin treatment. When added at the maximum of PCK mRNA at 2 h, PGE2 accelerated the decay of mRNA and reduced enzyme activity. This effect was not reversed by pertussis toxin treatment. Since in liver PGE2 is derived from Kupffer cells, which play a key role in the local inflammatory response, the present data imply that during inflammation PGE2 may reduce the hepatic gluconeogenic capacity via a Gi-linked signal chain.
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PMID:Inhibition by PGE2 of glucagon-induced increase in phosphoenolpyruvate carboxykinase mRNA and acceleration of mRNA degradation in cultured rat hepatocytes. 808 94

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.
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PMID:Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus. 820 Sep 93

We have investigated the mechanism of the rebound of glycogen stores in the liver of 72-h fasted rats. The liver of 72- and 96-h fasted rats contains significant amounts of glycogen (about 5 mg/g, wet weight) as compared to the liver of 24- and 48-h fasted rats, which contains less than 2 mg of glycogen/g of liver, wet weight. Rebound of glycogen does not involve glycogen synthase activation or glycogen phosphorylase inhibition. It could be dependent on the concentration of the precursor substrate of glycogenesis, i.e. glucose 6-phosphate (Glc-6-P), which is higher by about 45% in the liver of 72- and 96-h fasted rats than in the liver of 48-h fasted rats. The 72-h increase of Glc-6-P compared with the 48-h values could not be explained either by late modifications of the total activities of glucokinase, hexokinases, Glc-6-P dehydrogenase, and glucose-6-phosphatase (Glc-6-Pase) or by changes in plasma glucose and insulin/glucagon ratio. In agreement with the fact that total glucose output tends to decrease upon prolonged fasting, the increase of Glc-6-P concentration in the liver of 72-h fasted rats suggests the involvement of a metabolite inhibition of Glc-6-Pase. The increase of the alpha-ketoglutarate concentration in the 72- and 96-h fasted liver with regard to the 48-h fasted liver (about three times) might account for such an inhibition since we show here that Glc-6-Pase is inhibited in vitro in the presence of relevant concentrations of alpha-ketoglutarate, Glc-6-P, and Mg2+ ions.
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PMID:Investigation of the mechanism of glycogen rebound in the liver of 72-hour fasted rats. 820 76

In perfused rat livers, infusion of prostaglandin F2 alpha (PGF2 alpha) or noradrenaline increased glucose and lactate output and reduced flow. Glucagon increased glucose output and decreased lactate output without influence on flow. Infusion of phorbol 13-myristate 14-acetate (PMA) for 20 min prior to these stimuli strongly inhibited the metabolic and hemodynamic effects of noradrenaline, reduced the metabolic actions of PGF2 alpha but did not alter the effects of glucagon. In isolated rat hepatocytes PGF2 alpha, noradrenaline and glucagon activated glycogen phosphorylase but only PGF2 alpha and noradrenaline increased intracellular inositol 1,4,5-trisphosphate (InsP3). The noradrenaline- or PGF2 alpha-elicited activation of glycogen phosphorylase and increase in InsP3 were largely reduced after preincubation of the cells for 10 min with PMA, whereas the glucagon-mediated enzyme activation was not affected. In contrast to PMA, the phorbol ester 4 alpha-phorbol 13,14-didecanoate, which does not activate protein kinase C, did not attenuate the PGF2 alpha- and noradrenaline-elicited stimulation of glucose output, glycogen phosphorylase and InsP3 formation. Stimulation of InsP3 formation by AlF4-, which activates phospholipase C independently of the receptor, was not attenuated by prior incubation with PMA. Plasma membranes purified from isolated hepatocytes had both a high-capacity, low-affinity and a low-capacity, high-affinity binding site for PGF2 alpha. The Kd of the high-capacity, low-affinity binding site was close to the concentration of PGF2 alpha that increased glycogen phosphorylase activity half-maximally. Binding to the high-capacity, low-affinity binding site was enhanced by guanosine 5'-O-(3-thio)triphosphate (GTP[S]). This high-capacity, low-affinity site might thus represent the receptor. The Bmax and Kd of the high-capacity site, as well as the enhancement by GTP[S] of PGF2 alpha binding to this site, remained unaffected by PMA treatment. It is concluded that, in hepatocytes, activation of protein kinase C by PMA interrupted the InsP3-mediated signal pathway from PGF2 alpha via a PGF2 alpha receptor and phospholipase C to glycogen phosphorylase at a point distal of the receptor prior to phospholipase C.
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PMID:Inhibition by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate of the prostaglandin F2 alpha-mediated and noradrenaline-mediated but not glucagon-mediated activation of glycogenolysis in rat liver. 822 68

cAMP and Ca(2+)-dependent glycogenolytic pathways are regulated by different hormones involved in the activation of glycogen phosphorylase in isolated rat hepatocytes. Dose-dependent glucagon activation of glycogen phosphorylase and lowering of cAMP levels were obtained by vasopressin and angiotensin treatment. Similar time courses of Ca2+ fluxes and phosphorylase activation were induced by vasopressin, angiotensin and phenylephrine. Heterologous down-regulation of hormones was induced in glycogenolysis in hepatocytes. These results could be of significance in physiology studies in vivo.
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PMID:[Regulation of glycogenolysis against hormones in isolated rat hepatocytes]. 824 20


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