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)

1. Rat livers were dissociated into their constituent cells by perfusion through the portal vein with a medium containing collagenase, and hepatocytes separated from non-parenchymal cells. 2. It is shown that the procedure described by Wisher & Evans [(1975) Biochem. J. 146, 375-388] for preparation of plasma membranes from liver tissue when applied to isolated hepatocytes also yielded subfractions of similar morphology and marker-enzyme distribution. 3. Thus the distribution of alkaline phosphodiesterase, 5'-nucleotidase and the basal and glucagon-stimulated adenylate cyclase among two 'light' vesicular and one 'heavy' junction-containing plasma-membrane subfractions paralleled that reported for tissue-derived plasma-membrane subfractions. 4. Increased recoveries and specific activities of plasma-membrane marker enzymes were obtained when soya-bean trypsin inhibitor was included in the collagenase-containing perfusion media used to dissociate the liver. 5. Polyacrylamide-gel-electrophoretic analysis of the corresponding plasma-membrane subfractions prepared from liver tissue and isolated hepatocytes were generally similar. 6. The results indicate that the functional polarity of the hepatocyte's plasma membrane is retained after tissue dissociation. The damage occurring to plasma-membrane ectoenzymes by the collagenase-perfusion procedure is discussed.
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PMID:Preparation of plasma-membrane subfractions from isolated rat hepatocytes. 88 Feb 46

Gamma irradiation of rat liver plasma membranes leads to a decrease of the adenylcyclase activities stimulated by glucagon and fluoride. The observed inhibition is more important for the activity stimulated with glucagon. The 5'-nucleotisade activity is not changed by irradiation. When the phosphodiesterase system is submitted to gamma irradiation, the radiosensibility of enzymatic complex is more important.
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PMID:[Effect of gamma irradiation on the production and degradation system of the second hormonal messenger (author's transl)]. 100 9

To determine whether somatostatin inhibits glucagon secretion directly at the pancreatic level and to study quantitatively the relative effects of somatostatin on glucagon and insulin secretion, the effects of various concentrations of somatostatin on glucagon and insulin release from the in vitro perfused rat pancreas in response to arginine (14.2 mM), isoproterenol (2 mg/ml) and theophylline (10 MM) were studied. Glucagon and insulin responses to arginine were progressively inhibited by somatostatin over a concentration range from 0.1-100 ng/ml. At all doses, somatostatin caused greater inhibition of glucagon secretion than of insulin secretion. Approximately 4 ng/ml somatostatin reduced glucagon responses 50%, whereas 90 ng/ml was required to produce comparable inhibition of insulin responses. Glucagon responses to isoproterenol, an activator of adenylate cyclase, and to theophylline, a phosphodiesterase inhibitor, were completely abolished by 100 ng/ml somatostatin. Isoproterenol did cause insulin release in this system, but insulin responses to theophylline were diminished by somatostatin. The present studies thus indicate that somatostatin is a potent inhibitor of both glucagon and insulin secretion and indicate that it acts directly on the pancreatic alpha and beta cells. Glucagon secretion is approximately 20 times more sensitive to the inhibitory effects of somatostatin than is insulin secretion. Furthermore, the present results suggest that somatostatin may act by modifying cAMP-dependent systems rather than by altering cAMP levels.
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PMID:Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to arginine, isoproterenol and theophylline: evidence for a preferential effect on glucagon secretion. 111 81

In cultured rat hepatocytes, transcription of the glucokinase gene is turned on by insulin and turned off by glucagon/cAMP, the latter being the dominant effector system. It is thus possible that in the absence of hormones the gene is maintained in a repressed state by the basal level of cAMP and that insulin turns on transcription by relieving cAMP repression, for instance via activation of a cyclic-nucleotide phosphodiesterase. Three inhibitors of this class of enzymes were tested for their effect on the insulin-dependent induction of the glucokinase gene in hepatocytes. Isobutyl methylxanthine, the prototype inhibitor, abrogated the gene response to insulin, as shown by run-on transcription assay. Among the drugs investigated, Ly186126, a preferential inhibitor of type-III phosphodiesterase, proved the most potent in inhibiting insulin-induced accumulation of glucokinase mRNA. Type-III phosphodiesterase is inhibited by cGMP. Induction of glucokinase mRNA was prevented in hepatocytes challenged with insulin in presence of 8-bromoguanosine-3',5'-phosphate. These results are consistent with the involvement of type-III phosphodiesterase in transduction of the insulin signal to the glucokinase gene. However, we were unable to detect significant decreases in total cellular cAMP level or cAMP-dependent-protein-kinase ratio after the addition of insulin to hepatocytes. Many effects of glucagon are mediated via cAMP-dependent protein-kinase phosphorylation of regulatory proteins and, conversely, insulin effects are often accompanied by protein dephosphorylation. A specific inhibitor of protein phosphatases PP1 and PP2A, okadaic acid, was shown to abolish the transcriptional response of the glucokinase gene to insulin. Thus, interference of insulin with the cAMP signal transduction pathway at several steps may be a critical aspect of insulin action on hepatic glucokinase gene expression. In addition, insulin induction of glucokinase mRNA was suppressed by inhibitors of protein synthesis. The underlying mechanism was a severe inhibition of the transcriptional effect of insulin, rather than mRNA destabilization, as demonstrated by run-on transcription assays with nuclei from cycloheximide-treated or pactamycin-treated cells. Transcription of the glucokinase gene may therefore depend on de novo synthesis of the product of an early-response gene induced by insulin, or may require a short-lived trans-acting or accessory factor of transcription. Alternatively, insulin signalling may be compromised in hepatocytes by a mechanism indirectly related to the arrest of protein synthesis.
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PMID:Insulin signalling and regulation of glucokinase gene expression in cultured hepatocytes. 128 Feb 18

Short-term desensitization to hormone-induced cAMP accumulation was investigated in the medullary (MTAL) and the cortical (CTAL) thick ascending limbs of Henle's loop isolated by microdissection from the rat kidney. The following agonists were studied: vasopressin, glucagon and human calcitonin in the MTAL, and vasopressin, glucagon, human calcitonin, parathyroid hormone (PTH) and the beta-adrenergic agonist isoproterenol in the CTAL. Isolated tubules were preincubated in vitro for 60 min in the presence or absence of a maximal concentration of one of the five agonists (vasopressin 10 nM, glucagon 10 nM, calcitonin 100 nM, PTH 10 nM, isoproterenol 1 microM). Desensitization induced by each agent to its own action was then quantified by measuring the amount of cAMP accumulating in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine and the same agonist concentration as that used during preincubation. In the MTAL, as previously reported, preincubation with vasopressin led to a marked (80%-85%) desensitization to this hormone. A significant hormone self-induced desensitization of about 45% was also obtained with glucagon, but not with calcitonin. In the CTAL, the following order of potency to elicit desensitization was observed: vasopressin (80%) greater than isoproterenol (50%) greater than glucagon (30%) greater than PTH (20%, NS) greater than calcitonin (10%, NS). Thus, the magnitude of desensitization varied greatly from one hormone to another, but for a given hormone, was of roughly similar extent in both MTAL and CTAL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential short-term desensitization to vasopressin, isoproterenol, glucagon, parathyroid hormone and calcitonin in the thick ascending limb of rat kidney. 131 67

The aim of this study was to evaluate the insulin (IRI) response to different stimuli and insulin sensitivity in Type 2 diabetic patients responsive to oral hypoglycaemic agents (OHA) and in Type 2 diabetic patients with secondary failure of OHA (SF), all patients being of normal body weight (relative body weight less than 120%), and the possible role of cyclic AMP in the reduced IRI release. SF patients, without islet cell antibodies (ICA), with hyperglycaemia lasting more than 3 months, underwent tests with i.v. tolbutamide (n = 21), i.v. glucose (n = 14), i.v. glucagon (n = 19), i.v. arginine infusion (n = 18); the arginine infusion was repeated in 12 patients during administration of aminophylline, an inhibitor of phosphodiesterase. The same tests were performed in groups of 8 to 15 OHA patients and in groups of 6 to 17 healthy subjects. During all the tests, blood glucose levels were higher in SF patients, than in OHA patients and in healthy subjects. Both SF patients and OHA patients had no IRI response to glucose; SF patients, in contrast to OHA patients, had a reduced IRI response to tolbutamide and to glucagon. The IRI response to arginine was not different in OHA, in SF patients and in healthy controls, but was significantly enhanced by aminophylline only in healthy controls. Insulin infusions (1.66 mU/Kg/min for 90 min) were performed in OHA patients and in SF patients at blood glucose levels of 150 and of 250 mg/dl: during the last 60 min, the amount of glucose metabolized (M), and the insulin sensitivity (M/I) index were greater in OHA than in SF patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secondary failure of oral hypoglycaemic agents in lean patients with type 2 diabetes mellitus: insulin sensitivity, insulin response to different stimuli, and the role of cyclic-AMP. 131 98

Cyclic AMP (cAMP) is known to play a key role in regulating insulin action, and it is well documented that in several cases of physiological insulin resistance its concentration is increased. Since late pregnancy in the rat is associated with liver insulin resistance, we have studied possible alterations of some cellular mechanisms regulating the cAMP metabolism. (1) Liver cAMP concentration was shown to be increased by some 30% and 50% at 18 and 22 days of pregnancy respectively, compared with virgins. (2) Basal adenylate cyclase activity was higher only in the 18-days-pregnant rat, and the forskolin-stimulated maximal activity was similar in the three groups of animals. (3) alpha s protein is decreased in term-pregnant rats; however, coupling between Gs and adenylate cyclase is only impaired in the 18-days-pregnant animals, and stimulation by glucagon is impaired in both groups of pregnant animals. (4) Gi-2 protein was shown to be unable to elicit the tonic inhibition of adenylate cyclase in pregnant rats, although it was only decreased at 22 days of gestation. The increased alpha i-2 level detected by immunoblotting at 18 days of gestation did not correlate with its decreased ADP-ribosylation, suggesting that the protein is somehow modified at this stage. (5) Pregnancy is associated with a decrease in membrane phosphodiesterase activity. Our results show that late pregnancy is associated with increases in liver cAMP levels that might be involved in eliciting the characteristic insulin-resistant state, and suggest that mechanisms leading to these increments are changing during this phase of gestation.
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PMID:Regulation of cyclic AMP synthesis and degradation is modified in rat liver at late gestation. 132 41

Lipolytic activity of fish (Hoplias malabaricus), toad (Bufo paracnemis), and snake (Philodryas patagoniensis) adipose tissue was investigated in vivo and in vitro. Catecholamines or glucagon did not affect the release of free fatty acids (FFA) by incubated fish and toad adipose tissue. Catecholamines also failed to activate snake adipose tissue lipolysis, which even decreased in the presence of epinephrine. However, glucagon stimulated both the lipolytic activity of reptilian tissue in vitro and the mobilization of FFA to plasma when administered to snakes in vivo. The release of FFA from incubated fish, amphibian, and reptilian adipose tissue increased markedly in the presence of cAMP or xanthine derivatives, inhibitors of phosphodiesterase. Forskolin or fluoride, activators of specific components of the adenylate cyclase system, strongly stimulated toad adipose tissue lipolysis. The data suggest that adipocyte triacylglycerol lipase of ectotherm vertebrates is activated by a cAMP-mediated phosphorylation and that the organization of the membrane-bound adenylate cyclase system is similar to that of mammals.
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PMID:Control of adipose tissue lipolysis in ectotherm vertebrates. 132 67

A number of regulatory peptides were investigated for their ability to elevate plasma cAMP. Pituitary adenylate cyclase activating peptide (PACAP)-27, PACAP-38, helodermin, helospectin I and II, vasoactive intestinal peptide (VIP), glucagon, parathyroid hormone (PTH), calcitonin and calcitonin gene-related peptide were among the peptides that were highly effective in raising plasma cAMP when given intravenously in equimolar doses to conscious mice. PACAP-27 and -38 were more effective than any of the other peptides. PACAP 16-38, secretin, gastrin-17, galanin, somatostatin, cholecystokinin-8s, pancreatic polypeptide, substance P, peptide YY and neuropeptide Y were inactive and also did not interfere with the PACAP-27-evoked rise in plasma cAMP levels. Repeated injections of PACAP-27 every 30 min caused a progressive reduction in the plasma cAMP response (measured 5 min after each injection). Forskolin, an activator of adenylate cyclase, dose-dependently raised the plasma concentration of cAMP and displayed a synergistic effect when given in a low dose concurrently with PTH or PACAP-38. The phosphodiesterase inhibitor rolipram dose-dependently raised the plasma concentration of cAMP. Combined treatment with PACAP-27 and a threshold dose of rolipram resulted in an exaggerated plasma cAMP response. Kidney hilus ligation suppressed the responses to PACAP-38, PTH, helodermin, helospectin, VIP, glucagon and calcitonin. Hepatectomy suppressed the response to glucagon but was without effect on the response to the other peptides. Pancreatectomy and spleenectomy reduced the response to VIP, but was without effect on the response to the other peptides. PACAP-27 stimulated cAMP efflux from the isolated rat tail vein. Hence, it cannot be excluded that blood vessels contribute to the peptide evoked plasma cAMP response in vivo.
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PMID:Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. 133 41

Inclusions of glucagon (1.0 or 2.0 microM, final concentrations) in the media of cultured whole rat conceptuses resulted in concentration-dependent increases in measured rates of O-depentylation of pentoxyphenoxazone in cell-free preparations of conceptal tissues. Enzymic activities were assayed 24 h after initial exposure of the conceptuses to glucagon on day 10 of gestation. Glucagon elicited increases in tissue levels of cAMP that were parallel to those produced by 3-isobutyl-1-methylxanthine over the same time period. Tissue cAMP levels were maximal after 2 h, rapidly returned to control levels and were also equal to background levels in controls after the 24 h culture period. Dibutyryl cAMP, 3-isobutyl-1-methylxanthine, theophylline, and RO201724, a cAMP-selective phosphodiesterase inhibitor, each produced 75 to 100% increases in O-dealkylase activity. Dibutyryl cGMP and two phosphodiesterase inhibitors, enoximone (cGMP-inhibited) and zaprinast (cGMP-specific), each failed to produce statistically significant increases in O-depentylase activity. The O-depentylase was tentatively identified as a conceptus-specific P450 cytochrome that is synthesized predominantly in tissues of the visceral yolk sac. The results indicated that glucagon may upregulate a unique, xenobiotic-biotransforming P450(s) via a long-term mechanism(s) specifically involving tissue cAMP.
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PMID:Mechanisms of glucagon-induced increases in rates of cytochrome P450-dependent pentoxyphenoxazone O-depentylation in cultured rat conceptuses. 133 7


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