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)

In the search for selective and long-acting analogs of somatostatin, nearly 200 compounds were synthesized by solid-phase methods, purified, and tested biologically. Among these octapeptides, some contained N-terminal (Formula: see text) were 177 times and 113 times more potent, respectively, than somatostatin in tests for inhibition of growth hormone release. These two octapeptides containing tyrosine and valine in positions 3 and 6, respectively, were more active and more selective than their Phe-3 and Thr-6 counterparts, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 and D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2. D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 was also about 6 times more potent than its L-Trp-4 diastereoisomer. The analogs D-Phe-Cys-Tyr-Lys-Val-Cys-Thr-NH2 and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 showed a prolonged duration of action and were able to inhibit growth hormone release for at least 3 hr. Analogs of both Phe-3/Thr-6 and Tyr-3/Val-6 classes also suppressed the release of insulin and glucagon in rats and pentagastrin-induced secretion of gastric acid in dogs, but their potencies in these tests were much smaller than the growth-hormone-release inhibitory activity. Some of these analogs possessed antitumor activities as shown by the inhibition of growth of animal models of prostate, mammary, and ductal pancreatic tumors.
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PMID:Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. 286 90

The quantitative importance of the individual steps of aromatic amino acid metabolism in rat liver was determined by calculation of the respective Control Coefficients (Strengths). The Control Coefficient of tryptophan 2,3-dioxygenase for tryptophan degradation was determined in a variety of physiological conditions and with a range of activities of tryptophan 2,3-dioxygenase. The Control Coefficient varied from 0.75 with basal enzyme activity to 0.25 after maximal induction of the enzyme by dexamethasone. The remainder of the control for tryptophan degradation was associated with the transport of the amino acid across the plasma membrane, with only very small contributions from kynureninase and kynurenine hydroxylase. The Control Coefficients of tyrosine aminotransferase for tyrosine degradation were approx. 0.70 and 0.20 with basal and dexamethasone-induced tyrosine aminotransferase activities respectively; the Control Coefficients of the transport of the amino acid into the cell were 0.22 and 0.58 respectively. Phenylalanine hydroxylase was found to have a Control Coefficient for the degradation of phenylalanine of approx. 0.50 under conditions of basal enzyme activity; after maximal activation by glucagon, the Control Coefficient decreased to 0.12. The transport of phenylalanine was responsible for the remaining control in the pathway. These results have important implications, directly for the regulation of aromatic amino acid metabolism in the liver, and indirectly for the regulation of neuroamine synthesis in the brain.
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PMID:Quantification of the importance of individual steps in the control of aromatic amino acid metabolism. 287 85

Cyclic hexapeptide analogs of somatostatin with insulin, glucagon, and growth hormone (GH) release inhibitory potencies of 50-200 times those of somatostatin have been synthesized. Replacement of the Phe-7 residue with histidine has resulted in increased oral bioavailability and duration of action. Metabolic degradation of L-Trp containing analogs upon oral administration has also been overcome by incorporation of histidine. The all L-amino acid containing analog cyclo(NMePhe-His-Trp-Lys-Val-Ala) shows oral bioavailability comparable to D-Trp containing analogs.
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PMID:Somatostatin analogs with improved oral bioavailability. 288 53

Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phenomenon was time- and dose-dependent and irreversible. When hepatocytes were pretreated with somatostatin or with some of its synthetic analogues, formation of blebs was dramatically reduced. This cytoprotective effect was dose-dependent: the dose-response profiles enabled the determination of the CD50 values, i.e., the concentrations of analogues that yielded 50% cytoprotection. The analogues with sequences of amino acids in the retro form, compared to those in somatostatin-14, exhibited higher cytoprotection; the retro hexapeptide, cyclo(-Phe-Thr-Lys-D-Trp-Phe-D-Pro-), was 27 times more active than somatostatin-14. Specificity of cytoprotection was examined by pretreating hepatocytes with biologically active peptide hormones prior to exposure to phalloidin. On a molar basis, prolactin and thyroid-stimulating hormone possessed activity comparable to that of somatostatin-14, whereas glucagon was twice as active. Insulin, vitamin A and propranolol exercised less than 10% protection. The synthetic analogues of somatostatin are potent protective agents against cell lesions induced by phalloidin. Formation of blebs on hepatocytes by toxins and their prevention by agents of interest may serve as a suitable morphological assay for screening of cytotoxicity and cytoprotection.
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PMID:Prevention of phalloidin-induced lesions on isolated rat hepatocytes by novel synthetic analogues of somatostatin. 288 55

Biological activities of highly potent octapeptide analogs of somatostatin (SS), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), were investigated in male rats. When analog RC-160 was administered to rats in which serum growth hormone (GH) levels were elevated by pentobarbital anesthesia, a dose-related inhibition of GH was obtained at dose range of 0.1 to 2.5 micrograms/kg. The time course of GH inhibition by RC-160, RC-121 and SS-14 was studied in rats treated with phenobarbital, morphine and chlorpromazine. Analogs RC-160 and RC-121 induced a prolonged inhibition of GH levels, in contrast to SS-14, whose effect was short-lived. The analogs suppressed the GH level for more than 2 hr, the peak inhibition being seen 30 to 60 min after the injection. The effects of analogs RC-160 and RC-121 on insulin secretion were observed in rats, in which insulin levels had been elevated by intravenous administration of glucose (500 mg/rat). Administration of RC-160 suppressed insulin secretion, dose-dependently, maximum but not complete inhibition being achieved at a dose of 100 micrograms/kg. In this model, RC-160 and RC-121, in doses of 30 micrograms/kg, induced a similar inhibition of insulin release as 200 micrograms/kg of SS-14, whose action of SS-14 was transient. The effect of analog RC-160 on glucagon release was studied in rats with glucagon levels elevated by hypoglycemia. RC-160 suppressed the secretion of glucagon, the inhibition being dose-dependent in the range of 0.1 to 2 micrograms/kg. Doses of 2 and 10 micrograms/kg of this analog completely suppressed the hypoglycemia-induced glucagon release. These results indicate that analogs RC-160 and RC-121 possess prolonged and enhanced biological activities, the former analog showing a high selectivity in inhibiting GH and glucagon release in vivo as compared with that of insulin secretion.
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PMID:Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release. 288 86

The action of the new analog of somatostatin, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), on plasma glucagon and glucose levels was evaluated in streptozotocin-diabetic rats. The effect of this analog on the insulin-induced hypoglycemia in diabetic rats was also investigated in order to evaluate the risk of exacerbating hypoglycemia. Administration of analog RC-160, in a dose of 25 micrograms/kg b. wt. SC, inhibited plasma glucagon secretion and decreased plasma glucose levels. This effect also occurred when plasma glucagon and glucose levels were first elevated by arginine infusion, 1000 mg/kg/hr for 30 min. Subcutaneous injection of regular insulin, 15 U/kg b. wt., produced hypoglycemia with a progressive increase in glucagon levels. Analog RC-160 completely suppressed the hypoglycemia-induced glucagon release for up to 150 min after injection of the analog or insulin. A greater decrease in the plasma glucose level was observed in the group treated with insulin and the analog than in the group injected only with insulin. These results indicate that somatostatin analog RC-160 can produce a marked and prolonged inhibition of glucagon release and a decrease in the plasma glucose level in diabetic rats. This analog may be useful as an adjunct to insulin in the treatment of diabetic patients, although caution should be exercised, to prevent hypoglycemia when using somatostatin analogs together with insulin.
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PMID:Superactive somatostatin analog decreases plasma glucose and glucagon levels in diabetic rats. 290 37

Peptides derived from prosomatostatins I and II and from two distinct proglucagons have been isolated from the pancreas of a teleost fish, the European eel (Anguilla anguilla). The product of prosomatostatin I processing, somatostatin-14, is identical to mammalian somatostatin-14. A 25-amino-acid-residue peptide (Ser-Val-Asp-Asn-Gln5-Gln-Gly-Arg-Glu-Arg10-Lys-Ala-Gly-Cys- Lys15-Asn-Phe-Tyr- Trp-Lys20-Gly-Pro-Thr-Ser-Cys25) is derived from prosomatostatin II. Compared with the corresponding peptides from other teleost fish, the eel somatostatin-25 contains the unusual substitution Pro for Phe at position 22. This peptide was also isolated in a form containing a hydroxylsyl residue at position 20. A 29-amino-acid-residue eel glucagon contains four substitutions relative to human glucagon Asn for Ser8, Glu for Asp15, Thr for Ser16, and Ser for Thr29). In common with mammalian and avian glucagons but unlike most other fish glucagons, the eel peptide possesses a glutamine residue at position 3. A peptide derived from a second proglucagon comprises 36 amino acid residues. A 7-residue C-terminal extension to the glucagon sequence shows structural similarity to the corresponding extension in ratfish (Hydrolagus colliei) glucagon and mammalian oxyntomodulin.
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PMID:Somatostatin-related and glucagon-related peptides with unusual structural features from the European eel (Anguilla anguilla). 290 91

Low concentrations of six peptide hormones; glucagon, vasoactive intestinal peptide, substance P, angiotensin II, lysine-vasopressin, arginine-vasopressin, and the chemotactic peptide fMet-Leu-Phe, activated the capacity for pinocytosis in starved Amoeba proteus. Competitive inhibitors of the chemotactic peptide in leucocytes inhibited activation by fMet-Leu-Phe, suggesting that its action in the amoeba is mediated by specific receptors. The opioid peptides, beta-endorphin, dynorphin (1-13) and leu-enkephalin abolished through a naloxone-sensitive mechanism activation by hormones and several other activating agents. Also, low concentrations of beef and pork insulin inhibited activation by peptide hormones. An insulin analogue of low potency in mammalian cells was inactive in the amoeba. These results support the hypothesis that besides opioid receptors, there may be insulin receptors and possibly receptors for several other peptide hormones in Amoeba proteus.
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PMID:Peptides as modifiers of Na+-induced pinocytosis in starved Amoeba proteus. 300 25

The stimulation of phenylalanine hydroxylation in isolated liver cells by sub-maximally effective concentrations of glucagon (less than 0.1 microM) is antagonized by insulin (0.1 nM-0.1 microM). This phenomenon is a consequence of a decrease in the glucagon-stimulated phosphorylation of phenylalanine hydroxylase from liver cells incubated in the presence of insulin. The impact of insulin on the phosphorylation state and activity of the hydroxylase is mimicked by incubation of liver cells in the presence of orthovanadate (10 microM). A series of cyclic AMP and cyclic GMP analogues enhanced phenylalanine hydroxylation: in each case insulin diminished the stimulation of flux. These results are discussed in the light of the characteristics of insulin action on other metabolic processes.
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PMID:The role of insulin in the modulation of glucagon-dependent control of phenylalanine hydroxylation in isolated liver cells. 303 97

The effect of major operative trauma on skeletal muscle metabolism was examined in nine patients receiving a constant infusion of calories (1460 kcal/m2/day) and protein (75 gm of amino acids/m2/day) for 5 days before and 4 days after an operation. Compared with the preoperative state, 72 hours after the operation there was a significant rise in arterial levels of glucagon, cortisol, norepinephrine, and inactive triiodothyronine and a drop in concentrations of insulin, active triiodothyronine, and amino acids. Forearm blood flow increased, as well as the efflux from forearm muscle of lactate, taurine, serine, glycine, valine, methionine, isoleucine, leucine, phenylalanine, lysine, arginine, and total amino acid nitrogen (440%). This loss of muscle protein after trauma is associated with increased muscle proteolysis, as measured by increased urinary 3-methylhistidine excretion (83%), and accounts for increased nitrogen loss (54%) from the body. Increased activity of the sympathetic nervous system is manifested by increased levels of epinephrine and norepinephrine, a relative lack of insulin, and increased levels of glucagon. This hormonal milieu plays an important role in the production of hypoaminoacidemia, increased efflux of amino acids and lactate from muscle, and negative nitrogen balance observed in these traumatized patients.
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PMID:Major operative trauma increases peripheral amino acid release during the steady-state infusion of total parenteral nutrition in man. 308 29


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