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)

A novel form of the polypeptide termed PHI (peptide HI with N-terminal histidine and C-terminal isoleucine amide) has been isolated from bovine upper intestine. This bovine peptide was obtained in a 40 times higher yield than the corresponding polypeptide isolated from porcine intestine. Bovine PHI is, like porcine PHI, composed of 27 amino acid residues. The complete amino acid sequence of the bovine peptide is His-Ala-Asp-Gly-Val-Phe-Thr-Ser-Asp-Tyr-Ser-Arg-Leu-Leu-Gly-Gln-Leu-Ser- Ala- Lys-Lys-Tyr-Leu-Glu-Ser-Leu-Ile-NH2. This sequence differs from porcine PHI at position 10 and from human PHI at positions 10, 12 and 27. The amino acid residue exchange between porcine and bovine PHI makes the latter more similar to the vasoactive intestinal polypeptide (VIP), gastric inhibitory polypeptide (GIP), glucagon and the growth-hormone-releasing factor (GRF).
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PMID:A novel form of the polypeptide PHI isolated in high yield from bovine upper intestine. Relationships to other peptides of the glucagon-secretin family. 654 46

A new peptide, designated PHI (PHI-27), has been discovered and isolated from porcine upper intestinal tissue by using a chemical method for finding peptide hormones and other active peptides. The method is based on chemical detection of peptides having the cOOH-terminal alpha-amide structure, which is an unusual chemical feature of some peptide hormones and active peptides. Porcine PHI was found in the intestinal extract by the presence of its COOH-terminal isoleucine amide structure. It consists of 27 amino acid residues and has the following amino acid sequence: His-Ala-Asp-Gly-Val-Phe-Thr-Ser-Asp-Phe-Ser-Arg-Leu-Leu-Gly-Gln-Leu-Ser-Ala-Lys -Lys-Tyr-Leu-Glu-Ser-Leu-Ile-NH2. The remarkable sequence homology of PHI to the vasoactive intestinal peptide, secretin, glucagon, and gastric inhibitory polypeptide indicates that this peptide is a member of the glucagon-secretin family. Several biological activities of PHI, similar to those of vasoactive intestinal peptide and secretin, have been reported.
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PMID:Isolation and characterization of the intestinal peptide porcine PHI (PHI-27), a new member of the glucagon--secretin family. 694 44

1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10mug/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70+/-11% decrease in [3-hydroxybutyrate] and a 58+/-9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72+/-9% decrease in the rate of production of ketone bodies and a 57+/-8% decrease in disappearance rate as assessed by [3-(14)C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.
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PMID:A possible mechanism for the anti-ketogenic action of alanine in the rat. 700 81

Hepatic amino acid contents were determined at time-points regularly spaced over a light-dark cycle in rats fed either a 12% casein diet or a single daily meal given 2 hours after the onset of the light phase with a protein-free diet and libitum. In mixed-fed rats, non-essential amino acid hepatic content remained stable over 24 hours while that of essential amino acids rose during the early part of the night in connection with the onset of prandial activity, but long before portal levels increased. The possibility of factors related to food intake (insulin, glucagon, gastrointestinal hormones) or to its chronology (corticoids) stimulating active transport is discussed. In separately-fed rats, amino acid pools increased in the 30 minutes following protein administration in connection with rising portal levels. During the rest of the light phase, a general depletion of non-essential amino acids occurred. It was most rapid for glutamine, alanine and aspartic acid and was followed by accumulation during the night phase, a pattern fitting well with gluconeogenesis and ureogenesis stimulation following protein ingestion. Essential amino acid decrease was linear and spanned over both the light and dark phases in correlation with decreasing portal levels.
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PMID:Circadian variations of liver free amino acid content in mixed-fed and protein-meal-fed rats. 727 33

Chicken secretin has been isolated and its structure determined. It is composed of 27 amino acid residues, and has an amidated C terminus. The amino acid sequence is His-Ser-Asp-Gly-Leu-Phe-Thr-Ser-Glu-Tyr-Ser-Lys-Met-Arg-Gly-Asn-Ala-Gln-Val-Gln -Lys-Phe-Ile-Gln-Asn-Leu-Met-NH2. The structure shows distinct similarities to that of porcine secretin, amino acid identities occur at 14 positions (residues 1-4, 6-9, 11, 14, 17, 20, 24 and 26) but considerable differences are also present among the remaining 13 positions. Chicken secretin further shows a clear structural similarity to the vasoactive intestinal peptide (37% identical positions), the gastric inhibitory peptide (30% identical positions) and to glucagon (52% identical positions), suggesting wide evolutionary and functional relationships.
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PMID:Isolation and characterization of chicken secretin. 746 Sep 28

We have investigated the mitogenic effect of three mutant forms of human insulin on insulin-producing beta cells of the developing pancreas. We examined transgenic embryonic and adult mice expressing (i) human [AspB10]-proinsulin/insulin ([AspB10]ProIN/IN), produced by replacement of histidine by aspartic acid at position 10 of the B chain and characterized by an increased affinity for the insulin receptor; (ii) human [LeuA3]insulin, produced by the substitution of leucine for valine in position 3 of the A chain, which exhibits decreased receptor binding affinity; and (iii) human [LeuA3, AspB10]insulin "double" mutation. During development, beta cells of AspB10 embryos were twice as abundant and had a 3 times higher rate of proliferation compared with beta cells of littermate controls. The mitogenic effect of [AspB10]ProIN/IN was specific for embryonic beta cells because the rate of proliferation of beta cells of adults and of glucagon (alpha) cells and adrenal chromaffin cells of embryos was similar in AspB10 mice and controls. In contrast to AspB10 embryos, the number of beta cells in the LeuA3 and "double" mutant lines was similar to the number in controls. These findings indicate that the [AspB10]ProIN/IN analog increased the rate of fetal beta-cell proliferation. The mechanism or mechanisms that mediate this mitogenic effect remain to be determined.
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PMID:A transgene coding for a human insulin analog has a mitogenic effect on murine embryonic beta cells. 760 77

In order to facilitate structure-function studies of the glucagon receptor by site-directed mutagenesis, we have designed and synthesized a gene for the rat glucagon receptor. The gene codes for the native 485-amino-acid protein but contains 91 unique restriction sites. To characterize gene expression, a highly specific, high affinity antipeptide antibody was prepared against the receptor. The synthetic gene was expressed in transiently transfected monkey kidney (COS-1) cells. COS cells expressing the synthetic receptor gene bound glucagon with affinity and specificity similar to that of hepatocytes containing native receptor. The transfected COS cells also showed increased intracellular cAMP levels in response to glucagon. The functional role of an aspartic acid residue in the NH2-terminal tail of the receptor was tested by site-directed mutagenesis. This site in the related growth hormone releasing factor receptor was shown to be responsible for the little mouse (lit) genetic defect that results in mice of small size with hypoplastic pituitary glands. Mutant glucagon receptors with amino acid replacements of Asp64 were expressed at normal levels in COS cells but failed to bind glucagon. These results indicate that amino acid Asp64 may play a key role in glucagon binding to receptor.
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PMID:Synthesis and expression of a gene for the rat glucagon receptor. Replacement of an aspartic acid in the extracellular domain prevents glucagon binding. 796 3

The North American paddlefish, Polyodon spathula (Order Acipenseriformes) is an extant representative of a group of primitive Actinopterygian (ray-finned) fish that probably shared a common ancestor with present-day teleosts. Two molecular forms of insulin which differ by a single amino acid substitution, His or Asp at position 15 of the A chain, were isolated from the pancreas of the paddlefish. Paddlefish insulins show greatest structural similarity to insulin from the garfish (order Lepisosteiformes) and resemble mammalian insulins more strongly than do insulins from teleost fish. The primary structures of several proglucagon-derived peptides, two molecular forms of glucagon which differ by the single amino acid substitution Arg18-->Ser, and glucagon-like peptide, have been less well conserved during evolution. The paddlefish glucagons contain 31 amino acid residues, rather than the usual 29, and show several structural features, such as Met5, Glu24 and Gly29, not previously observed in glucagons from other species. In spite of considerable differences in structure between paddlefish and mammalian glucagons (10 or 11 amino acid substitutions), both paddlefish glucagons are equally as effective as bovine glucagon in stimulating glycogenolysis in dispersed hepatocytes from the teleost fish Sebastes caurinus (rockfish). However, the substitution Arg18-->Ser in the paddlefish glucagon results in a 6-fold decrease in potency in this system.
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PMID:Characterization of insulins and proglucagon-derived peptides from a phylogenetically ancient fish, the paddlefish (Polyodon spathula). 800 37

To examine the structure-activity relationships in the insulinotropic activity of glucagon-like peptide-1(7-36) amide (GLP-1(7-36)amide), we synthesized 16 analogues, including eight which were designed by amino acid substitutions at positions 10 (Alal0), 15 (Serl5), 16 (Try16), 17 (Arg17), 18 (Lys18), 21 (Gly21), 27 (Lys27) and 31 (Asp31) of GLP-1(7-36)amide with an amino acid of GH-releasing factor possessing only slight insulinotropic activity, and three tentative antagonists including [Glu15]-GLP-1(8-36)amide. Their insulinotropic activities were assessed by rat pancreas perfusion experiments, and binding affinity to GLP-1 receptors and stimulation of cyclic AMP (cAMP) production were evaluated using cultured RINm5F cells. Insulinotropic activity was estimated as GLP-1(7-36)amide = Tyr16 > Lys18, Lys27 > Gly21 > Asp31 >> Ser15, Arg17 > Ala10 >> GRF > [Glu15]-GLP-1(8-36) amide. Displacement activity against 125I-labelled GLP-1(7-36)amide binding and stimulatory activity for cAMP production in RINm5F cells correlated well with their insulinotropic activity in perfused rat pancreases. These results demonstrate that (1) positions 10 (glycine), 15 (aspartic acid) and 17 (serine) in the amino acid sequence of GLP-1(7-36)amide, in addition to the N-terminal histidine, are essential for its insulinotropic activity through its binding to the receptor, (2) the amino acid sequences for the C-terminal half of GLP-1(7-36)amide also contribute to its binding to the receptor, although they are less important compared with those of the N-terminal half, and (3) [Glu15]-GLP-1(8-36)amide is not an antagonist of GLP-1(7-36)amide as opposed to des-His1 [Glu9]-glucagon amide which is a potent glucagon antagonist.
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PMID:Structure-activity relationships of glucagon-like peptide-1(7-36)amide: insulinotropic activities in perfused rat pancreases, and receptor binding and cyclic AMP production in RINm5F cells. 813 51

Extensive structure activity analysis has allowed us to identify specific residues in the glucagon sequence that are responsible for either receptor recognition or signal transduction. For instance, we have demonstrated that aspartic acid 9 and histidine 1 are essential for activation, and that an ionic interaction between the negative carboxylate and the protonated imidazole may contribute to the activation reaction at the molecular level. In the absence of the carboxylic group at position 9, aspartic 21 or aspartic 15 might furnish distal electrostatic effects to maintain partial agonism. Further investigation established that each of the 4 serine residues in the hormone play distinct roles. Serine 8 provides an important determinant of binding. Whereas neither serines 2, 11, nor 16 are required for receptor recognition. We have shown that serine 16 is essential for signal transduction and thus have identified it to be the third residue in glucagon to participate in a putative catalytic triad together with aspartic 9 and histidine 1, in the transduction of the glucagon response. In this work, we utilized insights into the functional significance of particular residues in the peptide appropriated from our structure-function assignments, as the basis of a molecular approach for the design of active-site directed antagonists of glucagon. The importance as well as the accuracy of our findings are confirmed by the synthesis of a series of improved glucagon antagonists based on replacements at positions 1, 9, 11, 16, and 21. The inhibition index, (I/A)50, of our best antagonist des-His1-[Nle9-Ala11-Ala16]glucagon amide, has been improved 10-fold over the previous best glucagon inhibitor.
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PMID:Multiple-site replacement analogs of glucagon. A molecular basis for antagonist design. 817 63


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