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Gene Review

GCG  -  glucagon

Sus scrofa

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Disease relevance of GCG

  • Germ-free conditions and antiserum against Clostridium perfringens toxin prevented intestinal dysfunction and NEC in formula-fed pigs, whereas the gut trophic factors, epidermal growth factor, and glucagon-like peptide 2 had limited effects [1].
  • Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 +/- 6.3 vs. 92.2 +/- 2.5 pg/ml; P < 0.01) [2].
  • The latter prevented the hypoglycemia resulting from somatostatin infusion, and increased the glucagon level detectable by C-terminal specific antibodies in the blood of the animals [3].
  • Infusion glucagon, (3 ng x kg body weight-1.min-1) transiently increased blood glucose (p less than 0.01) and hepatic glucose production (p less than 0.01) in euthyroidism, but was without effect in hyperthyroidism [4].
  • Glucagon and insulin appeared to play no role in the hypocalcemia [5].

High impact information on GCG

  • Relationship of glicentin to proglucagon and glucagon in the porcine pancreas [6].
  • Glicentin-like material has been demonstrated in the pancreatic A cell, wherein it is located in the periphery of the secretory granules, whereas glucagon is located in the centre of the granules [6].
  • PHI is related to secretin, vasoactive intestinal polypeptide (VIP, glucagon and gastric inhibitory polypeptide (GIP); PYY is related to the pancreatic polypeptide and to neurotensin [7].
  • Simultaneously, the concentrations of arterial insulin and glucagon were slightly enhanced, whereas the plasma levels of glucose, lactate, pyruvate, alanine, alpha-amino-N, and free fatty acids (FFA) were all reduced [8].
  • Secretin, glucagon, and vasoactive intestinal peptide, at concentrations as high as 10(-5) M, failed to alter calcium outflux and did not affect stimulation by CCK-octapeptide or by carbamycholine [9].

Chemical compound and disease context of GCG


Biological context of GCG

  • At 4 weeks' gestation (the earliest stage studied), glucagon, insulin, and somatostatin cells occurred in the dorsal pancreatic primordium, whereas pancreatic polypeptide cells occurred in the ventral primordium [15].
  • 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 [16].
  • The enhanced phosphorylation was specific for insulin and its analogs; guinea pig insulin was about 2% as potent as pork insulin, whereas epidermal growth factor, adrenocorticotropic hormone, and glucagon, as well as cAMP, were ineffective [17].
  • Similarly, substitutions in especially the far COOH-terminal part of the GLP-1 molecule with the corresponding glucagon residues, e.g. des-Arg30-[Met27,Asn28,Thr29]GLP-1, decreased the affinity for the GLP-1 receptor several hundred-fold (IC50 = 0.4-190 nM) without increasing the affinity for the glucagon receptor [18].
  • RESULTS: Among the GFP-positive cells, the fraction of precursor cells decreased by more than 85% at day 8 after infection, while the fraction of glucagon-positive cells increased 2.5-fold and the beta cell number remained the same [19].

Anatomical context of GCG

  • The glycogenolytic activity of the 3,500 mol wt peptide in the perfused rat liver did not differ significantly from glucagon, and its adenylate cyclase stimulating activity in partially purified liver cell membranes was comparable to that of glucagon; the 2,900 mol wt peptide had less than 20% of these activities [20].
  • Their distribution corresponded to that of the 3,500 mol wt immunoreactivity resembling pancreatic glucagon, while the distribution of "A-like cells" in the lower small intestine corresponded to that of GLI [20].
  • Identification of glucagon in the gastrointestinal tract [20].
  • Prostaglandin E1, epinephrine, secretin, and glucagon are known inhibitors of gastric acid secretion, and each agent stimulated mucosal membrane (600 X g pellet) adenylyl cyclase activity from the corpus of the rat stomach [21].
  • The recently isolated 28-residue sequence of prosomatostatin, a putative somatostatin precursor from pig hypothalamus and intestine, was synthesized by solid-phase methodology, characterized, and tested in rats for its effects on the release of insulin, glucagon, growth hormone, and prolactin [22].

Associations of GCG with chemical compounds

  • In perfused rat hearts, 10-5 M glucagon increased myocardial cyclic AMP concentration from 1.5 plus and minus 0.1 pmoles/mg protein (N equal 12) to 2.6 plus and minus 0.1 pmoles/mg protein (N equal 12) (P less than 0.001) [23].
  • More importantly, in isolated guinea pig livers, perfused through the portal vein alone, secretin, glucagon and glycochenodeoxycholate produced changes in bile flow and composition similar to those seen in vivo [24].
  • Conversely, rat galanin increased unstimulated glucagon output (approximately 20%, P less than 0.05), potentiated the glucagon response to arginine (approximately 50%, P less than 0.05) and VIP (approximately 90%, P less than 0.05), and counteracted the suppressor effect of glucose on alpha-cell secretion [25].
  • This conclusion is supported by the observation that a "chimeric" peptide consisting of the NH2-terminal part of the glucagon molecule joined to the COOH-terminal part of the GLP-1 molecule was recognized with high affinity by both receptors [18].
  • Nevertheless, guinea pig cells bind more insulin per cell than rat cells, and insulin fully inhibits glucagon-stimulated glycerol release [26].

Physical interactions of GCG

  • The temperature dependence of glucagon binding by calmodulin shows that the association is enthalpy driven [27].

Regulatory relationships of GCG

  • Endogenous secretion of pancreatic and gut glucagon was blocked by somatostatin infusion, and then the purified gut glucagon preparation was infused [3].
  • We therefore infused synthetic porcine NPY directly into the pancreatic artery in anaesthetized pigs to study its direct in vivo influence on pancreatic blood flow and on insulin and glucagon secretion [28].
  • Contraction caused by cholecystokinin could be inhibited by proglumide and by glucagon [29].

Other interactions of GCG

  • Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig [30].
  • Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs [31].
  • Addition of salmon calcitonin, parathyroid hormone, or glucagon blocked only 12 to 18% of the binding [32].
  • On PBD 1, group A had the greatest jejunal mucosal weight and thickness (p less than 0.001), and mucosal weight had negative correlations with plasma cortisol (r = 0.829, p less than 0.001) and glucagon (r = 0.888, p less than 0.001) [33].
  • Pancreastatin in a concentration of 10(-8) mol/l had no effect on basal secretion of insulin, glucagon and somatostatin at a perfusate glucose concentration of 5 mmol/l (n = 4) and neither at 10(-8) nor 10(-7) mol/l influenced the hormone responses to acute elevations of perfusate glucose concentration from 3.5 to 11 mmol/l (n = 7) [34].

Analytical, diagnostic and therapeutic context of GCG

  • Gel filtration studies on Bio-Gel P-10 columns of a 50-fold purified porcine duodenal extract revealed a main peak of glucagon-like immunoreactivity (GLI) in the 2,900 mol wt zone and a smaller peak in the 3,500 mol wt zone, the same zone as the pancreatic glucagon marker [20].
  • Like pancreatic glucagon, samples of 3,500 mol wt material gave essentially identical measurements in radioimmunoassays employing the pancreatic glucagon-specific antiserum 30K and the GLI crossreacting antiserum 78J, whereas the 2,900 mol wt peptide gave 60-fold higher readings in the 78J assay [20].
  • Isoelectric focusing revealed the 3,500 mol wt moiety to have an isoelectric point (pI) of 6.2, the same as pancreatic glucagon, whereas the 2,900 mol wt peptide had an pI greater than 10 [20].
  • To further elucidate the nature of transient lysosomal enzyme release into bile during glucagon infusion, we analyzed pericanalicular distribution of lysosomes by quantitative electron microscopy [35].
  • This activity was separated from glucagon-(1-21) by high-performance liquid chromatography and quantitatively recovered in four minor hind peaks which eluted close to but not in a position identical to the elution position of native glucagon [36].


  1. Diet- and colonization-dependent intestinal dysfunction predisposes to necrotizing enterocolitis in preterm pigs. Sangild, P.T., Siggers, R.H., Schmidt, M., Elnif, J., Bjornvad, C.R., Thymann, T., Grondahl, M.L., Hansen, A.K., Jensen, S.K., Boye, M., Moelbak, L., Buddington, R.K., Weström, B.R., Holst, J.J., Burrin, D.G. Gastroenterology (2006) [Pubmed]
  2. Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig. Kjems, L.L., Kirby, B.M., Welsh, E.M., Veldhuis, J.D., Straume, M., McIntyre, S.S., Yang, D., Lefèbvre, P., Butler, P.C. Diabetes (2001) [Pubmed]
  3. Evidence for transformation of glucagon-like immunoreactivity of gut into pancreatic glucagon in vivo. Korányi, L., Péterfy, F., Szabó, J., Török, A., Guóth, M., Tamás, G. Diabetes (1981) [Pubmed]
  4. Glucoregulatory function of glucagon in hypo-, eu- and hyperthyroid miniature pigs. Müller, M.J., Mitchinson, P.E., Paschen, U., Seitz, H.J. Diabetologia (1988) [Pubmed]
  5. Biochemical changes in a porcine model of acute pancreatitis. Marenberg, S.P., Lott, J.A., Pflug, B.K., Kibbey, W.E., Carey, L.C. Clin. Chem. (1978) [Pubmed]
  6. Relationship of glicentin to proglucagon and glucagon in the porcine pancreas. Moody, A.J., Holst, J.J., Thim, L., Jensen, S.L. Nature (1981) [Pubmed]
  7. Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Tatemoto, K., Mutt, V. Nature (1980) [Pubmed]
  8. Effect of ketone bodies on glucose production and utilization in the miniature pig. Müller, M.J., Paschen, U., Seitz, H.J. J. Clin. Invest. (1984) [Pubmed]
  9. Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells. Gardner, J.D., Conlon, T.P., Kleveman, H.L., Adams, T.D., Ondetti, M.A. J. Clin. Invest. (1975) [Pubmed]
  10. Effects of porcine intestinal heptacosapeptide and vasoactive intestinal polypeptide on insulin and glucagon secretion in rats. Szecówka, J., Lins, P.E., Tatemoto, K., Efendić, S. Endocrinology (1983) [Pubmed]
  11. Acute hyperinsulinemia restrains endotoxin-induced systemic inflammatory response: an experimental study in a porcine model. Brix-Christensen, V., Andersen, S.K., Andersen, R., Mengel, A., Dyhr, T., Andersen, N.T., Larsson, A., Schmitz, O., Ørskov, H., Tønnesen, E. Anesthesiology (2004) [Pubmed]
  12. Mechanism of activation of adenylate cyclase by Vibrio cholerae enterotoxin. Relations to the mode of activation by hormones. Bennett, V., Mong, L., Cuatrecasas, P. J. Membr. Biol. (1975) [Pubmed]
  13. Endorphins in septic shock: hemodynamic and endocrine effects of an opiate receptor antagonist and agonist. Gahhos, F.N., Chiu, R.C., Hinchey, E.J., Richards, G.K. Archives of surgery (Chicago, Ill. : 1960) (1982) [Pubmed]
  14. Does hyperoxia affect glucose regulation and transport in the newborn? Bandali, K.S., Belanger, M.P., Wittnich, C. J. Thorac. Cardiovasc. Surg. (2003) [Pubmed]
  15. Ontogeny of endocrine cells in porcine gut and pancreas. An immunocytochemical study. Alumets, J., Håkanson, R., Sundler, F. Gastroenterology (1983) [Pubmed]
  16. Isolation and characterization of the intestinal peptide porcine PHI (PHI-27), a new member of the glucagon--secretin family. Tatemoto, K., Mutt, V. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  17. Characterization of insulin-mediated phosphorylation of the insulin receptor in a cell-free system. Zick, Y., Kasuga, M., Kahn, C.R., Roth, J. J. Biol. Chem. (1983) [Pubmed]
  18. Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes. Hjorth, S.A., Adelhorst, K., Pedersen, B.B., Kirk, O., Schwartz, T.W. J. Biol. Chem. (1994) [Pubmed]
  19. Ectopic expression of neurogenin 3 in neonatal pig pancreatic precursor cells induces (trans)differentiation to functional alpha cells. Harb, G., Heremans, Y., Heimberg, H., Korbutt, G.S. Diabetologia (2006) [Pubmed]
  20. Identification of glucagon in the gastrointestinal tract. Sasaki, H., Rubalcava, B., Baetens, D., Blazquez, E., Srikant, C.B., Orci, L., Unger, R.H. J. Clin. Invest. (1975) [Pubmed]
  21. Rat gastric mucosal adenylyl cyclase. Thompson, W.J., Chang, L.K., Jacobson, E.D. Gastroenterology (1977) [Pubmed]
  22. Synthesis and biological actions of prosomatostatin. Meyers, C.A., Murphy, W.A., Redding, T.W., Coy, D.H., Schally, A.V. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  23. Dissociations between changes in myocardial cyclic adenosine monophosphate and contractility. Henry, P.D., Dobson, J.G., Sobel, B.E. Circ. Res. (1975) [Pubmed]
  24. The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure? Tavoloni, N., Schaffner, F. Hepatology (1985) [Pubmed]
  25. Inhibition of insulin and somatostatin secretion and stimulation of glucagon release by homologous galanin in perfused rat pancreas. Miralles, P., Peiró, E., Dégano, P., Silvestre, R.A., Marco, J. Diabetes (1990) [Pubmed]
  26. Proposed mechanism of insulin-resistant glucose transport in the isolated guinea pig adipocyte. Small intracellular pool of glucose transporters. Horuk, R., Rodbell, M., Cushman, S.W., Wardzala, L.J. J. Biol. Chem. (1983) [Pubmed]
  27. Binding of hormones and neuropeptides by calmodulin. Malencik, D.A., Anderson, S.R. Biochemistry (1983) [Pubmed]
  28. Effects of neuropeptide Y on insulin and glucagon secretion in the pig. Ahrén, B., Mårtensson, H., Falck, B. Neuropeptides (1991) [Pubmed]
  29. Cholecystokinin-induced contraction of dispersed smooth muscle cells. Collins, S.M., Gardner, J.D. Am. J. Physiol. (1982) [Pubmed]
  30. Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Plamboeck, A., Holst, J.J., Carr, R.D., Deacon, C.F. Diabetologia (2005) [Pubmed]
  31. Neutral endopeptidase 24.11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. Trebbien, R., Klarskov, L., Olesen, M., Holst, J.J., Carr, R.D., Deacon, C.F. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  32. Solubilization of calcitonin-responsive renal cortical adenylate cyclase. Queener, S.F., Fleming, J.W., Bell, N.H. J. Biol. Chem. (1975) [Pubmed]
  33. Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. Mochizuki, H., Trocki, O., Dominioni, L., Brackett, K.A., Joffe, S.N., Alexander, J.W. Ann. Surg. (1984) [Pubmed]
  34. Porcine pancreastatin has no effect on endocrine secretion from the pig pancreas. Holst, J.J., Ostenson, C.G., Harling, H., Messell, T. Diabetologia (1990) [Pubmed]
  35. Glucagon effect on intracellular proteolysis and pericanalicular location of hepatocyte lysosomes in isolated perfused guinea pig livers. Lenzen, R., Stark, P., Kolb-Bachofen, V., Strohmeyer, G. Hepatology (1995) [Pubmed]
  36. Structure-function relationships in glucagon. Re-evaluation of glucagon-(1-21). Frandsen, E.K., Thim, L., Moody, A.J., Markussen, J. J. Biol. Chem. (1985) [Pubmed]
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