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Gene Review

GCG  -  glucagon

Homo sapiens

Synonyms: GLP1, GLP2, GRPP, Glucagon
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Disease relevance of GCG

  • Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus [1].
  • This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder [2].
  • GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome [3].
  • The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder [4].
  • BACKGROUND & AIMS: The gut-derived peptide glucagon-like peptide 2 (GLP-2) has been suggested as a potential drug candidate for the treatment of various intestinal diseases [5].

Psychiatry related information on GCG


High impact information on GCG

  • Recent studies have demonstrated that it is feasible to regenerate and expand the beta-cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others [10].
  • In addition to the energetic or nutritional contributions of VFA to the body, the VFA may indirectly influence cholesterol synthesis and even help regulate insulin or glucagon secretion [11].
  • We administered 1 mg of glucagon intravenously immediately before CT scanning to minimize the degree of smooth-muscle spasm and peristalsis and to reduce the patient's discomfort [12].
  • Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy [13].
  • Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor [14].

Chemical compound and disease context of GCG

  • Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis [3].
  • Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic effects should minimize any risk of severe hypoglycemia [15].
  • Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-microg GLP-2 group (p < 0.01) [16].
  • CONCLUSIONS: The results of this study suggest that apart from decreasing insulin resistance as a result of weight loss, orlistat may increase postprandial GLP-1 levels, thereby enhancing the insulin secretory response to the meal and blunting the postprandial rise in glucose in type 2 diabetic patients [17].
  • Tubular carcinoids lacked argentaffinity and serotonin but were diffusely and strongly positive for glucagon [18].

Biological context of GCG

  • The genomic sequence that includes GCG was found to have a long history of gene duplication events [19].
  • Some members of the glucagon-like family of genes, GCG on chromosome 2 and GIP on chromosome 17, may be products of ancient genome duplications on the early vertebrate lineage [19].
  • Recently, a processed pseudogene of the X-chromosome-linked gene TIMM8A was inserted downstream of GCG [19].
  • The human proglucagon gene (GCG) is encoded within a finished 576-kb DNA sequence generated by the Human Genome Project. GCG is flanked by 18 kb and 65 kb of DNA, 5' and 3', respectively, that do not encode genes [19].
  • Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37 [20].

Anatomical context of GCG


Associations of GCG with chemical compounds

  • The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors) [22].
  • Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates [1].
  • Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV) [3].
  • Postprandial plasma concentrations of triglycerides and free fatty acids were significantly higher during GLP-2 infusion compared with placebo (P < .01), while glycerol concentrations were similar (P = .07) [5].
  • METHODS: Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 or placebo over 120 minutes in the fasting state, and pentagastrin-stimulated gastric acid output was assessed [5].

Physical interactions of GCG

  • All three Xenopus GLP-1-like peptides bind effectively to the hGLP-1R and stimulate cAMP production [21].
  • In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus [23].
  • The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist [24].
  • DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects [25].
  • Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line [26].

Enzymatic interactions of GCG


Co-localisations of GCG

  • TFF3 immunoreactivity was colocalized with insulin and glucagon in distinct cell clusters in human fetal pancreas at wk 14 and in the newborn rat pancreas [30].
  • IAPP was colocalized with insulin and glucagon in the immature and nondifferentiated cell granules in both species [31].

Regulatory relationships of GCG


Other interactions of GCG

  • In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity [1].
  • Infusion of somatostatin, an inhibitor of glucagon secretion, in insulin-dependent diabetics resulted in a 75-100% reduction in the blood-glucose rise after oral glucose administration, but did not improve intravenous glucose tolerance [37].
  • Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases [3].
  • In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms [38].
  • These results demonstrate that despite an average of nine amino acid differences between the predicted Xenopus GLPs and hGLP-1, all act as hGLP-1R agonists [21].

Analytical, diagnostic and therapeutic context of GCG


  1. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. Nauck, M.A., Heimesaat, M.M., Orskov, C., Holst, J.J., Ebert, R., Creutzfeldt, W. J. Clin. Invest. (1993) [Pubmed]
  2. Glucagon receptor of human liver. Studies of its molecular weight and binding properties, and its ability to activate hepatic adenylyl cyclase of non-obese and obese subjects. Livingston, J.N., Einarsson, K., Backman, L., Ewerth, S., Arner, P. J. Clin. Invest. (1985) [Pubmed]
  3. Biological actions and therapeutic potential of the glucagon-like peptides. Drucker, D.J. Gastroenterology (2002) [Pubmed]
  4. Glucagon-like peptide-1 7-36: a physiological incretin in man. Kreymann, B., Williams, G., Ghatei, M.A., Bloom, S.R. Lancet (1987) [Pubmed]
  5. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Meier, J.J., Nauck, M.A., Pott, A., Heinze, K., Goetze, O., Bulut, K., Schmidt, W.E., Gallwitz, B., Holst, J.J. Gastroenterology (2006) [Pubmed]
  6. Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans. Pannacciulli, N., Le, D.S., Salbe, A.D., Chen, K., Reiman, E.M., Tataranni, P.A., Krakoff, J. Neuroimage (2007) [Pubmed]
  7. GLP-1 as a satiety factor in children with eating disorders. Tomasik, P.J., Sztefko, K., Malek, A. Horm. Metab. Res. (2002) [Pubmed]
  8. Reversal of a neurologic paraneoplastic syndrome with octreotide (Sandostatin) in a patient with glucagonoma. Holmes, A., Kilpatrick, C., Proietto, J., Green, M.D. Am. J. Med. (1991) [Pubmed]
  9. Appetite regulatory hormone responses to various dietary proteins differ by body mass index status despite similar reductions in ad libitum energy intake. Bowen, J., Noakes, M., Clifton, P.M. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  10. Regulation of pancreatic beta-cell mass. Bouwens, L., Rooman, I. Physiol. Rev. (2005) [Pubmed]
  11. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Bergman, E.N. Physiol. Rev. (1990) [Pubmed]
  12. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. Fenlon, H.M., Nunes, D.P., Schroy, P.C., Barish, M.A., Clarke, P.D., Ferrucci, J.T. N. Engl. J. Med. (1999) [Pubmed]
  13. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Brais, B., Bouchard, J.P., Xie, Y.G., Rochefort, D.L., Chrétien, N., Tomé, F.M., Lafrenière, R.G., Rommens, J.M., Uyama, E., Nohira, O., Blumen, S., Korczyn, A.D., Heutink, P., Mathieu, J., Duranceau, A., Codère, F., Fardeau, M., Rouleau, G.A., Korcyn, A.D. Nat. Genet. (1998) [Pubmed]
  14. A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Hager, J., Hansen, L., Vaisse, C., Vionnet, N., Philippi, A., Poller, W., Velho, G., Carcassi, C., Contu, L., Julier, C. Nat. Genet. (1995) [Pubmed]
  15. Therapeutic strategies based on glucagon-like peptide 1. Deacon, C.F. Diabetes (2004) [Pubmed]
  16. Role of gastrointestinal hormones in postprandial reduction of bone resorption. Henriksen, D.B., Alexandersen, P., Bjarnason, N.H., Vilsbøll, T., Hartmann, B., Henriksen, E.E., Byrjalsen, I., Krarup, T., Holst, J.J., Christiansen, C. J. Bone Miner. Res. (2003) [Pubmed]
  17. Orlistat augments postprandial increases in glucagon-like peptide 1 in obese type 2 diabetic patients. Damci, T., Yalin, S., Balci, H., Osar, Z., Korugan, U., Ozyazar, M., Ilkova, H. Diabetes Care (2004) [Pubmed]
  18. Appendiceal carcinoids: correlation of histology and immunohistochemistry. Burke, A.P., Sobin, L.H., Federspiel, B.H., Shekitka, K.M. Mod. Pathol. (1989) [Pubmed]
  19. Ancient duplications of the human proglucagon gene. Irwin, D.M. Genomics (2002) [Pubmed]
  20. Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37. Schroeder, W.T., Lopez, L.C., Harper, M.E., Saunders, G.F. Cytogenet. Cell Genet. (1984) [Pubmed]
  21. The Xenopus proglucagon gene encodes novel GLP-1-like peptides with insulinotropic properties. Irwin, D.M., Satkunarajah, M., Wen, Y., Brubaker, P.L., Pederson, R.A., Wheeler, M.B. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  22. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Sherwood, N.M., Krueckl, S.L., McRory, J.E. Endocr. Rev. (2000) [Pubmed]
  23. Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. Runge, S., Gram, C., Brauner-Osborne, H., Madsen, K., Knudsen, L.B., Wulff, B.S. J. Biol. Chem. (2003) [Pubmed]
  24. The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist. Thulesen, J., Knudsen, L.B., Hartmann, B., Hastrup, S., Kissow, H., Jeppesen, P.B., Ørskov, C., Holst, J.J., Poulsen, S.S. Regul. Pept. (2002) [Pubmed]
  25. Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes. Mest, H.J., Mentlein, R. Diabetologia (2005) [Pubmed]
  26. Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line. Gros, L., Thorens, B., Bataille, D., Kervran, A. Endocrinology (1993) [Pubmed]
  27. mRNA levels of dipeptidyl peptidase IV decrease during intestinal adaptation. Dunphy, J.L., Justice, F.A., Taylor, R.G., Fuller, P.J. J. Surg. Res. (1999) [Pubmed]
  28. Glucagon-mediated internalization of serine-phosphorylated glucagon receptor and Gsalpha in rat liver. Merlen, C., Fabrega, S., Desbuquois, B., Unson, C.G., Authier, F. FEBS Lett. (2006) [Pubmed]
  29. The specificity of cathepsin B. Hydrolysis of glucagon at the C-terminus by a peptidyldipeptidase mechanism. Aronson, N.N., Barrett, A.J. Biochem. J. (1978) [Pubmed]
  30. Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone. Jackerott, M., Lee, Y.C., M??llg??rd, K., Kofod, H., Jensen, J., Rohleder, S., Neubauer, N., Gaarn, L.W., Lykke, J., Dodge, R., Dalgaard, L.T., S??strup, B., Jensen, D.B., Thim, L., Nex??, E., Thams, P., Bisgaard, H.C., Nielsen, J.H. Endocrinology (2006) [Pubmed]
  31. Expression of islet amyloid polypeptide in fetal and adult porcine and human pancreatic islet cells. Lukinius, A., Korsgren, O., Grimelius, L., Wilander, E. Endocrinology (1997) [Pubmed]
  32. The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Toft-Nielson, M., Madsbad, S., Holst, J.J. Diabetes (1996) [Pubmed]
  33. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Buteau, J., Foisy, S., Joly, E., Prentki, M. Diabetes (2003) [Pubmed]
  34. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Meier, J.J., Gallwitz, B., Siepmann, N., Holst, J.J., Deacon, C.F., Schmidt, W.E., Nauck, M.A. Diabetologia (2003) [Pubmed]
  35. Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Huypens, P., Ling, Z., Pipeleers, D., Schuit, F. Diabetologia (2000) [Pubmed]
  36. Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors. Longenecker, K.L., Stewart, K.D., Madar, D.J., Jakob, C.G., Fry, E.H., Wilk, S., Lin, C.W., Ballaron, S.J., Stashko, M.A., Lubben, T.H., Yong, H., Pireh, D., Pei, Z., Basha, F., Wiedeman, P.E., von Geldern, T.W., Trevillyan, J.M., Stoll, V.S. Biochemistry (2006) [Pubmed]
  37. Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. Wahren, J. Lancet (1976) [Pubmed]
  38. Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Kvols, L.K., Buck, M., Moertel, C.G., Schutt, A.J., Rubin, J., O'Connell, M.J., Hahn, R.G. Ann. Intern. Med. (1987) [Pubmed]
  39. Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Munroe, D.G., Gupta, A.K., Kooshesh, F., Vyas, T.B., Rizkalla, G., Wang, H., Demchyshyn, L., Yang, Z.J., Kamboj, R.K., Chen, H., McCallum, K., Sumner-Smith, M., Drucker, D.J., Crivici, A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  40. Complete sequences of glucagon-like peptide-1 from human and pig small intestine. Orskov, C., Bersani, M., Johnsen, A.H., Højrup, P., Holst, J.J. J. Biol. Chem. (1989) [Pubmed]
  41. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Meier, J.J., Nauck, M.A., Kranz, D., Holst, J.J., Deacon, C.F., Gaeckler, D., Schmidt, W.E., Gallwitz, B. Diabetes (2004) [Pubmed]
  42. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Orskov, C., Wettergren, A., Holst, J.J. Diabetes (1993) [Pubmed]
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