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Glucagon




Glucagon
PDB rendering based on 1d0r.
Available structures: 1d0r, 1gcn, 1kx6, 2g49
Identifiers
Symbol(s) GCG; GLP1; GLP2; GRPP
External IDs OMIM: 138030 MGI: 95674 Homologene: 1553
RNA expression pattern

More reference expression data

Orthologs
Human Mouse
Entrez 2641 14526
Ensembl ENSG00000115263 ENSMUSG00000000394
Uniprot P01275 P55095
Refseq NM_002054 (mRNA)
NP_002045 (protein)
NM_008100 (mRNA)
NP_032126 (protein)
Location Chr 2: 162.71 - 162.71 Mb Chr 2: 62.28 - 62.28 Mb
Pubmed search [1] [2]
 

  Glucagon is an important hormone involved in carbohydrate metabolism. Produced by the pancreas, it is released when the glucose level in the blood is low (hypoglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin, which instructs the body's cells to take in glucose from the blood in times of satiation.

Additional recommended knowledge

Contents

History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[1] The amino acid sequence of glucagon was described in the late-1950s.[2] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

Structure

Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser- Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu- Met-Asn-Thr-COOH.

The polypeptide has a molecular weight of 3485 daltons.

Physiology

Production

The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet.

Regulatory mechanism

Increased secretion of glucagon is caused by:

Decreased secretion of glucagon (inhibition) is caused by:

Function

Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia.

  • Increased free fatty acids and ketoacids into the blood
  • Increased urea production

Mechanism of action

Glucagon binds to the glucagon receptor, a G protein-coupled receptor located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. The subunits breakup under GTP hydrolysis and the alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cAMP (cyclical AMP) which activates protein kinase A (cAMP-dependent protein kinase). This enzyme in turn activates phosphorylase B kinase, which in turn, phosphorylates phosphorylase B, converting into the active form called phosphorylase A. Phosphorylase A is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

Pathology

Abnormally-elevated levels of glucagon may be caused by pancreatic tumors such as glucagonoma, symptoms of which include necrolytic migratory erythema (NME), elevated amino acids and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.

Uses

An injectable form of glucagon is vital first aid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally. The dose for an adult is typically 1 milligram, and the glucagon is given by intramuscular, intravenous or subcutaneous injection, and quickly raises blood glucose levels. Glucagon can also be administered intravenously at 0.25 - 0.5 unit.

Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, effectively bypassing the inhibitory action of the β-adrenergic second messenger system.[3]

Glucagon acts very quickly: common side effects include headache and nausea.

Media

    Glucagon stereogram

    Rotating stereogram animation of glucagon. (1.70 MB, animated GIF format).


  • Problems seeing the videos? See media help.

References in pop culture

  • American parodist "Weird Al" Yankovic released a song entitled Pancreas on his album Straight Outta Lynwood, which uses the lyric "Insulin, Glucagon, flowing from the Islets of Langerhans" as a repeated catchy chorus in the final minute of the song.

References

  1. ^ Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. J Biol Chem 1923;58:337-348. PDF fulltext.
  2. ^ Bromer W, Winn L, Behrens O. The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence. J Am Chem Soc 1957;79:2807-2810.
  3. ^ White CM. A review of potential cardiovascular uses of intravenous glucagon administration. J Clin Pharmacol 1999;39:442-7. PMID 10234590.

Further reading

  • Kieffer TJ, Habener JF (2000). "The glucagon-like peptides.". Endocr. Rev. 20 (6): 876-913. PMID 10605628.
  • Drucker DJ (2003). "Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis.". Mol. Endocrinol. 17 (2): 161-71. PMID 12554744.
  • Jeppesen PB (2004). "Clinical significance of GLP-2 in short-bowel syndrome.". J. Nutr. 133 (11): 3721-4. PMID 14608103.
  • Brubaker PL, Anini Y (2004). "Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2.". Can. J. Physiol. Pharmacol. 81 (11): 1005-12. doi:10.1139/y03-107. PMID 14719035.
  • Baggio LL, Drucker DJ (2005). "Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2.". Best Pract. Res. Clin. Endocrinol. Metab. 18 (4): 531-54. doi:10.1016/j.beem.2004.08.001. PMID 15533774.
  • Holz GG, Chepurny OG (2006). "Diabetes outfoxed by GLP-1?". Sci. STKE 2005 (268): pe2. doi:10.1126/stke.2682005pe2. PMID 15671479.
  • Dunning BE, Foley JE, Ahrén B (2006). "Alpha cell function in health and disease: influence of glucagon-like peptide-1.". Diabetologia 48 (9): 1700-13. doi:10.1007/s00125-005-1878-0. PMID 16132964.
  • Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C (2005). "Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes.". Diabetes Metab. 31 (3 Pt 1): 233-42. PMID 16142014.
  • De León DD, Crutchlow MF, Ham JY, Stoffers DA (2006). "Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus.". Int. J. Biochem. Cell Biol. 38 (5-6): 845-59. doi:10.1016/j.biocel.2005.07.011. PMID 16202636.
  • Beglinger C, Degen L (2007). "Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY?". Physiol. Behav. 89 (4): 460-4. doi:10.1016/j.physbeh.2006.05.048. PMID 16828127.
  • Stephens JW, Bain SC (2007). "Safety and adverse effects associated with GLP-1 analogues.". Expert opinion on drug safety 6 (4): 417-22. doi:10.1517/14740338.6.4.417. PMID 17688385.
  • Orskov C, Bersani M, Johnsen AH, et al. (1989). "Complete sequences of glucagon-like peptide-1 from human and pig small intestine.". J. Biol. Chem. 264 (22): 12826-9. PMID 2753890.
  • Drucker DJ, Asa S (1988). "Glucagon gene expression in vertebrate brain.". J. Biol. Chem. 263 (27): 13475-8. PMID 2901414.
  • Novak U, Wilks A, Buell G, McEwen S (1987). "Identical mRNA for preproglucagon in pancreas and gut.". Eur. J. Biochem. 164 (3): 553-8. PMID 3569278.
  • White JW, Saunders GF (1986). "Structure of the human glucagon gene.". Nucleic Acids Res. 14 (12): 4719-30. PMID 3725587.
  • Schroeder WT, Lopez LC, Harper ME, Saunders GF (1984). "Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37.". Cytogenet. Cell Genet. 38 (1): 76-9. PMID 6546710.
  • Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC (1983). "Exon duplication and divergence in the human preproglucagon gene.". Nature 304 (5924): 368-71. PMID 6877358.
  • Kärgel HJ, Dettmer R, Etzold G, et al. (1982). "Action of rat liver cathepsin L on glucagon.". Acta Biol. Med. Ger. 40 (9): 1139-43. PMID 7340337.
  • Wayman GA, Impey S, Wu Z, et al. (1994). "Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo.". J. Biol. Chem. 269 (41): 25400-5. PMID 7929237.
  • Unson CG, Macdonald D, Merrifield RB (1993). "The role of histidine-1 in glucagon action.". Arch. Biochem. Biophys. 300 (2): 747-50. doi:10.1006/abbi.1993.1103. PMID 8382034.

See also

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Glucagon". A list of authors is available in Wikipedia.
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