Glucagon 249953 225137658 2008-07-12T02:10:03Z Borgx 271227 +id {{PBB|geneid=2641}} '''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. == History == In the 1920s, Kimball and Murlin studied [[pancreas|pancreatic]] extracts and found an additional substance with [[hyperglycemia|hyperglycemic]] properties. They described glucagon in 1923.<ref>Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. ''J Biol Chem'' 1923;58:337-348. [http://www.jbc.org/cgi/reprint/58/1/337 PDF fulltext].</ref> The amino acid sequence of glucagon was described in the late-1950s.<ref>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.</ref> A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific [[radioimmunoassay]] was developed. ==Structure== [[Image:Glucagon.png|thumb|right|200px|Glucagon ball and stick model, with the [[carboxyl]] terminus above and the [[amino]] terminus below]] Glucagon is a 29-[[amino acid]] [[polypeptide]]. Its [[primary structure]] in humans is: [[amine|NH<sub>2</sub>]]-[[Histidine|His]]-[[Serine|Ser]]-[[Glutamine|Gln]]-[[Glycine|Gly]]-[[Threonine|Thr]]-[[Phenylalanine|Phe]]- [[Threonine|Thr]]-[[Serine|Ser]]-[[Aspartic acid|Asp]]-[[Tyrosine|Tyr]]-[[Serine|Ser]]-[[Lysine|Lys]]-[[Tyrosine|Tyr]]-[[Leucine|Leu]]-[[Aspartic acid|Asp]]-[[Serine|Ser]]- [[Arginine|Arg]]-[[Arginine|Arg]]-[[Alanine|Ala]]-[[Glutamine|Gln]]-[[Aspartic acid|Asp]]-[[Phenylalanine|Phe]]-[[Valine|Val]]-[[Glutamine|Gln]]-[[Tryptophan|Trp]]-[[Leucine|Leu]]- [[Methionine|Met]]-[[Asparagine|Asn]]-[[Threonine|Thr]]-[[carboxyl group|COOH]]. The polypeptide has a [[molecular weight]] of 3485 [[Atomic mass unit|dalton]]s. ==Physiology== [[Image:Glucagon rednblue.png|thumb|right|200px|A microscopic image stained for glucagon.]] ===Production=== The hormone is synthesized and secreted from [[alpha cell]]s (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 [[plasma glucose]] * Increased [[catecholamines]] - [[norepinephrine]] and [[epinephrine]] * Increased plasma [[amino acids]] (to protect from [[hypoglycemia]] if an all protein meal is consumed) * [[Sympathetic nervous system]] * [[Acetylcholine]] * [[Cholecystokinin]] Decreased secretion of glucagon (inhibition) is caused by: * [[Somatostatin]] * [[Insulin]] ===Function=== Glucagon helps maintain the level of [[glucose]] in the [[blood]] by binding to [[glucagon receptor]]s on [[hepatocyte]]s, 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]]. Glucagon also regulates the rate of glucose production through [[lipolysis]]. Glucagon production appears to be dependent on the central nervous system through pathways which are yet to be defined. It has been reported that in invertebrate animals eyestalk removal can affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia. <ref> RL Leinen, AJ Giannini. Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish. Society for Neuroscience Abstracts. 9:604, 1983 </ref> * 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 protein]]s, a heterotrimeric protein with α, β, and γ subunits. The subunits breakup as a result of substitution of a GDP molecule with a GTP mol, 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 kinase]], which in turn, phosphorylates [[glycogen phosphorylase]], 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 [[tumor]]s 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 blocker]]s; the likely mechanism of action is the increase of cAMP in the [[myocardium]], effectively bypassing the inhibitory action of the [[Adrenergic receptor|β-adrenergic]] [[second messenger system]].<ref>White CM. A review of potential cardiovascular uses of intravenous glucagon administration. ''J Clin Pharmacol'' 1999;39:442-7. PMID 10234590.</ref> Glucagon acts very quickly: common side effects include headache and nausea. Drug interactions: Glucagon interacts only with oral anticoagulants increasing the tendency to bleed. ==Media== [[image:Glucagon stereo animation.gif|thumb|center|Rotating [[stereogram]] animation of glucagon. (1.70 [[Megabyte|MB]], [[animated GIF]] format).]] ==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== <references/> ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{cite journal | author=Kieffer TJ, Habener JF |title=The glucagon-like peptides |journal=Endocr. Rev. |volume=20 |issue= 6 |pages= 876–913 |year= 2000 |pmid= 10605628 |doi= }} *{{cite journal | author=Drucker DJ |title=Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis |journal=Mol. Endocrinol. |volume=17 |issue= 2 |pages= 161–71 |year= 2003 |pmid= 12554744| doi=10.1210/me.2002-0306}} *{{cite journal | author=Jeppesen PB |title=Clinical significance of GLP-2 in short-bowel syndrome |journal=J. Nutr. |volume=133 |issue= 11 |pages= 3721–4 |year= 2004 |pmid= 14608103 |doi= }} *{{cite journal | author=Brubaker PL, Anini Y |title=Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2 |journal=Can. J. Physiol. Pharmacol. |volume=81 |issue= 11 |pages= 1005–12 |year= 2004 |pmid= 14719035 |doi= 10.1139/y03-107 }} *{{cite journal | author=Baggio LL, Drucker DJ |title=Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2 |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=18 |issue= 4 |pages= 531–54 |year= 2005 |pmid= 15533774 |doi= 10.1016/j.beem.2004.08.001 }} *{{cite journal | author=Holz GG, Chepurny OG |title=Diabetes outfoxed by GLP-1? |journal=Sci. STKE |volume=2005 |issue= 268 |pages= pe2 |year= 2006 |pmid= 15671479 |doi= 10.1126/stke.2682005pe2 }} *{{cite journal | author=Dunning BE, Foley JE, Ahrén B |title=Alpha cell function in health and disease: influence of glucagon-like peptide-1 |journal=Diabetologia |volume=48 |issue= 9 |pages= 1700–13 |year= 2006 |pmid= 16132964 |doi= 10.1007/s00125-005-1878-0 }} *{{cite journal | author=Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C |title=Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes |journal=Diabetes Metab. |volume=31 |issue= 3 Pt 1 |pages= 233–42 |year= 2005 |pmid= 16142014| doi=10.1016/S1262-3636(07)70190-8}} *{{cite journal | author=De León DD, Crutchlow MF, Ham JY, Stoffers DA |title=Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus |journal=Int. J. Biochem. Cell Biol. |volume=38 |issue= 5-6 |pages= 845–59 |year= 2006 |pmid= 16202636 |doi= 10.1016/j.biocel.2005.07.011 }} *{{cite journal | author=Beglinger C, Degen L |title=Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY? |journal=Physiol. Behav. |volume=89 |issue= 4 |pages= 460–4 |year= 2007 |pmid= 16828127 |doi= 10.1016/j.physbeh.2006.05.048 }} *{{cite journal | author=Stephens JW, Bain SC |title=Safety and adverse effects associated with GLP-1 analogues |journal=Expert opinion on drug safety |volume=6 |issue= 4 |pages= 417–22 |year= 2007 |pmid= 17688385 |doi= 10.1517/14740338.6.4.417 }} *{{cite journal | author=Orskov C, Bersani M, Johnsen AH, ''et al.'' |title=Complete sequences of glucagon-like peptide-1 from human and pig small intestine |journal=J. Biol. Chem. |volume=264 |issue= 22 |pages= 12826–9 |year= 1989 |pmid= 2753890 |doi= }} *{{cite journal | author=Drucker DJ, Asa S |title=Glucagon gene expression in vertebrate brain |journal=J. Biol. Chem. |volume=263 |issue= 27 |pages= 13475–8 |year= 1988 |pmid= 2901414 |doi= }} *{{cite journal | author=Novak U, Wilks A, Buell G, McEwen S |title=Identical mRNA for preproglucagon in pancreas and gut |journal=Eur. J. Biochem. |volume=164 |issue= 3 |pages= 553–8 |year= 1987 |pmid= 3569278| doi=10.1111/j.1432-1033.1987.tb11162.x}} *{{cite journal | author=White JW, Saunders GF |title=Structure of the human glucagon gene |journal=Nucleic Acids Res. |volume=14 |issue= 12 |pages= 4719–30 |year= 1986 |pmid= 3725587| doi=10.1093/nar/14.12.4719}} *{{cite journal | author=Schroeder WT, Lopez LC, Harper ME, Saunders GF |title=Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37 |journal=Cytogenet. Cell Genet. |volume=38 |issue= 1 |pages= 76–9 |year= 1984 |pmid= 6546710 |doi= }} *{{cite journal | author=Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC |title=Exon duplication and divergence in the human preproglucagon gene |journal=Nature |volume=304 |issue= 5924 |pages= 368–71 |year= 1983 |pmid= 6877358| doi=10.1038/304368a0}} *{{cite journal | author=Kärgel HJ, Dettmer R, Etzold G, ''et al.'' |title=Action of rat liver cathepsin L on glucagon |journal=Acta Biol. Med. Ger. |volume=40 |issue= 9 |pages= 1139–43 |year= 1982 |pmid= 7340337 |doi= }} *{{cite journal | author=Wayman GA, Impey S, Wu Z, ''et al.'' |title=Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo |journal=J. Biol. Chem. |volume=269 |issue= 41 |pages= 25400–5 |year= 1994 |pmid= 7929237 |doi= }} *{{cite journal | author=Unson CG, Macdonald D, Merrifield RB |title=The role of histidine-1 in glucagon action |journal=Arch. Biochem. Biophys. |volume=300 |issue= 2 |pages= 747–50 |year= 1993 |pmid= 8382034 |doi= 10.1006/abbi.1993.1103 }} }} {{refend}} ==See also== * [[Insulin]] * [[Diabetes mellitus]] * [[Proglucagon]] * [[Glucagon-like peptide-1]] * [[Glucagon-like peptide-2]] * [[Islets of Langerhans]] * [[Pancreas]] {{Hormones}} {{Proglucagon}} [[Category:Peptide hormones]] [[Category:Pancreatic hormones]] [[Category:Hepatology]] [[Category:Metabolism]] [[bs:Glukagon]] [[bg:Глюкагон]] [[cs:Glukagon]] [[da:Glukagon]] [[de:Glucagon]] [[dv:ގްލޫކަގޮން]] [[es:Glucagón]] [[eo:Glukagono]] [[fr:Glucagon]] [[id:Glukagon]] [[is:Glúkagon]] [[it:Glucagone]] [[he:גלוקגון]] [[pam:Glucagon]] [[la:Glucagon]] [[lt:Gliukagonas]] [[mk:Глукагон]] [[ms:Glukagon]] [[nl:Glucagon]] [[ja:グルカゴン]] [[no:Glukagon]] [[pl:Glukagon]] [[pt:Glucagon]] [[ru:Глюкагон]] [[sq:Glukagoni]] [[sr:Глукагон]] [[fi:Glukagoni]] [[sv:Glukagon]] [[ta:குளூக்கொகான்]] [[tr:Glükagon]] [[zh:胰高血糖素]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}