Glucagon

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

tructure

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 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 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. 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. [ RL Leinen, AJ Giannini. Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish. Society for Neuroscience Abstracts. 9:604, 1983 ]
* 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 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 tumors such as glucagonoma, symptoms of which include necrolytic migratory erythema (NME), reduced 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. [White CM. A review of potential cardiovascular uses of intravenous glucagon administration. "J Clin Pharmacol" 1999;39:442-7. PMID 10234590.]

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

[
stereogram animation of glucagon. (1.70 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.

ee also

* Insulin
* Diabetes mellitus
* Proglucagon
* Glucagon-like peptide-1
* Glucagon-like peptide-2
* Islets of Langerhans
* Pancreas

References

Further reading

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

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