Glucagon

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Glucagon

PDB rendering based on 1GCN.
Identifiers
Symbols GCG; GLP1; GLP2; GRPP
External IDs OMIM: 138030 MGI: 95674 HomoloGene: 1553 GeneCards: GCG Gene
RNA expression pattern
PBB GE GCG 206422 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2641 14526
Ensembl ENSG00000115263 ENSMUSG00000000394
UniProt P01275 P55095
RefSeq (mRNA) NM_002054.3 NM_008100.3
RefSeq (protein) NP_002045.1 NP_032126.1
Location (UCSC) Chr 2:
163 – 163.01 Mb		 Chr 2:
62.31 – 62.32 Mb
PubMed search [1] [2]

Glucagon,is a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels.[1] The pancreas releases glucagon when blood sugar (glucose) levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High blood glucose levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level. Glucagon belongs to a family of several other related hormones.

Contents

[hide]

[edit] Physiology

[edit] 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.

[edit] Regulatory mechanism

Increased secretion of glucagon is caused by:

Decreased secretion (inhibition) of glucagon is caused by:

[edit] Function

A microscopic image stained for glucagon

Glucagon helps maintain the level of glucose in the blood.

Glucagon
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
ATC code  ?
PubChem CID 16186314
ChemSpider 10481928
UNII 76LA80IG2G YesY
ChEMBL CHEMBL266481
Chemical data
Formula  ?


Glucose is stored in the liver in the form of glycogen, which is a starch-like polymer chain made up of glucose molecules. Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen polymer into individual glucose molecules, and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.

Glucagon also regulates the rate of glucose production through lipolysis.

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.[2]

[edit] 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. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), 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.

[edit] History

In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[3] The amino acid sequence of glucagon was described in the late 1950s.[4] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

[edit] 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. Glucagon is a peptide (nonsteroid) hormone.

[edit] Pathology

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

[edit] Uses

An injectable form of glucagon, manufactured by Eli Lilly and Company, is vital first aid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally. A competing product, sold by Novo Nordisk, is branded as the GlucaGen HypoKit. With both products, 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. To use the injectable form, it must be reconstituted prior to use, a step that requires a sterile diluent to be injected into a vial containing powdered glucagon, because the hormone is highly unstable when dissolved in solution. When dissolved in a fluid state, glucagon can form amyloid fibrils, or tightly woven chains of proteins made up of the individual glucagon peptides, and once glucagon begins to fibrilize, it becomes useless when injected, as the glucagon cannot be absorbed and used by the body. The reconstitution process makes using glucagon cumbersome, although there are a number of products now in development from a number of companies which aim to make the product easier to use.

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 β-adrenergic second messenger system.[5]

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

Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed.

[edit] Media

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

[edit] See also

[edit] References

  1. ^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5. 
  2. ^ Leinen RL, Giannini AJ (1983). "Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish". Society for Neuroscience Abstracts 9: 604. 
  3. ^ Kimball C, Murlin J (1923). "Aqueous extracts of pancreas III. Some precipitation reactions of insulin". J. Biol. Chem. 58 (1): 337–348. http://www.jbc.org/cgi/reprint/58/1/337. 
  4. ^ Bromer W, Winn L, Behrens O (1957). "The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence.". J. Am. Chem. Soc. 79 (11): 2807–2810. doi:10.1021/ja01568a038. 
  5. ^ White CM (May 1999). "A review of potential cardiovascular uses of intravenous glucagon administration". J Clin Pharmacol 39 (5): 442–7. PMID 10234590. 

[edit] Further reading

Retrieved from "http://en.wikipedia.org/wiki/Glucagon"
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