Glucagon

From Wikipedia, the free encyclopedia

Glucagon is a 29-amino acid polypeptide acting as an important hormone in carbohydrate metabolism. The polypeptide has a molecular weight of 3485 daltons and was discovered in 1923 by Kimball and Murlin.

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

Contents 1 History 2 Physiology 2.1 Production 2.2 Regulatory mechanism 2.3 Function 2.4 Mechanism of action 3 Pathology 4 Uses 5 Media 6 References in pop culture 7 References 8 See also

[edit] History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties.^[1] Glucagon was sequenced 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.

[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. The alpha cells are located in the outer rim of the islet.

[edit] 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 consumed)
• Sympathetic nervous system
• Acetylcholine
• Cholecystokinin

Decreased secretion of glucagon (inhibition) is caused by:

• Somatostatin
• Insulin

[edit] 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

[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 alpha, beta and gamma 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 cAMP-dependent protein kinase. This enzyme in turn activates phosphorylase B kinase, which in turn, phosphorylates phosphorylase B. Phosphorylase B is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

[edit] 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.

[edit] Uses

An injectable form of glucagon is essential first aid in cases of severe hypoglycemia, usually in a dose of 1 milligram. The glucagon is given by intramuscular injection, and quickly raises blood glucose levels. Glucagon can be administered IV 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]

[edit] Media

[edit] References in pop culture

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

[edit] 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.

[edit] See also

• Insulin
• Diabetes mellitus
• Proglucagon
• Islets of Langerhans
• Pancreas