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

1 History
2 Physiology
3 Pathology
4 Uses
5 Media
6 References
7 See also

[edit] History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties.<ref>Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. J Biochem 1923;58:337-348.</ref> Glucagon was sequenced 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.

[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 - norepinphrine 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:

[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 phosphorylation 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 glucose-6-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.<ref>White CM. A review of potential cardiovascular uses of intravenous glucagon administration. J Clin Pharmacol 1999;39:442-7. PMID 10234590.</ref>