Glucagon

Template:PBB Glucagon is a hormone, secreted by the pancreas, that raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels.^[1] The pancreas releases glucagon when blood glucose levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. Glucagon also stimulates the release of insulin, so that glucose can 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 the right level.

Function

Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below

Glucagon helps maintain the level of glucose in the blood.

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 also regulates the rate of glucose production through lipolysis.

Glucagon production appears to be dependent on the central nervous system through pathways that 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. ^[2]

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 subunit. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cAMP (cyclic 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.

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.

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 (non-steroid) hormone.

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 (inhibition) of glucagon is caused by:

Somatostatin
Insulin
Increased free fatty acids and ketoacids into the blood
Increased urea production

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 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.

Media

References

^ Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ RL Leinen, AJ Giannini. Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish. Society for Neuroscience Abstracts. 9:604, 1983
^ Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. J Biol Chem 1923;58:337-348. PDF fulltext.
^ 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.
^ White CM. A review of potential cardiovascular uses of intravenous glucagon administration. J Clin Pharmacol 1999;39:442-7. PMID 10234590.