PBB: geneid=2641 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. However, glucagon also paradoxically stimulates the release of insulin, so that newly available glucose in the bloodstream can be taken up and used by insulin-dependent tissues.

History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties. They described glucagon in 1923. The amino acid sequence of glucagon was described in the late-1950s. 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.

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
• Increased free fatty acids and ketoacids into the blood
• Increased urea production

Function

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.

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 GDP molecule, that was bound to the α subunit, to be replaced with a GTP molecule. This substitution results in the α subunit releasing from the β and γ subunit. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.