Glucagon

Glucagon is a is_associated_with::peptide hormone, produced by is_associated_with::alpha cells of the is_associated_with::pancreas, that raises the concentration of is_associated_with::glucose in the bloodstream. Its effect is opposite that of is_associated_with::insulin, which lowers the glucose concentration. The pancreas releases glucagon when the concentration of glucose in the bloodstream falls too low. Glucagon causes the is_associated_with::liver to convert stored is_associated_with::glycogen into is_associated_with::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.

Function
Glucagon generally elevates the concentration of is_associated_with::glucose in the is_associated_with::blood by promoting is_associated_with::gluconeogenesis and is_associated_with::glycogenolysis.

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

Glucagon also regulates the rate of glucose production through is_associated_with::lipolysis. Glucagon induces is_associated_with::lipolysis in humans under conditions of insulin suppression (such as is_associated_with::diabetes mellitus type 1).

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



Hypoglycemia
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 is_associated_with::blood glucose levels. 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 that aim to make the product easier to use.

Beta blocker overdose
Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with is_associated_with::beta blockers; the likely mechanism of action is the increase of cAMP in the is_associated_with::myocardium, in effect bypassing the β-adrenergic is_associated_with::second messenger system.

Anaphylaxis
Some people who have is_associated_with::anaphylaxis and are on beta blockers are resistant to is_associated_with::epinephrine. In this situation glucagon intravenously may be useful to treat their low blood pressure.

Impacted food bolus
Glucagon relaxes the is_associated_with::lower esophageal sphincter and may be used in those with an impacted food bolus in the esophagus ("steakhouse syndrome"). There is little evidence for glucagon's effectiveness in this condition, and glucagon may induce nausea and vomiting, but considering the safety of glucagon this is still considered an acceptable option as long it does not lead to delays in arranging other treatments.

ERCP (Endoscopic Retrograde Cholangiopancreatography)
Glucagon's effect of decreasing cAMP causes relaxation of splanchic smooth muscle, allowing cannulation of the duodenum during the ERCP procedure.

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

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

Contraindications
While glucagon can be used clinically to treat various forms of hypoglycemia, it is severely contraindicated in patients with is_associated_with::pheochromocytoma, as the drug interaction with elevated levels of is_associated_with::adrenaline produced by the tumor may produce an exponential increase in blood sugar levels, leading to a hyperglycemic state, which may incur a fatal elevation in blood pressure. Likewise, glucagon is contraindicated in patients with an is_associated_with::insulinoma, as its use may lead to rebound hypoglycemia.

Mechanism of action
Glucagon binds to the is_associated_with::glucagon receptor, a is_associated_with::G protein-coupled receptor, located in the is_associated_with::plasma membrane. The conformation change in the receptor activates is_associated_with::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, is_associated_with::adenylate cyclase.

Adenylate cyclase manufactures is_associated_with::cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates is_associated_with::protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates is_associated_with::phosphorylase kinase, which then phosphorylates is_associated_with::glycogen phosphorylase b, converting it into the active form called phosphorylase a. Phosphorylase a is the enzyme responsible for the release of is_associated_with::glucose-1-phosphate from glycogen polymers.

Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate. The enzyme protein kinase A that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis) by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA also inactivates the glycolytic enzyme is_associated_with::pyruvate kinase.

Production
The hormone is synthesized and secreted from is_associated_with::alpha cells (α-cells) of the is_associated_with::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 in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.

Regulation
Secretion of glucagon is stimulated by:
 * is_associated_with::Hypoglycemia
 * is_associated_with::Epinephrine (via β2, α2, and α1 adrenergic receptors)
 * is_associated_with::Arginine
 * is_associated_with::Alanine (often from muscle-derived pyruvate/glutamate transamination (see is_associated_with::alanine transaminase reaction).
 * is_associated_with::Acetylcholine
 * is_associated_with::Cholecystokinin

Secretion of glucagon is inhibited by:
 * is_associated_with::Somatostatin
 * is_associated_with::Insulin (via is_associated_with::GABA)
 * PPARγ/is_associated_with::retinoid X receptor heterodimer.
 * Increased free is_associated_with::fatty acids and is_associated_with::keto acids into the blood
 * Increased is_associated_with::urea production

Structure
Glucagon is a 29-is_associated_with::amino acid is_associated_with::polypeptide. Its is_associated_with::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 is_associated_with::molecular weight of 3485 daltons. Glucagon is a is_associated_with::peptide (nonis_associated_with::steroid) hormone.

Glucagon is generated from the cleavage of is_associated_with::proglucagon by is_associated_with::proprotein convertase 2 in pancreatic islet α cells. In intestinal is_associated_with::L cells, is_associated_with::proglucagon is cleaved to the alternate products is_associated_with::glicentin, is_associated_with::GLP-1 (an is_associated_with::incretin), IP-2, and is_associated_with::GLP-2 (promotes intestinal growth).

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

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 is_associated_with::radioimmunoassay was developed.

Etymology
Glucagon was named in 1923, probably from the Greek γλυκός sweet, and ἄγειν to lead.