Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose in the bloodstream. Its effect is opposite to that of insulin, which lowers the glucose.
The pancreas releases glucagon when the concentration of glucose in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into 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. It increases energy expenditure and is elevated under conditions of stress. Glucagon belongs to a family of several other related hormones.
Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have 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 glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.
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|Molar mass||3482.747314 g/mol|
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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. 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 beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, in effect bypassing the β-adrenergic second messenger system.
Impacted food bolus
Glucagon relaxes the 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.
Endoscopic retrograde cholangiopancreatography
Glucagon's effect of decreasing cAMP causes relaxation of splanchnic smooth muscle, allowing cannulation of the duodenum during the endoscopic retrograde cholangiopancreatography (ERCP) procedure.
Glucagon acts very quickly; common side-effects include headache and nausea.
While glucagon can be used clinically to treat various forms of hypoglycemia, it is contraindicated in patients with pheochromocytoma, as it can induce the tumor to release catecholamines, leading to a sudden elevation in blood pressure. Likewise, glucagon is contraindicated in patients with an insulinoma, as its hyperglycemic effect can induce the tumor to release insulin, leading to rebound hypoglycemia.
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 subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.
Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b, converting it into the active form called phosphorylase a. Phosphorylase a is the enzyme responsible for the release of 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 pyruvate kinase.
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. Production, which is otherwise freerunning, is suppressed/regulated by insulin from the adjacent beta cells. When blood sugar drops, insulin production drops and more glucagon is produced. 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.
Secretion of glucagon is stimulated by:
- Epinephrine (via β2, α2, and α1 adrenergic receptors)
- Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
Secretion of glucagon is inhibited by:
- Insulin (via GABA)
- PPARγ/retinoid X receptor heterodimer.
- Increased free fatty acids and keto acids into the blood.
- Increased urea production
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.
Glucagon is generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).
Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema, reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.
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.
- Diabetes mellitus
- Glucagon-like peptide-1
- Glucagon-like peptide-2
- Islets of Langerhans
- Tyrosine kinase
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