Glucagon is a peptide hormone
, produced by alpha cells
of the pancreas
. It works to raise the concentration of glucose
and fatty acid
s in the bloodstream, and is considered to be the main catabolic
hormone of the body. It is also used as a medication
to treat a number of health conditions. Its effect is opposite to that of insulin
, which lowers extracellular glucose.
It is produced from proglucagon
, encoded by the ''GCG'' gene.
The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver
to engage in glycogenolysis
: converting stored glycogen
, which is released into the bloodstream. High blood-glucose levels, on the other hand, 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 stable. Glucagon increases energy expenditure and is elevated under conditions of stress. Glucagon belongs to the secretin family
Glucagon generally elevates the concentration of glucose
in the blood
by promoting gluconeogenesis
. Glucagon also decreases fatty acid synthesis in adipose tissue
and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised
to generate energy in tissues such as skeletal muscle
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 receptor
s. 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 also regulates the rate of glucose production through lipolysis
. Glucagon induces lipolysis
in humans under conditions of insulin suppression (such as diabetes mellitus type 1
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals
removal has been reported to 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
of the cell. The conformation change in the receptor activates G protein
s, 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 (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate
from glycogen polymers.
An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gɑ separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates phosphorylase kinase. Phosphorylated phosphorylase kinase phosphorylates phosphorylase. Phosphorylated phosphorylase clips glucose units from glycogen as glucose 1-phosphate.
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 (PKA) 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
A microscopic image stained for glucagon
The hormone is synthesized and secreted from alpha cell
s (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 amylin, a peptide hormone co-secreted with insulin from the pancreatic β cells. As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.
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.
Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.
Secretion of glucagon is stimulated by:
(via β2, α2,
(often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase
* Gastric inhibitory polypeptide
Secretion of glucagon is inhibited by:
/retinoid X receptor heterodimer
* Increased free fatty acids
and keto acids
into the blood.
* Increased urea
* Glucagon-like peptide-1
Glucagon is a 29-amino acid polypeptide
. Its primary structure
in humans is: NH2
The polypeptide has a molecular mass
of 3485 dalton
s. Glucagon is a peptide
Glucagon is generated from the cleavage of proglucagon
by proprotein convertase 2
in pancreatic islet α cells. In intestinal L cell
is cleaved to the alternate products glicentin, GLP-1
), IP-2, and GLP-2
(promotes intestinal growth).
Abnormally elevated levels of glucagon may be caused by pancreatic tumor
s, 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
Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis.
It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes
in patients with adequately stable blood glucose.
The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy
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
Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the ''gluc''ose ''agon''ist.
* Diabetes mellitus
* Glucagon-like peptide-1
* Glucagon-like peptide-2
* Islets of Langerhans
* Tyrosine kinase
provides an overview of all the structure information available in the PDB for Human Glucagon
Category:Hormones of glucose metabolism