Glucagon is an important
hormoneA hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms...
involved in
carbohydrate metabolismCarbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
. Produced by the
pancreasThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
, it is released when blood glucose levels start to fall too low, causing the
liverThe liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
to convert stored
glycogenGlycogen is the molecule that functions as the secondary long-term energy storage in animal cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach...
into
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
and release it into the bloodstream, raising blood glucose levels and ultimately preventing the development of
hypoglycemiaHypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" Hypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally...
. The action of glucagon is thus opposite to that of
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
, which instructs the body's cells to take in glucose from the blood. However, glucagon also 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
pancreaticThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
extracts and found an additional substance with
hyperglycemicHyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood glucose level of 10+ mmol/L , but symptoms may not start to become noticeable until later numbers such as 15-20+ mmol/L or...
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
radioimmunoassayRadioimmunoassay is a very sensitive technique used to measure concentrations of antigens without the need to use a bioassay. It was developed by Rosalyn Yalow and Solomon Aaron Berson in the 1950s...
was developed.
Structure
Glucagon is a 29-
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
polypeptide. Its
primary structureIn biochemistry, the primary structure of a biological molecule is the exact specification of its atomic composition and the chemical bonds connecting those atoms...
in humans is:
NH2Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
-
HisHistidine is one of the 20 standard amino acids present in proteins. Nutritionally, histidine is considered an essential amino acid in human infants. After reaching several years of age, humans begin to synthesize it and it thus becomes a non-essential amino acid...
-
SerSerine is an organic compound with the formula HO
2CCHCH
2OH.-Occurrence:...
-
GlnGlutamine is one of the 20 amino acids encoded by the standard genetic code. Its side chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group. It can therefore be considered the amide of glutamic acid. Its codons are CAA and CAG. Glutamine is...
-
GlyGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
-
ThrThreonine is an α-amino acid with the chemical formula HO
2CCHCHCH
3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-
PhePhenylalanine is an α-amino acid with the formula HO
2CCHCH
2C
6H
5. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. The codons for
L-phenylalanine are UUU and UUC...
-
ThrThreonine is an α-amino acid with the chemical formula HO
2CCHCHCH
3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-
SerSerine is an organic compound with the formula HO
2CCHCH
2OH.-Occurrence:...
-
AspAspartic acid is an α-amino acid with the chemical formula HO2CCHCH2CO2H. The carboxylate anion of aspartic acid is known as aspartate...
-
TyrTyrosine or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
-
SerSerine is an organic compound with the formula HO
2CCHCH
2OH.-Occurrence:...
-
LysLysine is an α-amino acid with the chemical formula HO
2CCH
4NH
2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.Lysine is a base, as are arginine and histidine...
-
TyrTyrosine or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
-
LeuLeucine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2. It is an essential amino acid, which means that humans cannot synthesise it. Its codons are UUA, UUG, CUU, CUC, CUA, and CUG. With a hydrocarbon side chain, leucine is classified as a hydrophobic...
-
AspAspartic acid is an α-amino acid with the chemical formula HO2CCHCH2CO2H. The carboxylate anion of aspartic acid is known as aspartate...
-
SerSerine is an organic compound with the formula HO
2CCHCH
2OH.-Occurrence:...
-
ArgArginine is an α-amino acid. The
L-form is one of the 20 most common natural amino acids. Its codons are CGU, CGC, CGA, CGG, AGA, and AGG. In mammals, arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health...
-
ArgArginine is an α-amino acid. The
L-form is one of the 20 most common natural amino acids. Its codons are CGU, CGC, CGA, CGG, AGA, and AGG. In mammals, arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health...
-
AlaAlanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 proteinogenic amino acids, i.e. the building blocks of proteins. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
-
GlnGlutamine is one of the 20 amino acids encoded by the standard genetic code. Its side chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group. It can therefore be considered the amide of glutamic acid. Its codons are CAA and CAG. Glutamine is...
-
AspAspartic acid is an α-amino acid with the chemical formula HO2CCHCH2CO2H. The carboxylate anion of aspartic acid is known as aspartate...
-
PhePhenylalanine is an α-amino acid with the formula HO
2CCHCH
2C
6H
5. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. The codons for
L-phenylalanine are UUU and UUC...
-
ValValine is an α-amino acid with the chemical formula HO
2CCHCH
2.
L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
-
GlnGlutamine is one of the 20 amino acids encoded by the standard genetic code. Its side chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group. It can therefore be considered the amide of glutamic acid. Its codons are CAA and CAG. Glutamine is...
-
TrpTryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
-
LeuLeucine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2. It is an essential amino acid, which means that humans cannot synthesise it. Its codons are UUA, UUG, CUU, CUC, CUA, and CUG. With a hydrocarbon side chain, leucine is classified as a hydrophobic...
-
MetMethionine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2SCH
3. This essential amino acid is classified as nonpolar.-Function:...
-
AsnAsparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side chain's functional group. It is not an essential amino acid...
-
ThrThreonine is an α-amino acid with the chemical formula HO
2CCHCHCH
3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-
COOHA carboxyl group is a set of four atoms bonded together and present in carboxylic acids, including amino acids. Usually abbreviated as either CO2H or COOH, this set of atoms constitutes a functional group. In every carboxyl group the carbon atom is attached to an oxygen atom by a...
.
The polypeptide has a molecular weight of 3485
daltonThe unified atomic mass unit or atomic mass unit , or dalton or, sometimes, universal mass unit , is a unit of mass used to express atomic and molecular masses...
s. Glucagon is a peptide (non-
steroidA steroid is a terpenoid lipid characterized by its sterane core and additional functional groups. The core is a carbon structure of four fused rings: three cyclohexane rings and one cyclopentane ring. The steroids vary by the functional groups attached to these rings and the oxidation state of the...
) hormone.
Production
The hormone is synthesized and secreted from
alpha cellAlpha cells are endocrine cells in the islets of Langerhans of the pancreas. They make up 33-46% of the human islet cells and are responsible for synthesizing and secreting the peptide hormone glucagon, which elevates the glucose levels in the blood....
s (α-cells) of the
islets of LangerhansThe islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
, 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
Noradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
and epinephrineEpinephrine is a hormone and neurotransmitter that participates in the "fight or flight" response of the sympathetic nervous system...
- Increased plasma amino acids (to protect from hypoglycemia
Hypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" Hypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally...
if an all protein meal is consumed)
- Sympathetic nervous system
The Sympathetic Nervous System is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level and becomes more active during times of stress...
- Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
- Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...
Decreased secretion of glucagon (inhibition) is caused by:
- Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
- Insulin
Insulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
- Increased free fatty acids and ketoacids into the blood
- Increased urea
Urea or carbamide is an organic compound with the chemical formula
2CO. The molecule has two amine residues joined by a carbonyl functional group....
production
Function
Glucagon helps maintain the level of
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
in the
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
by binding to
glucagon receptorThe glucagon receptor is a 62 kDa peptide that is activated by glucagon and is a member of the G-protein coupled family of receptors, coupled to Gs...
s on
hepatocyteHepatocytes make up 70-80% of the cytoplasmic mass of the liver.These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous...
s, causing the
liverThe liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
to release glucose - stored in the form of
glycogenGlycogen is the molecule that functions as the secondary long-term energy storage in animal cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach...
- through a process known as
glycogenolysisGlycogenolysis is the catabolism of glycogen by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate...
. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by
gluconeogenesisGluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of
hypoglycemiaHypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" Hypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally...
.
Glucagon also regulates the rate of glucose production through
lipolysisLipolysis is the breakdown of fat stored in fat cells. During this process, free fatty acids are released into the bloodstream and circulate throughout the body. Ketones are produced, and are found in large quantities in ketosis...
.
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 receptorThe glucagon receptor is a 62 kDa peptide that is activated by glucagon and is a member of the G-protein coupled family of receptors, coupled to Gs...
, a
G protein-coupled receptorG protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
located in the plasma membrane. The conformation change in the receptor activates
G proteinG proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.G proteins are so called because they function as "molecular switches," alternating between an inactive guanosine diphosphate and active guanosine triphosphate bound state,...
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 GDP molecule, that was bound to the α subunit, to be replaced 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 cyclaseAdenylate cyclase is a lyase enzyme. It is a part of the cAMP-dependent pathway-Types:There are ten known adenylate cyclases in mammals:* ADCY1* ADCY2* ADCY3* ADCY4* ADCY5...
.
Adenylate cyclase manufactures
cAMPCAMP may stand for:* Cyclic adenosine monophosphate * Cathelicidin antimicrobial peptide* Campaign Against Marijuana Planting* Central Atlantic Magmatic Province* CAMP, an Italian manufacturer of climbing equipment....
(cyclical AMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates
phosphorylase kinasePhosphorylase kinase is a serine/threonine-specific protein kinase which converts glycogen phosphorylase b to glycogen phosphorylase a, activating it to release glucose-1-phosphate from glycogen....
, which, in turn, phosphorylates
glycogen phosphorylaseGlycogen phosphorylase is one of the phosphorylase enzymes . Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond.- Isozymes :...
, converting into the active form called phosphorylase A. Phosphorylase A is the enzyme responsible for the release of
glucose-1-phosphateGlucose 1-phosphate is a glucose molecule with a phosphate group on the 1'-carbon.-Catabolic:In glycogenolysis, it is the direct product of the reaction in which glycogen phosphorylase cleaves off a molecule of glucose from a greater glycogen structure.To be utilized in cellular catabolism it must...
from
glycogenGlycogen is the molecule that functions as the secondary long-term energy storage in animal cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach...
polymers.
Pathology
Abnormally-elevated levels of glucagon may be caused by pancreatic
tumorA tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells . Tumor is not synonymous with cancer. A tumor can be benign, pre-malignant or malignant, whereas cancer is by definition malignant....
s such as
glucagonomaA glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of the hormone glucagon. Alpha cell tumors are commonly associated with glucagonoma syndrome, though similar symptoms are present in cases of pseudoglucagonoma syndrome in the absence...
, symptoms of which include
necrolytic migratory erythemaNecrolytic migratory erythema is a classical symptom observed in patients with glucagonoma and is present in 80% of cases.-Presentation:...
(NME), reduced amino acids, and
hyperglycemiaHyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood glucose level of 10+ mmol/L , but symptoms may not start to become noticeable until later numbers such as 15-20+ mmol/L or...
. It may occur alone or in the context of
multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer syndrome is part of a group of disorders that affect the endocrine system.- Explanation :...
.
Uses
An injectable form of glucagon is vital first aid in cases of severe
hypoglycemiaHypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" Hypoglycemia or hypoglycaemia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally...
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 blockerBeta blockers is a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction , and hypertension. Propranolol was the first clinically useful beta adrenergic receptor antagonist. Invented by Sir James W...
s; the likely mechanism of action is the increase of cAMP in the myocardium, effectively bypassing the inhibitory action of the
β-adrenergicThe adrenergic receptors are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
second messenger systemIn cell physiology, a secondary messenger system is a method of cellular signaling whereby a diffusable signaling molecule is rapidly produced/secreted, which can then go on to activate effector proteins within the cell to exert a cellular response...
.
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
See also
- Insulin
Insulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
- Diabetes mellitus
Diabetes mellitus —often referred to simply as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy...
- Proglucagon
Proglucagon is a precursor of glucagon, and several other components. It is generated in the alpha cells of the pancreas, and it consists of the following:* Glicentin** Glicentin-related pancreatic polypeptide ** Oxyntomodulin*** Glucagon...
- Glucagon-like peptide-1
Glucagon-like peptide-1 is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1- and GLP-1-NH2.GLP-1 secretion by L cells is dependent...
- Glucagon-like peptide-2
Glucagon-like peptide-2 is a 33 amino acid peptide with the sequence HADGSFSDEMNTILDNLAARDFINWLIQTKITD in humans. GLP-2 is created by specific post-translational proteolytic cleavage of proglucagon in a process that also liberates the related glucagon-like peptide-1 . GLP-2 is produced by the...
- Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
- Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
- Cortisol
Cortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal cortex, that is part of the adrenal gland . It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by CRH...
Further reading