Glucagon

Glucagon
PDB rendering based on 1GCN.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BH0, 1D0R, 1NAU, 2G49, 2L63, 2L64, 2M5P, 2M5Q, 3IOL, 4APD
Identifiers
Symbols	GCG ; GLP1; GLP2; GRPP
External IDs	OMIM: 138030 MGI: 95674 HomoloGene: 136497 ChEMBL: 5736 GeneCards: GCG Gene
Gene ontology Molecular function • receptor binding • hormone activity • protein binding • glucagon receptor binding • identical protein binding Cellular component • extracellular region • extracellular space • endoplasmic reticulum lumen • plasma membrane • secretory granule lumen Biological process • energy reserve metabolic process • signal transduction • G-protein coupled receptor signaling pathway • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • feeding behavior • cell proliferation • protein kinase A signaling • positive regulation of peptidyl-threonine phosphorylation • positive regulation of cAMP biosynthetic process • positive regulation of protein binding • negative regulation of appetite • positive regulation of peptidyl-serine phosphorylation • positive regulation of insulin secretion involved in cellular response to glucose stimulus • positive regulation of gluconeogenesis by positive regulation of transcription from RNA polymerase II promoter • response to starvation • negative regulation of apoptotic process • cellular protein metabolic process • small molecule metabolic process • positive regulation of protein kinase activity • regulation of insulin secretion • positive regulation of histone H3-K4 methylation • positive regulation of ERK1 and ERK2 cascade • cellular response to glucagon stimulus • positive regulation of calcium ion import • negative regulation of execution phase of apoptosis • negative regulation of intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2641	14526
Ensembl	ENSG00000115263	ENSMUSG00000000394
UniProt	P01275	P55095
RefSeq (mRNA)	NM_002054	NM_008100
RefSeq (protein)	NP_002045	NP_032126
Location (UCSC)	Chr 2: 162.14 – 162.15 Mb	Chr 2: 62.47 – 62.48 Mb
PubMed search	[1]	[2]

Glucagon is a peptide hormone, produced by alpha cells of the pancreas, and it raises the concentration of glucose in the bloodstream. Its effect is opposite that of insulin, which lowers the glucose concentration. 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. Glucagon belongs to a family of several other related hormones.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Function

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

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 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, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.

Medical uses

Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below
Identifiers
PubChem	CID: 16186314
IUPHAR/BPS	1136
ChemSpider	10481928 Y
UNII	76LA80IG2G Y
ChEMBL	CHEMBL266481 N
Chemical data
Formula	C153H225N43O49S
Molecular mass	3482.747314 g/mol
InChI InChI=1S/C153H225N43O49S/c1-72(2)52-97(133(226)176-96(47-51-246-11)132(225)184-104(60-115(159)209)143(236)196-123(78(10)203)151(244)245)179-137(230)103(58-83-64-167-89-29-19-18-28-87(83)89)183-131(224)95(43-46-114(158)208)177-148(241)120(74(5)6)194-141(234)101(54-79-24-14-12-15-25-79)182-138(231)105(61-117(211)212)185-130(223)94(42-45-113(157)207)171-124(217)75(7)170-127(220)91(31-22-49-165-152(160)161)172-128(221)92(32-23-50-166-153(162)163)174-146(239)110(69-199)191-140(233)107(63-119(215)216)186-134(227)98(53-73(3)4)178-135(228)99(56-81-33-37-85(204)38-34-81)180-129(222)90(30-20-21-48-154)173-145(238)109(68-198)190-136(229)100(57-82-35-39-86(205)40-36-82)181-139(232)106(62-118(213)214)187-147(240)111(70-200)192-150(243)122(77(9)202)195-142(235)102(55-80-26-16-13-17-27-80)188-149(242)121(76(8)201)193-116(210)66-168-126(219)93(41-44-112(156)206)175-144(237)108(67-197)189-125(218)88(155)59-84-65-164-71-169-84/h12-19,24-29,33-40,64-65,71-78,88,90-111,120-123,167,197-205H,20-23,30-32,41-63,66-70,154-155H2,1-11H3,(H2,156,206)(H2,157,207)(H2,158,208)(H2,159,209)(H,164,169)(H,168,219)(H,170,220)(H,171,217)(H,172,221)(H,173,238)(H,174,239)(H,175,237)(H,176,226)(H,177,241)(H,178,228)(H,179,230)(H,180,222)(H,181,232)(H,182,231)(H,183,224)(H,184,225)(H,185,223)(H,186,227)(H,187,240)(H,188,242)(H,189,218)(H,190,229)(H,191,233)(H,192,243)(H,193,210)(H,194,234)(H,195,235)(H,196,236)(H,211,212)(H,213,214)(H,215,216)(H,244,245)(H4,160,161,165)(H4,162,163,166)/t75-,76+,77+,78?,88-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,120-,121-,122-,123-/m0/s1 Y Key:MASNOZXLGMXCHN-GVLKBUBXSA-N Y
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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 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.

Anaphylaxis

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

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 (ERCP)

Glucagon's effect of decreasing cAMP causes relaxation of splanchnic 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 pheochromocytoma, as the drug interaction with elevated levels of 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 insulinoma, as its use may lead to rebound hypoglycemia.

Mechanism of action

Metabolic regulation of glycogen by glucagon.

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.

Physiology

Production

A microscopic image stained for glucagon

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 in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.

Regulation

Secretion of glucagon is stimulated by:

• Hypoglycemia
• Epinephrine (via β2, α2, and α1 adrenergic receptors)
• Arginine
• Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
• Acetylcholine
• Cholecystokinin

Secretion of glucagon is inhibited by:

• Somatostatin
• Insulin (via GABA)
• PPARγ/retinoid X receptor heterodimer.
• Increased free fatty acids and keto acids into the blood.
• Increased urea production

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 (nonsteroid) hormone.

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).

Pathology

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.

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.

Etymology

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

See also

• Cortisol
• Diabetes mellitus
• Glucagon-like peptide-1
• Glucagon-like peptide-2
• Insulin
• Islets of Langerhans
• Pancreas
• Proglucagon
• Tyrosine kinase