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PDB rendering based on 1GCN.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; GLP1; GLP2; GRPP
External IDs ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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Glucagon is a peptide hormone, produced by alpha cells of the pancreas, that raises the concentration of glucose in the bloodstream. Its effect is opposite that of insulin, which lowers the glucose concentration.[1] 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.


  • Function 1
  • Medical uses 2
    • Hypoglycemia 2.1
    • Beta blocker overdose 2.2
    • Anaphylaxis 2.3
    • Impacted food bolus 2.4
    • ERCP (Endoscopic Retrograde Cholangiopancreatography) 2.5
  • Adverse effects 3
    • Contraindications 3.1
  • Mechanism of action 4
  • Physiology 5
    • Production 5.1
    • Regulation 5.2
  • Structure 6
  • Pathology 7
  • History 8
    • Etymology 8.1
  • See also 9
  • References 10
  • Further reading 11


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).[2]

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.[3]

Metabolic regulation of glycogen by glucagon.

Medical uses

Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below
PubChem CID:
ChemSpider  Y
Chemical data
Formula C153H225N43O49S
Molecular mass 3482.747314 g/mol


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.[4]


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.[5]

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").[6] There is little evidence for glucagon's effectiveness in this condition,[7][8][9] and glucagon may induce nausea and vomiting,[9] 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.[10][11]

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.[12]


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.[13] Likewise, glucagon is contraindicated in patients with an insulinoma, as its use may lead to rebound hypoglycemia.[13]

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.[14] 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)[15] 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.[16]



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.[17]


Secretion of glucagon is stimulated by:

Secretion of glucagon is inhibited by:


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).[23]


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.[24] The amino acid sequence of glucagon was described in the late 1950s.[25] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.


Glucagon was named in 1923, probably from the Greek γλυκός sweet, and ἄγειν to lead.[26]

See also


  1. ^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings.  
  2. ^ Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW (Jan 1974). "Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men" (PDF). The Journal of Clinical Investigation 53 (1): 190–7.  
  3. ^ Leinen RL, Giannini AJ (1983). "Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish". Society for Neuroscience Abstracts 9: 604. 
  4. ^ White CM (May 1999). "A review of potential cardiovascular uses of intravenous glucagon administration". Journal of Clinical Pharmacology 39 (5): 442–7.  
  5. ^ Tang AW (Oct 2003). "A practical guide to anaphylaxis". American Family Physician 68 (7): 1325–32.  
  6. ^ Ko HH, Enns R (Oct 2008). "Review of food bolus management". Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie 22 (10): 805–8.  
  7. ^ Arora S, Galich P (Mar 2009). "Myth: glucagon is an effective first-line therapy for esophageal foreign body impaction". Cjem 11 (2): 169–71.  
  8. ^ Leopard D, Fishpool S, Winter S (Sep 2011). "The management of oesophageal soft food bolus obstruction: a systematic review". Annals of the Royal College of Surgeons of England 93 (6): 441–4.  
  9. ^ a b Weant KA, Weant MP (Apr 2012). "Safety and efficacy of glucagon for the relief of acute esophageal food impaction". American Journal of Health-System Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists 69 (7): 573–7.  
  10. ^ Ikenberry SO, Jue TL, Anderson MA, Appalaneni V, Banerjee S, Ben-Menachem T, Decker GA, Fanelli RD, Fisher LR, Fukami N, Harrison ME, Jain R, Khan KM, Krinsky ML, Maple JT, Sharaf R, Strohmeyer L, Dominitz JA (Jun 2011). "Management of ingested foreign bodies and food impactions" (PDF). Gastrointestinal Endoscopy 73 (6): 1085–1091.  
  11. ^ Chauvin A, Viala J, Marteau P, Hermann P, Dray X (Jul 2013). "Management and endoscopic techniques for digestive foreign body and food bolus impaction". Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 45 (7): 529–42.  
  12. ^ Koch-Weser J (Mar 1970). "Potentiation by glucagon of the hypoprothrombinemic action of warfarin". Annals of Internal Medicine 72 (3): 331–5.  
  13. ^ a b "Information for the Physician: Glucagon for Injection (rDNA origin)" (PDF). Eli Lilly and Company. Retrieved 2011-11-19. 
  14. ^ Hue L, Rider MH (Jul 1987). "Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues". The Biochemical Journal 245 (2): 313–24.  
  15. ^ Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ (1984). "The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism". Current Topics in Cellular Regulation 23: 57–86.  
  16. ^ Feliú JE, Hue L, Hers HG (Aug 1976). "Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes". Proceedings of the National Academy of Sciences of the United States of America 73 (8): 2762–6.  
  17. ^ Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. The Journal of Clinical Investigation. 2012;122(1):4-12. doi:10.1172/JCI60016.
  18. ^ Layden BT, Durai V, Lowe WL (2010). "G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes". Nature Education 3 (9): 13. 
  19. ^ Skoglund G, Lundquist I, Ahrén B (Nov 1987). "Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse". European Journal of Pharmacology 143 (1): 83–8.  
  20. ^ Honey RN, Weir GC (Oct 1980). "Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas". Endocrinology 107 (4): 1065–8.  
  21. ^ Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q (Jan 2006). "Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system". Cell Metabolism 3 (1): 47–58.  
  22. ^ Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W (Feb 2008). "A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription". Molecular Pharmacology 73 (2): 509–517.  
  23. ^ Orskov C, Holst JJ, Poulsen SS, Kirkegaard P (Nov 1987). "Pancreatic and intestinal processing of proglucagon in man". Diabetologia 30 (11): 874–81.  
  24. ^ Kimball C, Murlin J (1923). "Aqueous extracts of pancreas III. Some precipitation reactions of insulin". J. Biol. Chem. 58 (1): 337–348. 
  25. ^ Bromer W, Winn L, Behrens O (1957). "The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence". J. Am. Chem. Soc. 79 (11): 2807–2810.  
  26. ^ glucagon on

Further reading

  • Kieffer TJ, Habener JF (Dec 1999). "The glucagon-like peptides". Endocrine Reviews 20 (6): 876–913.  
  • Drucker DJ (Feb 2003). "Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis". Molecular Endocrinology (Baltimore, Md.) 17 (2): 161–71.  
  • Jeppesen PB (Nov 2003). "Clinical significance of GLP-2 in short-bowel syndrome". The Journal of Nutrition 133 (11): 3721–4.  
  • Brubaker PL, Anini Y (Nov 2003). "Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2". Canadian Journal of Physiology and Pharmacology 81 (11): 1005–12.  
  • Baggio LL, Drucker DJ (Dec 2004). "Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2". Best Practice & Research. Clinical Endocrinology & Metabolism 18 (4): 531–54.  
  • Holz GG, Chepurny OG (Jan 2005). "Diabetes outfoxed by GLP-1?". Science's STKE : Signal Transduction Knowledge Environment 2005 (268): pe2.  
  • Dunning BE, Foley JE, Ahrén B (Sep 2005). "Alpha cell function in health and disease: influence of glucagon-like peptide-1". Diabetologia 48 (9): 1700–13.  
  • Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C (Jun 2005). "Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes". Diabetes & Metabolism 31 (3 Pt 1): 233–42.  
  • De León DD, Crutchlow MF, Ham JY, Stoffers DA (2006). "Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus". The International Journal of Biochemistry & Cell Biology 38 (5-6): 845–59.  
  • Beglinger C, Degen L (Nov 2006). "Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY?". Physiology & Behavior 89 (4): 460–4.  
  • Stephens JW, Bain SC (Jul 2007). "Safety and adverse effects associated with GLP-1 analogues". Expert Opinion on Drug Safety 6 (4): 417–22.  
  • Orskov C, Bersani M, Johnsen AH, Højrup P, Holst JJ (Aug 1989). "Complete sequences of glucagon-like peptide-1 from human and pig small intestine". The Journal of Biological Chemistry 264 (22): 12826–9.  
  • Drucker DJ, Asa S (Sep 1988). "Glucagon gene expression in vertebrate brain". The Journal of Biological Chemistry 263 (27): 13475–8.  
  • Novak U, Wilks A, Buell G, McEwen S (May 1987). "Identical mRNA for preproglucagon in pancreas and gut". European Journal of Biochemistry / FEBS 164 (3): 553–8.  
  • White JW, Saunders GF (Jun 1986). "Structure of the human glucagon gene". Nucleic Acids Research 14 (12): 4719–30.  
  • Schroeder WT, Lopez LC, Harper ME, Saunders GF (1984). "Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37". Cytogenetics and Cell Genetics 38 (1): 76–9.  
  • Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC (1983). "Exon duplication and divergence in the human preproglucagon gene". Nature 304 (5924): 368–71.  
  • Kärgel HJ, Dettmer R, Etzold G, Kirschke H, Bohley P, Langner J (1982). "Action of rat liver cathepsin L on glucagon". Acta Biologica Et Medica Germanica 40 (9): 1139–43.  
  • Wayman GA, Impey S, Wu Z, Kindsvogel W, Prichard L, Storm DR (Oct 1994). "Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo". The Journal of Biological Chemistry 269 (41): 25400–5.  
  • Unson CG, Macdonald D, Merrifield RB (Feb 1993). "The role of histidine-1 in glucagon action". Archives of Biochemistry and Biophysics 300 (2): 747–50.  
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