Wikipedia

Glucagon

This article is about the natural hormone. For the medication, seeGlucagon (medication).

Glucagonis apeptide hormone,produced byalpha cellsof thepancreas.It raises the concentration ofglucoseandfatty acidsin the bloodstream and is considered to be the maincatabolichormone of the body.[1]It is also used as amedicationto treat a number of health conditions. Its effect is opposite to that ofinsulin,which lowers extracellular glucose.[2]It is produced fromproglucagon,encoded by theGCGgene.

glucagon
Identifiers
AliasesGCG(53-81)glucagoneglucagon recombinant
External IDsGeneCards:[1];OMA:- orthologs
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n
a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMedsearchn/an/a
Wikidata
View/Edit Human

The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes theliverto engage inglycogenolysis:converting storedglycogenintoglucose,which is released into the bloodstream.[3]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.[4]Glucagon belongs to thesecretin familyof hormones.

Structure

edit

Glucagon is a 29-amino acidpolypeptide.Itsprimary structurein 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(HSQGTFTSDYSKYLDSRRAQDFVQWLMNT).

The polypeptide has amolecular massof 3485daltons.[5]Glucagon is apeptide(nonsteroid) hormone.

Physiology

edit

Production

edit
A microscopic image stained for glucagon

The hormone is synthesized and secreted fromalpha cells(α-cells) of theislets of Langerhans,which are located in the endocrine portion of the pancreas. Glucagon is produced from thepreproglucagongeneGcg.Preproglucagon first has itssignal peptideremoved bysignal peptidase,forming the 160-amino acidprotein proglucagon.[6]Proglucagon is then cleaved byproprotein convertase 2to glucagon (amino acids 33-61) in pancreatic islet α cells. In intestinalL cells,proglucagon is cleaved to the alternate productsglicentin(1–69),glicentin-related pancreatic polypeptide(1–30), oxyntomodulin (33–69),glucagon-like peptide 1(72–107 or 108), andglucagon-like peptide 2(126–158).[6]

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.[7]

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.[8]

Regulation

edit

Production, which is otherwise freerunning, is suppressed/regulated byamylin,a peptide hormone co-secreted with insulin from the pancreatic β cells.[9]As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.

Secretion of glucagon is stimulated by:

Secretion of glucagon is inhibited by:

Function

edit

Glucagon generally elevates the concentration ofglucosein thebloodby promotinggluconeogenesisandglycogenolysis.[17]Glucagon also decreases fatty acid synthesis inadipose tissueand the liver, as well as promotinglipolysisin these tissues, which causes them to release fatty acids into circulation where they can becatabolisedto generate energy in tissues such asskeletal musclewhen required.[18]

Glucose is stored in the liver in the form of thepolysaccharideglycogen, which is aglucan(a polymer made up of glucose molecules). Liver cells (hepatocytes) haveglucagon 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 asglycogenolysis.As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose bygluconeogenesis.Glucagon turns offglycolysisin 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 asdiabetes mellitus type 1).[19]

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. Ininvertebrate animals,eyestalkremoval has been reported to affect glucagon production. Excising the eyestalk in youngcrayfishproduces glucagon-inducedhyperglycemia.[20]

Mechanism of action

edit
Metabolic regulation of glycogen by glucagon.

Glucagon binds to theglucagon receptor,aG protein-coupled receptor,located in theplasma membraneof the cell. The conformation change in the receptor activates aG protein,a heterotrimeric protein with αs,β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of theGDPmolecule that was bound to the α subunit with aGTPmolecule.[21]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.

Glucagon (in red) bound to glucagon receptor

Adenylate cyclase manufacturescyclic adenosine monophosphate(cyclic AMP or cAMP), which activatesprotein kinase A(cAMP-dependent protein kinase). This enzyme, in turn, activatesphosphorylase kinase,which then phosphorylatesglycogen phosphorylaseb (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release ofglucose 1-phosphatefrom glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾.Gαsseparates 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 glycogen phosphorylase kinase.[22]Phosphorylated glycogen phosphorylase kinase phosphorylatesglycogen phosphorylase.Phosphorylated glycogen 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.[23]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)[24]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 inactivates the glycolytic enzymepyruvate kinase,[25]inactivatesglycogen synthase,[26]and activateshormone-sensitive lipase,[27]which catabolizes glycerides into glycerol and free fatty acid(s), in hepatocytes.

Glucagon also inactivatesacetyl-CoA carboxylase,which creates malonyl-CoA from acetyl-CoA, through cAMP-dependent and/or cAMP-independent kinases.[28]

Malonyl-CoAis a product formed byACCduringdenovo synthesisand an allosteric inhibitor ofCarnitine palmitoyltransferase I (CPT1),a mitochondrial enzyme important for bringing fatty acids into the intermembrane space of the mitochondria for β-oxidation.[29]Glucagon decreases malonyl-CoA through inhibition of acetyl-CoA carboxylase and through reduced glycolysis through its aforementioned reduction in Fructose 2,6-bisphosphate. Thus, reduction in malonyl-CoA is a common regulator for the increased fatty acid metabolism effects of glucagon.

Pathology

edit

Abnormally elevated levels of glucagon may be caused by pancreatictumors,such asglucagonoma,symptoms of which includenecrolytic migratory erythema,[30]reduced amino acids, and hyperglycemia. It may occur alone or in the context ofmultiple endocrine neoplasia type 1.[31]

Elevated glucagon is the main contributor tohyperglycemic ketoacidosisin 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 a rapid breakdown of glycogen to glucose and fastketogenesis.[32]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.[citation needed]Inhibiting glucagon has been a popular idea of diabetes treatment, however, some have warned that doing so will give rise tobrittle diabetesin patients with adequately stable blood glucose.[citation needed]

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 totalpancreatectomy.

History

edit

In the early 1920s, several groups noted that pancreatic extracts injected into diabetic animals would result in a brief increase in blood sugar prior to the insulin-driven decrease in blood sugar.[6]In 1922, C. Kimball and John R. Murlin identified a component of pancreatic extracts responsible for this blood sugar increase, terming it "glucagon", a portmanteau of "glucoseagonist ".[6][33]In the 1950s, scientists atEli Lillyisolated pure glucagon,crystallizedit, and determined its amino acid sequence.[6][34][35]This led to the development of the firstradioimmunoassayfor detecting glucagon, described byRoger Unger's group in 1959.[6]

A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specificradioimmunoassaywas developed.[36]

In 1979, while working inJoel Habener's laboratory atMassachusetts General Hospital,Richard Goodman collectedislet cellsfromBrockman bodiesofAmerican anglerfishin order to investigatesomatostatin.[37]By splicing DNA from anglerfish islet cells into bacteria, Goodman was able to identify the gene which codes for somatostatin.[37]P. Kay Lund joined the Habener lab and used Goodman's bacteria to search for the gene for glucagon.[37]In 1982, Lund and Goodman published their discovery that the proglucagon gene codes for three distinct peptides: glucagon and two novel peptides.[37]Graeme Bell atChiron Corporationled a team which isolated the two latter peptides, which are now known as glucagon-like peptide-1 and glucagon-like peptide-2.[37]This opened the door to the discovery of theglucagon-like peptide-1 receptorand then drugs which target that receptor, known asGLP-1 receptor agonists.[37]

See also

edit

References

edit
  1. ^Voet D, Voet JG (2011).Biochemistry(4th ed.). New York: Wiley.
  2. ^Reece J, Campbell N (2002).Biology.San Francisco: Benjamin Cummings.ISBN978-0-8053-6624-2.
  3. ^Orsay J (2014).Biology 1: Molecules.Examkrackers Inc. p. 77.ISBN978-1-893858-70-1.
  4. ^Jones BJ, Tan T, Bloom SR (March 2012)."Minireview: Glucagon in stress and energy homeostasis".Endocrinology.153(3):1049–54.doi:10.1210/en.2011-1979.PMC3281544.PMID22294753.
  5. ^Unger RH, Orci L (June 1981). "Glucagon and the A cell: physiology and pathophysiology (first two parts)".The New England Journal of Medicine.304(25):1518–24.doi:10.1056/NEJM198106183042504.PMID7015132.
  6. ^abcdefMüller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH (April 2017). "The New Biology and Pharmacology of Glucagon".Physiol Rev.97(2):721–766.doi:10.1152/physrev.00025.2016.PMID28275047.
  7. ^Unger RH, Cherrington AD (January 2012)."Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover".The Journal of Clinical Investigation.122(1):4–12.doi:10.1172/JCI60016.PMC3248306.PMID22214853.
  8. ^Holst JJ, Holland W, Gromada J, Lee Y, Unger RH, Yan H, Sloop KW, Kieffer TJ, Damond N, Herrera PL (April 2017)."Insulin and Glucagon: Partners for Life".Endocrinology.158(4):696–701.doi:10.1210/en.2016-1748.PMC6061217.PMID28323959.
  9. ^abZhang XX, Pan YH, Huang YM, Zhao HL (May 2016)."Neuroendocrine hormone amylin in diabetes".World Journal of Diabetes.7(9):189–197.doi:10.4239/wjd.v7.i9.189.PMC4856891.PMID27162583.
  10. ^Layden BT, Durai V, Lowe WL (2010)."G-Protein-Coupled Receptors, PANCREATIC Islets, and DiAbetes".Nature Education.3(9): 13.
  11. ^Skoglund G, Lundquist I, Ahrén B (November 1987). "Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse".European Journal of Pharmacology.143(1):83–8.doi:10.1016/0014-2999(87)90737-0.PMID2891547.
  12. ^Honey RN, Weir GC (October 1980). "Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas".Endocrinology.107(4):1065–8.doi:10.1210/endo-107-4-1065.PMID6105951.
  13. ^Rehfeld JF, Holst JJ, Kühl C (February 1978). "The effect of gastrin on basal and aminoacid-stimulated insulin and glucagon secretion in man".European Journal of Clinical Investigation.8(1):5–9.doi:10.1111/j.1365-2362.1978.tb00800.x.PMID417933.S2CID38154468.
  14. ^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 (January 2006)."Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system".Cell Metabolism.3(1):47–58.doi:10.1016/j.cmet.2005.11.015.PMID16399504.
  15. ^Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W (February 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):509–17.doi:10.1124/mol.107.035568.PMID17962386.S2CID10108970.
  16. ^Johnson LR (2003).Essential Medical Physiology.Academic Press. pp.643–.ISBN978-0-12-387584-6.
  17. ^Voet D, Voet JG (2011).Biochemistry(4th ed.). New York: Wiley.
  18. ^Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH (December 2010)."The metabolic actions of glucagon revisited".Nature Reviews. Endocrinology.6(12):689–697.doi:10.1038/nrendo.2010.187.PMC3563428.PMID20957001.
  19. ^Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW (January 1974)."Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men".The Journal of Clinical Investigation.53(1):190–7.doi:10.1172/JCI107537.PMC301453.PMID4808635.
  20. ^Leinen RL, Giannini AJ (1983). "Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish".Society for Neuroscience Abstracts.9:604.
  21. ^"Glucagon Signaling Pathway".News-Medical.net.2018-03-01.Retrieved2021-03-30.
  22. ^Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A (July 2019)."Glucose controls glucagon secretion by directly modulating cAMP in alpha cells".Diabetologia.62(7):1212–1224.doi:10.1007/s00125-019-4857-6.PMC6560012.PMID30953108.
  23. ^Hue L, Rider MH (July 1987)."Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues".The Biochemical Journal.245(2):313–24.doi:10.1042/bj2450313.PMC1148124.PMID2822019.
  24. ^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. Vol. 23. pp.57–86.doi:10.1016/b978-0-12-152823-2.50006-4.ISBN9780121528232.PMID6327193.
  25. ^Feliú JE, Hue L, Hers HG (August 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.Bibcode:1976PNAS...73.2762F.doi:10.1073/pnas.73.8.2762.PMC430732.PMID183209.
  26. ^Jiang G, Zhang BB (April 2003)."Glucagon and regulation of glucose metabolism".Am J Physiol Endocrinol Metab.284(4): E671-8.doi:10.1152/ajpendo.00492.2002.PMID12626323.
  27. ^Hayashi Y (January 2021)."Glucagon regulates lipolysis and fatty acid oxidation through inositol triphosphate receptor 1 in the liver".Diabetes Investig.12(1):32–34.doi:10.1111/jdi.13315.PMC7779274.PMID32506830.
  28. ^Swenson TL, Porter JW (Mar 25, 1985)."Mechanism of glucagon inhibition of liver acetyl-CoA carboxylase. Interrelationship of the effects of phosphorylation, polymer-protomer transition, and citrate on enzyme activity".The Journal of Biological Chemistry.2460(6):3791–3797.doi:10.1016/S0021-9258(19)83693-1.PMID2857722.
  29. ^Wang Y, Yu W, Li S, Guo D, He J, Wang Y (March 11, 2022)."Acetyl-CoA Carboxylases and Diseases".Frontiers in Oncology.12.doi:10.3389/fonc.2022.836058.PMC8963101.PMID35359351.
  30. ^John AM, Schwartz RA (December 2016). "Glucagonoma syndrome: a review and update on treatment".Journal of the European Academy of Dermatology and Venereology.30(12):2016–2022.doi:10.1111/jdv.13752.PMID27422767.S2CID1228654.
  31. ^Oberg K (December 2010). "Pancreatic endocrine tumors".Seminars in Oncology.37(6):594–618.doi:10.1053/j.seminoncol.2010.10.014.PMID21167379.
  32. ^Fasanmade OA, Odeniyi IA, Ogbera AO (June 2008). "Diabetic ketoacidosis: diagnosis and management".African Journal of Medicine and Medical Sciences.37(2):99–105.PMID18939392.
  33. ^Kimball C, Murlin J (1923)."Aqueous extracts of pancreas III. Some precipitation reactions of insulin".J. Biol. Chem.58(1):337–348.doi:10.1016/S0021-9258(18)85474-6.
  34. ^Staub A, Sinn L, Behrens OK (June 1953). "Purification and crystallization of hyperglycemic glycogenolytic factor (HGF)".Science.117(3049):628–9.Bibcode:1953Sci...117..628S.doi:10.1126/science.117.3049.628.PMID13056638.
  35. ^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.Bibcode:1957JAChS..79.2807B.doi:10.1021/ja01568a038.
  36. ^Lundqvist G, Edwards J, Wide L (January 1976)."A solid phase radioimmunoassay for pancreatic glucagon".Upsala Journal of Medical Sciences.81(2):65–69.doi:10.3109/03009737609179024.PMID785743.
  37. ^abcdefMolteni M, Chen E (September 30, 2023)."GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?".STAT News.RetrievedOctober 16,2024.
edit
Listen to this article(10minutes)
This audio filewas created from a revision of this article dated 16 August 2019(2019-08-16),and does not reflect subsequent edits.
(Audio help·More spoken articles)
  • PDBe-KBprovides an overview of all the structure information available in the PDB for Human Glucagon
Retrieved from "https://en.wikipedia.org/w/index.php?title=Glucagon&oldid=1265098218"