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{{About|the natural hormone|the medication|Glucagon (medication)}}
|authorTag={{DB}}
{{Infobox_gene}}
|genericName=Glucagon
'''Glucagon''' is a [[peptide hormone]], produced by [[alpha cells]] of the [[pancreas]].  It works to raise the concentration of [[glucose]] and [[fat]] in the bloodstream, and is considered to be the main catabolic hormone of the body <ref>{{cite book|last1=Voet D, Voet JG.|title=Biochemistry|date=2011|publisher=Wiley|location=New York|edition=4th}}</ref>. It is also used as a [[Glucagon (medication)|medication]] to treat a number of health conditions. Its effect is opposite to that of [[insulin]], which lowers the extracellular glucose.<ref name="Campbell">{{cite book | vauthors = Reece J, Campbell N | title = Biology | edition = | publisher = Benjamin Cummings | location = San Francisco | year = 2002 | origyear = | pages = | quote = | isbn = 0-8053-6624-5 }}</ref>
|aOrAn=a
|drugClass=gastrointestinal agent
|indicationType=treatment
|indication=severe [[hypoglycemia]], and as a diagnostic acid
|adverseReactions=[[nausea]] and [[vomiting]], temporary increase in [[blood pressure]] and [[pulse]] may occur after administration
|blackBoxWarningTitle=Title
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>


* Content
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.<ref>{{cite book | last1 = Orsay | first1 = Jonathan | name-list-format = vanc | title = Biology 1: Molecules | date = 2014 | publisher = Examkrackers Inc. | isbn = 978-1-893858-70-1 | page=77 }}</ref> 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.<ref>{{cite journal | vauthors = Jones BJ, Tan T, Bloom SR | title = Minireview: Glucagon in stress and energy homeostasis | journal = Endocrinology | volume = 153 | issue = 3 | pages = 1049–54 | date = March 2012 | pmid = 22294753 | pmc = 3281544 | doi = 10.1210/en.2011-1979 }}</ref> Glucagon belongs to [[Glucagon hormone family|the secritin family of hormones]].


<!--Adult Indications and Dosage-->
== Function ==
Glucagon generally elevates the concentration of [[glucose]] in the [[blood]] by promoting [[gluconeogenesis]] and [[glycogenolysis]] <ref>{{cite book|last1=Voet D, Voet JG|title=Biochemistry.|date=2011|publisher=Wiley|location=New York|edition=4th}}</ref>. 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 when required <ref>{{cite journal|last1=HABEGGER, K. M., HEPPNER, K. M., GEARY, N., BARTNESS, T. J., DIMARCHI, R. & TSCHÖP, M. H.|title=The metabolic actions of glucagon revisited.|journal=Nature reviews. Endocrinology|date=2010|volume=6|page=689-697}}</ref>.


<!--FDA-Labeled Indications and Dosage (Adult)-->
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.
|fdaLIADAdult======Hypoglycemia (Severe)=====


* Dosing Information
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]]).<ref>{{cite journal | vauthors = Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW | title = Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men | journal = The Journal of Clinical Investigation | volume = 53 | issue = 1 | pages = 190–7 | date = January 1974 | pmid = 4808635 | pmc = 301453 | doi = 10.1172/JCI107537 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC301453/pdf/jcinvest00157-0198.pdf }}</ref>


:* Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen powder and inject all the liquid from the syringe into the vial.
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.<ref name="Leinen_1983">{{cite journal | vauthors = Leinen RL, Giannini AJ | title = Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish | journal = Society for Neuroscience Abstracts | year = 1983 | volume = 9 | pages = 604 }}</ref>
:*Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.
:*The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL [[glucagon]].
:*The reconstituted GlucaGen should be used immediately after reconstitution.  
:*Inject 1 mL (adults , weighing more than 55 lbs (25 kg))  subcutaneously, intramuscularly, or intravenously.
:*Discard any unused portion.
:*Emergency assistance should be sought immediately after subcutaneous or intramuscular injection of [[glucagon]].
:*The glucagon injection may be repeated using a new kit while waiting for emergency assistance.  
:*Intravenous glucose MUST be administered if the patient fails to respond to glucagon.  
:*When the patient has responded to the treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.


=====Radiography of gastrointestinal tract=====
== Mechanism of action ==


* Dosing Information
[[File:Glucagon Activation.png|thumb|right|350px|Metabolic regulation of glycogen by glucagon.]]


:*GlucaGen should be reconstituted with 1 mL of Sterile Water for Reconstitution (if supplied) or 1 mL of Sterile Water for Injection, USP. Using a syringe, withdraw all of the Sterile Water for Reconstitution (if supplied) or 1 mL Sterile Water for Injection, USP and inject into the GlucaGen vial.  
Glucagon binds to the [[glucagon receptor]], a [[G protein-coupled receptor]], located in the [[plasma membrane]]. 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 [[guanosine diphosphate|GDP]] molecule that was bound to the α subunit with a [[guanosine triphosphate|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]].
:*Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.
:*The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL glucagon.  
:*The reconstituted GlucaGen should be used immediately after reconstitution.
:*GlucaGen must be administered by medical personnel.
:*Discard any unused portion.
:*Onset of action after an injection will depend on the organ under examination and route of administration.
:*The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5 mg to 0.75 mg intravenously and 1 mg to 2 mg intramuscularly.
:*After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure applied.  


:*The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are intended only for use by healthcare providers as a diagnostic aid. The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are not intended for use by patients to treat severe hypoglycemia because they are not packaged with a syringe and diluent necessary for rapid preparation and administration during an emergency outside of a healthcare facility.
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.


====Dosage forms and strengths====
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.<ref name="Hue L & Rider MH_1987">{{cite journal | vauthors = Hue L, Rider MH | title = Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues | journal = The Biochemical Journal | volume = 245 | issue = 2 | pages = 313–24 | date = July 1987 | pmid = 2822019 | pmc = 1148124 | doi =  }}</ref> 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)<ref name="Claus, TH et al_1984">{{cite journal | vauthors = Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ | title = The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism | journal = Current Topics in Cellular Regulation | volume = 23 | issue =  | pages = 57–86 | year = 1984 | pmid = 6327193 | doi = 10.1016/b978-0-12-152823-2.50006-4 }}</ref> 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).


*GlucaGen is supplied in a vial, alone, or accompanied by Sterile Water for Reconstitution (1 mL) also in a vial (10 pack or diagnostic kit). It is also supplied as GlucaGen HypoKit®, a presentation with a disposable prefilled syringe containing 1 mL Sterile Water for Reconstitution. When the glucagon powder is reconstituted with Sterile Water for Reconstitution (if supplied) or with Sterile Water for Injection, USP, it forms a solution of 1 mg/mL (1 unit/mL) glucagon for subcutaneous, intramuscular, or intravenous injection.
Glucagon stimulation of PKA also inactivates the glycolytic enzyme [[pyruvate kinase]] in hepatocytes.<ref name="Feliu JE, Hue L & Hers HG_1976">{{cite journal | vauthors = Feliú JE, Hue L, Hers HG | title = Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 8 | pages = 2762–6 | date = August 1976 | pmid = 183209 | pmc = 430732 | doi = 10.1073/pnas.73.8.2762 }}</ref>
|offLabelAdultGuideSupport=*There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Glucagon in adult patients.
|offLabelAdultNoGuideSupport=*There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Glucagon in adult patients.
|fdaLIADPed======Hypoglycemia (Severe)=====


* Dosing Information
== Physiology ==


:*Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen powder and inject all the liquid from the syringe into the vial.  
=== Production ===
:*Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.  
[[Image:Glucagon rednblue.png|thumb|A microscopic image stained for glucagon]]
:*The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL 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 insulin from the adjacent beta cells. When blood sugar drops, insulin production drops and more glucagon is produced<ref name = "Unger_2012" /> 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.<ref name = "Unger_2012">{{cite journal | vauthors = Unger RH, Cherrington AD | title = Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover | journal = The Journal of Clinical Investigation | volume = 122 | issue = 1 | pages = 4–12 | date = January 2012 | pmid = 22214853 | pmc = 3248306 | doi = 10.1172/JCI60016 }}</ref>
:*The reconstituted GlucaGen should be used immediately after reconstitution.
:*Inject 1 mL (children, weighing more than 55 lbs (25 kg)) or 0.5 mL (children weighing less than 55 lbs (25 kg)) subcutaneously, intramuscularly, or intravenously. If the weight is not known: children younger than 6 years should be given a 0.5 mL and children 6 years and older should be given 1 mL.
:*Discard any unused portion.
:*Emergency assistance should be sought immediately after subcutaneous or intramuscular injection of glucagon.
:*The glucagon injection may be repeated using a new kit while waiting for emergency assistance.
:*Intravenous glucose MUST be administered if the patient fails to respond to glucagon.
:*When the patient has responded to the treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Glucagon in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Glucagon in pediatric patients.
|contraindications=*GlucaGen is contraindicated in patients with:


:*Known [[hypersensitivity]] to glucagon, lactose or any other constituent in GlucaGen
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.<ref>{{cite journal | vauthors = Holst JJ, Holland W, Gromada J, Lee Y, Unger RH, Yan H, Sloop KW, Kieffer TJ, Damond N, Herrera PL | title = Insulin and Glucagon: Partners for Life | journal = Endocrinology | volume = 158 | issue = 4 | pages = 696–701 | date = April 2017 | pmid = 28323959 | doi = 10.1210/en.2016-1748 | url = https://academic.oup.com/endo/article/2965091 }}</ref>
:*[[Pheochromocytoma]]
:*[[Insulinoma]]
|warnings='''Pheochromocytoma'''


*Glucagon is contraindicated in patients with pheochromocytoma because Glucagon may stimulate the release of catecholamines from the tumor. If the patient develops a dramatic increase in blood pressure, 5 to 10 mg of phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.
=== Regulation ===
Secretion of glucagon is stimulated by:
* [[Hypoglycemia]]
* [[Epinephrine]] (via β2, α2,<ref name="Layden_2010">{{cite journal | vauthors = Layden BT, Durai V, Lowe WL | title = G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes | journal = Nature Education | volume = 3 | issue = 9 | pages = 13 | year = 2010 | url = http://www.nature.com/scitable/topicpage/g-protein-coupled-receptors-pancreatic-islets-and-14257267 }}</ref> and α1<ref name=alpha1and2>{{cite journal | vauthors = Skoglund G, Lundquist I, Ahrén B | title = Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse | journal = European Journal of Pharmacology | volume = 143 | issue = 1 | pages = 83–8 | date = November 1987 | pmid = 2891547 | doi = 10.1016/0014-2999(87)90737-0 }}</ref> adrenergic receptors)
* [[Arginine]]
* [[Alanine]] (often from muscle-derived pyruvate/glutamate transamination (see [[alanine transaminase]] reaction).
* [[Acetylcholine]]<ref name="HoneyWEIRf1980">{{cite journal | vauthors = Honey RN, Weir GC | title = Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas | journal = Endocrinology | volume = 107 | issue = 4 | pages = 1065–8 | date = October 1980 | pmid = 6105951 | doi = 10.1210/endo-107-4-1065 }}</ref>
* [[Cholecystokinin]]


'''Insulinoma and Glucagonoma'''
Secretion of glucagon is inhibited by:
* [[Somatostatin]]
* [[Insulin]] (via [[GABA]])<ref name="pmid16399504">{{cite journal | vauthors = 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 | title = Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system | journal = Cell Metabolism | volume = 3 | issue = 1 | pages = 47–58 | date = January 2006 | pmid = 16399504 | doi = 10.1016/j.cmet.2005.11.015 }}</ref>
* [[Peroxisome proliferator-activated receptor gamma|PPARγ]]/[[retinoid X receptor]] [[protein dimer|heterodimer]].<ref name="pmid17962386">{{cite journal | vauthors = Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W | title = A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription | journal = Molecular Pharmacology | volume = 73 | issue = 2 | pages = 509–17 | date = February 2008 | pmid = 17962386 | doi = 10.1124/mol.107.035568 }}</ref>
* Increased free [[fatty acids]] and [[keto acids]] into the blood.<ref name="Johnson2003">{{cite book | first = Leonard R. | last = Johnson | name-list-format = vanc | title = Essential Medical Physiology | year = 2003 | publisher = Academic Press | isbn = 978-0-12-387584-6 | pages = 643– }}</ref>
* Increased [[urea]] production


*GlucaGen should be administered cautiously to patients suspected of having [[insulinoma]] or [[glucagonoma]]. In patients with insulinoma, intravenous administration of glucagon may produce an initial increase in blood glucose; however, glucagon administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma. A patient developing symptoms of hypoglycemia after a dose of glucagon should be given glucose orally or intravenously, whichever is most appropriate. Caution should also be observed in administering GlucaGen to patients with glucagonoma.
== Structure ==
Glucagon is a 29-[[amino acid]] [[polypeptide]]. Its [[primary structure]] in humans is: [[amine|NH<sub>2</sub>]]-[[Histidine|His]]-[[Serine|Ser]]-[[Glutamine|Gln]]-[[Glycine|Gly]]-[[Threonine|Thr]]-[[Phenylalanine|Phe]]-[[Threonine|Thr]]-[[Serine|Ser]]-[[Aspartic acid|Asp]]-[[Tyrosine|Tyr]]-[[Serine|Ser]]-[[Lysine|Lys]]-[[Tyrosine|Tyr]]-[[Leucine|Leu]]-[[Aspartic acid|Asp]]-[[Serine|Ser]]-[[Arginine|Arg]]-[[Arginine|Arg]]-[[Alanine|Ala]]-[[Glutamine|Gln]]-[[Aspartic acid|Asp]]-[[Phenylalanine|Phe]]-[[Valine|Val]]-[[Glutamine|Gln]]-[[Tryptophan|Trp]]-[[Leucine|Leu]]-[[Methionine|Met]]-[[Asparagine|Asn]]-[[Threonine|Thr]]-[[carboxyl group|COOH]].


'''Hypersensitivity and Allergic Reactions'''
The polypeptide has a [[molecular weight]] of 3485 [[Atomic mass unit|dalton]]s.<ref>{{cite journal | vauthors = Unger RH, Orci L | title = Glucagon and the A cell: physiology and pathophysiology (first two parts) | journal = The New England Journal of Medicine | volume = 304 | issue = 25 | pages = 1518–24 | date = June 1981 | pmid = 7015132 | doi = 10.1056/NEJM198106183042504 }}</ref> Glucagon is a [[peptide]] (non[[steroid]]) hormone.


*Allergic reactions may occur and include generalized [[rash]], and in some cases [[anaphylactic shock]] with breathing difficulties, and [[hypotension]]. The anaphylactic reactions have generally occurred in association with endoscopic examination during which patients often received other agents including contrast media and local anesthetics. The patients should be given standard treatment for [[anaphylaxis]] including an injection of epinephrine if they encounter respiratory difficulties after GlucaGen injection.
Glucagon is generated from the cleavage of [[proglucagon]] by [[proprotein convertase 2]] in pancreatic islet α cells. In intestinal [[L cell]]s, [[proglucagon]] is cleaved to the alternate products [[glicentin]], [[GLP-1]] (an [[incretin]]), [[Intervening peptide 2|IP-2]], and [[GLP-2]] (promotes intestinal growth).<ref name="pmid3446554">{{cite journal | vauthors = Orskov C, Holst JJ, Poulsen SS, Kirkegaard P | title = Pancreatic and intestinal processing of proglucagon in man | journal = Diabetologia | volume = 30 | issue = 11 | pages = 874–81 | date = November 1987 | pmid = 3446554 | doi = 10.1007/BF00274797 }}</ref>


'''Glycogen Stores and Hypoglycemia'''
== Pathology ==
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]].


*In order for GlucaGen treatment to reverse [[hypoglycemia]], adequate amounts of glucose must be stored in the liver (as glycogen). Therefore, GlucaGen should be used with caution in patients with conditions such as prolonged fasting, [[starvation]], [[adrenal insufficiency]] or [[chronic hypoglycemia]] because these conditions result in low levels of releasable glucose in the liver and an inadequate reversal of hypoglycemia by GlucaGen treatment.
== History ==
In the 1920s, Kimball and Murlin studied [[pancreas|pancreatic]] extracts, and found an additional substance with [[hyperglycemia|hyperglycemic]] properties. They described glucagon in 1923.<ref name="Kimball_1923">{{cite journal | vauthors = Kimball C, Murlin J | title = Aqueous extracts of pancreas III. Some precipitation reactions of insulin | journal = J. Biol. Chem. | year = 1923 | volume = 58 | pages = 337–348 | url = http://www.jbc.org/cgi/reprint/58/1/337 | issue=1}}</ref> The amino acid sequence of glucagon was described in the late 1950s.<ref name="Bromer_1957">{{cite journal | vauthors = Bromer W, Winn L, Behrens O | title = The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence | journal = J. Am. Chem. Soc. | year = 1957 | volume = 79 | issue = 11 | pages = 2807–2810|doi=10.1021/ja01568a038 }}</ref> A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific [[radioimmunoassay]] was developed.


'''Cardiac Disease'''
=== Etymology ===
Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the ''gluc''ose ''agon''ist. <ref>{{Cite web|url=https://www.diapedia.org/metabolism-insulin-and-other-hormones/5105141812/history-of-glucagon|title=History of glucagon - Metabolism, insulin and other hormones - Diapedia, The Living Textbook of Diabetes|website=www.diapedia.org|language=en|access-date=2017-03-26}}</ref>


*Caution should be observed when glucagon is used as an adjunct in endoscopic or radiographic procedures to inhibit gastrointestinal motility in patients with known cardiac disease.
== See also ==
{{div col||20em|small=yes}}
* [[Cortisol]]
* [[Diabetes mellitus]]
* [[Glucagon-like peptide-1]]
* [[Glucagon-like peptide-2]]
* [[Insulin]]
* [[Islets of Langerhans]]
* [[Pancreas]]
* [[Proglucagon]]
* [[Tyrosine kinase]]
{{div col end}}


'''Laboratory Tests'''
== References ==
 
{{Reflist|30em}}
*Blood glucose measurements may be considered to monitor the patient’s response.
|clinicalTrials=*Side effects may include nausea and vomiting at doses above 1 mg or with rapid injection. *[[Hypotension]] has been reported up to 2 hours after administration in patients receiving GlucaGen as premedication for upper GI endoscopy procedures. Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause tachycardia and hypertension. Adverse reactions indicating toxicity of GlucaGen have not been reported. A temporary increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be temporary because of glucagon’s short half-life. The increase in blood pressure and pulse rate may require therapy in patients with [[pheochromocytoma]] or [[coronary artery disease]]. Anaphylactic reactions may occur in some cases.
 
*The following adverse reactions have been identified during postapproval use of GlucaGen. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency.
 
[[File:Glucagon table 1.png|600px|thumbnail|left]]
{{clear}}
|drugInteractions='''Beta-blockers'''
 
*Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be temporary because of glucagon’s short half-life. The increase in blood pressure and pulse rate may require therapy in patients with [[pheochromocytoma]] or [[coronary artery disease]].
 
'''Indomethacin'''
 
*When used with [[indomethacin]], glucagon may lose its ability to raise blood glucose or may even produce hypoglycemia. Therefore, caution should be exercised for patients taking indomethacin when glucagon will be administered.
 
'''Anticholinergic Drugs'''
 
*Coadministration with an anticholinergic drug is not recommended due to increased gastrointestinal side effects.
 
'''Warfarin'''
 
*Glucagon may increase the anticoagulant effect of [[warfarin]]. Therefore, caution should be exercised for patients taking warfarin when glucagon will be administered.
 
'''Insulin'''
 
*Insulin reacts antagonistically towards glucagon. Therefore, caution should be exercised when glucagon is used as a diagnostic aid in [[diabetes]] patients.
|FDAPregCat=B
|useInPregnancyFDA=*Pregnancy Category B. Reproduction studies were performed in rats and rabbits at GlucaGen doses of 0.4, 2.0, and 10 mg/kg. These doses represent exposures of up to 100 and 200 times the human dose based on mg/m2 for rats and rabbits, respectively, and revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Glucagon does not cross the human placenta barrier.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=*It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GlucaGen is administered to a nursing woman. No clinical studies have been performed in nursing mothers, however, GlucaGen is a peptide and intact glucagon is not absorbed from the GI tract. Therefore, even if the infant ingested glucagon it would be unlikely to have any effect on the infant. Additionally, GlucaGen has a short plasma half-life thus limiting amounts available to the child. Glucagon does not cross the human placental barrier.
|useInPed=*For the treatment of severe hypoglycemia: The use of glucagon in pediatric patients has been reported to be safe and effective.
 
*For use as a diagnostic aid: Safety and effectiveness in pediatric patients have not been established.
|useInGeri=*There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
 
<!--Administration and Monitoring-->
|administration=*For GlucaGenHypoKit:
 
'''Treatment of severe hypoglycemia'''
 
*Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen powder and inject all the liquid from the syringe into the vial.
*Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.
*The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL glucagon.
*The reconstituted GlucaGen should be used immediately after reconstitution.
*Inject 1 mL (adults and children, weighing more than 55 lbs (25 kg)) or 0.5 mL (children weighing less than 55 lbs (25 kg)) subcutaneously, intramuscularly, or intravenously. If the weight is not known: children younger than 6 years should be given a 0.5 mL and children 6 years and older should be given 1 mL.
*Discard any unused portion.
*Emergency assistance should be sought immediately after subcutaneous or intramuscular injection of glucagon.
*The glucagon injection may be repeated using a new kit while waiting for emergency assistance.
*Intravenous glucose MUST be administered if the patient fails to respond to glucagon.
*When the patient has responded to the treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
 
*For GlucaGen Diagnostic Kit and the GlucaGen 10-pack:
 
'''Use as a diagnostic aid'''
 
*GlucaGen should be reconstituted with 1 mL of Sterile Water for Reconstitution (if supplied) or 1 mL of Sterile Water for Injection, USP. Using a syringe, withdraw all of the Sterile Water for Reconstitution (if supplied) or 1 mL Sterile Water for Injection, USP and inject into the GlucaGen vial.
*Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency.
*The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL glucagon.
*The reconstituted GlucaGen should be used immediately after reconstitution.
*GlucaGen must be administered by medical personnel.
*Discard any unused portion.
*Onset of action after an injection will depend on the organ under examination and route of administration.
*The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5 mg to 0.75 mg intravenously and 1 mg to 2 mg intramuscularly.
*After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure applied.
 
*The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are intended only for use by healthcare providers as a diagnostic aid. The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are not intended for use by patients to treat severe hypoglycemia because they are not packaged with a syringe and diluent necessary for rapid preparation and administration during an emergency outside of a healthcare facility.
 
====Dosage forms and strengths====
 
*GlucaGen is supplied in a vial, alone, or accompanied by Sterile Water for Reconstitution (1 mL) also in a vial (10 pack or diagnostic kit). It is also supplied as GlucaGen HypoKit®, a presentation with a disposable prefilled syringe containing 1 mL Sterile Water for Reconstitution. When the glucagon powder is reconstituted with Sterile Water for Reconstitution (if supplied) or with Sterile Water for Injection, USP, it forms a solution of 1 mg/mL (1 unit/mL) glucagon for subcutaneous, intramuscular, or intravenous injection.
|monitoring=*Blood glucose measurements may be considered to monitor the patient’s response.
|IVCompat=*There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
 
<!--Overdosage-->
|overdose=*No reports of overdosage with GlucaGen have been reported. If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure and pulse rate. In case of suspected overdosing, the serum potassium may decrease and should be monitored and corrected if needed. If the patient develops a dramatic increase in blood pressure, phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.
|drugBox=[[File:Glucagon image.png|600px|thumbnail|left]]
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|mechAction=*Antihypoglycemic Action: Glucagon induces liver glycogen breakdown, releasing glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect.
 
*Gastrointestinal Motility Inhibition: Extra hepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon.
|structure=*GlucaGen (glucagon [rDNA origin] for injection) is an antihypoglycemic agent and a gastrointestinal motility inhibitor. It is produced by expression of recombinant DNA in a Saccharomyces cerevisiae vector with subsequent purification. The chemical structure of the glucagon in GlucaGen is identical to human glucagon and to glucagon extracted from beef and pork pancreas. Glucagon with the empirical formula of C153H225N43O49S, and a molecular weight of 3483, is a single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is:
 
[[File:Glucagon structure.png|600px|thumbnail|left]]
{{clear}}
 
*GlucaGen is a sterile, lyophilized white powder in a 2 mL vial. The reconstituted solution contains glucagon as hydrochloride 1 mg/mL (1 unit/mL) and lactose monohydrate (107 mg). GlucaGen is supplied at pH 2.5-3.5 and is soluble in water.
|PD='''For the treatment of severe hypoglycemia:'''
 
*Blood glucose concentration rises within 10 minutes of injection and maximal concentrations are attained at approximately 30 minutes after injection (see Figure 1). The duration of hyperglycemic action after intravenous or intramuscular injection is 60 – 90 minutes.
 
[[File:Glucagon pharmacodynamics.png|600px|thumbnail|left]]
{{clear}}
|PK=*Intramuscular injection of 1 mg GlucaGen resulted in a mean Cmax (CV%) of 1686 pg/mL (43%) and median Tmax of 12.5 minutes. The mean apparent half-life of 45 minutes after intramuscular injection probably reflects prolonged absorption from the injection site. Glucagon is degraded in the liver, kidney, and plasma.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
 
*Long term studies in animals to evaluate carcinogenic potential have not been performed. Several studies have been conducted to evaluate the mutagenic potential of glucagon. The mutagenic potential tested in the Ames and human lymphocyte assays, was borderline positive under certain conditions for both glucagon (pancreatic) and glucagon (rDNA) origin. In vivo, very high doses (100 and 200 mg/kg) of glucagon (both origins) gave a slightly higher incidence of micronucleus formation in male mice but there was no effect in females. The weight of evidence indicates that GlucaGen is not different from glucagon pancreatic origin and does not pose a genotoxic risk to humans. GlucaGen (rDNA origin) was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility.
|clinicalStudies=*There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
|howSupplied=*GlucaGen is supplied as a sterile, lyophilized white powder in a vial, alone, or accompanied by Sterile Water for Reconstitution also in a vial (Diagnostic Kit or 10-pack). It is also supplied as GlucaGen HypoKit with a disposable prefilled syringe containing Sterile Water for Reconstitution.
 
*GlucaGenHypoKit includes:
 
*1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
 
*1 disposable syringe containing 1 mL Sterile Water for Reconstitution
 
*NDC 0169-7065-15
 
*GlucaGen Diagnostic Kit includes:
 
*1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
 
*1 vial containing 1 mL Sterile Water for Reconstitution
 
*NDC 55390-004-01
 
*GlucaGenHypoKit (Two-Pack) includes: 2 packs of GlucaGen HypoKit,
 
*Each HypoKit contains:
 
*1 vial containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
 
*1 disposable syringe containing 1 mL Sterile Water for Reconstitution
 
*NDC 0169-7065-21
 
*The GlucaGen 10-pack includes:
 
*10 vials, each containing 1 mg (1 unit) GlucaGen (glucagon [rDNA origin] for injection)
 
*NDC 55390-004-10
|storage='''Before Reconstitution:'''
 
*The GlucaGen package may be stored up to 24 months at controlled room temperature 20o to 25o C (68o to 77o F) prior to reconstitution. Do not freeze. Keep in the original package to protect from light. GlucaGen should not be used after the expiry date on the vials.
 
'''After Reconstitution:'''
 
*Reconstituted GlucaGen should be used immediately. Discard any unused portion. If the solution shows any sign of gel formation or particles, it should be discarded.
|packLabel=[[File:Glucagon pdp.png|600px|thumbnail|left]]
{{clear}}
 
[[File:Glucagon label.png|600px|thumbnail|left]]
{{clear}}
|fdaPatientInfo=*[See FDA-Approved Patient Labeling (Patient Instructions for Emergency Use).]
 
'''Physician Instructions'''
 
*Refer patients and family members to the FDA-approved patient labeling for instructions describing the method of preparing and injecting GlucaGen. Advise the patient and family members to become familiar with the technique of preparing glucagon before an emergency arises. Instruct patients to use 1 mg for adults or ½ the adult dose (0.5 mg) for children weighing less than 55 lb (25 kg). To prevent severe hypoglycemia, patients and family members should be informed of the symptoms of mild hypoglycemia and how to treat it appropriately. Family members should be informed to arouse the patient as quickly as possible because prolonged hypoglycemia may result in damage to the central nervous system. Patients should be advised to inform their physician when hypoglycemic reactions occur so that the treatment regimen may be adjusted if necessary.
 
*No studies on the effects on the ability to drive and use machines have been performed. After diagnostic procedures, hypoglycemia has been reported infrequently. The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating machinery. Therefore, these activities should be avoided until the patient has had a meal with oral carbohydrates.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
<!--Brand Names-->
|brandNames=Glucagen,
Glucagen Diagnostic Kit,
Glucagon,
Glucagon Diagnostic Kit,
Glucagon Emergency Kit.
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
 
<!--Drug Shortage Status-->
|drugShortage=
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{{PillImage
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{{LabelImage
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[[Category:Drug]]

Revision as of 20:26, 26 November 2017

This article is about the natural hormone. For the medication, see Glucagon (medication).
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Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fat in the bloodstream, and is considered to be the main catabolic hormone of the body [1]. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers the extracellular glucose.[2]

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.[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 the secritin family of hormones.

Function

Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis [5]. 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 when required [6].

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).[7]

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.[8]

Mechanism of action

File:Glucagon Activation.png
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.[9] 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)[10] 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 in hepatocytes.[11]

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. Production, which is otherwise freerunning, is suppressed/regulated by insulin from the adjacent beta cells. When blood sugar drops, insulin production drops and more glucagon is produced[12] 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.[12]

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.[13]

Regulation

Secretion of glucagon is stimulated by:

Secretion of glucagon is inhibited by:

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.[20] 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).[21]

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.[22] The amino acid sequence of glucagon was described in the late 1950s.[23] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

Etymology

Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist. [24]

See also

References

  1. ↑ Voet D, Voet JG. (2011). Biochemistry (4th ed.). New York: Wiley.
  2. ↑ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.
  3. ↑ Orsay J (2014). Biology 1: Molecules. Examkrackers Inc. p. 77. ISBN 978-1-893858-70-1.
  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. PMC 3281544. PMID 22294753.
  5. ↑ Voet D, Voet JG (2011). Biochemistry (4th ed.). New York: Wiley.
  6. ↑ HABEGGER, K. M., HEPPNER, K. M., GEARY, N., BARTNESS, T. J., DIMARCHI, R. & TSCHÖP, M. H. (2010). "The metabolic actions of glucagon revisited". Nature reviews. Endocrinology. 6: 689-697.
  7. ↑ 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" (PDF). The Journal of Clinical Investigation. 53 (1): 190–7. doi:10.1172/JCI107537. PMC 301453. PMID 4808635.
  8. ↑ Leinen RL, Giannini AJ (1983). "Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish". Society for Neuroscience Abstracts. 9: 604.
  9. ↑ 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. PMC 1148124. PMID 2822019.
  10. ↑ 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. doi:10.1016/b978-0-12-152823-2.50006-4. PMID 6327193.
  11. ↑ 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. doi:10.1073/pnas.73.8.2762. PMC 430732. PMID 183209.
  12. ↑ 12.0 12.1 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. PMC 3248306. PMID 22214853.
  13. ↑ 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. PMID 28323959.
  14. ↑ Layden BT, Durai V, Lowe WL (2010). "G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes". Nature Education. 3 (9): 13.
  15. ↑ 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. PMID 2891547.
  16. ↑ 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. PMID 6105951.
  17. ↑ 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. PMID 16399504.
  18. ↑ 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. PMID 17962386.
  19. ↑ Johnson LR (2003). Essential Medical Physiology. Academic Press. pp. 643–. ISBN 978-0-12-387584-6.
  20. ↑ 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. PMID 7015132.
  21. ↑ Orskov C, Holst JJ, Poulsen SS, Kirkegaard P (November 1987). "Pancreatic and intestinal processing of proglucagon in man". Diabetologia. 30 (11): 874–81. doi:10.1007/BF00274797. PMID 3446554.
  22. ↑ Kimball C, Murlin J (1923). "Aqueous extracts of pancreas III. Some precipitation reactions of insulin". J. Biol. Chem. 58 (1): 337–348.
  23. ↑ 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. doi:10.1021/ja01568a038.
  24. ↑ "History of glucagon - Metabolism, insulin and other hormones - Diapedia, The Living Textbook of Diabetes". www.diapedia.org. Retrieved 2017-03-26.
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