glucagon

[Probably GLUC(O)- + Greek agōn, present participle of agein, to lead, drive.]

The protein hormone secreted by the pancreas which is known to influence a wide variety of metabolic reactions. Glucagon, along with insulin and other hormones, plays a role in the complex and dynamic process of maintaining adequate supplies of sugar in the blood. Glucagon has often been called the hyperglycemic-glycogenolytic factor because it causes the breakdown of liver glycogen to sugar (a process known as glycogenolysis) and thereby increases the concentration of sugar in the bloodstream (a condition known as hyperglycemia). Glucagon may also be involved in the regulation of protein and fat metabolism, gastric acid secretion and gut motility, excretion of electrolytes (such as sodium, potassium and chloride) by the kidney, contractility of heart muscle, and release of insulin from the pancreas. Glucagon is used in human medicine chiefly in certain diabetic conditions when a dangerously low blood sugar must be rapidly raised. See also Carbohydrate metabolism; Diabetes; Glycogen; Hormone; Insulin; Pancreas.

A hormone secreted by the α-cells of the pancreas which causes an increase in blood sugar by increasing the breakdown of liver glycogen and stimulating the synthesis of glucose from amino acids.

A protein hormone secreted by the pancreas. It has the opposite action to insulin, causing blood glucose levels to rise. Glucagon is secreted in the fasting state to maintain blood glucose levels and mobilize fatty acids. Secretion usually increases during exercise because of the increased need for fuel mobilization, but the response is lower in people who are physically fit. Consequently, blood glucose levels tend to fluctuate less in those who exercise regularly.

(hyperglycemic factor, hyperglycemic-glycogenolytic factor [HGF]) a hormone from the a cells of the pancreas that raises the blood sugar by increasing hepatic glycogenolysis.

Brand names: GlucaGen®, Glucagon®

Chemical formula:

Drug Forms:
• Glucagon Hydrochloride Solution for injection (below)
• Glucagon injection

Español:
• Clorhidrato de Glucagón, Solución para inyección
• Inyección de glucagón

Glucagon Hydrochloride Solution for injection

What is this medicine?

GLUCAGON occurs naturally in the body. It increases blood sugar. This medicine is used as an emergency treatment for severely low blood sugar in diabetic patients, especially if they are not able to take sugar by mouth. It is also used as a diagnostic aid in X-ray examinations of the stomach and other digestive organs.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• pancreatic tumors
• pheochromocytoma
• an unusual or allergic reaction to glucagon, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

This medicine is for injection into a muscle. You will be taught how to prepare and give this medicine. Instructions for mixing and giving the injection are included in the package. Before an emergency arises, you and the person(s) most likely to give you the injection should read these instructions carefully. Use exactly as directed. Do not take your medicine more often than directed.

It is important that you put your used needles and syringes in a special sharps container. Do not put them in a trash can. If you do not have a sharps container, call your pharmacist or healthcare provider to get one.

Talk to your pediatrician regarding the use of this medicine in children. While this medicine may be prescribed for selected conditions, precautions do apply.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

This medicine is only used during an emergency. Significant drug interactions are not likely during that time.

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

If you often have periods of low blood sugar, keep this kit with you at all times. Wear a medical identification bracelet or chain to say you have diabetes, and carry a card that lists all your medications.

Show your family members and others where you keep this kit and how to use it. They need to know how to use it before you need it. They can practice by giving you your normal insulin shots. It is important that they practice. A person who has never given you a shot will probably not be able to do it in an emergency.

Symptoms of low blood sugar vary from person to person. Learn to recognize your own. They can include: confusion, cool, pale skin or cold sweats, drowsiness, extreme hunger, fast heartbeat, headache, nausea, vomiting, nervousness or anxiety, shakiness or unsteadiness, tiredness, weakness, or visual changes. Eat or drink something sweet (fruit juice, honey, soft drinks, sugar or sugar water, or syrup) if you get these symptoms. If you do not feel better, ask someone to help you get to a doctor, health care professional or emergency room right away. Do not attempt to drive yourself. Also, remind the person that he/she may need to give you a glucagon injection before medical treatment is available.

After a response to an injection of glucagon, you should eat or drink some carbohydrates to prevent secondary hypoglycemia.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
• chest pain or fast, irregular heartbeat
• difficulty breathing
• dizziness or light headedness
• muscle cramps
• unusual weakness

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
• nausea, vomiting
• rash, itching

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 20 and 25 degrees C (68 and 77 degrees F) before mixing the solution. After dissolving the powder in the diluting solution, use it immediately. Do not store for later use. Throw away any unused solution. Throw away the kit after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

A polypeptide hormone secreted by alpha cells of the islets of Langerhans in the pancreas. Glucagon increases the conversion of glycogen to glucose, causing blood glucose levels to rise (compare insulin). Glucagon levels generally increase in response to exercise, but this response is lessened by training.

A polypeptide hormone secreted by the alpha cells of the islets of Langerhans in response to hypoglycemia or to stimulation by growth hormone. It increases blood glucose concentration by stimulating glycogenolysis in the liver and is administered to relieve hypoglycemic coma from any cause, especially hyperinsulinism.

• g. diabetes — glucagon elevates blood glucose levels and may contribute to the severity of diabetes if there is already an insulin deficit but it is not necessary to, nor sufficient for, the development of diabetes.
• g. stimulation test — a provocative test of growth hormone (GH) function in which the fasting serum level of GH is measured before and after administration of glucagon.
• g. tolerance test — evaluates the insulin response to elevation of blood glucose induced by administration of glucagon. Used in diagnosing hyperinsulinism.

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Glucagon
PDB rendering based on 1d0r.
Available structures
1d0r, 1gcn, 1kx6, 2g49
Identifiers
Symbols	GCG; GLP1; GLP2; GRPP
External IDs	OMIM: 138030 MGI: 95674 HomoloGene: 1553
Gene ontology Molecular function • hormone activity Cellular component • extracellular region • soluble fraction Biological process • signal transduction • G-protein coupled receptor protein signaling pathway • feeding behavior • cell proliferation • regulation of insulin secretion
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2641	14526
Ensembl	ENSG00000115263	ENSMUSG00000000394
UniProt	P01275	P55095
RefSeq	NM_002054 (mRNA)	NM_008100 (mRNA)
	NP_002045 (protein)	NP_032126 (protein)
Location	Chr 2: 162.71 - 162.71 Mb	Chr 2: 62.28 - 62.28 Mb
PubMed search	[1]	[2]

Glucagon is an important hormone involved in carbohydrate metabolism. Produced by the pancreas, it is released when blood glucose levels start to fall too low, causing the liver to convert stored glycogen into glucose and release it into the bloodstream, raising blood glucose levels and ultimately preventing the development of hypoglycemia. The action of glucagon is thus opposite to that of insulin, which instructs the body's cells to take in glucose from the blood. However, glucagon also stimulates the release of insulin, so that newly-available glucose in the bloodstream can be taken up and used by insulin-dependent tissues.

Contents 1 History 2 Structure 3 Physiology 3.1 Production 3.2 Regulatory mechanism 3.3 Function 3.4 Mechanism of action 4 Pathology 5 Uses 6 Media 7 See also 8 References 9 Further reading

History

In the 1920s, Kimball and Murlin studied pancreatic extracts and found an additional substance with hyperglycemic properties. They described glucagon in 1923.^[1] The amino acid sequence of glucagon was described in the late-1950s.^[2] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

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 (non-steroid) hormone.

Physiology

Production

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.

Regulatory mechanism

Increased secretion of glucagon is caused by:

• Decreased plasma glucose
• Increased catecholamines - norepinephrine and epinephrine
• Increased plasma amino acids (to protect from hypoglycemia if an all-protein meal is consumed)
• Sympathetic nervous system
• Acetylcholine
• Cholecystokinin

Decreased secretion (inhibition) of glucagon is caused by:

• Somatostatin
• Insulin
• Increased free fatty acids and ketoacids into the blood
• Increased urea production

Function

Glucagon ball and stick model, with the carboxyl terminus above and the amino terminus below

A microscopic image stained for glucagon.

Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia. Glucagon also regulates the rate of glucose production through lipolysis.

Glucagon production appears to be dependent on the central nervous system through pathways that are yet to be defined. It has been reported that in invertebrate animals eyestalk removal can affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia. ^[3]

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 GDP molecule, that was bound to the α subunit, to be replaced with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunit. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cAMP (cyclic AMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which, in turn, phosphorylates glycogen phosphorylase, converting into the active form called phosphorylase A. Phosphorylase A is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

Pathology

Abnormally-elevated levels of glucagon may be caused by pancreatic tumors such as glucagonoma, symptoms of which include necrolytic migratory erythema (NME), reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.

Uses

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. Glucagon can also be administered intravenously at 0.25 - 0.5 unit.

Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, effectively bypassing the inhibitory action of the β-adrenergic second messenger system.^[4]

Glucagon acts very quickly; common side-effects include headache and nausea.

Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed.

Media

Rotating stereogram animation of glucagon. (1.70 MB, animated GIF format).

See also

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

References

1. ^ Kimball C, Murlin J. Aqueous extracts of pancreas III. Some precipitation reactions of insulin. J Biol Chem 1923;58:337-348. PDF fulltext.
2. ^ Bromer W, Winn L, Behrens O. The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence. J Am Chem Soc 1957;79:2807-2810.
3. ^ RL Leinen, AJ Giannini. Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish. Society for Neuroscience Abstracts. 9:604, 1983
4. ^ White CM. A review of potential cardiovascular uses of intravenous glucagon administration. J Clin Pharmacol 1999;39:442-7. PMID 10234590.

Further reading

• Kieffer TJ, Habener JF (2000). "The glucagon-like peptides". Endocr. Rev. 20 (6): 876–913. doi:10.1210/er.20.6.876. PMID 10605628. 
• Drucker DJ (2003). "Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis". Mol. Endocrinol. 17 (2): 161–71. doi:10.1210/me.2002-0306. PMID 12554744. 
• Jeppesen PB (2004). "Clinical significance of GLP-2 in short-bowel syndrome". J. Nutr. 133 (11): 3721–4. PMID 14608103. 
• Brubaker PL, Anini Y (2004). "Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2". Can. J. Physiol. Pharmacol. 81 (11): 1005–12. doi:10.1139/y03-107. PMID 14719035. 
• Baggio LL, Drucker DJ (2005). "Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2". Best Pract. Res. Clin. Endocrinol. Metab. 18 (4): 531–54. doi:10.1016/j.beem.2004.08.001. PMID 15533774. 
• Holz GG, Chepurny OG (2006). "Diabetes outfoxed by GLP-1?". Sci. STKE 2005 (268): pe2. doi:10.1126/stke.2682005pe2. PMID 15671479. 
• Dunning BE, Foley JE, Ahrén B (2006). "Alpha cell function in health and disease: influence of glucagon-like peptide-1". Diabetologia 48 (9): 1700–13. doi:10.1007/s00125-005-1878-0. PMID 16132964. 
• Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C (2005). "Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes". Diabetes Metab. 31 (3 Pt 1): 233–42. doi:10.1016/S1262-3636(07)70190-8. PMID 16142014. 
• De León DD, Crutchlow MF, Ham JY, Stoffers DA (2006). "Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus". Int. J. Biochem. Cell Biol. 38 (5-6): 845–59. doi:10.1016/j.biocel.2005.07.011. PMID 16202636. 
• Beglinger C, Degen L (2007). "Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY?". Physiol. Behav. 89 (4): 460–4. doi:10.1016/j.physbeh.2006.05.048. PMID 16828127. 
• Stephens JW, Bain SC (2007). "Safety and adverse effects associated with GLP-1 analogues". Expert opinion on drug safety 6 (4): 417–22. doi:10.1517/14740338.6.4.417. PMID 17688385. 
• Orskov C, Bersani M, Johnsen AH, et al. (1989). "Complete sequences of glucagon-like peptide-1 from human and pig small intestine". J. Biol. Chem. 264 (22): 12826–9. PMID 2753890. 
• Drucker DJ, Asa S (1988). "Glucagon gene expression in vertebrate brain". J. Biol. Chem. 263 (27): 13475–8. PMID 2901414. 
• Novak U, Wilks A, Buell G, McEwen S (1987). "Identical mRNA for preproglucagon in pancreas and gut". Eur. J. Biochem. 164 (3): 553–8. doi:10.1111/j.1432-1033.1987.tb11162.x. PMID 3569278. 
• White JW, Saunders GF (1986). "Structure of the human glucagon gene". Nucleic Acids Res. 14 (12): 4719–30. doi:10.1093/nar/14.12.4719. PMID 3725587. 
• Schroeder WT, Lopez LC, Harper ME, Saunders GF (1984). "Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37". Cytogenet. Cell Genet. 38 (1): 76–9. doi:10.1159/000132034. PMID 6546710. 
• Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC (1983). "Exon duplication and divergence in the human preproglucagon gene". Nature 304 (5924): 368–71. doi:10.1038/304368a0. PMID 6877358. 
• Kärgel HJ, Dettmer R, Etzold G, et al. (1982). "Action of rat liver cathepsin L on glucagon". Acta Biol. Med. Ger. 40 (9): 1139–43. PMID 7340337. 
• Wayman GA, Impey S, Wu Z, et al. (1994). "Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo". J. Biol. Chem. 269 (41): 25400–5. PMID 7929237. 
• Unson CG, Macdonald D, Merrifield RB (1993). "The role of histidine-1 in glucagon action". Arch. Biochem. Biophys. 300 (2): 747–50. doi:10.1006/abbi.1993.1103. PMID 8382034. 

v • d • e PDB Gallery 1d0r: SOLUTION STRUCTURE OF GLUCAGON-LIKE PEPTIDE-1-(7-36)-AMIDE IN TRIFLUOROETHANOL/WATER   1gcn: X-RAY ANALYSIS OF GLUCAGON AND ITS RELATIONSHIP TO RECEPTOR BINDING   1kx6: NMR solution structure of Glucagon in a lipid-water interphase   2g49: Crystal structure of human insulin-degrading enzyme in complex with glucagon

v • d • e Endocrine system: hormones (Peptide hormones · Steroid hormones) Endocrine glands Hypothalamic- pituitary Hypothalamus GnRH · TRH · Dopamine · CRH · GHRH/Somatostatin Posterior pituitary Vasopressin · Oxytocin Anterior pituitary α (FSH FSHB, LH LHB, TSH TSHB, CGA) · Prolactin · POMC (CLIP, ACTH, MSH, Endorphins, Lipotropin) · GH Adrenal axis Adrenal cortex: aldosterone · cortisol · DHEA Adrenal medulla: epinephrine · norepinephrine Thyroid axis Thyroid: thyroid hormone (T3 and T4) · calcitonin Parathyroid: PTH Gonadal axis Testis: testosterone · AMH · inhibin Ovary: estradiol · progesterone · activin and inhibin · relaxin (pregnancy) Placenta: hCG · HPL · estrogen · progesterone Other end. glands Pancreas: glucagon · insulin · somatostatin Pineal gland: melatonin Thymus: Thymosin · Thymopoietin · Thymulin Non-end. glands digestive system: Stomach: gastrin · ghrelin · Duodenum: CCK · GIP · secretin · motilin · VIP · Ileum: enteroglucagon · Liver/other: Insulin-like growth factor (IGF-1, IGF-2) Adipose tissue: leptin · adiponectin · resistin Skeleton: Osteocalcin Kidney: JGA (renin) · peritubular cells (EPO) · calcitriol · prostaglandin Heart: Natriuretic peptide (ANP, BNP) endocrine navs: anat/physio/dev/hormones, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc

v • d • e Gastrointestinal hormones, pancreatic hormones: proglucagon Oxyntomodulin (Glucagon) - Glucagon-Like Peptides (GLP1, GLP2)

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