Glucagon
Glucagon, a peptide hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels.[1] The pancreas releases glucagon when blood sugar (glucose) levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High blood glucose levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level. Glucagon belongs to a family of several other related hormones.
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Physiology [edit]
Production [edit]
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.
Regulation [edit]
Secretion of glucagon is stimulated by:
- Hypoglycemia
- Epinephrine (via β2, α2,[2] and α1[3] adrenergic receptors)
- Arginine
- Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
- Acetylcholine[4]
- Cholecystokinin
Secretion of glucagon is inhibited by:
- Somatostatin
- Insulin (via GABA)[5]
- Increased free fatty acids and keto acids into the blood
- Increased urea production
Function [edit]
Glucagon generally elevates the amount of glucose in the blood by promoting gluconeogenesis and glycogenolysis.
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| Clinical data | |
| Pregnancy cat. | ? |
| Legal status | ? |
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| ATC code | ? |
| PubChem | CID 16186314 |
| IUPHAR ligand | 1136 |
| ChemSpider | 10481928  |
| UNII | 76LA80IG2G |
| ChEMBL | CHEMBL266481 |
| Chemical data | |
| Formula | ? |
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Glucose is stored in the liver in the form of glycogen, which is a starch-like polymer chain made up of glucose molecules. Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen polymer 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 has a minimal effect on lipolysis in humans.
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.[6]
Mechanism of action [edit]
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, 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.
History [edit]
In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[7] The amino acid sequence of glucagon was described in the late 1950s.[8] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.
Etymology [edit]
Glucagon was named in 1923, probably from the Greek γλυκός sweet, and ἄγειν to lead.[9]
Structure [edit]
Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH.
The polypeptide has a molecular weight of 3485 daltons. Glucagon is a peptide (nonsteroid) hormone.
Glucagon is generated from the cleavage of proglucagon secreted by pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).
Pathology [edit]
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.
Uses and contraindications [edit]
Hypoglycemia [edit]
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. To use the injectable form, it must be reconstituted prior to use, a step that requires a sterile diluent to be injected into a vial containing powdered glucagon, because the hormone is highly unstable when dissolved in solution. When dissolved in a fluid state, glucagon can form amyloid fibrils, or tightly woven chains of proteins made up of the individual glucagon peptides, and once glucagon begins to fibrilize, it becomes useless when injected, as the glucagon cannot be absorbed and used by the body. The reconstitution process makes using glucagon cumbersome, although there are a number of products now in development from a number of companies that aim to make the product easier to use.
Beta blocker overdose [edit]
Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, in effect bypassing the β-adrenergic second messenger system.[10]
Impacted food bolus [edit]
Glucagon relaxes the lower esophageal sphincter and is used in emergencies involving an impacted food bolus in the esophagus.[11]
Side-effects and interactions [edit]
Glucagon acts very quickly; common side-effects include headache and nausea.
Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed.
Contraindications [edit]
While glucagon can be used clinically to treat various forms of hypoglycemia, it is severely contraindicated in patients with pheochromocytoma, as the drug interaction with elevated levels of adrenaline produced by the tumor may produce an exponential increase in blood sugar levels, leading to a hyperglycemic state, which may incur a fatal elevation in blood pressure.[12] Likewise, glucagon is contraindicated in patients with an insulinoma, as its use may lead to rebound hypoglycemia.[12]
Media [edit]
See also [edit]
- Cortisol
- Diabetes mellitus
- Glucagon-like peptide-1
- Glucagon-like peptide-2
- Insulin
- Islets of Langerhans
- Pancreas
- Proglucagon
References [edit]
- ^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.
- ^ Layden BT, Durai V, Lowe WL (2010). "G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes". Nature Education 3 (9): 13.
- ^ Skoglund G, Lundquist I, Ahrén B (November 1987). "Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse". Eur. J. Pharmacol. 143 (1): 83–8. doi:10.1016/0014-2999(87)90737-0. PMID 2891547.
- ^ 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.
- ^ 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 Metab. 3 (1): 47–58. doi:10.1016/j.cmet.2005.11.015. PMID 16399504.
- ^ Leinen RL, Giannini AJ (1983). "Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish". Society for Neuroscience Abstracts 9: 604.
- ^ Kimball C, Murlin J (1923). "Aqueous extracts of pancreas III. Some precipitation reactions of insulin". J. Biol. Chem. 58 (1): 337–348.
- ^ 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.
- ^ glucagon on dictionary.com
- ^ White CM (May 1999). "A review of potential cardiovascular uses of intravenous glucagon administration". J Clin Pharmacol 39 (5): 442–7. PMID 10234590.
- ^ Ko HH, Enns R (October 2008). "Review of food bolus management". Can. J. Gastroenterol. 22 (10): 805–8. PMC 2661297. PMID 18925301.
- ^ a b "Information for the Physician: Glucagon for Injection (rDNA origin)". Eli Lilly and Company. Retrieved 2011-11-19.
Further reading [edit]
- 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. PMC 2909599. 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. PMC 311486. 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.
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