Glucagon is apeptide hormone, produced byalpha cells of thepancreas. It raises the concentration ofglucose andfatty acids in the bloodstream and is considered to be the maincatabolic hormone of the body.[1] It is also used as amedication to treat a number of health conditions. Its effect is opposite to that ofinsulin, which lowers extracellular glucose.[2] It is produced fromproglucagon, encoded by theGCG gene.
The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes theliver to engage inglycogenolysis: converting storedglycogen intoglucose, 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 family of hormones.
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]
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.
Glucagon generally elevates the concentration ofglucose in theblood by promotinggluconeogenesis andglycogenolysis.[17] Glucagon also decreases fatty acid synthesis inadipose tissue and the liver, as well as promotinglipolysis in these tissues, which causes them to release fatty acids into circulation where they can becatabolised to generate energy in tissues such asskeletal muscle when required.[18]
Glucose is stored in the liver in the form of thepolysaccharide glycogen, 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 offglycolysis 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 asdiabetes mellitus type 1).[19]
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. Ininvertebrate animals,eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in youngcrayfish produces glucagon-inducedhyperglycemia.[20]
Glucagon binds to theglucagon receptor, aG protein-coupled receptor, located in theplasma membrane of 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 theGDP molecule that was bound to the α subunit with aGTP molecule.[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 phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release ofglucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾.Gαs separates 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 also inactivatesacetyl-CoA carboxylase, which creates malonyl-CoA from acetyl-CoA, through cAMP-dependent and/or cAMP-independent kinases.[28]
Malonyl-CoA is a product formed byACC duringdenovo synthesis and an allosteric inhibitor of Carnitine 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.
Elevated glucagon is the main contributor tohyperglycemic ketoacidosis in 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 diabetes in 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.
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][failed verification] In the 1950s, scientists atEli Lilly isolated pure glucagon,crystallized it, and determined its amino acid sequence.[6][34][35] This led to the development of the firstradioimmunoassay for 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 specificradioimmunoassay was developed.[36]
In 1979, while working inJoel Habener's laboratory atMassachusetts General Hospital, Richard Goodman collectedislet cells fromBrockman bodies ofAmerican anglerfish in 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 Corporation led 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 receptor and then drugs which target that receptor, known asGLP-1 receptor agonists.[37]
^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.
^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.
^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.
^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.
^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.
^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.
^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.
^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.
^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.
