Glucagon

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 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT).

The polypeptide has a molecular mass of 3485 Daltons.[5] Glucagon is a peptide (nonsteroid) hormone.

Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.[17] 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.[18]

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).[19]

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.[20]

Metabolic regulation of glycogen by glucagon.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates a G protein, a heterotrimeric protein with α_s, 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.[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.

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 (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 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 glyocogen phosphorylase kinase.[22] Phosphorylated glyocogen phosphorylase kinase phosphorylates glycogen phosphorylase. Phosphorylated glycogen phosphorylase clips glucose units from glycogen as glucose 1-phosphate.

Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate.[23] The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose 2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)[24] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA inactivates the glycolytic enzyme pyruvate kinase,[25] inactivates glycogen synthase,[26] and activates hormone-sensitive lipase,[27] which catabolizes glycerides into glycerol and free fatty acid(s), in hepatocytes.

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

Malonyl-CoA is a byproduct of the Krebs cycle (downstream of glycolysis) 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.

Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema,[30] reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.[31]

Elevated glucagon is the main contributor to hyperglycemic 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 fast ketogenesis .[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. Inhibiting glucagon has been a popular idea of diabetes treatment, however, some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.

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 total pancreatectomy.

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 "glucose agonist".[6][33] In the 1950s, scientists at Eli Lilly isolated pure glucagon, crystallized it, and determined its amino acid sequence.[6][34][35] This led to the development of the first radioimmunoassay for detecting glucagon, described by Roger 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 specific radioimmunoassay was developed.[36]

• PDBe-KB provides an overview of all the structure information available in the PDB for Human Glucagon