Editing Insulin (section)

=== Signal transduction ===
The effects of insulin are initiated by its binding to a receptor, [[Insulin receptor|the insulin receptor (IR)]], present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer. Insulin binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin.<ref name="diabetesincontrol.com">{{cite news|url=http://www.diabetesincontrol.com/handbook-of-diabetes-4th-edition-excerpt-4-normal-physiology-of-insulin-secretion-and-action/|title=Handbook of Diabetes, 4th Edition, Excerpt #4: Normal Physiology of Insulin Secretion and Action|date=28 July 2014|work=Diabetes In Control. A free weekly diabetes newsletter for Medical Professionals.|access-date=1 June 2017|language=en-US}}</ref>

The cascade that leads to the insertion of GLUT4 glucose transporters into the cell membranes of muscle and fat cells, and to the synthesis of glycogen in liver and muscle tissue, as well as the conversion of glucose into triglycerides in liver, adipose, and lactating mammary gland tissue, operates via the activation, by IRS-1, of phosphoinositol 3 kinase ([[phosphoinositide 3-kinase|PI3K]]). This enzyme converts a [[phospholipid]] in the cell membrane by the name of [[phosphatidylinositol 4,5-bisphosphate]] (PIP2), into [[Phosphatidylinositol (3,4,5)-trisphosphate|phosphatidylinositol 3,4,5-triphosphate]] (PIP3), which, in turn, activates [[AKT|protein kinase B]] (PKB). Activated PKB facilitates the fusion of GLUT4 containing [[endosome]]s with the cell membrane, resulting in an increase in GLUT4 transporters in the plasma membrane.<ref name="pmid15791206">{{cite journal | vauthors = McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR | title = Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis | journal = The EMBO Journal | volume = 24 | issue = 8 | pages = 1571–83 | date = April 2005 | pmid = 15791206 | pmc = 1142569 | doi = 10.1038/sj.emboj.7600633 }}</ref> PKB also phosphorylates [[GSK-3|glycogen synthase kinase]] (GSK), thereby inactivating this enzyme.<ref name="pmid11035810">{{cite journal | vauthors = Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB | title = Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 22 | pages = 11960–75 | date = October 2000 | pmid = 11035810 | pmc = 17277 | doi = 10.1073/pnas.220413597 | bibcode = 2000PNAS...9711960F | doi-access = free }}</ref> This means that its substrate, [[glycogen synthase]] (GS), cannot be phosphorylated, and remains dephosphorylated, and therefore active. The active enzyme, glycogen synthase (GS), catalyzes the rate limiting step in the synthesis of glycogen from glucose. Similar dephosphorylations affect the enzymes controlling the rate of [[glycolysis]] leading to the synthesis of fats via [[malonyl-CoA]] in the tissues that can generate [[triglycerides]], and also the enzymes that control the rate of [[gluconeogenesis]] in the liver. The overall effect of these final enzyme dephosphorylations is that, in the tissues that can carry out these reactions, glycogen and fat synthesis from glucose are stimulated, and glucose production by the liver through [[glycogenolysis]] and [[gluconeogenesis]] are inhibited.<ref name="stryer2">{{cite book|title=Biochemistry.|publisher=W.H. Freeman and Company|isbn=0-7167-2009-4|edition= Fourth|location=New York|date=1995|pages=351–56, 494–95, 505, 605–06, 773–75| vauthors = Stryer L }}</ref> The breakdown of triglycerides by adipose tissue into [[free fatty acids]] and [[glycerol]] is also inhibited.<ref name=stryer2 />

After the intracellular signal that resulted from the binding of insulin to its receptor has been produced, termination of signaling is then needed.  As mentioned below in the section on degradation, endocytosis and degradation of the receptor bound to insulin is a main mechanism to end signaling.<ref name="Najjar_2001" />  In addition, the signaling pathway is also terminated by dephosphorylation of the tyrosine residues in the various signaling pathways by tyrosine phosphatases.  Serine/Threonine kinases are also known to reduce the activity of insulin.

The structure of the insulin–[[insulin receptor]] complex has been determined using the techniques of [[X-ray crystallography]].<ref name="Menting_2013">{{cite journal |vauthors=Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Záková L, Kletvíková E, Jiráček J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC |title=How insulin engages its primary binding site on the insulin receptor |journal=Nature |volume=493 |issue=7431 |pages=241–245 |date=January 2013 |pmid=23302862 |pmc=3793637 |doi=10.1038/nature11781 |bibcode=2013Natur.493..241M}}<br/>{{cite web |title=Australian researchers crack insulin binding mechanism |author=Simon Lauder |date=9 January 2013 |url=http://www.abc.net.au/news/2013-01-10/australian-researchers-crack-insulin-mechanism/4458974 |publisher=Australian Broadcasting Commission}}</ref>