Editing Insulin (section)

== Function ==

=== Secretion ===
{{See also|Blood glucose regulation}}

[[Beta Cell|Beta cells]] in the [[islets of Langerhans]] release insulin in two phases. The first-phase release is rapidly triggered in response to increased blood glucose levels, and lasts about 10 minutes. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar, peaking in 2 to 3 hours. The two phases of the insulin release suggest that insulin granules are present in diverse stated populations or "pools". During the first phase of insulin exocytosis, most of the granules predispose for exocytosis are released after the calcium internalization. This pool is known as Readily Releasable Pool (RRP). The RRP granules represent 0.3-0.7% of the total insulin-containing granule population, and they are found immediately adjacent to the plasma membrane. During the second phase of exocytosis, insulin granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release.<ref>{{cite journal |vauthors=Omar-Hmeadi M, Idevall-Hagren O |title=Insulin granule biogenesis and exocytosis |journal=Cellular and Molecular Life Sciences |volume=78 |issue=5 |pages=1957–1970 |date=March 2021 |pmid=33146746 |pmc=7966131 |doi=10.1007/s00018-020-03688-4}}</ref> Thus, the second phase of insulin release is governed by the rate at which granules get ready for release. This pool is known as a Reserve Pool (RP). The RP is released slower than the RRP (RRP: 18 granules/min; RP: 6 granules/min).<ref>{{cite journal |vauthors=Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW |title=Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion |journal=Diabetes |volume=51 |issue=Suppl 1 |pages=S83–S90 |date=February 2002 |pmid=11815463 |doi=10.2337/diabetes.51.2007.S83 |doi-access=free}}</ref> Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of [[type 2 diabetes|type&nbsp;2 diabetes]].<ref name="pmid11815469">{{cite journal |vauthors=Gerich JE |title=Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? |journal=Diabetes |volume=51 |issue=Suppl 1 |pages=S117–S121 |date=February 2002 |pmid=11815469 |doi=10.2337/diabetes.51.2007.s117 |doi-access=free}}</ref> First-phase release and [[Insulin resistance|insulin sensitivity]] are independent predictors of diabetes.<ref name="pmid20805282">{{cite journal |vauthors=Lorenzo C, Wagenknecht LE, Rewers MJ, Karter AJ, Bergman RN, Hanley AJ, Haffner SM |title=Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS) |journal=Diabetes Care |volume=33 |issue=9 |pages=2098–2103 |date=September 2010 |pmid=20805282 |pmc=2928371 |doi=10.2337/dc10-0165}}</ref>

The description of first phase release is as follows:
* Glucose enters the β-cells through the [[glucose transporters]], [[Glucose transporter|GLUT 2]]. At low blood sugar levels little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells.<ref name=schuit>{{cite journal | vauthors = Schuit F, Moens K, Heimberg H, Pipeleers D | title = Cellular origin of hexokinase in pancreatic islets | journal = The Journal of Biological Chemistry | volume = 274 | issue = 46 | pages = 32803–09 | date = November 1999 | pmid = 10551841 | publication-date = 1999 | doi=10.1074/jbc.274.46.32803| doi-access = free }}</ref>
* The glucose that enters the β-cell is phosphorylated to [[glucose-6-phosphate]] (G-6-P) by [[glucokinase]] ([[Hexokinase#Types of mammalian hexokinase|hexokinase IV]]) which is not inhibited by G-6-P in the way that the hexokinases in other tissues (hexokinase I – III) are affected by this product. This means that the intracellular G-6-P concentration remains proportional to the blood sugar concentration.<ref name=koeslag /><ref name=schuit />
* Glucose-6-phosphate enters [[Glycolysis|glycolytic pathway]] and then, via the [[pyruvate dehydrogenase]] reaction, into the [[Krebs cycle]], where multiple, high-energy [[adenosine triphosphate|ATP]] molecules are produced by the oxidation of [[acetyl CoA]] (the Krebs cycle substrate), leading to a rise in the ATP:ADP ratio within the cell.<ref>{{cite journal | vauthors = Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T, Prentki M | title = Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18572–79 | date = July 1997 | pmid = 9228023 | publication-date = 1997 | doi=10.1074/jbc.272.30.18572| doi-access = free }}</ref>
* An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/[[Kir6.2]] [[potassium channel]] (see [[sulfonylurea receptor]]). This prevents potassium ions (K<sup>+</sup>) from leaving the cell by facilitated diffusion, leading to a buildup of intracellular potassium ions. As a result, the inside of the cell becomes less negative with respect to the outside, leading to the depolarization of the cell surface membrane.
* Upon [[depolarization]], voltage-gated [[calcium channels|calcium ion (Ca<sup>2+</sup>) channels]] open, allowing calcium ions to move into the cell by facilitated diffusion.
* The cytosolic calcium ion concentration can also be increased by calcium release from intracellular stores via activation of ryanodine receptors.<ref name="SP2015">{{cite journal | vauthors = Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR | title = Calcium release channel RyR2 regulates insulin release and glucose homeostasis | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1968–78 | date = May 2015 | pmid = 25844899 | doi = 10.1172/JCI79273 | pmc=4463204}}</ref>
* The calcium ion concentration in the cytosol of the beta cells can also, or additionally, be increased through the activation of [[phospholipase|phospholipase C]] resulting from the binding of an extracellular [[ligand]] (hormone or neurotransmitter) to a [[G protein]]-coupled membrane receptor. Phospholipase C cleaves the membrane phospholipid, [[phosphatidyl inositol 4,5-bisphosphate]], into [[inositol 1,4,5-trisphosphate]] and [[diglyceride|diacylglycerol]]. Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the plasma membrane of the [[endoplasmic reticulum]] (ER). This allows the release of Ca<sup>2+</sup> ions from the ER via IP3-gated channels, which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration. [[Parasympathetic nervous system|Parasympathetic]] stimulation of the pancreatic islets operates via this pathway to increase insulin secretion into the blood.<ref name=stryer1>{{cite book | vauthors = Stryer L | title = Biochemistry. |edition=  Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 343–44|isbn= 0-7167-2009-4 }}</ref>
* The significantly increased amount of calcium ions in the cells' cytoplasm causes the release into the blood of previously synthesized insulin, which has been stored in intracellular [[secretion|secretory]] [[vesicle (biology)|vesicles]].

This is the primary mechanism for release of insulin. Other substances known to stimulate insulin release include the amino acids arginine and leucine, parasympathetic release of [[acetylcholine]] (acting via the phospholipase C pathway), [[sulfonylurea]], [[cholecystokinin]] (CCK, also via phospholipase C),<ref name="pmid19922535">{{cite journal | vauthors = Cawston EE, Miller LJ | title = Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor | journal = British Journal of Pharmacology | volume = 159 | issue = 5 | pages = 1009–21 | date = March 2010 | pmid = 19922535 | pmc = 2839260 | doi = 10.1111/j.1476-5381.2009.00489.x }}</ref> and the gastrointestinally derived [[incretins]], such as [[glucagon-like peptide-1]] (GLP-1) and [[glucose-dependent insulinotropic peptide]] (GIP).

Release of insulin is strongly inhibited by [[norepinephrine]] (noradrenaline), which leads to increased blood glucose levels during stress.  It appears that release of [[catecholamines]] by the [[sympathetic nervous system]] has conflicting influences on insulin release by beta cells, because insulin release is inhibited by α<sub>2</sub>-adrenergic receptors<ref name="pmid6252481">{{cite journal | vauthors = Nakaki T, Nakadate T, Kato R | title = Alpha 2-adrenoceptors modulating insulin release from isolated pancreatic islets | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 313 | issue = 2 | pages = 151–53 | date = August 1980 | pmid = 6252481 | doi = 10.1007/BF00498572 | s2cid = 30091529 }}</ref> and stimulated by β<sub>2</sub>-adrenergic receptors.<ref name="Layden_2010">{{cite journal | vauthors = Layden BT, Durai V, ((Lowe WL Jr)) | title = G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes | journal = Nature Education | volume = 3 | issue = 9 | page = 13 | year = 2010 | url = http://www.nature.com/scitable/topicpage/g-protein-coupled-receptors-pancreatic-islets-and-14257267  }}</ref> The net effect of [[norepinephrine]] from sympathetic nerves and [[epinephrine]] from adrenal glands on insulin release is inhibition due to dominance of the α-adrenergic receptors.<ref name="sabyasachi">{{cite book  | vauthors = Sircar S | title = Medical Physiology | publisher = Thieme Publishing Group | location = Stuttgart | year = 2007 | pages = 537–38 | isbn = 978-3-13-144061-7  }}</ref>

When the glucose level comes down to the usual physiologic value, insulin release from the β-cells slows or stops. If the blood glucose level drops lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently [[glucagon]] from islet of Langerhans alpha cells) forces release of glucose into the blood from the liver glycogen stores, supplemented by [[gluconeogenesis]] if the glycogen stores become depleted. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia.

Evidence of impaired first-phase insulin release can be seen in the [[glucose tolerance test]], demonstrated by a substantially elevated blood glucose level at 30 minutes after the ingestion of a glucose load (75 or 100 g of glucose), followed by a slow drop over the next 100 minutes, to remain above 120&nbsp;mg/100 mL after two hours after the start of the test. In a normal person the blood glucose level is corrected (and may even be slightly over-corrected) by the end of the test. An insulin spike is a 'first response' to blood glucose increase, this response is individual and dose specific although it was always previously assumed to be food type specific only.

=== Oscillations ===
{{Main|Insulin oscillations}}

[[File:Pancreas insulin oscillations.svg|thumb|250px|Insulin release from pancreas oscillates with a period of 3–6&nbsp;minutes.<ref name="hellman" />]]

Even during digestion, in general, one or two hours following a meal, insulin release from the pancreas is not continuous, but [[oscillates]] with a period of 3–6&nbsp;minutes, changing from generating a blood insulin concentration more than about 800 [[pico-|p]] [[unit mole|mol]]/l to less than 100 pmol/L (in rats).<ref name="hellman">{{cite journal | vauthors = Hellman B, Gylfe E, Grapengiesser E, Dansk H, Salehi A |url= https://www.researchgate.net/publication/6018588 | title = [Insulin oscillations—clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release] |language=sv | journal = Läkartidningen | volume = 104 | issue = 32–33 | pages = 2236–39 | year = 2007 | pmid = 17822201 }}</ref> This is thought to avoid [[receptor downregulation|downregulation]] of [[insulin receptor]]s in target cells, and to assist the liver in extracting insulin from the blood.<ref name="hellman" /> This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be achieved, not a constant high concentration.<ref name="hellman" /> This may be achieved by [[Pulsatile insulin|delivering insulin rhythmically]] to the [[portal vein]], by light activated delivery, or by [[islet cell transplantation]] to the liver.<ref name="hellman" /><ref>{{cite journal | vauthors = Sarode BR, Kover K, Tong PY, Zhang C, Friedman SH | title = Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot | journal = Molecular Pharmaceutics | volume = 13 | issue = 11 | pages = 3835–3841 | date = November 2016 | pmid = 27653828 | pmc = 5101575 | doi = 10.1021/acs.molpharmaceut.6b00633 }}</ref><ref>{{cite journal | vauthors = Jain PK, Karunakaran D, Friedman SH | url = https://piyushjain.mit.edu/sites/default/files/images/Construction%20of%20a%20Photoactivated%20Insulin%20Depot.pdf | title = Construction of a photoactivated insulin depot | journal = Angewandte Chemie | volume = 52 | issue = 5 | pages = 1404–9 | date = January 2013 | pmid = 23208858 | doi = 10.1002/anie.201207264 | access-date = 3 November 2019 | archive-date = 2 November 2019 | archive-url = https://web.archive.org/web/20191102205134/http://piyushjain.mit.edu/sites/default/files/images/Construction%20of%20a%20Photoactivated%20Insulin%20Depot.pdf | url-status = dead }}</ref>

=== Blood insulin level ===
{{Further |Insulin index}}
[[File:Suckale08 fig3 glucose insulin day.png|250px|thumb|The idealized diagram shows the fluctuation of [[blood sugar]] (red) and the sugar-lowering hormone '''insulin''' (blue) in humans during the course of a day containing three meals. In addition, the effect of a [[sucrose|sugar]]-rich versus a [[starch]]-rich meal is highlighted.]]
The blood insulin level can be measured in [[international unit]]s, such as μIU/mL or in [[molar concentration]], such as pmol/L, where 1 μIU/mL equals 6.945 pmol/L.<ref>{{cite web |title=A Dictionary of Units of Measurement |url=http://www.unc.edu/~rowlett/units/scales/clinical_data.html |archive-url=https://web.archive.org/web/20131028105836/http://www.unc.edu/~rowlett/units/scales/clinical_data.html |archive-date=28 October 2013 |vauthors=Rowlett R |publisher=The University of North Carolina at Chapel Hill |date=13 June 2001}}</ref> A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).<ref name="pmid11056282">{{cite journal |vauthors=Iwase H, Kobayashi M, Nakajima M, Takatori T |title=The ratio of insulin to C-peptide can be used to make a forensic diagnosis of exogenous insulin overdosage |journal=Forensic Science International |volume=115 |issue=1–2 |pages=123–127 |date=January 2001 |pmid=11056282 |doi=10.1016/S0379-0738(00)00298-X}}</ref>

=== 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>

=== Physiological effects ===
[[File:Insulin glucose metabolism ZP.svg|thumbnail|upright=1.8|'''Effect of insulin on glucose uptake and metabolism.''' Insulin binds to its receptor (1), which starts many protein activation cascades (2). These include translocation of Glut-4 transporter to the [[plasma membrane]] and influx of glucose (3), [[glycogen]] synthesis (4), [[glycolysis]] (5) and triglyceride synthesis (6).]]

[[File:Signal Transduction Diagram- Insulin.svg|thumb|upright=1.8|The insulin signal transduction pathway begins when insulin binds to the insulin receptor proteins. Once the transduction pathway is completed, the GLUT-4 storage vesicles becomes one with the cellular membrane. As a result, the GLUT-4 protein channels become embedded into the membrane, allowing glucose to be transported into the cell.]]

The actions of insulin on the global human metabolism level include:
* Increase of cellular intake of certain substances, most prominently glucose in muscle and [[adipose tissue]] (about two-thirds of body cells)<ref name="pmid21864752">{{cite journal | vauthors = Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA | title = Insulin effects in muscle and adipose tissue | journal = Diabetes Research and Clinical Practice | volume = 93 | issue = Suppl 1 | pages = S52–59 | date = August 2011 | pmid = 21864752 | doi = 10.1016/S0168-8227(11)70014-6 }}</ref>
* Increase of [[DNA replication]] and [[protein synthesis]] via control of amino acid uptake
* Modification of the activity of numerous [[enzymes]].

The actions of insulin (indirect and direct) on cells include:
* Stimulates the uptake of glucose –  Insulin decreases blood glucose concentration by inducing [[cellular glucose intake|intake of glucose]] by the cells. This is possible because Insulin causes the insertion of the GLUT4 transporter in the cell membranes of muscle and fat tissues which allows glucose to enter the cell.<ref name="diabetesincontrol.com"/>
* Increased [[Fatty acid metabolism#Glycolytic endy products are used in the conversion of carbohydrates into fatty acids|fat synthesis]] – insulin forces fat cells to take in blood glucose, which is converted into [[triglyceride]]s; decrease of insulin causes the reverse.<ref name="pmid21864752" />
* Increased [[esterification]] of fatty acids – forces adipose tissue to make neutral fats (i.e., [[triglycerides]]) from fatty acids; decrease of insulin causes the reverse.<ref name="pmid21864752" />
* Decreased [[lipolysis]] in  – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse.<ref name="pmid21864752" />
* Induced glycogen synthesis – When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphate group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis.<ref>{{cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html|title=Physiologic Effects of Insulin|website=www.vivo.colostate.edu|language=en|access-date=1 June 2017|archive-date=7 May 2023|archive-url=https://web.archive.org/web/20230507054119/http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html|url-status=dead}}</ref>
* Decreased [[gluconeogenesis]] and [[glycogenolysis]] – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); decrease of insulin causes glucose production by the liver from assorted substrates.<ref name="pmid21864752" />
* Decreased [[proteolysis]] – decreasing the breakdown of protein<ref name="pmid21864752" />
* Decreased [[Autophagy (cellular)|autophagy]] – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.<ref name="pmid17934054">{{cite journal | vauthors = Bergamini E, Cavallini G, Donati A, Gori Z | title = The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction | journal = Annals of the New York Academy of Sciences | volume = 1114 | issue =  1| pages = 69–78 | date = October 2007 | pmid = 17934054 | doi = 10.1196/annals.1396.020 | bibcode = 2007NYASA1114...69B | s2cid = 21011988 }}</ref>
* Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption.<ref name="pmid21864752" />
* Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; decrease of insulin reduces flow by allowing these muscles to contract.<ref name="Zheng">{{cite journal | vauthors = Zheng C, Liu Z | title = Vascular function, insulin action, and exercise: an intricate interplay | journal = Trends in Endocrinology and Metabolism | volume = 26 | issue = 6 | pages = 297–304 | date = June 2015 | pmid = 25735473 | pmc = 4450131 | doi = 10.1016/j.tem.2015.02.002 }}</ref>
* Increase in the secretion of [[hydrochloric acid]] by parietal cells in the stomach.{{Citation needed|date=March 2017}}
* Increased potassium uptake – forces cells synthesizing [[glycogen]] (a very spongy, "wet" substance, that [[Glycogen#Structure|increases the content of intracellular water, and its accompanying K<sup>+</sup> ions]])<ref name="pmid1615908">{{cite journal | vauthors = Kreitzman SN, Coxon AY, Szaz KF |url= http://ajcn.nutrition.org/content/56/1/292S.full.pdf | title = Glycogen storage: illusions of easy weight loss, excessive weight regain, and distortions in estimates of body composition | journal = The American Journal of Clinical Nutrition | volume = 56 | issue = Suppl 1 | pages = 292S–93S | date = July 1992 | pmid = 1615908 | doi = 10.1093/ajcn/56.1.292S |archive-url= https://web.archive.org/web/20121018174037/http://ajcn.nutrition.org/content/56/1/292S.full.pdf |archive-date= 18 October 2012 }}</ref> to absorb potassium from the extracellular fluids; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood plasma.  This possibly occurs via insulin-induced translocation of the [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup>-ATPase]] to the surface of skeletal muscle cells.<ref>{{cite journal | vauthors = Benziane B, Chibalin AV | title = Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 3 | pages = E553–58 | date = September 2008 | pmid = 18430962 | doi = 10.1152/ajpendo.90261.2008 | s2cid = 10153197 | doi-access =  }}</ref><ref>{{cite journal | vauthors = Clausen T | title = Regulatory role of translocation of Na+-K+ pumps in skeletal muscle: hypothesis or reality? | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 3 | pages = E727–28; author reply 729 | date = September 2008 | pmid = 18775888 | doi = 10.1152/ajpendo.90494.2008 | s2cid = 13410719 | doi-access =  }}</ref>
* Decreased renal sodium excretion.<ref>{{cite journal | vauthors = Gupta AK, Clark RV, Kirchner KA | title = Effects of insulin on renal sodium excretion | journal = Hypertension | volume = 19 | issue = Suppl 1 | pages = I78–82 | date = January 1992 | pmid = 1730458 | doi = 10.1161/01.HYP.19.1_Suppl.I78 }}</ref>
* In hepatocytes, insulin binding acutely leads to activation of protein phosphatase 2A (PP2A){{Citation needed|date=September 2023}}, which dephosphorylates the bifunctional enzyme [[Phosphofructokinase_2#PFKB1:_Liver,_muscle,_and_fetal | fructose bisphosphatase-2 (PFKB1)]],<ref name="Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L_2004">{{cite journal | vauthors = Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L | title = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis | journal = Biochemical Journal | date = 1 August 2004 | volume = 381 | issue = 3 | pages = 561–579 | pmid = 15170386 | pmc = 1133864 | doi = 10.1042/BJ20040752}}</ref> activating the phosphofructokinase-2 (PFK-2) active site. PFK-2 increases production of fructose 2,6-bisphosphate. [[Fructose 2,6-bisphosphate]] allosterically activates [[PFK-1]], which favors glycolysis over gluconeogenesis. Increased glycolysis increases the formation of [[malonyl-CoA]], a molecule that can be shunted into lipogenesis and that allosterically inhibits of [[Carnitine palmitoyltransferase I | carnitine palmitoyltransferase I (CPT1)]], a mitochondrial enzyme necessary for the translocation of fatty acids into the intermembrane space of the mitochondria for fatty acid metabolism.<ref name="Wang Y, Yu W, Li S, Guo D, He J, Wang Y_2022">{{cite journal | vauthors = Wang Y, Yu W, Li S, Guo D, He J, Wang Y | title = Acetyl-CoA Carboxylases and Diseases | journal = Frontiers in Oncology | date = 11 March 2022 | volume = 12 | pmid = 35359351 | pmc = 8963101 | doi = 10.3389/fonc.2022.836058 | doi-access = free }}</ref>

Insulin also influences other body functions, such as [[Capacitance of blood vessels|vascular compliance]] and [[cognition]]. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular.<ref name="pmid15288712">{{cite journal |vauthors=Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W |url=https://www.gwern.net/docs/nootropics/2004-benedict.pdf |title=Intranasal insulin improves memory in humans |journal=Psychoneuroendocrinology |volume=29 |issue=10 |pages=1326–1334 |date=November 2004 |pmid=15288712 |doi=10.1016/j.psyneuen.2004.04.003 |s2cid=20321892}}</ref> Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the co-ordination of a wide variety of [[Homeostasis|homeostatic or regulatory processes]] in the human body.<ref name="pmid20876713">{{cite journal |vauthors=Benedict C, Brede S, Schiöth HB, Lehnert H, Schultes B, Born J, Hallschmid M |title=Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men |journal=Diabetes |volume=60 |issue=1 |pages=114–118 |date=January 2011 |pmid=20876713 |pmc=3012162 |doi=10.2337/db10-0329}}</ref> Insulin also has stimulatory effects on [[gonadotropin-releasing hormone]] from the [[hypothalamus]], thus favoring [[fertility]].<ref name="pmid24173881">{{cite journal |vauthors=Comninos AN, Jayasena CN, Dhillo WS | title = The relationship between gut and adipose hormones, and reproduction |journal=Human Reproduction Update |volume=20 |issue=2 |pages=153–174 |year=2014 |pmid=24173881 |doi=10.1093/humupd/dmt033 |s2cid=18645125 |doi-access=free}}</ref>

=== Degradation ===
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment, or it may be degraded by the cell. The two primary sites for insulin clearance are the liver and the kidney.<ref>{{cite journal | vauthors = Koh HE, Cao C, Mittendorfer B | title = Insulin Clearance in Obesity and Type 2 Diabetes | journal = International Journal of Molecular Sciences | volume = 23 | issue = 2 | pages = 596 | date = January 2022 | pmid = 35054781 | pmc = 8776220 | doi = 10.3390/ijms23020596 | doi-access = free }}</ref> It is broken down by the enzyme, [[protein-disulfide reductase (glutathione)]],<ref name="EC">{{cite web |title=EC 1.8.4.2 |url=https://iubmb.qmul.ac.uk/enzyme/EC1/8/4/2.html |website=iubmb.qmul.ac.uk |access-date=25 July 2022}}</ref> which breaks the disulphide bonds between the A and B chains. The liver clears most insulin during first-pass transit, whereas the kidney clears most of the insulin in systemic circulation. Degradation normally involves [[endocytosis]] of the insulin-receptor complex, followed by the action of [[insulin-degrading enzyme]]. An insulin molecule produced endogenously by the beta cells is estimated to be degraded within about one hour after its initial release into circulation (insulin [[biological half-life|half-life]] ~ 4–6&nbsp;minutes).<ref name="pmid">{{cite journal | vauthors = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocrine Reviews | volume = 19 | issue = 5 | pages = 608–24 | date = October 1998 | pmid = 9793760 | doi = 10.1210/edrv.19.5.0349 | doi-access = free }}</ref><ref name="urlCarbohydrate and insulin metabolism in chronic kidney disease">{{cite web | url = http://www.uptodate.com/contents/carbohydrate-and-insulin-metabolism-in-chronic-kidney-disease | title = Carbohydrate and insulin metabolism in chronic kidney disease |vauthors=Palmer BF, Henrich WL | work = UpToDate, Inc }}</ref>

=== Regulator of endocannabinoid metabolism ===
Insulin is a major regulator of [[Endocannabinoids|endocannabinoid]] (EC) [[metabolism]] and insulin treatment has been shown to reduce [[intracellular]] ECs, the [[2-Arachidonoylglycerol|2-arachidonoylglycerol]] (2-AG) and [[anandamide]] (AEA), which correspond with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant [[adipocyte]]s, patterns of insulin-induced enzyme expression is disturbed in a manner consistent with elevated EC [[Biosynthesis|synthesis]] and reduced EC degradation. Findings suggest that [[Insulin resistance|insulin-resistant]] adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation, whereby [[Obesity|obese]] insulin-resistant individuals exhibit increased concentrations of ECs.<ref>{{cite journal | vauthors = D'Eon TM, Pierce KA, Roix JJ, Tyler A, Chen H, Teixeira SR | title = The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids |language=en | journal = Diabetes | volume = 57 | issue = 5 | pages = 1262–68 | date = May 2008 | pmid = 18276766 | doi = 10.2337/db07-1186 | doi-access = free }}</ref><ref name="pmid26374449">{{cite journal | vauthors = Gatta-Cherifi B, Cota D | title = New insights on the role of the endocannabinoid system in the regulation of energy balance | journal = International Journal of Obesity | volume = 40 | issue = 2 | pages = 210–19 | date = February 2016 | pmid = 26374449 | doi = 10.1038/ijo.2015.179 | s2cid = 20740277 | doi-access = free }}</ref> This dysregulation contributes to excessive [[Adipose tissue|visceral fat]] accumulation and reduced [[adiponectin]] release from abdominal adipose tissue, and further to the onset of several cardiometabolic risk factors that are associated with obesity and [[type 2 diabetes]].<ref>{{cite journal | vauthors = Di Marzo V | title = The endocannabinoid system in obesity and type 2 diabetes | journal = Diabetologia | volume = 51 | issue = 8 | pages = 1356–67 | date = August 2008 | pmid = 18563385 | doi = 10.1007/s00125-008-1048-2 | doi-access = free }}</ref>