Array ( [0] => {{Short description|Peptide hormone}} [1] => {{About|the naturally occurring protein|uses of insulin in treating diabetes|Insulin (medication)}} [2] => {{Distinguish|Inulin}} [3] => {{Use dmy dates|date=March 2024}} [4] => {{cs1 config |name-list-style=vanc |display-authors=6}} [5] => {{#invoke:Infobox_gene|getTemplateData|QID=Q21163221}} [6] => [[File: Insulin chain A and B linked by disulfide bridges.gif|frame|right|Insulin is a peptide hormone containing two chains cross-linked by disulfide bridges.]] [7] => '''Insulin''' ({{IPAc-en|ˈ|ɪ|n|.|sj|ʊ|.|l|ɪ|n}},{{Cite web|url=https://www.lexico.com/definition/insulin|archive-url=https://web.archive.org/web/20200801205157/https://www.lexico.com/definition/insulin|url-status=dead|archive-date=1 August 2020|title=Insulin | Meaning of Insulin by Lexico|website=Lexico Dictionaries | English}}{{Cite web|url=https://www.wordreference.com/definition/insulin|title=insulin - WordReference.com Dictionary of English|website=www.wordreference.com}} from [[Latin]] ''insula'', 'island') is a [[peptide hormone]] produced by [[beta cell]]s of the [[pancreatic islets]] encoded in humans by the insulin (''INS)'' [[gene]]. It is considered to be the main [[Anabolism|anabolic]] [[hormone]] of the body.{{cite book | vauthors = Voet D, Voet JG | title = Biochemistry | date = 2011 | publisher = Wiley | location = New York | edition = 4th }} It regulates the [[metabolism]] of [[carbohydrate]]s, [[fat]]s and [[protein]] by promoting the absorption of [[glucose]] from the blood into [[liver]], [[fat cell|fat]] and [[skeletal muscle]] cells.{{cite book | vauthors = Stryer L | title=Biochemistry. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 773–74|isbn= 0-7167-2009-4 }} In these tissues the absorbed glucose is converted into either [[glycogen]] via [[glycogenesis]] or [[Fatty acid metabolism#Glycolytic end products are used in the conversion of carbohydrates into fatty acids|fats]] ([[triglyceride]]s) via [[lipogenesis]], or, in the case of the liver, into both. [[Glucose]] production and [[secretion]] by the liver is strongly inhibited by high concentrations of insulin in the blood.{{cite journal |vauthors = Sonksen P, Sonksen J |title = Insulin: understanding its action in health and disease |journal = British Journal of Anaesthesia |volume = 85 |issue = 1 |pages = 69–79 |date = July 2000 |pmid = 10927996 |doi = 10.1093/bja/85.1.69 |doi-access = free }} Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread [[catabolism]], especially of [[obesity|reserve body fat]]. [8] => [9] => [10] => [[Beta cell]]s are sensitive to [[blood sugar level]]s so that they secrete insulin into the blood in response to high level of glucose, and inhibit secretion of insulin when glucose levels are low.{{cite journal |vauthors = Koeslag JH, Saunders PT, Terblanche E |title = A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex |journal = The Journal of Physiology |volume = 549 |issue = Pt 2 |pages = 333–46 |date = June 2003 | pmid = 12717005 |pmc = 2342944 |doi = 10.1113/jphysiol.2002.037895 |publication-date = 2003 }} Insulin production is also regulated by glucose: high glucose promotes insulin production while low glucose levels lead to lower production.{{Cite journal |last1=Andrali |first1=Sreenath S. |last2=Sampley |first2=Megan L. |last3=Vanderford |first3=Nathan L. |last4=Ozcan |first4=Sabire |date=1 October 2008 |title=Glucose regulation of insulin gene expression in pancreatic beta-cells |url=https://pubmed.ncbi.nlm.nih.gov/18778246 |journal=The Biochemical Journal |volume=415 |issue=1 |pages=1–10 |doi=10.1042/BJ20081029 |issn=1470-8728 |pmid=18778246}} Insulin enhances glucose uptake and metabolism in the cells, thereby reducing blood sugar level. Their neighboring [[alpha cell]]s, by taking their cues from the beta cells, secrete [[glucagon]] into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high. Glucagon increases blood glucose level by stimulating [[glycogenolysis]] and [[gluconeogenesis]] in the liver. The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of [[Blood sugar regulation|glucose homeostasis]]. [11] => [12] => [13] => Decreased or absent insulin activity results in [[diabetes]], a condition of high blood sugar level ([[hyperglycaemia]]). There are two types of the disease. In [[type 1 diabetes]], the beta cells are destroyed by an [[autoimmunity|autoimmune reaction]] so that insulin can no longer be synthesized or be secreted into the blood.{{cite web |url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000729 |title = Insulin Injection [|author = American Society of Health-System Pharmacists |date = 1 February 2009 |work = PubMed Health |publisher = National Center for Biotechnology Information, U.S. National Library of Medicine |access-date = 12 October 2012 }} In [[type 2 diabetes]], the destruction of beta cells is less pronounced than in type 1, and is not due to an autoimmune process. Instead, there is an accumulation of [[amyloid]] in the pancreatic islets, which likely disrupts their anatomy and physiology. The [[pathogenesis]] of type 2 diabetes is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance are known to be involved. Type 2 diabetes is characterized by increased glucagon secretion which is unaffected by, and unresponsive to the concentration of blood glucose. But insulin is still secreted into the blood in response to the blood glucose. As a result, glucose accumulates in the blood. [14] => [15] => [16] => The human insulin protein is composed of 51 [[amino acid]]s, and has a [[molecular mass]] of 5808 [[Dalton (unit)|Da]]. It is a hetero[[protein dimer|dimer]] of an A-chain and a B-chain, which are linked together by [[disulfide bond]]s. Insulin's structure varies slightly between [[species]] of animals. Insulin from non-human animal sources differs somewhat in effectiveness (in [[carbohydrate metabolism]] effects) from human insulin because of these variations. [[Pig|Porcine]] insulin is especially close to the [[human]] version, and was widely used to treat type 1 diabetics before human insulin could be produced in large quantities by [[Recombinant DNA#Applications of recombinant DNA technology|recombinant DNA]] technologies.Drug Information Portal NLM – Insulin human USAN [http://druginfo.nlm.nih.gov/drugportal/ druginfo.nlm.nih.gov] {{Webarchive|url=https://web.archive.org/web/20221119233123/https://druginfo.nlm.nih.gov/drugportal/ |date=19 November 2022 }}{{cite web |url=http://www.gene.com/media/press-releases/4160/1978-09-06/first-successful-laboratory-production-o |title=First Successful Laboratory Production of Human Insulin Announced |date=6 September 1978 |publisher=Genentech |work=News Release |access-date=26 September 2016 |archive-date=27 September 2016 |archive-url=https://web.archive.org/web/20160927073029/http://www.gene.com/media/press-releases/4160/1978-09-06/first-successful-laboratory-production-o |url-status=dead }}{{cite web |url = http://www.littletree.com.au/dna.htm |title = Recombinant DNA technology in the synthesis of human insulin | vauthors = Tof I |year = 1994 |publisher = Little Tree Publishing |access-date = 3 November 2009 }}{{cite journal |vauthors = Aggarwal SR |title = What's fueling the biotech engine-2011 to 2012 |journal = Nature Biotechnology |volume = 30 | issue = 12 |pages = 1191–7 |date = December 2012 |pmid = 23222785 |doi = 10.1038/nbt.2437 |s2cid = 8707897 }} [17] => [18] => [19] => Insulin was the first peptide hormone discovered.{{cite book |vauthors = Weiss M, Steiner DF, Philipson LH |chapter = Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships |title = Endotext |date = 2000 |pmid = 25905258 |chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK279029/ |access-date = 18 February 2020 |publisher = MDText.com, Inc. |veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP |display-editors = 6 }} [[Frederick Banting]] and [[Charles Best (medical scientist)|Charles Best]], working in the laboratory of [[John Macleod (physiologist)|John Macleod]] at the [[University of Toronto]], were the first to isolate insulin from dog pancreas in 1921. [[Frederick Sanger]] sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced. The [[crystal structure]] of insulin in the solid state was determined by [[Dorothy Hodgkin]] in 1969. Insulin is also the first protein to be chemically synthesised and produced by [[Recombinant DNA|DNA recombinant technology]].{{Cite web |url=https://www.diabetes.co.uk/insulin/history-of-insulin.html |title=The discovery and development of insulin as a medical treatment can be traced back to the 19th century. |date=15 January 2019 |website=Diabetes |language=en-GB |access-date=17 February 2020}} It is on the [[WHO Model List of Essential Medicines]], the most important medications needed in a basic [[health system]].{{cite book |url=https://iris.who.int/bitstream/handle/10665/189763/9789241209946_eng.pdf |title=19th WHO Model List of Essential Medicines (April 2015) |date=April 2015 |access-date=10 May 2015 |publisher=WHO |page=455 |hdl=10665/189763|isbn=978-92-4-120994-6 }} [20] => [21] => == Evolution and species distribution == [22] => [23] => Insulin may have originated more than a billion years ago.{{cite journal |vauthors=de Souza AM, López JA |title=Insulin or insulin-like studies on unicellular organisms: a review |journal=Braz. Arch. Biol. Technol. |volume=47 |issue=6 |date=November 2004 |pages=973–81 |doi=10.1590/S1516-89132004000600017 |issn=1516-8913 |url=https://www.scielo.br/j/babt/a/dbK6VRHwStd7jfRwkJR6gvt/?format=pdf |access-date=30 June 2022|doi-access=free }} The molecular origins of insulin go at least as far back as the simplest unicellular [[eukaryotes]].{{cite journal |vauthors=LeRoith D, Shiloach J, Heffron R, Rubinovitz C, Tanenbaum R, Roth J |title=Insulin-related material in microbes: similarities and differences from mammalian insulins |journal=Canadian Journal of Biochemistry and Cell Biology |volume=63 |issue=8 |pages=839–849 |date=August 1985 |pmid=3933801 |doi=10.1139/o85-106}} Apart from animals, insulin-like proteins are also known to exist in [[fungi]] and [[protists]]. [24] => [25] => Insulin is produced by [[beta cells]] of the [[pancreatic islets]] in most vertebrates and by the [[Brockmann body]] in some [[teleost fish]].{{cite journal | vauthors = Wright JR, Yang H, Hyrtsenko O, Xu BY, Yu W, Pohajdak B | title = A review of piscine islet xenotransplantation using wild-type tilapia donors and the production of transgenic tilapia expressing a "humanized" tilapia insulin | journal = Xenotransplantation | volume = 21 | issue = 6 | pages = 485–95 | date = 2014 | pmid = 25040337 | pmc = 4283710 | doi = 10.1111/xen.12115 }} [[Cone snail]]s: ''[[Conus geographus]]'' and ''[[Conus tulipa]]'', venomous sea snails that hunt small fish, use modified forms of insulin in their venom cocktails. The insulin toxin, closer in structure to fishes' than to snails' native insulin, slows down the prey fishes by lowering their blood glucose levels.{{cite news |title= Deadly sea snail uses weaponised insulin to make its prey sluggish|url=https://www.theguardian.com/science/2015/jan/19/venomous-sea-snail-insulin-prey-conus-geographus |newspaper=The Guardian |date=19 January 2015}}{{cite journal | vauthors = Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM | title = Specialized insulin is used for chemical warfare by fish-hunting cone snails | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 6 | pages = 1743–48 | date = February 2015 | pmid = 25605914 | doi = 10.1073/pnas.1423857112 | pmc=4330763| bibcode = 2015PNAS..112.1743S | doi-access = free }} [26] => [27] => == Production == [28] => [[File:Insulin gene activation.png|thumb|upright=1.8|Diagram of insulin regulation upon high blood glucose]] [29] => Insulin is produced exclusively in the beta cells of the [[pancreatic islet]]s in mammals, and the Brockmann body in some fish. Human insulin is produced from the ''INS'' [[gene]], located on chromosome 11.{{cite journal |vauthors=Tokarz VL, MacDonald PE, Klip A |title=The cell biology of systemic insulin function |journal=J Cell Biol |volume=217 |issue=7 |pages=2273–2289 |date=July 2018 |pmid=29622564 |pmc=6028526 |doi=10.1083/jcb.201802095 }} Rodents have two functional insulin genes; one is the homolog of most mammalian genes (''Ins2''), and the other is a retroposed copy that includes promoter sequence but that is missing an intron (''Ins1'').{{cite journal | vauthors = Shiao MS, Liao BY, Long M, Yu HT | title = Adaptive evolution of the insulin two-gene system in mouse | journal = Genetics | volume = 178 | issue = 3 | pages = 1683–91 | date = March 2008 | pmid = 18245324 | doi = 10.1534/genetics.108.087023 | pmc = 2278064 }} [[Transcription (biology)|Transcription]] of the insulin gene increases in response to elevated blood glucose.{{cite journal |vauthors=Fu Z, Gilbert ER, Liu D |title=Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes |journal=Curr Diabetes Rev |volume=9 |issue=1 |pages=25–53 |date=January 2013 |pmid=22974359 |pmc=3934755 |doi= 10.2174/157339913804143225}} This is primarily controlled by [[transcription factor]]s that bind [[Enhancer (genetics)|enhancer sequences]] in the ~400 [[base pair]]s before the gene's transcription start site. [30] => [31] => The major transcription factors influencing insulin secretion are [[PDX1]], [[NeuroD1]], and [[MafA]].{{cite journal | vauthors = Bernardo AS, Hay CW, Docherty K | title = Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell | journal = Molecular and Cellular Endocrinology | volume = 294 | issue = 1–2 | pages = 1–9 | date = November 2008 | pmid = 18687378 | doi = 10.1016/j.mce.2008.07.006 | s2cid = 28027796 | department = review | url = https://hal.archives-ouvertes.fr/hal-00532050/file/PEER_stage2_10.1016%252Fj.mce.2008.07.006.pdf }}{{cite journal | vauthors = Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A | title = Pancreatic β-cell identity, glucose sensing and the control of insulin secretion | journal = The Biochemical Journal | volume = 466 | issue = 2 | pages = 203–18 | date = March 2015 | pmid = 25697093 | doi = 10.1042/BJ20141384 | s2cid = 2193329 | doi-access = | department = review }}{{cite journal | vauthors = Rutter GA, Tavaré JM, Palmer DG | title = Regulation of Mammalian Gene Expression by Glucose | journal = News in Physiological Sciences | volume = 15 | issue = 3| pages = 149–54 | date = June 2000 | pmid = 11390898 | doi = 10.1152/physiologyonline.2000.15.3.149 | doi-access = | department = review }}{{cite journal | vauthors = Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS | title = Regulation of the insulin gene by glucose and d acids | journal = The Journal of Nutrition | volume = 136 | issue = 4 | pages = 873–76 | date = April 2006 | pmid = 16549443 | pmc = 1853259 | doi = 10.1093/jn/136.4.873 | department = review }} [32] => [33] => During a low-glucose state, [[PDX1]] (pancreatic and duodenal homeobox protein 1) is located in the nuclear periphery as a result of interaction with [[HDAC1]] and [[HDAC2|2]],{{cite journal|vauthors=Vaulont S, Vasseur-Cognet M, Kahn A|date=October 2000|title=Glucose regulation of gene transcription|department=review|journal=The Journal of Biological Chemistry|volume=275|issue=41|pages=31555–58|doi=10.1074/jbc.R000016200|pmid=10934218|doi-access=free}} which results in downregulation of insulin secretion.{{cite journal | vauthors = Christensen DP, Dahllöf M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, Grunnet LG, Mandrup-Poulsen T | title = Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus | journal = Molecular Medicine | volume = 17 | issue = 5–6 | pages = 378–90 | date = 2011 | pmid = 21274504 | pmc = 3105132 | doi = 10.2119/molmed.2011.00021 }} An increase in blood [[glucose]] levels causes [[phosphorylation]] of [[PDX1]], which leads it to undergo nuclear translocation and bind the A3 element within the insulin promoter.{{cite journal | vauthors = Wang W, Shi Q, Guo T, Yang Z, Jia Z, Chen P, Zhou C | title = PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations | journal = Molecular and Cellular Endocrinology | volume = 428 | pages = 38–48 | date = June 2016 | pmid = 26994512 | doi = 10.1016/j.mce.2016.03.019 | doi-access = free }} Upon translocation it interacts with coactivators [[EP300|HAT p300]] and [[SETD7]]. [[PDX1]] affects the [[histone]] modifications through [[acetylation]] and deacetylation as well as [[methylation]]. It is also said to suppress [[glucagon]].{{cite journal | vauthors = Wang X, Wei X, Pang Q, Yi F | title = Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus |journal=Acta Pharmaceutica Sinica B |date=August 2012 |volume=2 |issue=4 |pages=387–95 |doi=10.1016/j.apsb.2012.06.005|doi-access=free }} [34] => [35] => [[NeuroD1]], also known as β2, regulates insulin exocytosis in pancreatic [[β cells]] by directly inducing the expression of [[genes]] involved in exocytosis.{{cite journal | vauthors = Andrali SS, Sampley ML, Vanderford NL, Ozcan S | title = Glucose regulation of insulin gene expression in pancreatic beta-cells | journal = The Biochemical Journal | volume = 415 | issue = 1 | pages = 1–10 | date = October 2008 | pmid = 18778246 | doi = 10.1042/BJ20081029 | doi-access = | department = review }} It is localized in the [[cytosol]], but in response to high [[glucose]] it becomes [[glycosylated]] by [[OGT (gene)|OGT]] and/or [[phosphorylated]] by [[Extracellular signal-regulated kinases|ERK]], which causes translocation to the nucleus. In the nucleus β2 heterodimerizes with [[TCF3|E47]], binds to the E1 element of the insulin promoter and recruits co-activator [[EP300|p300]] which acetylates β2. It is able to interact with other transcription factors as well in activation of the insulin gene. [36] => [37] => [[MafA]] is degraded by [[proteasomes]] upon low blood [[glucose]] levels. Increased levels of [[glucose]] make an unknown protein [[glycosylated]]. This protein works as a transcription factor for [[MafA]] in an unknown manner and [[MafA]] is transported out of the cell. [[MafA]] is then translocated back into the nucleus where it binds the C1 element of the insulin promoter.{{cite journal | vauthors = Kaneto H, Matsuoka TA, Kawashima S, Yamamoto K, Kato K, Miyatsuka T, Katakami N, Matsuhisa M | title = Role of MafA in pancreatic beta-cells | journal = Advanced Drug Delivery Reviews | volume = 61 | issue = 7–8 | pages = 489–96 | date = July 2009 | pmid = 19393272 | doi = 10.1016/j.addr.2008.12.015 }}{{cite journal | vauthors = Aramata S, Han SI, Kataoka K | title = Roles and regulation of transcription factor MafA in islet beta-cells | journal = Endocrine Journal | volume = 54 | issue = 5 | pages = 659–66 | date = December 2007 | pmid = 17785922 | doi = 10.1507/endocrj.KR-101| doi-access = free }} [38] => [39] => These transcription factors work synergistically and in a complex arrangement. Increased blood [[glucose]] can after a while destroy the binding capacities of these proteins, and therefore reduce the amount of insulin secreted, causing [[diabetes]]. The decreased binding activities can be mediated by [[glucose]] induced [[oxidative stress]] and [[antioxidants]] are said to prevent the decreased insulin secretion in glucotoxic pancreatic [[β cells]]. Stress signalling molecules and [[reactive oxygen species]] inhibits the insulin gene by interfering with the cofactors binding the transcription factors and the transcription factors itself.{{cite journal | vauthors = Kaneto H, Matsuoka TA | title = Involvement of oxidative stress in suppression of insulin biosynthesis under diabetic conditions | journal = International Journal of Molecular Sciences | volume = 13 | issue = 10 | pages = 13680–90 | date = October 2012 | pmid = 23202973 | pmc = 3497347 | doi = 10.3390/ijms131013680 | doi-access = free }} [40] => [41] => Several [[regulatory sequence]]s in the [[Promoter (biology)|promoter]] region of the human insulin gene bind to [[transcription factor]]s. In general, the [[A-box]]es bind to [[Pdx1]] factors, [[E-box]]es bind to [[NeuroD]], C-boxes bind to [[MafA]], and [[cAMP response element]]s to [[CREB]]. There are also [[silencer (genetics)|silencers]] that inhibit transcription. [42] => [43] => === Synthesis === [44] => [[File:Insulin path.svg|thumb|upright=1.8|Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.]] [45] => [46] => Insulin is synthesized as an inactive precursor molecule, a 110 amino acid-long protein called "preproinsulin". Preproinsulin is [[translation (biology)|translated]] directly into the rough [[endoplasmic reticulum]] (RER), where its [[signal peptide]] is removed by [[signal peptidase]] to form "proinsulin". As the proinsulin [[protein folding|folds]], opposite ends of the protein, called the "A-chain" and the "B-chain", are fused together with three [[disulfide bond]]s. Folded proinsulin then transits through the [[Golgi apparatus]] and is packaged into specialized [[Vesicle (biology and chemistry)#Secretory vesicles|secretory vesicle]]s. In the granule, proinsulin is cleaved by [[Proprotein convertase 1|proprotein convertase 1/3]] and [[proprotein convertase 2]], removing the middle part of the protein, called the "[[C-peptide]]". Finally, [[carboxypeptidase E]] removes two pairs of amino acids from the protein's ends, resulting in active insulin – the insulin A- and B- chains, now connected with two disulfide bonds. [47] => [48] => The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and [[Vagus nerve stimulation|vagal nerve stimulation]] to be exocytosed from the cell into the circulation.{{cite book | vauthors = Najjar S | title = eLS | chapter = Insulin Action: Molecular Basis of Diabetes | date = 2003 | journal = Encyclopedia of Life Sciences | publisher = John Wiley & Sons | doi = 10.1038/npg.els.0001402 | isbn = 978-0-470-01617-6 }} [49] => [50] => Insulin and its related proteins have been shown to be produced inside the brain, and reduced levels of these proteins are linked to Alzheimer's disease.{{cite web | url = http://www.eurekalert.org/pub_releases/2005-03/l-rdl030205.php | title = Researchers discover link between insulin and Alzheimer's | vauthors = Gustin N | date = 7 March 2005 | work = EurekAlert! | publisher = American Association for the Advancement of Science | access-date = 1 January 2009}}{{cite journal | vauthors = de la Monte SM, Wands JR |url= https://www.alzforum.org/sites/default/files/legacy/res/for/journal/delamonte/jad00401.pdf | title = Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 7 | issue = 1 | pages = 45–61 | date = February 2005 | pmid = 15750214 | doi = 10.3233/JAD-2005-7106 }}{{cite journal | vauthors = Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM | title = Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? | journal = Journal of Alzheimer's Disease | volume = 7 | issue = 1 | pages = 63–80 | date = February 2005 | pmid = 15750215 | doi = 10.3233/jad-2005-7107| s2cid = 28173722 | url = https://www.alzforum.org/sites/default/files/legacy/res/for/journal/delamonte/jad00400.pdf }} [51] => [52] => Insulin release is stimulated also by beta-2 receptor stimulation and inhibited by alpha-1 receptor stimulation. In addition, cortisol, glucagon and growth hormone antagonize the actions of insulin during times of stress. Insulin also inhibits fatty acid release by [[hormone-sensitive lipase]] in adipose tissue. [53] => [54] => == Structure == [55] => {{See also|Insulin/IGF/Relaxin family|Insulin and its analog structure}} [56] => [57] => [[Image:InsulinMonomer.jpg|250px|thumb|'''The structure of insulin.''' The left side is a space-filling model of the insulin monomer, believed to be biologically active. [[Carbon]] is green, [[hydrogen]] white, [[oxygen]] red, and [[nitrogen]] blue. On the right side is a [[ribbon diagram]] of the insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions.]] [58] => [59] => Contrary to an initial belief that hormones would be generally small chemical molecules, as the first peptide hormone known of its structure, insulin was found to be quite large. A single protein (monomer) of human insulin is composed of 51 [[amino acid]]s, and has a [[molecular mass]] of 5808 [[Dalton (unit)|Da]]. The [[molecular formula]] of human insulin is C257H383N65O77S6.{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/16129672|title=Insulin human|publisher=[[PubChem]]|access-date=26 February 2019}} It is a combination of two peptide chains ([[protein dimer|dimer]]) named an A-chain and a B-chain, which are linked together by two [[disulfide bond]]s. The A-chain is composed of 21 amino acids, while the B-chain consists of 30 residues. The linking (interchain) disulfide bonds are formed at cysteine residues between the positions A7-B7 and A20-B19. There is an additional (intrachain) disulfide bond within the A-chain between cysteine residues at positions A6 and A11. The A-chain exhibits two α-helical regions at A1-A8 and A12-A19 which are antiparallel; while the B chain has a central α -helix (covering residues B9-B19) flanked by the disulfide bond on either sides and two β-sheets (covering B7-B10 and B20-B23).{{cite journal | vauthors = Fu Z, Gilbert ER, Liu D | title = Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes | journal = Current Diabetes Reviews | volume = 9 | issue = 1 | pages = 25–53 | date = January 2013 | pmid = 22974359 | pmc = 3934755 | doi = 10.2174/157339913804143225 }} [60] => [61] => The amino acid sequence of insulin is [[conserved sequence|strongly conserved]] and varies only slightly between species. [[Cow|Bovine]] insulin differs from human in only three [[amino acid]] residues, and [[Pig|porcine]] insulin in one. Even insulin from some species of fish is similar enough to human to be clinically effective in humans. Insulin in some invertebrates is quite similar in sequence to human insulin, and has similar physiological effects. The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history. The C-peptide of [[proinsulin]], however, differs much more among species; it is also a hormone, but a secondary one. [62] => [63] => Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is about 36000 Da in size. The six molecules are linked together as three dimeric units to form symmetrical molecule. An important feature is the presence of zinc atoms (Zn2+) on the axis of symmetry, which are surrounded by three water molecules and three histidine residues at position B10. [64] => [65] => The hexamer is an inactive form with long-term stability, which serves as a way to keep the highly reactive insulin protected, yet readily available. The hexamer-monomer conversion is one of the central aspects of insulin formulations for injection. The hexamer is far more stable than the monomer, which is desirable for practical reasons; however, the monomer is a much faster-reacting drug because diffusion rate is inversely related to particle size. A fast-reacting drug means insulin injections do not have to precede mealtimes by hours, which in turn gives people with diabetes more flexibility in their daily schedules.{{cite journal | vauthors = Dunn MF | title = Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a review | journal = Biometals | volume = 18 | issue = 4 | pages = 295–303 | date = August 2005 | pmid = 16158220 | doi = 10.1007/s10534-005-3685-y | s2cid = 8857694 }} Insulin can aggregate and form [[fibrillar]] interdigitated [[beta-sheet]]s. This can cause injection [[amyloidosis]], and prevents the storage of insulin for long periods.{{cite journal | vauthors = Ivanova MI, Sievers SA, Sawaya MR, Wall JS, Eisenberg D | title = Molecular basis for insulin fibril assembly | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 45 | pages = 18990–5 | date = November 2009 | pmid = 19864624 | pmc = 2776439 | doi = 10.1073/pnas.0910080106 | bibcode = 2009PNAS..10618990I | doi-access = free }} [66] => [67] => == Function == [68] => [69] => === Secretion === [70] => {{See also|Blood glucose regulation}} [71] => [72] => [[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.{{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}} 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).{{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}} Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of [[type 2 diabetes|type 2 diabetes]].{{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}} First-phase release and [[Insulin resistance|insulin sensitivity]] are independent predictors of diabetes.{{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}} [73] => [74] => The description of first phase release is as follows: [75] => * 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.{{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 }} [76] => * 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. [77] => * 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.{{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 }} [78] => * An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/[[Kir6.2]] [[potassium channel]] (see [[sulfonylurea receptor]]). This prevents potassium ions (K+) 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. [79] => * Upon [[depolarization]], voltage-gated [[calcium channels|calcium ion (Ca2+) channels]] open, allowing calcium ions to move into the cell by facilitated diffusion. [80] => * The cytosolic calcium ion concentration can also be increased by calcium release from intracellular stores via activation of ryanodine receptors.{{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}} [81] => * 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 Ca2+ 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.{{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 }} [82] => * 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]]. [83] => [84] => 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),{{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 }} and the gastrointestinally derived [[incretins]], such as [[glucagon-like peptide-1]] (GLP-1) and [[glucose-dependent insulinotropic peptide]] (GIP). [85] => [86] => 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 α2-adrenergic receptors{{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 }} and stimulated by β2-adrenergic receptors.{{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 }} 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.{{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 }} [87] => [88] => 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. [89] => [90] => 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 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. [91] => [92] => === Oscillations === [93] => {{Main|Insulin oscillations}} [94] => [95] => [[File:Pancreas insulin oscillations.svg|thumb|250px|Insulin release from pancreas oscillates with a period of 3–6 minutes.]] [96] => [97] => 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 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).{{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 }} 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. 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. 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.{{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 }}{{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 }} [98] => [99] => === Blood insulin level === [100] => {{Further |Insulin index}} [101] => [[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.]] [102] => 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.{{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}} A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).{{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}} [103] => [104] => === Signal transduction === [105] => 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.{{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}} [106] => [107] => 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.{{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 }} PKB also phosphorylates [[GSK-3|glycogen synthase kinase]] (GSK), thereby inactivating this enzyme.{{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 }} 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.{{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 }} The breakdown of triglycerides by adipose tissue into [[free fatty acids]] and [[glycerol]] is also inhibited. [108] => [109] => 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. 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. [110] => [111] => The structure of the insulin–[[insulin receptor]] complex has been determined using the techniques of [[X-ray crystallography]].{{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}}
{{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}} [112] => [113] => === Physiological effects === [114] => [[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).]] [115] => [116] => [[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.]] [117] => [118] => The actions of insulin on the global human metabolism level include: [119] => * Increase of cellular intake of certain substances, most prominently glucose in muscle and [[adipose tissue]] (about two-thirds of body cells){{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 }} [120] => * Increase of [[DNA replication]] and [[protein synthesis]] via control of amino acid uptake [121] => * Modification of the activity of numerous [[enzymes]]. [122] => [123] => The actions of insulin (indirect and direct) on cells include: [124] => * 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. [125] => * 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. [126] => * Increased [[esterification]] of fatty acids – forces adipose tissue to make neutral fats (i.e., [[triglycerides]]) from fatty acids; decrease of insulin causes the reverse. [127] => * Decreased [[lipolysis]] in – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse. [128] => * 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.{{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}} [129] => * 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. [130] => * Decreased [[proteolysis]] – decreasing the breakdown of protein [131] => * Decreased [[Autophagy (cellular)|autophagy]] – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.{{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 }} [132] => * Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption. [133] => * 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.{{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 }} [134] => * Increase in the secretion of [[hydrochloric acid]] by parietal cells in the stomach.{{Citation needed|date=March 2017}} [135] => * 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+ ions]]){{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 }} 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+/K+-ATPase]] to the surface of skeletal muscle cells.{{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 = }}{{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 = }} [136] => * Decreased renal sodium excretion.{{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 }} [137] => * 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)]],{{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 = Biochemistry Journal | date = 1 August 2004 | volume = 381 | issue = 3 | pages = 561–579 | pmid = 15170386 | pmc = 1133864 | doi = 10.1042/BJ20040752}} 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.{{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 }} [138] => [139] => 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.{{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}} 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.{{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}} Insulin also has stimulatory effects on [[gonadotropin-releasing hormone]] from the [[hypothalamus]], thus favoring [[fertility]].{{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}} [140] => [141] => === Degradation === [142] => 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.{{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 }} It is broken down by the enzyme, [[protein-disulfide reductase (glutathione)]],{{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}} 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 minutes).{{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 }}{{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 }} [143] => [144] => === Regulator of endocannabinoid metabolism === [145] => 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.{{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 }}{{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 }} 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]].{{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 }} [146] => [147] => == Hypoglycemia == [148] => {{Main|Hypoglycemia}} [149] => [[Hypoglycemia]], also known as "low blood sugar", is when [[blood sugar]] decreases to below normal levels. This may result in a variety of [[symptoms]] including clumsiness, trouble talking, confusion, [[loss of consciousness]], [[seizures]] or death. A feeling of hunger, sweating, shakiness and weakness may also be present. Symptoms typically come on quickly.{{cite web|title=Hypoglycemia|url=http://www.niddk.nih.gov/health-information/health-topics/Diabetes/hypoglycemia/Pages/index.aspx|website=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=28 June 2015|date=October 2008|url-status=dead|archive-url=https://web.archive.org/web/20150701034430/http://www.niddk.nih.gov/health-information/health-topics/Diabetes/hypoglycemia/Pages/index.aspx|archive-date=1 July 2015}} [150] => [151] => The most common cause of hypoglycemia is [[Anti-diabetic medication|medications]] used to treat [[diabetes]] such as insulin and [[sulfonylurea]]s.{{cite journal | vauthors = Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A | title = Causative anti-diabetic drugs and the underlying clinical factors for hypoglycemia in patients with diabetes | journal = World Journal of Diabetes | volume = 6 | issue = 1 | pages = 30–6 | date = February 2015 | pmid = 25685276 | pmc = 4317315 | doi = 10.4239/wjd.v6.i1.30 | doi-access = free }}{{cite book| vauthors = Schrier RW |title=The internal medicine casebook real patients, real answers|date=2007|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-6529-9|page=119|edition= 3rd|url=https://books.google.com/books?id=zbuKcQwh2b0C&pg=PA119|url-status=live|archive-url=https://web.archive.org/web/20150701020033/https://books.google.ca/books?id=zbuKcQwh2b0C&pg=PA119|archive-date=1 July 2015}} Risk is greater in diabetics who have eaten less than usual, exercised more than usual or have consumed [[ethanol|alcohol]]. Other causes of hypoglycemia include [[kidney failure]], certain [[tumors]], such as [[insulinoma]], [[liver disease]], [[hypothyroidism]], [[starvation]], [[inborn error of metabolism]], [[sepsis|severe infections]], [[reactive hypoglycemia]] and a number of drugs including alcohol. Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.{{cite book| vauthors = Perkin RM |title=Pediatric hospital medicine : textbook of inpatient management|date=2008|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-7032-3|page=105|edition= 2nd|url=https://books.google.com/books?id=sV6-ifUGoMYC&pg=PA105|url-status=live|archive-url=https://web.archive.org/web/20150701020159/https://books.google.ca/books?id=sV6-ifUGoMYC&pg=PA105|archive-date=1 July 2015}} [152] => [153] => == Diseases and syndromes == [154] => There are several conditions in which insulin disturbance is pathologic: [155] => * [[Diabetes]] – general term referring to all states characterized by hyperglycemia. It can be of the following types:{{cite journal | vauthors = Macdonald IA | title = A review of recent evidence relating to sugars, insulin resistance and diabetes | journal = European Journal of Nutrition | volume = 55 | issue = Suppl 2 | pages = 17–23 | date = November 2016 | pmid = 27882410 | pmc = 5174139 | doi = 10.1007/s00394-016-1340-8 }} [156] => **[[Type 1 diabetes]] – autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency [157] => ** [[Type 2 diabetes]] – either inadequate insulin production by the β-cells or [[insulin resistance]] or both because of reasons not completely understood. [158] => *** there is correlation with [[Diet (nutrition)|diet]], with sedentary lifestyle, with [[obesity]], with age and with [[metabolic syndrome]]. Causality has been demonstrated in multiple model organisms including mice and monkeys; importantly, non-obese people do get Type 2 diabetes due to diet, sedentary lifestyle and unknown risk factors, though this may not be a causal relationship. [159] => *** it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions [160] => ** Other types of impaired glucose tolerance (see [[Diabetes]]) [161] => * [[Insulinoma]] – a tumor of beta cells producing excess insulin or [[reactive hypoglycemia]].{{cite journal | vauthors = Guettier JM, Gorden P | title = Insulin secretion and insulin-producing tumors | journal = Expert Review of Endocrinology & Metabolism | volume = 5 | issue = 2 | pages = 217–227 | date = March 2010 | pmid = 20401170 | pmc = 2853964 | doi = 10.1586/eem.09.83 }} [162] => * [[Metabolic syndrome]] – a poorly understood condition first called syndrome X by [[Gerald Reaven]]. It is not clear whether the syndrome has a single, treatable cause, or is the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance that precedes type 2 diabetes, which is a diminished capacity for [[#Physiological effects|insulin response]] in some tissues (e.g., muscle, fat). It is common for morbidities such as essential [[hypertension]], [[obesity]], type 2 diabetes, and [[cardiovascular disease]] (CVD) to develop.{{cite journal | vauthors = Saklayen MG | title = The Global Epidemic of the Metabolic Syndrome | journal = Current Hypertension Reports | volume = 20 | issue = 2 | pages = 12 | date = February 2018 | pmid = 29480368 | pmc = 5866840 | doi = 10.1007/s11906-018-0812-z }} [163] => * [[Polycystic ovary syndrome]] – a complex syndrome in women in the reproductive years where [[anovulation]] and [[androgen]] excess are commonly displayed as [[hirsutism]]. In many cases of PCOS, insulin resistance is present.{{cite journal | vauthors = El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G | title = Poly Cystic Ovarian Syndrome: An Updated Overview | journal = Frontiers in Physiology | volume = 7 | pages = 124 | date = 5 April 2016 | pmid = 27092084 | pmc = 4820451 | doi = 10.3389/fphys.2016.00124 | doi-access = free }} [164] => [165] => == Medical uses == [166] => {{Main|Insulin (medication)}} [167] => [[File:Inzulín.jpg|thumb|right|Two vials of insulin. They have been given trade names, Actrapid (left) and NovoRapid (right) by the manufacturers.]] [168] => Biosynthetic [[human insulin]] (insulin human rDNA, INN) for clinical use is manufactured by [[Recombinant DNA#Synthetic insulin production using recombinant DNA|recombinant DNA]] technology. Biosynthetic human insulin has increased purity when compared with extractive animal insulin, enhanced purity reducing antibody formation. Researchers have succeeded in introducing the gene for human insulin into plants as another method of producing insulin ("biopharming") in [[safflower]].{{cite web | title = From SemBiosys, A New Kind Of Insulin | work = Inside Wall Street | date = 13 August 2007 | vauthors = Marcial GG | url = http://www.businessweek.com/magazine/content/07_33/b4046083.htm | archive-url = https://web.archive.org/web/20071117132739/http://www.businessweek.com/magazine/content/07_33/b4046083.htm | archive-date = 17 November 2007 | url-status = dead}} This technique is anticipated to reduce production costs. [169] => [170] => Several analogs of human insulin are available. These [[insulin analog]]s are closely related to the human insulin structure, and were developed for specific aspects of glycemic control in terms of fast action (prandial insulins) and long action (basal insulins).[[Insulin analog]] The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), [[Humalog]] (insulin lispro),{{cite journal | vauthors = Vecchio I, Tornali C, Bragazzi NL, Martini M | title = The Discovery of Insulin: An Important Milestone in the History of Medicine | journal = Frontiers in Endocrinology | volume = 9 | pages = 613 | date = 23 October 2018 | pmid = 30405529 | pmc = 6205949 | doi = 10.3389/fendo.2018.00613 | doi-access = free }} it is more rapidly absorbed after subcutaneous injection than regular insulin, with an effect 15 minutes after injection. Other rapid-acting analogues are [[NovoRapid]] and [[Apidra]], with similar profiles.{{cite journal | vauthors = Gast K, Schüler A, Wolff M, Thalhammer A, Berchtold H, Nagel N, Lenherr G, Hauck G, Seckler R | title = Rapid-Acting and Human Insulins: Hexamer Dissociation Kinetics upon Dilution of the Pharmaceutical Formulation | journal = Pharmaceutical Research | volume = 34 | issue = 11 | pages = 2270–2286 | date = November 2017 | pmid = 28762200 | pmc = 5643355 | doi = 10.1007/s11095-017-2233-0 }} All are rapidly absorbed due to amino acid sequences that will reduce formation of dimers and hexamers (monomeric insulins are more rapidly absorbed). Fast acting insulins do not require the injection-to-meal interval previously recommended for human insulin and animal insulins. The other type is long acting insulin; the first of these was [[Lantus]] (insulin glargine). These have a steady effect for an extended period from 18 to 24 hours. Likewise, another protracted insulin analogue ([[Levemir]]) is based on a fatty acid acylation approach. A [[myristic acid]] molecule is attached to this analogue, which associates the insulin molecule to the abundant serum albumin, which in turn extends the effect and reduces the risk of hypoglycemia. Both protracted analogues need to be taken only once daily, and are used for type 1 diabetics as the basal insulin. A combination of a rapid acting and a protracted insulin is also available, making it more likely for patients to achieve an insulin profile that mimics that of the body's own insulin release.{{cite journal | vauthors = Ulrich H, Snyder B, Garg SK | title = Combining insulins for optimal blood glucose control in type I and 2 diabetes: focus on insulin glulisine | journal = Vascular Health and Risk Management | volume = 3 | issue = 3 | pages = 245–54 | date = 2007 | pmid = 17703632 | pmc = 2293970 }}{{cite journal | vauthors = Silver B, Ramaiya K, Andrew SB, Fredrick O, Bajaj S, Kalra S, Charlotte BM, Claudine K, Makhoba A | title = EADSG Guidelines: Insulin Therapy in Diabetes | journal = Diabetes Therapy | volume = 9 | issue = 2 | pages = 449–492 | date = April 2018 | pmid = 29508275 | pmc = 6104264 | doi = 10.1007/s13300-018-0384-6 }} Insulin is also used in many cell lines, such as CHO-s, HEK 293 or Sf9, for the manufacturing of monoclonal antibodies, virus vaccines, and gene therapy products.{{Cite news|date=22 October 2021|title=Insulin Human for innovative biologics|newspaper=Novo Nordisk Pharmatech|url=https://novonordiskpharmatech.com/products/insulin-human-af/}} [171] => [172] => Insulin is usually taken as [[subcutaneous injection]]s by single-use [[syringe]]s with [[hypodermic needle|needles]], via an [[insulin pump]], or by repeated-use [[insulin pen]]s with disposable needles. [[Inhaled insulin]] is also available in the U.S. market. [173] => [174] => The Dispovan Single-Use Pen Needle by HMD{{Cite web |title=क्या आप डायबिटीज के मरीज है? अगर हां तो उचित दाम में मिलेगी HMD की डिस्पोवन इंसुलिन पेन नीडल |url=https://www.amarujala.com/lifestyle/fitness/hmd-dispovan-insulin-pen-needles-for-diabetes-patients |access-date=8 July 2022 |website=amarujala.com}} is India’s first insulin pen needle that makes self-administration easy. Featuring extra-thin walls and a multi-bevel tapered point, these pen needles prioritise patient comfort by minimising pain and ensuring seamless medication delivery. The product aims to provide affordable Pen Needles to the developing part of the country through its wide distribution channel. Additionally, the universal design of these needles guarantees compatibility with all insulin pens. [175] => [176] => Unlike many medicines, insulin cannot be taken [[Oral administration|by mouth]] because, like nearly all other proteins introduced into the [[Human gastrointestinal tract|gastrointestinal tract]], it is reduced to fragments, whereupon all activity is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered orally or sublingually.{{cite journal | vauthors = Wong CY, Martinez J, Dass CR | title = Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities | journal = The Journal of Pharmacy and Pharmacology | volume = 68 | issue = 9 | pages = 1093–108 | year = 2016 | pmid = 27364922 | doi = 10.1111/jphp.12607 | doi-access = free }}{{cite journal | vauthors = Shah RB, Patel M, Maahs DM, Shah VN | title = Insulin delivery methods: Past, present and future | journal = International Journal of Pharmaceutical Investigation | volume = 6 | issue = 1 | pages = 1–9 | year = 2016 | pmid = 27014614 | pmc = 4787057 | doi = 10.4103/2230-973X.176456 | doi-access = free }} [177] => [178] => In 2021, the [[World Health Organization]] added insulin to its [[WHO Model List of Essential Medicines|model list of essential medicines]].{{Cite web| vauthors = Sharma NC |date=1 October 2021|title=WHO adds new drugs to its essential medicines' list|url=https://www.livemint.com/news/world/who-adds-new-drugs-to-its-essential-medicines-list-11633112107174.html|access-date=9 October 2021|website=mint|language=en}} [179] => [180] => Insulin, and all other medications, are supplied free of charge to people with diabetes by the [[National Health Service]] in the countries of the United Kingdom.{{cite web | title=Free prescriptions (England) | website=Diabetes UK | url=https://www.diabetes.org.uk/guide-to-diabetes/life-with-diabetes/free-prescriptions | quote=If you use insulin or medicine to manage your diabetes, ... you don't pay for any item you're prescribed.|access-date=21 November 2022}} [181] => [182] => == History of study == [183] => [184] => === Discovery === [185] => In 1869, while studying the structure of the [[pancreas]] under a [[microscope]], [[Paul Langerhans]], a medical student in [[Berlin]], identified some previously unnoticed tissue clumps scattered throughout the bulk of the pancreas.{{cite journal | vauthors = Sakula A | title = Paul Langerhans (1847-1888): a centenary tribute | journal = Journal of the Royal Society of Medicine | volume = 81 | issue = 7 | pages = 414–5 | date = July 1988 | pmid = 3045317 | pmc = 1291675 | doi = 10.1177/014107688808100718 }} The function of the "little heaps of cells", later [[eponym|known as]] the ''[[islets of Langerhans]]'', initially remained unknown, but [[Édouard Laguesse]] later suggested they might produce secretions that play a regulatory role in digestion.{{cite web |url=http://musee.chru-lille.fr/Memoire/Medecins/48029.html |title=Edouard Laguesse (1861–1927) | vauthors = Petit H |language=fr |website=Museum of the Regional Hospital of Lille |access-date=25 July 2018 }} Paul Langerhans' son, Archibald, also helped to understand this regulatory role. [186] => [187] => In 1889, the physician [[Oskar Minkowski]], in collaboration with [[Joseph von Mering]], removed the pancreas from a healthy dog to test its assumed role in digestion. On testing the urine, they found sugar, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by the American physician and scientist [[Eugene Lindsay Opie]], when he isolated the role of the pancreas to the islets of Langerhans: "Diabetes mellitus when the result of a lesion of the pancreas is caused by destruction of the islands of Langerhans and occurs only when these bodies are in part or wholly destroyed".{{cite journal | vauthors = Opie EL | title = Diabetes Mellitus Associated with Hyaline Degeneration of the islands of Langerhans of the Pancreas | journal = Bulletin of the Johns Hopkins Hospital | volume = 12 | issue = 125 | pages = 263–64 | year = 1901 | hdl = 2027/coo.31924069247447 }}{{cite journal | vauthors = Opie EL | title = On the Relation of Chronic Interstitial Pancreatitis to the Islands of Langerhans and to Diabetes Mellitus | journal = Journal of Experimental Medicine | volume = 5 | issue = 4 | pages = 397–428 | year = 1901 | doi=10.1084/jem.5.4.397| pmid = 19866952 | pmc = 2118050 }}{{cite journal | vauthors = Opie EL | title = The Relation of Diabetes Mellitus to Lesions of the Pancreas. Hyaline Degeneration of the Islands of Langerhans | journal = Journal of Experimental Medicine | volume = 5 | issue = 5 | pages = 527–40 | year = 1901 | doi=10.1084/jem.5.5.527| pmid = 19866956 | pmc = 2118021 }} [188] => [189] => Over the next two decades researchers made several attempts to isolate the islets' secretions. In 1906 [[George Ludwig Zuelzer]] achieved partial success in treating dogs with pancreatic extract, but he was unable to continue his work. Between 1911 and 1912, [[Ernest Lyman Scott|E.L. Scott]] at the [[University of Chicago]] tried aqueous pancreatic extracts and noted "a slight diminution of glycosuria", but was unable to convince his director of his work's value; it was shut down. [[Israel Kleiner (biochemist)|Israel Kleiner]] demonstrated similar effects at [[Rockefeller University]] in 1915, but [[World War I]] interrupted his work and he did not return to it.{{cite journal | author = The American Institute of Nutrition |title=Proceedings of the Thirty-First Annual Meeting of the American Institute of Nutrition | journal = Journal of Nutrition | volume = 92 | issue = 4 | year = 1967 | page = 509 |doi= 10.1093/jn/92.4.507 }} [190] => [191] => In 1916, [[Nicolae Paulescu]] developed an [[aqueous]] [[Pancreas|pancreatic]] extract which, when injected into a [[Diabetes|diabetic]] dog, had a normalizing effect on [[blood sugar]] levels. He had to interrupt his experiments because of [[World War I]], and in 1921 he wrote four papers about his work carried out in [[Bucharest]] and his tests on a diabetic dog. Later that year, he published "Research on the Role of the [[Pancreas]] in Food Assimilation".{{cite journal | vauthors = Paulesco NC | journal = Archives Internationales de Physiologie |url= https://insulin.library.utoronto.ca/islandora/object/insulin%3AT10137 | title= Recherche sur le rôle du pancréas dans l'assimilation nutritive|volume= 17|pages= 85–109| date=31 August 1921 }} [192] => [193] => {{cite journal | vauthors = Lestradet H | journal = Diabetes & Metabolism | title = Le 75e anniversaire de la découverte de l'insuline | volume = 23 | issue = 1| page = 112 | year = 1997 | url= http://www.em-consulte.com/en/article/79613 }} [194] => [195] => [196] => The name "insulin" was coined by [[Edward Albert Sharpey-Schafer]] in 1916 for a hypothetical molecule produced by pancreatic islets of Langerhans (Latin ''insula'' for islet or island) that controls glucose metabolism. Unbeknown to Sharpey-Schafer, Jean de Meyer had introduced the very similar word "insuline" in 1909 for the same molecule.{{Cite journal| vauthors = de Leiva A, Brugués E, de Leiva-Pérez A |date=2011|title=The discovery of insulin: Continued controversies after ninety years|journal=Endocrinología y Nutrición (English Edition)|language=en|volume=58|issue=9|pages=449–456|doi=10.1016/j.endoen.2011.10.001}}{{cite journal | vauthors = Vecchio I, Tornali C, Bragazzi NL, Martini M | title = The Discovery of Insulin: An Important Milestone in the History of Medicine | journal = Frontiers in Endocrinology | volume = 9 | pages = 613 | date = 23 October 2018 | pmid = 30405529 | pmc = 6205949 | doi = 10.3389/fendo.2018.00613 | doi-access = free }} [197] => [198] => === Extraction and purification === [199] => In October 1920, Canadian [[Frederick Banting]] concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion, thereby making it impossible to extract successfully. A surgeon by training, Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. He jotted a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these + relieve glycosurea[sic]."{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AN10002|title=Note dated Oct 31/20 from loose leaf notebook 1920/21| vauthors = Banting FG |date=31 October 1920|website=University of Toronto Libraries}}{{cite journal | vauthors = Rosenfeld L | title = Insulin: discovery and controversy | journal = Clinical Chemistry | volume = 48 | issue = 12 | pages = 2270–88 | date = December 2002 | pmid = 12446492 | doi = 10.1093/clinchem/48.12.2270 | doi-access = free }} [200] => [[File:Charles H. Best and Clark Noble ca. 1920.jpg|thumb|left|[[Charles Best (medical scientist)|Charles Best]] and Clark Noble ca. 1920]] [201] => In the spring of 1921, Banting traveled to [[Toronto]] to explain his idea to [[John Macleod (physiologist)|John Macleod]], Professor of Physiology at the [[University of Toronto]]. Macleod was initially skeptical, since Banting had no background in research and was not familiar with the latest literature, but he agreed to provide lab space for Banting to test out his ideas. Macleod also arranged for two undergraduates to be Banting's lab assistants that summer, but Banting required only one lab assistant. [[Charles Best (medical scientist)|Charles Best]] and Clark Noble flipped a coin; Best won the coin toss and took the first shift. This proved unfortunate for Noble, as Banting kept Best for the entire summer and eventually shared half his Nobel Prize money and credit for the discovery with Best.{{cite journal | vauthors = Wright JR | title = Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine | journal = CMAJ | volume = 167 | issue = 12 | pages = 1391–96 | date = December 2002 | pmid = 12473641 | pmc = 137361 }} On 30 July 1921, Banting and Best successfully isolated an extract ("isletin") from the islets of a duct-tied dog and injected it into a diabetic dog, finding that the extract reduced its blood sugar by 40% in 1 hour.{{cite book | vauthors = Krishnamurthy K | title = Pioneers in scientific discoveries | url = https://books.google.com/books?id=dAXYzzDL_9oC&pg=PA266 | access-date = 26 July 2011 | year = 2002 | publisher = Mittal Publications | isbn = 978-81-7099-844-0 | page=266 }} [202] => [203] => Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but Macleod pointed out flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. He moved Banting and Best into a better laboratory and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments was also a success, and Macleod helped publish their results privately in Toronto that November. Bottlenecked by the time-consuming task of duct-tying dogs and waiting several weeks to extract insulin, Banting hit upon the idea of extracting insulin from the fetal calf pancreas, which had not yet developed digestive glands. By December, they had also succeeded in extracting insulin from the adult cow pancreas. Macleod discontinued all other research in his laboratory to concentrate on the purification of insulin. He invited biochemist [[James Collip]] to help with this task, and the team felt ready for a clinical test within a month. [204] => [[File:Chart for Elizabeth Hughes (12308739143).jpg|thumb|Chart for Elizabeth Hughes, used to track blood, urine, diet in grams, and dietary prescriptions in grams]] [205] => On 11 January 1922, [[Leonard Thompson (diabetic)|Leonard Thompson]], a 14-year-old diabetic who lay dying at the [[Toronto General Hospital]], was given the first injection of insulin.{{cite journal | vauthors = Bliss M | title = Rewriting medical history: Charles Best and the Banting and Best myth | journal = Journal of the History of Medicine and Allied Sciences | volume = 48 | issue = 3 | pages = 253–74 | date = July 1993 | pmid = 8409364 | doi = 10.1093/jhmas/48.3.253 | url = https://academic.oup.com/jhmas/article-pdf/48/3/253/9838324/253.pdf | doi-access = free }}{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AC10024|title=Work on diabetes shows progress against disease| work = Toronto Star Weekly|date=14 January 1922| publisher = University of Toronto Libraries}}{{cite journal | vauthors = Fletcher AA | title = Early clinical experiences with insulin | journal = Canadian Medical Association Journal | volume = 87 | pages = 1052–5 | date = November 1962 | issue = 20 | pmid = 13945508 | pmc = 1849803 | url = https://insulin.library.utoronto.ca/islandora/object/insulin%3AT10053 }}{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AM10015|title=Patient records for Leonard Thompson| vauthors = Banting FG |date=Dec 1921 – Jan 1922|website=University of Toronto Libraries}} However, the extract was so impure that Thompson had a severe [[anaphylaxis|allergic reaction]], and further injections were cancelled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract. A second dose was injected on 23 January, eliminating the [[glycosuria]] that was typical of diabetes without causing any obvious side-effects. The first American patient was [[Elizabeth Hughes Gossett|Elizabeth Hughes]], the daughter of U.S. Secretary of State [[Charles Evans Hughes]].{{cite news | vauthors = Zuger A | title = Rediscovering the First Miracle Drug | url = https://www.nytimes.com/2010/10/05/health/05insulin.html | quote = Elizabeth Hughes was a cheerful, pretty little girl, five feet tall, with straight brown hair and a consuming interest in birds. On Allen's diet her weight fell to 65 pounds, then 52 pounds, and then, after an episode of diarrhea that almost killed her in the spring of 1922, 45 pounds. By then she had survived three years, far longer than expected. And then her mother heard the news: Insulin had finally been isolated in Canada. |work=[[The New York Times]] |date=4 October 2010 |access-date=6 October 2010 }}{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AM10011|title=Chart for Elizabeth Hughes| vauthors = Banting FG |date=16 August 1922|website=University of Toronto Libraries}} The first patient treated in the U.S. was future woodcut artist [[James D. Havens]];{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AT10060|title=Please save my son!| vauthors = Woodbury DO |date=February 1963|website=University of Toronto Libraries}} [[John Ralston Williams]] imported insulin from Toronto to [[Rochester, New York]], to treat Havens.{{cite news| vauthors = Marcotte B |title=Rochester's John Williams a man of scientific talents |url=http://www.democratandchronicle.com/apps/pbcs.dll/article?AID=201011220301 |access-date=22 November 2010 |newspaper=[[Democrat and Chronicle]] |date=22 November 2010 |agency=[[Gannett Company]] |archive-url=https://archive.today/20101123001049/http://www.democratandchronicle.com/apps/pbcs.dll/article?AID=201011220301 |archive-date=23 November 2010 |location=[[Rochester, New York]] |pages=1B, 4B |url-status=dead }} [206] => [207] => Banting and Best never worked well with Collip, regarding him as something of an interloper,{{citation needed|date=July 2021}} and Collip left the project soon after. Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm [[Eli Lilly and Company]] had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly's head chemist, [[George B. Walden]] discovered [[Protein precipitation#Isoelectric precipitation|isoelectric precipitation]] and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public. [208] => [209] => === Patent === [210] => Toward the end of January 1922, tensions mounted between the four "co-discoverers" of insulin and Collip briefly threatened to separately [[patent]] his purification process. [[John G. FitzGerald]], director of the non-commercial public health institution [[Connaught Laboratories]], therefore stepped in as peacemaker. The resulting agreement of 25 January 1922 established two key conditions: 1) that the collaborators would sign a contract agreeing not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught; and 2) that no changes in research policy would be allowed unless first discussed among FitzGerald and the four collaborators.{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AW10033|title=Memorandum in reference to the co-operation of the Connaught Antitoxin Laboratories in the researches conducted by Dr. Banting, Mr. Best and Dr. Collip under the general direction of Professor J.J.R. Macleod to obtain an extract of pancreas having a specific effect on blood sugar concentration|last=University of Toronto Board of Governors Insulin Committee|date=25 January 1922|website=University of Toronto Libraries}} It helped contain disagreement and tied the research to Connaught's public mandate. [211] => [212] => Initially, Macleod and Banting were particularly reluctant to patent their process for insulin on grounds of [[medical ethics]]. However, concerns remained that a private third-party would hijack and monopolize the research (as [[Eli Lilly and Company]] had hinted{{cite book | vauthors = Bliss M |title=The discovery of insulin |date=2007|publisher=University of Chicago Press|isbn=978-0-226-05899-3|edition= 25th anniversary |location=Chicago|pages=132|oclc=74987867|quote=The Lilly company would be delighted to work with Toronto, [[George Henry Alexander Clowes|Clowes]] wrote, and hinted, perhaps intentionally, perhaps not, that Toronto could be bypassed: "I have thus far refrained from starting work in our laboratories on the field of this question as I was anxious to avoid in any way intruding on the field of yourself and your associates until you had published your results. I feel, however, that the matter is now one of such immediate importance that we should take up the experimental end of the question without delay, preferably cooperating with you and your associates..."}}), and that safe distribution would be difficult to guarantee without capacity for quality control. To this end, [[Edward Calvin Kendall]] gave valuable advice. He had isolated [[thyroxin]] at the [[Mayo Clinic]] in 1914 and patented the process through an arrangement between himself, the brothers Mayo, and the [[University of Minnesota]], transferring the patent to the public university.{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AL10262|title=Letter to Dr. J. J. R. Macleod 10/04/1922| vauthors = Kendall EC |date=10 April 1922|website=University of Toronto Libraries: Discovery and Early Development of Insulin}} On 12 April, Banting, Best, Collip, Macleod, and FitzGerald wrote jointly to the president of the [[University of Toronto]] to propose a similar arrangement with the aim of assigning a patent to the Board of Governors of the university.{{cite web|url=https://insulin.library.utoronto.ca/islandora/object/insulin%3AW10029|title=Statement read by J. J. R. Macleod at the Insulin Committee meeting regarding patents and royalties 28/04/1924| vauthors = Macleod JJ |date=28 April 1924|website=University of Toronto Libraries: The Discovery and Early Development of Insulin}} The letter emphasized that:{{cite book | vauthors = Bliss M |title=The discovery of insulin |date=2007|publisher=University of Chicago Press|isbn=978-0-226-05899-3|edition= 25th anniversary |location=Chicago|pages=131–133|oclc=74987867}}{{blockquote|The patent would not be used for any other purpose than to prevent the taking out of a patent by other persons. When the details of the method of preparation are published anyone would be free to prepare the extract, but no one could secure a profitable monopoly.}}The assignment to the University of Toronto Board of Governors was completed on 15 January 1923, for the token payment of $1.00.{{cite web |url= https://insulin.library.utoronto.ca/islandora/object/insulin%3AQ10013 |title=Assignment to the Governors of the University of Toronto| vauthors = Banting FG, Best C, Collip JS |date=15 January 1923|website=University of Toronto Libraries: Discovery and Early Development of Insulin}} The arrangement was congratulated in ''[[The World's Work]]'' in 1923 as "a step forward in medical ethics".{{cite web |url= https://insulin.library.utoronto.ca/islandora/object/insulin%3AW10031 |title=Copy of the article: A step forward in medical ethics|date=February 1923|website=University of Toronto Libraries: The Discovery and Early Development of Insulin|publisher=The World's Work}} It has also received much media attention in the 2010s regarding the issue of [[Health care prices in the United States|healthcare]] and [[Prescription drug prices in the United States|drug affordability]]. [213] => [214] => Following further concern regarding Eli Lilly's attempts to separately patent parts of the manufacturing process, Connaught's Assistant Director and Head of the Insulin Division [[Robert Defries]] established a patent pooling policy which would require producers to freely share any improvements to the manufacturing process without compromising affordability.{{cite book |title=The discovery of insulin | vauthors = Bliss M |date=2007 |publisher=University of Chicago Press |isbn=978-0-226-05899-3 |edition= 25th anniversary |location=Chicago |pages=181 |oclc=74987867}} [215] => [216] => === Structural analysis and synthesis === [217] => {{multiple image [218] => | align = right [219] => | direction = vertical [220] => | width = 200 [221] => | image1 = Insulin monomer 4INS.png [222] => | alt1 = Black-and-white ribbon diagram of a pig insulin monomer. [223] => | caption1 = [[Ribbon diagram|Richardson diagram]] of a [[pig|porcine]] insulin monomer, showing its characteristic [[secondary structure]]. This is the biologically active form of insulin. [224] => | image2 = Insulin hexamer 4INS.png [225] => | alt2 = Black-and-white ribbon diagram of a pig insulin hexamer, showing its characteristic quaternary structure. At the center is a pale blue-gray sphere representing a zinc atom. [226] => | caption2 = Richardson diagram of a porcine insulin hexamer. The sphere at the center is a stabilizing [[zinc]] atom, surrounded by coordinating [[histidine]] residues. This is the form in which insulin is stored in beta cells. {{PDB|4INS}}. [227] => }} [228] => Purified animal-sourced insulin was initially the only type of insulin available for experiments and diabetics. [[John Jacob Abel]] was the first to produce the crystallised form in 1926.{{cite journal | vauthors = Abel JJ | title = Crystalline Insulin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 12 | issue = 2 | pages = 132–6 | date = February 1926 | pmid = 16587069 | pmc = 1084434 | doi = 10.1073/pnas.12.2.132 | bibcode = 1926PNAS...12..132A | doi-access = free }} Evidence of the protein nature was first given by [[Michael Somogyi]], [[Edward Adelbert Doisy|Edward A. Doisy]], and [[Philip Anderson Shaffer|Philip A. Shaffer]] in 1924.{{Cite journal| vauthors = Somogyi M, Doisy EA, Shaffer PA |date = May 1924 |title=On the Preparation of Insulin |url= https://www.jbc.org/content/60/1/31.full.pdf |journal=Journal of Biological Chemistry |volume=60 |issue=1 |pages=31–58 |doi = 10.1016/S0021-9258(18)85220-6 |doi-access=free }} It was fully proven when Hans Jensen and Earl A. Evans Jr. isolated the amino acids phenylalanine and proline in 1935.{{cite journal| vauthors = Jensen H, Evans EA |date=1 January 1935|title=Studies on Crystalline Insulin Xviii. the Nature of the Free Amino Groups in Insulin and the Isolation of Phenylalanine and Proline from Crystalline Insulin |url= https://www.jbc.org/content/108/1/1.full.pdf |journal=Journal of Biological Chemistry |volume=108 |issue=1 |pages=1–9 |doi=10.1016/S0021-9258(18)75301-5|doi-access=free }} [229] => [230] => The amino acid structure of insulin was first characterized in 1951 by [[Frederick Sanger#Sequencing insulin|Frederick Sanger]],{{cite journal | vauthors = Sanger F, Tuppy H | title = The amino-acid sequence in the phenylalanyl chain of insulin. I. The identification of lower peptides from partial hydrolysates | journal = The Biochemical Journal | volume = 49 | issue = 4 | pages = 463–81 | date = September 1951 | pmid = 14886310 | pmc = 1197535 | doi = 10.1042/bj0490463 }}; {{cite journal | vauthors = Sanger F, Tuppy H | title = The amino-acid sequence in the phenylalanyl chain of insulin. 2. The investigation of peptides from enzymic hydrolysates | journal = The Biochemical Journal | volume = 49 | issue = 4 | pages = 481–90 | date = September 1951 | pmid = 14886311 | pmc = 1197536 | doi = 10.1042/bj0490481 }}; {{cite journal | vauthors = Sanger F, Thompson EO | title = The amino-acid sequence in the glycyl chain of insulin. I. The identification of lower peptides from partial hydrolysates | journal = The Biochemical Journal | volume = 53 | issue = 3 | pages = 353–66 | date = February 1953 | pmid = 13032078 | pmc = 1198157 | doi = 10.1042/bj0530353 }}; {{cite journal | vauthors = Sanger F, Thompson EO | title = The amino-acid sequence in the glycyl chain of insulin. II. The investigation of peptides from enzymic hydrolysates | journal = The Biochemical Journal | volume = 53 | issue = 3 | pages = 366–74 | date = February 1953 | pmid = 13032079 | pmc = 1198158 | doi = 10.1042/bj0530366 }} and the first synthetic insulin was produced simultaneously in the labs of [[Panayotis Katsoyannis]] at the [[University of Pittsburgh]] and [[Helmut Zahn]] at [[RWTH Aachen University]] in the mid-1960s.{{cite journal|vauthors=Katsoyannis PG, Fukuda K, Tometsko A, Suzuki K, Tilak M|year=1964|title=Insulin Peptides. X. The Synthesis of the B-Chain of Insulin and Its Combination with Natural or Synthetis A-Chin to Generate Insulin Activity|journal=Journal of the American Chemical Society|volume=86|issue=5|pages=930–32|doi=10.1021/ja01059a043}}{{cite journal | vauthors = Kung YT, Du YC, Huang WT, Chen CC, Ke LT | title = Total synthesis of crystalline bovine insulin | journal = Scientia Sinica | volume = 14 | issue = 11 | pages = 1710–6 | date = November 1965 | pmid = 5881570 }} {{free access}}{{cite journal | vauthors = Marglin A, Merrifield RB | title = The synthesis of bovine insulin by the solid phase method | journal = Journal of the American Chemical Society | volume = 88 | issue = 21 | pages = 5051–2 | date = November 1966 | pmid = 5978833 | doi = 10.1021/ja00973a068 }}{{cite journal | vauthors = Costin GE | title = What is the advantage of having melanin in parts of the central nervous system (e.g. substantia nigra)? | journal = IUBMB Life | volume = 56 | issue = 1 | pages = 47–9 | date = January 2004 | pmid = 14992380 | doi = 10.1080/15216540310001659029 | doi-access =free | publisher = Time Inc. | s2cid = 85423381 }}{{cite book |vauthors = Wollmer A, Dieken ML, Federwisch M, De Meyts P | title = Insulin & related proteins structure to function and pharmacology | publisher = Kluwer Academic Publishers | location = Boston | year = 2002 | isbn = 978-1-4020-0655-5 | url = https://books.google.com/books?id=Ula72_FSwy8C&q=Panayotis%20Katsoyannis&pg=PP11 }} [[Synthetic crystalline bovine insulin]] was achieved by Chinese researchers in 1965.{{cite journal | vauthors = Tsou CL |author-link1=Chen-Lu Tsou |script-title=zh:对人工合成结晶牛胰岛素的回忆 |trans-title=Memory on the research of synthesizing bovine insulin|journal= 生命科学 [Chinese Bulletin of Life Science] |year=2015 |volume=27 |issue=6 |language=zh-hans |pages=777–79}} The complete 3-dimensional structure of insulin was determined by [[X-ray crystallography]] in [[Dorothy Hodgkin]]'s laboratory in 1969.{{cite journal | vauthors = Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DC, Mercola DA, Vijayan M | title = Atomic positions in rhombohedral 2-zinc insulin crystals | journal = Nature | volume = 231 | issue = 5304 | pages = 506–11 | date = June 1971 | pmid = 4932997 | doi = 10.1038/231506a0 | bibcode = 1971Natur.231..506B | s2cid = 4158731 }} [231] => [232] => Hans E. Weber discovered preproinsulin while working as a research fellow at the University of California Los Angeles in 1974. In 1973–1974, Weber learned the techniques of how to isolate, purify, and translate messenger RNA. To further investigate insulin, he obtained pancreatic tissues from a slaughterhouse in Los Angeles and then later from animal stock at UCLA. He isolated and purified total messenger RNA from pancreatic islet cells which was then translated in oocytes from ''[[Xenopus laevis]]'' and precipitated using anti-insulin antibodies. When total translated protein was run on an SDS-polyacrylamide gel electrophoresis and sucrose gradient, peaks corresponding to insulin and proinsulin were isolated. However, to the surprise of Weber a third peak was isolated corresponding to a molecule larger than proinsulin. After reproducing the experiment several times, he consistently noted this large peak prior to proinsulin that he determined must be a larger precursor molecule upstream of proinsulin. In May 1975, at the American Diabetes Association meeting in New York, Weber gave an oral presentation of his workWeber, H.E. (1975) Diabetes 24, 405. (see figure) where he was the first to name this precursor molecule "preproinsulin". Following this oral presentation, Weber was invited to dinner to discuss his paper and findings by [[Donald Steiner]], a researcher who contributed to the characterization of proinsulin. A year later in April 1976, this molecule was further characterized and sequenced by Steiner, referencing the work and discovery of Hans Weber.Chan SJ, Keim P, Steiner DF. Cell-free synthesis of rat preproinsulins: Characterization and partial amino acid sequence determination. Proc Natl Acad Sci. USA 1976;73:1964-1968. Preproinsulin became an important molecule to study the process of transcription and translation. [233] => [234] => The first genetically engineered, synthetic "human" insulin was produced using [[Escherichia coli|''E. coli'']] in 1978 by [[Arthur Riggs (geneticist)|Arthur Riggs]] and [[Keiichi Itakura]] at the [[Beckman Research Institute]] of the [[City of Hope National Medical Center|City of Hope]] in collaboration with [[Herbert Boyer]] at [[Genentech]]. Genentech, founded by Swanson, Boyer and [[Eli Lilly and Company]], went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name [[Humulin]]. The vast majority of insulin used worldwide is biosynthetic recombinant "human" insulin or its analogues. Recently, another approach has been used by a pioneering group of Canadian researchers, using an easily grown [[safflower]] plant, for the production of much cheaper insulin.{{Cite web|url=https://www.ctvnews.ca/new-source-of-insulin-blossoming-on-the-prairies-1.479043|title=Safflowers may provide new insulin source {{!}} CTV News|website=www.ctvnews.ca|access-date=12 November 2019|date=February 2010}} [235] => [236] => Recombinant insulin is produced either in yeast (usually ''[[baker's yeast|Saccharomyces cerevisiae]]'') or ''E. coli''.{{cite journal | vauthors = Kjeldsen T | title = Yeast secretory expression of insulin precursors | journal = Applied Microbiology and Biotechnology | volume = 54 | issue = 3 | pages = 277–86 | date = September 2000 | pmid = 11030562 | doi = 10.1007/s002530000402 | s2cid = 9246671 | url = http://w3.ualg.pt/~jvarela/biotecnol/pdf/humaninsulin.pdf | archive-url = https://web.archive.org/web/20170927000623/http://w3.ualg.pt/~jvarela/biotecnol/pdf/humaninsulin.pdf | archive-date = 27 September 2017 }} In yeast, insulin may be engineered as a single-chain protein with a KexII endoprotease (a yeast homolog of PCI/PCII) site that separates the insulin A chain from a C-terminally truncated insulin B chain. A chemically synthesized C-terminal tail is then grafted onto insulin by reverse proteolysis using the inexpensive protease trypsin; typically the lysine on the C-terminal tail is protected with a chemical protecting group to prevent proteolysis. The ease of modular synthesis and the relative safety of modifications in that region accounts for common insulin analogs with C-terminal modifications (e.g. lispro, aspart, glulisine). The Genentech synthesis and completely chemical synthesis such as that by [[Bruce Merrifield]] are not preferred because the efficiency of recombining the two insulin chains is low, primarily due to competition with the precipitation of insulin B chain. [237] => [238] => === Nobel Prizes === [239] => [[File:C. H. Best and F. G. Banting ca. 1924.png|thumb|left|[[Frederick Banting]] (right) joined by [[Charles Best (medical scientist)|Charles Best]] in 1924]] [240] => [241] => The [[Nobel Prize]] committee in 1923 credited the practical extraction of insulin to a team at the [[University of Toronto]] and awarded the Nobel Prize to two men: [[Frederick Banting]] and [[John Macleod (physiologist)|John Macleod]].{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1923/ | title = The Nobel Prize in Physiology or Medicine 1923 | publisher = The Nobel Foundation }} They were awarded the [[Nobel Prize in Physiology or Medicine]] in 1923 for the discovery of insulin. Banting, incensed that Best was not mentioned,{{cite web | vauthors = Felman A | date = 22 November 2018 | title = Who discovered insulin? | work = Medical News Today | url = https://www.medicalnewstoday.com/articles/323774.php}} shared his prize with him, and Macleod immediately shared his with [[James Collip]]. The patent for insulin was sold to the [[University of Toronto]] for one dollar. [242] => [243] => Two other Nobel Prizes have been awarded for work on insulin. British molecular biologist [[Frederick Sanger]], who determined the [[primary structure]] of insulin in 1955, was awarded the 1958 [[Nobel Prize in Chemistry]].{{cite journal | vauthors = Stretton AO | title = The first sequence. Fred Sanger and insulin | journal = Genetics | volume = 162 | issue = 2 | pages = 527–32 | date = October 2002 | doi = 10.1093/genetics/162.2.527 | pmid = 12399368 | pmc = 1462286 }} [[Rosalyn Sussman Yalow]] received the 1977 Nobel Prize in Medicine for the development of the [[radioimmunoassay]] for insulin. [244] => [245] => Several Nobel Prizes also have an indirect connection with insulin. [[George Minot]], co-recipient of the 1934 Nobel Prize for the development of the first effective treatment for [[pernicious anemia]], had [[diabetes]]. [[William Bosworth Castle|William Castle]] observed that the 1921 discovery of insulin, arriving in time to keep Minot alive, was therefore also responsible for the discovery of a cure for [[pernicious anemia]].{{cite journal | vauthors = Castle WB | title = The Gordon Wilson Lecture. A Century of Curiosity About Pernicious Anemia | journal = Transactions of the American Clinical and Climatological Association | volume = 73 | pages = 54–80 | year = 1962 | pmid = 21408623 | pmc = 2249021 | author-link = William Bosworth Castle }} [[Dorothy Hodgkin]] was awarded a Nobel Prize in Chemistry in 1964 for the development of [[crystallography]], the technique she used for deciphering the complete molecular structure of insulin in 1969. [246] => [247] => ==== Controversy ==== [248] => [[File:Nicolae Paulescu - Foto03.jpg|thumb|upright=0.65|[[Nicolae Paulescu]]]] [249] => [250] => The work published by Banting, Best, Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients.{{cite journal | vauthors = Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA | title = Pancreatic Extracts in the Treatment of Diabetes Mellitus | journal = Canadian Medical Association Journal | volume = 12 | issue = 3 | pages = 141–46 | date = March 1922 | pmid = 20314060 | pmc = 1524425 }} Although Paulescu discovered the principles of the treatment, his saline extract could not be used on humans; he was not mentioned in the 1923 Nobel Prize. Ian Murray was particularly active in working to correct "the historical wrong" against [[Nicolae Paulescu]]. Murray was a professor of physiology at the Anderson College of Medicine in [[Glasgow]], [[Scotland]], the head of the department of Metabolic Diseases at a leading Glasgow hospital, vice-president of the British Association of Diabetes, and a founding member of the [[International Diabetes Federation]]. Murray wrote: [251] => [252] => {{blockquote|Insufficient recognition has been given to Paulescu, the distinguished [[Romania]]n scientist, who at the time when the Toronto team were commencing their research had already succeeded in extracting the antidiabetic hormone of the pancreas and proving its efficacy in reducing the hyperglycaemia in diabetic dogs.{{cite journal | vauthors = Drury MI | title = The golden jubile of insulin | journal = Journal of the Irish Medical Association | volume = 65 | issue = 14 | pages = 355–63 | date = July 1972 | pmid = 4560502 }} [253] => }} [254] => [255] => In a private communication, [[Arne Tiselius]], former head of the Nobel Institute, expressed his personal opinion that Paulescu was equally worthy of the award in 1923.{{cite journal | vauthors = Murray I | title = Paulesco and the isolation of insulin | journal = Journal of the History of Medicine and Allied Sciences | volume = 26 | issue = 2 | pages = 150–57 | date = April 1971 | pmid = 4930788 | doi = 10.1093/jhmas/XXVI.2.150 }} [256] => [257] => == References == [258] => {{reflist}} [259] => [260] => == Further reading == [261] => {{refbegin}} [262] => * {{cite book | vauthors = Laws GM, Reaven A | title = Insulin resistance : the metabolic syndrome X | date = 1999 | publisher = Humana Press | location = Totowa, NJ | isbn = 978-0-89603-588-1 }} [263] => * {{cite book | vauthors = Leahy JL, Cefalu WT | title = Insulin Therapy | edition = 1st | date = 22 March 2002 | publisher = Marcel Dekker | location = New York | isbn = 978-0-8247-0711-8 | url = https://archive.org/details/insulintherapy00will }} [264] => * {{cite book | vauthors = Kumar S, O'Rahilly S | title = Insulin Resistance: Insulin Action and Its Disturbances in Disease | date = 14 January 2005 |publisher=Wiley |location=Chichester, England |isbn=978-0-470-85008-4 }} [265] => * {{cite book | vauthors = Ehrlich A, Schroeder CL | title = Medical Terminology for Health Professions | edition = 4th | date = 16 June 2000 | publisher = Thomson Delmar Learning | isbn = 978-0-7668-1297-0 | url-access = registration | url = https://archive.org/details/medicalterminolo0000ehrl }} [266] => * {{cite book | vauthors = Draznin B, LeRoith D | author-link1 = Derek LeRoith | title=Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion |date= September 1994 |publisher=Humana Press |location=Totowa, New Jersey |isbn=978-0-89603-286-6 }} [267] => * {{cite book | vauthors = Misbin RI | title = INSULIN - History from an FDA Insider | date = February 2022 | publisher = Politics and Prose Publishing | place = Washington, DC | isbn = 978-1-62429-391-7 | url = https://www.politics-prose.com/book/9781624293917 | access-date = 29 June 2022 | archive-date = 29 June 2022 | archive-url = https://web.archive.org/web/20220629190025/https://www.politics-prose.com/book/9781624293917 | url-status = dead }} [268] => * [https://web.archive.org/web/20070323090430/http://www.collectionscanada.ca/physicians/002032-200-e.html Famous Canadian Physicians: Sir Frederick Banting] at Library and Archives Canada [269] => * {{cite journal | vauthors = McKeage K, Goa KL | title = Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus | journal = Drugs | volume = 61 | issue = 11 | pages = 1599–624 | year = 2001 | pmid = 11577797 | doi = 10.2165/00003495-200161110-00007 | s2cid = 46972328 }} [270] => * {{cite journal | vauthors = de Leiva A, Brugués E, de Leiva-Pérez A | title = [The discovery of insulin: continued controversies after ninety years] | language = es | journal = Endocrinologia y Nutricion | volume = 58 | issue = 9 | pages = 449–56 | date = November 2011 | pmid = 22036099 | doi = 10.1016/j.endonu.2011.10.001 }} [271] => * {{cite journal | vauthors = Vecchio I, Tornali C, Bragazzi NL, Martini M | title = The Discovery of Insulin: An Important Milestone in the History of Medicine | journal = Frontiers in Endocrinology | volume = 9 | pages = 613 | date = 2018 | pmid = 30405529 | pmc = 6205949 | doi = 10.3389/fendo.2018.00613 | doi-access = free }} [272] => {{refend}} [273] => [274] => == External links == [275] => {{commons category|Insulin}} [276] => * [http://link.library.utoronto.ca/insulin/ University of Toronto Libraries Collection: Discovery and Early Development of Insulin, 1920–1925] [277] => * [http://www.cbc.ca/archives/categories/health/medical-research/chasing-a-cure-for-diabetes/topic-chasing-a-cure-for-diabetes.html CBC Digital Archives – Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes] [278] => * [https://web.archive.org/web/20110309114721/http://www.aboutkidshealth.ca/En/ResourceCentres/Diabetes/AboutDiabetes/Pages/Insulin-An-Overview.aspx Animations of insulin's action in the body] at AboutKidsHealth.ca (archived 9 March 2011) [279] => * {{PDBe-KB2|P01308|Insulin}} [280] => [281] => {{PDB Gallery|geneid=3630}} [282] => {{Hormones}} [283] => {{Growth factor receptor modulators}} [284] => {{Portal bar | Medicine}} [285] => {{Authority control}} [286] => [287] => [[Category:Animal products]] [288] => [[Category:Genes on human chromosome 11]] [289] => [[Category:Hormones of glucose metabolism]] [290] => [[Category:Human hormones]] [291] => [[Category:Insulin receptor agonists]] [292] => [[Category:Insulin-like growth factor receptor agonists]] [293] => [[Category:Pancreatic hormones]] [294] => [[Category:Peptide hormones]] [295] => [[Category:Recombinant proteins]] [296] => [[Category:Tumor markers]] [] => )
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Insulin

Insulin is a hormone produced by the pancreas that plays a crucial role in regulating blood sugar (glucose) levels in the body. It is essential for maintaining normal metabolism and preventing conditions such as diabetes.

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It is essential for maintaining normal metabolism and preventing conditions such as diabetes. This Wikipedia page provides a comprehensive overview of insulin, covering its discovery, structure, function, biosynthesis, and regulation. It discusses the different types of insulin, their administration methods, and the diagnosis and treatment of insulin-related disorders, including type 1 and type 2 diabetes. The page also delves into the history of insulin research and the significant contributions made by scientists in understanding and utilizing this hormone. In addition, it explores insulin analogs and advances in insulin therapy, as well as recent developments in insulin delivery systems. The page serves as an informative resource for anyone seeking to gain a comprehensive understanding of insulin and its importance in maintaining optimal health.

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