Insulin: Difference between revisions
Content deleted Content added
m Reverted edits by 2409:4042:241A:B175:8FC0:E3A2:3507:DD0D (talk) (HG) (3.4.6) |
I made it a lot better, im diabetic too Tags: Replaced blanking |
||
| Line 2: | Line 2: | ||
{{Distinguish|Inulin}} |
{{Distinguish|Inulin}} |
||
{{Infobox gene}} |
{{Infobox gene}} |
||
INSULIN IS GAY |
|||
'''Insulin''' (from [[Latin]] ''insula'', island) is a [[peptide hormone]] produced by [[beta cell]]s of the [[pancreatic islets]]; it is considered to be the main [[Anabolism|anabolic]] hormone of the body.<ref name="Biochemistry">{{cite book | vauthors = Voet D, Voet JG | title = Biochemistry | date = 2011 | publisher = Wiley | location = New York | edition = 4th }}</ref> It regulates the [[metabolism]] of [[carbohydrate]]s, [[fat]]s and [[protein]] by promoting the absorption of carbohydrates, especially [[glucose]] from the blood into [[liver]], [[fat cell|fat]] and [[skeletal muscle]] cells.<ref name=stryer>{{cite book |last1= Stryer |first1= Lubert | name-list-format = vanc | title=Biochemistry. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|publication-date= 1995 |pages= 773–74|isbn= 0 7167 2009 4 }}</ref> 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.<ref name=stryer /> [[Glucose]] production and [[secretion]] by the liver is strongly inhibited by high concentrations of insulin in the blood.<ref name="pmid10927996">{{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 }}</ref> 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]]. |
|||
<!-- Regulation --> |
|||
[[Beta cell]]s are sensitive to glucose concentrations, also known as [[blood sugar level]]s. When the glucose level is high, the beta cells secrete insulin into the blood; when glucose levels are low, secretion of insulin is inhibited.<ref name=koeslag>{{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 | doi = 10.1113/jphysiol.2002.037895 | publication-date = 2003 | pmc=2342944}}</ref> Their neighboring [[alpha cell]]s, by taking their cues from the beta cells,<ref name=koeslag /> secrete [[glucagon]] into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high.<ref name=stryer /><ref name=koeslag /> [[Glucagon]], through stimulating the liver to release glucose by [[glycogenolysis]] and [[gluconeogenesis]], has the opposite effect of insulin.<ref name=stryer /><ref name=koeslag /> 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]].<ref name=koeslag /> |
|||
<!-- Clinical significance --> |
|||
If beta cells are destroyed by an [[autoimmunity|autoimmune reaction]], insulin can no longer be synthesized or be secreted into the blood. This results in [[Diabetes mellitus type 1|type 1 diabetes mellitus]], which is characterized by abnormally high blood glucose concentrations, and generalized body wasting.<ref name="urlInsulin Injection - PubMed Health">{{cite web | url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000729 | title = Insulin Injection | author = American Society of Health-System Pharmacists | date = 2009-02-01 | work = PubMed Health | publisher = National Center for Biotechnology Information, U.S. National Library of Medicine | accessdate = 2012-10-12 }}</ref> In [[Diabetes mellitus type 2|type 2 diabetes mellitus]] the destruction of beta cells is less pronounced than in type 1 diabetes, 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.<ref name=koeslag /> The pathogenesis of type 2 diabetes is not well understood but patients exhibit a reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance.<ref name="Biochemistry"/> Type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, and unresponsive to the concentration of glucose in the blood. Insulin is still secreted into the blood in response to the blood glucose.<ref name=koeslag /> As a result, the insulin levels, even when the blood sugar level is normal, are much higher than they are in healthy persons. |
|||
<!-- Structure --> |
|||
The human insulin protein is composed of 51 [[amino acid]]s, and has a [[molecular mass]] of 5808 [[Dalton (unit)|Da]]. It is a [[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 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.<ref name=recombination>Drug Information Portal NLM – Insulin human USAN http://druginfo.nlm.nih.gov/drugportal/</ref><ref name="urlGenentech">{{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=1978-09-06 |publisher=Genentech|access-date=|work=News Release|accessdate=2016-09-26}}</ref><ref name="urlRecombinant DNA technology in the synthesis of human insulin">{{cite web | url = http://www.littletree.com.au/dna.htm | title = Recombinant DNA technology in the synthesis of human insulin | author = Tof I | year = 1994 | work = | publisher = Little Tree Publishing | accessdate = 2009-11-03 }}</ref><ref name="pmid23222785">{{cite journal | vauthors = Aggarwal SR | title = What's fueling the biotech engine-2011 to 2012 | journal = Nature Biotechnology | volume = 30 | issue = 12 | pages = 1191–97 | date = December 2012 | pmid = 23222785| doi = 10.1038/nbt.2437 }}</ref> |
|||
<!-- History, society and culture --> |
|||
The [[crystal structure]] of insulin in the solid state was determined by [[Dorothy Hodgkin]]. It is on the [[WHO Model List of Essential Medicines]], the most important medications needed in a basic [[health system]].<ref name=WHO2015E>{{cite web |url=http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |title=19th WHO Model List of Essential Medicines (April 2015) |date=April 2015 |accessdate=May 10, 2015 |publisher=WHO }}</ref> |
|||
== Evolution and species distribution == |
|||
Insulin may have originated more than a billion years ago.<ref name='Alzira'>{{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 | year = 2004 | doi = 10.1590/S1516-89132004000600017 | pages=973–81}}</ref> The molecular origins of insulin go at least as far back as the simplest unicellular [[eukaryotes]].<ref name='LeRoith'>{{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 = Revue Canadienne de Biochimie et Biologie Cellulaire | volume = 63 | issue = 8 | pages = 839–49 | date = August 1985 | pmid = 3933801 | doi = 10.1139/o85-106 }}</ref> Apart from animals, insulin-like proteins are also known to exist in the Fungi and Protista kingdoms.<ref name='Alzira' /> |
|||
Insulin is produced by [[beta cells]] of the [[pancreatic islets]] in most vertebrates and by the [[Brockmann body]] in some [[teleost fish]].<ref>{{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 }}</ref> [[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.<ref>{{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 |work= |date=19 January 2015}}</ref><ref name="pmid25605914">{{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 | url = http://arrow.monash.edu.au/vital/access/services/Download/monash:160381/DOC }}</ref> |
|||
== Gene == |
|||
The [[preproinsulin]] precursor of insulin is encoded by the ''INS'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: INS insulin| url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3630| accessdate = }}</ref><ref name="pmid6243748">{{cite journal | vauthors = Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM | title = Sequence of the human insulin gene | journal = Nature | volume = 284 | issue = 5751 | pages = 26–32 | date = March 1980 | pmid = 6243748 | doi = 10.1038/284026a0 | bibcode = 1980Natur.284...26B }}</ref> |
|||
=== Alleles === |
|||
A variety of mutant [[allele]]s with changes in the coding region have been identified. A [[Conjoined gene|read-through gene]], INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.<ref name="entrez"/> |
|||
=== Regulation === |
|||
[[File:Insulin gene activation.png|thumb|500px|Diagram of insulin regulation upon high blood glucose]] |
|||
In the pancreatic [[β cells]], [[glucose]] is the primary physiological stimulus for the regulation of insulin synthesis. Insulin is mainly regulated through the transcription factors [[PDX1]], [[NeuroD1]], and [[MafA]].<ref name="Bernardo_2008">{{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 | department = review }}</ref><ref name="Rutter_2015">{{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 | department = review }}</ref><ref name = "Rutter_2000">{{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 = | pages = 149–54 | date = June 2000 | pmid = 11390898 | doi = 10.1152/physiologyonline.2000.15.3.149 | department = review }}</ref><ref name = "Poitout_2006">{{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 }}</ref> |
|||
[[PDX1]] (Pancreatic and duodenal homeobox protein 1) is in the nuclear periphery upon low blood glucose levels<ref name = "Vaulont_2000">{{cite journal | vauthors = Vaulont S, Vasseur-Cognet M, Kahn A | title = Glucose regulation of gene transcription | journal = The Journal of Biological Chemistry | volume = 275 | issue = 41 | pages = 31555–58 | date = October 2000 | pmid = 10934218 | doi = 10.1074/jbc.R000016200 | department = review }}</ref> interacting with corepressors [[HDAC1]] and [[HDAC2|2]] which is downregulating the insulin secretion.<ref name="Christensen_2011">{{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 (Cambridge, Mass.) | volume = 17 | issue = 5-6 | pages = 378–90 | date = 2011 | pmid = 21274504 | pmc = 3105132 | doi = 10.2119/molmed.2011.00021 | url = }}</ref> An increase in blood [[glucose]] levels causes [[phosphorylation]] of [[PDX1]] and it translocates centrally and binds the A3 element within the insulin promoter.<ref name="Wang_2016">{{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 | issue = | pages = 38–48 | date = June 2016 | pmid = 26994512 | doi = 10.1016/j.mce.2016.03.019 }}</ref> Upon translocation it interacts with coactivators [[EP300|HAT p300]] and [[acetyltransferase set 7/9]]. [[PDX1]] affects the [[histone]] modifications through [[acetylation]] and deacetylation as well as [[methylation]]. It is also said to suppress [[glucagon]].<ref>{{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}}</ref> |
|||
[[NeuroD1]], also known as β2, regulates insulin exocytosis in pancreatic [[β cells]] by directly inducing the expression of [[genes]] involved in exocytosis.<ref name = "Andrali_2008">{{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 | department = review }}</ref> 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.<ref name = "Andrali_2008" /> |
|||
[[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.<ref name="pmid19393272">{{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 | url = }}</ref><ref name="Aramata_2007">{{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 = | url = }}</ref> |
|||
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 it self.<ref name="Kaneto_2012">{{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 | url = }}</ref> |
|||
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. |
|||
{|class="wikitable" |
|||
|+ Regulatory sequences and their transcription factors for the insulin gene.<ref name="pmid11914736">{{cite journal | vauthors = Melloul D, Marshak S, Cerasi E | title = Regulation of insulin gene transcription | journal = Diabetologia | volume = 45 | issue = 3 | pages = 309–26 | date = March 2002 | pmid = 11914736 | doi = 10.1007/s00125-001-0728-y }}</ref> |
|||
! [[Regulatory sequence]] !! binding [[transcription factors]] |
|||
|-=P |
|||
| [[ILPR]] || [[DBP (gene)|Par1]] |
|||
|- |
|||
| [[A-box 5 of insulin gene|A5]] || [[Pdx1]] |
|||
|- |
|||
| [[negative regulatory element]] (NRE)<ref name="pmid17150186">{{cite journal | vauthors = Jang WG, Kim EJ, Park KG, Park YB, Choi HS, Kim HJ, Kim YD, Kim KS, Lee KU, Lee IK | title = Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha | journal = Biochemical and Biophysical Research Communications | volume = 352 | issue = 3 | pages = 716–21 | date = January 2007 | pmid = 17150186 | doi = 10.1016/j.bbrc.2006.11.074 }}</ref> || [[glucocorticoid receptor]], [[POU2F1|Oct1]] |
|||
|- |
|||
| [[Z-box of insulin gene|Z]] (overlapping NRE and C2) || [[ISF (transcription factor)|ISF]] |
|||
|- |
|||
| [[C2 regulatory sequence|C2]] || [[Pax4]], [[MafA]](?) |
|||
|- |
|||
| [[E-box 2 of insulin gene|E2]] || [[USF1]]/[[USF2]] |
|||
|- |
|||
| [[A-box 3 of insulin gene|A3]] || [[Pdx1]] |
|||
|- |
|||
| [[CAMP response element|CREB RE]] || – |
|||
|- |
|||
| [[CAMP response element|CREB RE]] || [[CREB]], [[CREM]] |
|||
|- |
|||
| [[A-box 2 of insulin gene|A2]] || – |
|||
|- |
|||
| [[CAAT enhancer binding]] (CEB) (partly overlapping A2 and C1) || – |
|||
|- |
|||
| [[C-box 1 of insulin gene|C1]] || – |
|||
|- |
|||
| [[E-box 1 of insulin gene|E1]] || [[E2A]]{{dn|date=January 2019}}, [[NeuroD1]], [[TCF12|HEB]] |
|||
|- |
|||
| [[A-box 1 of insulin gene|A1]] || [[Pdx1]] |
|||
|- |
|||
| [[G-box 1 of insulin gene|G1]] || – |
|||
|} |
|||
== Protein structure == |
|||
{{See also|Insulin/IGF/Relaxin family|Insulin and its analog structure}} |
|||
Within vertebrates, the amino acid sequence of insulin is [[conserved sequence|strongly conserved]]. [[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]] (discussed later), however, differs much more among species; it is also a hormone, but a secondary one. |
|||
[[File:Insulin worm bw.jpg|thumb|right|160px| SS-linked insulin monomer]] |
|||
The primary structure of bovine insulin was first determined by [[Frederick Sanger]] in 1951.<ref name = "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 }}</ref> After that, this polypeptide was synthesized independently by several groups.<ref name="Katsoyannis_1964" >{{cite journal|vauthors=Katsoyannis PG, Fukuda K, Tometsko A, Suzuki K, Tilak M | 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 | year = 1964 | volume = 86 | issue = 5 | pages=930–32 | doi = 10.1021/ja01059a043 }}</ref><ref name="pmid5881570">{{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 = 1710–16 | date = November 1965 | pmid = 5881570 | doi = }}</ref><ref name=Marglin_1966>{{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 = 5051–52 | date = November 1966 | pmid = 5978833 | doi = 10.1021/ja00973a068 }}</ref> The 3-dimensional structure of insulin was determined by [[X-ray crystallography]] in [[Dorothy Hodgkin]]'s laboratory in 1969 (PDB file 1ins).<ref>{{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 }}</ref> |
|||
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 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.<ref name="pmid16158220">{{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 }}</ref> Insulin can aggregate and form [[fibrillar]] interdigitated [[beta-sheet]]s. This can cause injection [[amyloidosis]], and prevents the storage of insulin for long periods.<ref name="pmid19864624">{{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 = 18990–95 | date = November 2009 | pmid = 19864624 | pmc = 2776439 | doi = 10.1073/pnas.0910080106 | bibcode = 2009PNAS..10618990I }}</ref> |
|||
== Synthesis, physiological effects, and degradation == |
|||
=== Synthesis === |
|||
Insulin is produced in the [[pancreas]] and the Brockmann body (in some fish), and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food.<ref name=MedicalPhysiology>{{cite book|last1=Rhoades|first1=Rodney A.|last2=Bell|first2=David R.| name-list-format = vanc | title=Medical physiology : principles for clinical medicine|date=2009|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-6852-8|pages=644–47|edition=3rd}}</ref> [[Carbohydrate]]s can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a [[signal transduction]], which has the effect of increasing [[glucose]] uptake and storage. Finally, insulin is degraded, terminating the response. |
|||
[[File:Insulin path.svg|thumb|400px|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.]] |
|||
In mammals, insulin is synthesized in the pancreas within the beta cells. One million to three million pancreatic islets form the [[endocrine]] part of the pancreas, which is primarily an [[exocrine]] [[gland]]. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the pancreatic islets, beta cells constitute 65–80% of all the cells. |
|||
Insulin consists of two polypeptide chains, the A- and B- chains, linked together by disulfide bonds. It is however first synthesized as a single polypeptide called [[preproinsulin]] in beta cells. Preproinsulin contains a 24-residue [[signal peptide]] which directs the nascent polypeptide chain to the rough [[endoplasmic reticulum]] (RER). The signal peptide is cleaved as the polypeptide is translocated into lumen of the RER, forming [[proinsulin]].<ref>{{cite book |url= https://books.google.com/?id=ohgjG0qAvfgC&pg=PA66#v=onepage&q&f=false |title= Joslin's Diabetes Mellitus | vauthors = Kahn CR, Weir GC | author-link = C. Ronald Kahn | edition = 14th |pages= |publisher= Lippincott Williams & Wilkins |year=2005 |isbn=978-8493531836 }}</ref> In the RER the proinsulin folds into the correct conformation and 3 disulfide bonds are formed. About 5–10 min after its assembly in the endoplasmic reticulum, proinsulin is transported to the trans-Golgi network (TGN) where immature granules are formed. Transport to the TGN may take about 30 min. |
|||
Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases known as [[prohormone convertase]]s ([[Proprotein convertase 1|PC1]] and [[proprotein convertase 2|PC2]]), as well as the exoprotease [[carboxypeptidase E]].<ref name="pmid16591494">{{cite journal | vauthors = Steiner DF, Oyer PE | title = The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 57 | issue = 2 | pages = 473–80 | date = February 1967 | pmid = 16591494 | pmc = 335530 | doi = 10.1073/pnas.57.2.473 | bibcode = 1967PNAS...57..473S }}</ref> The endopeptidases cleave at 2 positions, releasing a fragment called the [[C-peptide]], and leaving 2 peptide chains, the B- and A- chains, linked by 2 disulfide bonds. The cleavage sites are each located after a pair of basic residues (lysine-64 and arginine-65, and arginine-31 and −32). After cleavage of the C-peptide, these 2 pairs of basic residues are removed by the carboxypeptidase.<ref name="creighton">{{cite book | first = Thomas E | last = Creighton | name-list-format = vanc | title = Proteins: Structures and Molecular Properties |edition=2nd |pages=81–83 |year=1993 |publisher=W H Freeman and Company |isbn=0-7167-2317-4 }}</ref> The [[C-peptide]] is the central portion of proinsulin, and the primary sequence of proinsulin goes in the order "B-C-A" (the B and A chains were identified on the basis of mass and the C-peptide was discovered later). |
|||
The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the cell into the circulation.<ref name = "Najjar_2001">{{cite journal | vauthors = Najjar S | title = Insulin Action: Molecular Basis of Diabetes | journal = Encyclopedia of Life Sciences | publisher = John Wiley & Sons | year=2001 | doi = 10.1038/npg.els.0001402 | isbn = 0470016175 }}</ref> |
|||
The endogenous production of insulin is regulated in several steps along the synthesis pathway: |
|||
* At [[DNA transcription|transcription]] from the [[insulin gene]] |
|||
* In [[mRNA]] stability |
|||
* At the [[mRNA translation]] |
|||
* In the [[posttranslational modification]]s |
|||
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.<ref name="urlResearchers discover link between insulin and Alzheimers">{{cite web | url = http://www.eurekalert.org/pub_releases/2005-03/l-rdl030205.php | title = Researchers discover link between insulin and Alzheimer's | author = Gustin N | date = 2005-03-07 | work = EurekAlert! | publisher = American Association for the Advancement of Science | pages = | quote = | accessdate = 2009-01-01}}</ref><ref name="pmid15750214">{{cite journal | vauthors = de la Monte SM, Wands JR | 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 = | url = http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=7&issue=1&spage=45 }}</ref><ref name="pmid15750215">{{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| url = http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=7&issue=1&spage=63 }}</ref> |
|||
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.<ref name="stryer" /> |
|||
=== Release === |
|||
{{See also|Blood glucose regulation}} |
|||
[[Beta Cell|Beta cells]] in the [[islets of Langerhans]] release insulin in two phases. The first-phase release is rapidly triggered in response to increased blood glucose levels, and lasts about 10 minutes. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar, peaking in 2 to 3 hours. Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of [[Diabetes mellitus type 2|type 2 diabetes]].<ref name="pmid11815469">{{cite journal | vauthors = Gerich JE | title = Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? | journal = Diabetes | volume = 51 | issue = Suppl 1 | pages = S117–21 | date = February 2002 | pmid = 11815469 | doi = 10.2337/diabetes.51.2007.s117}}</ref> First-phase release and [[Insulin resistance|insulin sensitivity]] are independent predictors of diabetes.<ref name="pmid20805282">{{cite journal | vauthors = Lorenzo C, Wagenknecht LE, Rewers MJ, Karter AJ, Bergman RN, Hanley AJ, Haffner SM | title = Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS) | journal = Diabetes Care | volume = 33 | issue = 9 | pages = 2098–103 | date = September 2010 | pmid = 20805282 | pmc = 2928371 | doi = 10.2337/dc10-0165 }}</ref> |
|||
The description of first phase release is as follows: |
|||
* Glucose enters the β-cells through the [[glucose transporters]], [[GLUT2]]. These glucose transporters have a relatively low affinity for glucose, ensuring that the rate of glucose entry into the β-cells is proportional to the extracellular glucose concentration (within the physiological range). At low blood sugar levels very little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells.<ref name=schuit>{{cite journal | vauthors = Schuit F, Moens K, Heimberg H, Pipeleers D | title = Cellular origin of hexokinase in pancreatic islets | journal = The Journal of Biological Chemistry | volume = 274 | issue = 46 | pages = 32803–09 | date = November 1999 | pmid = 10551841 | publication-date = 1999 | doi=10.1074/jbc.274.46.32803}}</ref> |
|||
* The glucose that enters the β-cell is phosphorylated to [[glucose-6-phosphate]] (G-6-P) by [[glucokinase]] ([[Hexokinase#Types of mammalian hexokinase|hexokinase IV]]) which is not inhibited by G-6-P in the way that the hexokinases in other tissues (hexokinase I – III) are affected by this product. This means that the intracellular G-6-P concentration remains proportional to the blood sugar concentration.<ref name=koeslag /><ref name=schuit /> |
|||
* Glucose-6-phosphate enters [[Glycolysis|glycolytic pathway]] and then, via the [[pyruvate dehydrogenase]] reaction, into the [[Krebs cycle]], where multiple, high-energy [[adenosine triphosphate|ATP]] molecules are produced by the oxidation of [[acetyl CoA]] (the Krebs cycle substrate), leading to a rise in the ATP:ADP ratio within the cell.<ref>{{cite journal | vauthors = Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T, Prentki M | title = Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18572–79 | date = July 1997 | pmid = 9228023 | publication-date = 1997 | doi=10.1074/jbc.272.30.18572}}</ref> |
|||
* An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/[[Kir6.2]] [[potassium channel]] (see [[sulfonylurea receptor]]). This prevents potassium ions (K<sup>+</sup>) from leaving the cell by facilitated diffusion, leading to a buildup of intracellular potassium ions. As a result, the inside of the cell becomes less negative with respect to the outside, leading to the depolarization of the cell surface membrane. |
|||
* Upon [[depolarization]], voltage-gated [[calcium channels|calcium ion (Ca<sup>2+</sup>) channels]] open, allowing calcium ions to move into the cell by facilitated diffusion. |
|||
* The cytosolic calcium ion concentration can also be increased by calcium release from intracellular stores via activation of ryanodine receptors.<ref name="SP2015">{{cite journal | vauthors = Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR | title = Calcium release channel RyR2 regulates insulin release and glucose homeostasis | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1968–78 | date = May 2015 | pmid = 25844899 | doi = 10.1172/JCI79273 | pmc=4463204}}</ref> |
|||
* The calcium ion concentration in the cytosol of the beta cells can also, or additionally, be increased through the activation of [[phospholipase|phospholipase C]] resulting from the binding of an extracellular [[ligand]] (hormone or neurotransmitter) to a [[G protein]]-coupled membrane receptor. Phospholipase C cleaves the membrane phospholipid, [[phosphatidyl inositol 4,5-bisphosphate]], into [[inositol 1,4,5-trisphosphate]] and [[diglyceride|diacylglycerol]]. Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the plasma membrane of the [[endoplasmic reticulum]] (ER). This allows the release of Ca<sup>2+</sup> ions from the ER via IP3-gated channels, which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration. [[Parasympathetic nervous system|Parasympathetic]] stimulation of the pancreatic islets operates via this pathway to increase insulin secretion into the blood.<ref name=stryer1>{{cite book |last1= Stryer |first1= Lubert | name-list-format = vanc | title = Biochemistry. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|publication-date= 1995 |pages= 343–44|isbn= 0 7167 2009 4 }}</ref> |
|||
* The significantly increased amount of calcium ions in the cells' cytoplasm causes the release into the blood of previously synthesized insulin, which has been stored in intracellular [[secretion|secretory]] [[vesicle (biology)|vesicles]]. |
|||
This is the primary mechanism for release of insulin. Other substances known to stimulate insulin release include the amino acids arginine and leucine, parasympathetic release of [[acetylcholine]] (acting via the phospholipase C pathway), [[sulfonylurea]], [[cholecystokinin]] (CCK, also via phospholipase C),<ref name="pmid19922535">{{cite journal | vauthors = Cawston EE, Miller LJ | title = Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor | journal = British Journal of Pharmacology | volume = 159 | issue = 5 | pages = 1009–21 | date = March 2010 | pmid = 19922535 | pmc = 2839260 | doi = 10.1111/j.1476-5381.2009.00489.x }}</ref> and the gastrointestinally derived [[incretins]], such as [[glucagon-like peptide-1]] (GLP-1) and [[glucose-dependent insulinotropic peptide]] (GIP). |
|||
Release of insulin is strongly inhibited by [[norepinephrine]] (noradrenaline), which leads to increased blood glucose levels during stress. It appears that release of [[catecholamines]] by the [[sympathetic nervous system]] has conflicting influences on insulin release by beta cells, because insulin release is inhibited by α<sub>2</sub>-adrenergic receptors<ref name="pmid6252481">{{cite journal | vauthors = Nakaki T, Nakadate T, Kato R | title = Alpha 2-adrenoceptors modulating insulin release from isolated pancreatic islets | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 313 | issue = 2 | pages = 151–53 | date = August 1980 | pmid = 6252481 | doi = 10.1007/BF00498572 }}</ref> and stimulated by β<sub>2</sub>-adrenergic receptors.<ref name="Layden_2010">{{cite journal | vauthors = Layden BT, Durai V, ((Lowe WL Jr)) | title = G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes | journal = Nature Education | volume = 3 | issue = 9 | pages = 13 | year = 2010 | url = http://www.nature.com/scitable/topicpage/g-protein-coupled-receptors-pancreatic-islets-and-14257267 }}</ref> The net effect of [[norepinephrine]] from sympathetic nerves and [[epinephrine]] from adrenal glands on insulin release is inhibition due to dominance of the α-adrenergic receptors.<ref name="sabyasachi">{{cite book | vauthors = Sircar S | title = Medical Physiology | publisher = Thieme Publishing Group | location = Stuttgart | year = 2007 | pages = 537–38 | isbn = 3-13-144061-9 }}</ref> |
|||
When the glucose level comes down to the usual physiologic value, insulin release from the β-cells slows or stops. If the blood glucose level drops lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently [[glucagon]] from islet of Langerhans alpha cells) forces release of glucose into the blood from the liver glycogen stores, supplemented by [[gluconeogenesis]] if the glycogen stores become depleted. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. |
|||
Evidence of impaired first-phase insulin release can be seen in the [[glucose tolerance test]], demonstrated by a substantially elevated blood glucose level at 30 minutes after the ingestion of a glucose load (75 or 100 g of glucose), followed by a slow drop over the next 100 minutes, to remain above 120 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. |
|||
=== Oscillations === |
|||
{{Main|Insulin oscillations}} |
|||
[[Image:Pancreas insulin oscillations.svg|thumb|250px|Insulin release from pancreas oscillates with a period of 3–6 minutes.<ref name="hellman" />]] |
|||
Even during digestion, in general, one or two hours following a meal, insulin release from the pancreas is not continuous, but [[oscillates]] with a period of 3–6 minutes, changing from generating a blood insulin concentration more than about 800 [[pico-|p]] [[unit mole|mol]]/l to less than 100 pmol/l.<ref name="hellman">{{cite journal | vauthors = Hellman B, Gylfe E, Grapengiesser E, Dansk H, Salehi A | title = [Insulin oscillations—clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release] |language=Swedish | journal = Läkartidningen | volume = 104 | issue = 32–33 | pages = 2236–39 | year = 2007 | pmid = 17822201 | doi = }}</ref> This is thought to avoid [[receptor downregulation|downregulation]] of [[insulin receptor]]s in target cells, and to assist the liver in extracting insulin from the blood.<ref name="hellman" /> This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be achieved, not a constant high concentration.<ref name="hellman" /> This may be achieved by [[Pulsatile insulin|delivering insulin rhythmically]] to the [[portal vein]] or by [[islet cell transplantation]] to the liver.<ref name="hellman" /> |
|||
=== Blood insulin level === |
|||
{{Further |Insulin index}} |
|||
[[Image:Suckale08 fig3 glucose insulin day.png|270px|thumb|The idealized diagram shows the fluctuation of [[blood sugar]] (red) and the sugar-lowering hormone '''insulin''' (blue) in humans during the course of a day containing three meals. In addition, the effect of a [[sucrose|sugar]]-rich versus a [[starch]]-rich meal is highlighted.]] |
|||
The blood insulin level can be measured in [[international unit]]s, such as µIU/mL or in [[molar concentration]], such as pmol/L, where 1 µIU/mL equals 6.945 pmol/L.<ref>[http://www.unc.edu/~rowlett/units/scales/clinical_data.html A Dictionary of Units of Measurement] {{webarchive|url=https://web.archive.org/web/20131028105836/http://www.unc.edu/~rowlett/units/scales/clinical_data.html |date=2013-10-28 }} By Russ Rowlett, the University of North Carolina at Chapel Hill. June 13, 2001</ref> A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).<ref name="pmid11056282">{{cite journal | vauthors = Iwase H, Kobayashi M, Nakajima M, Takatori T | title = The ratio of insulin to C-peptide can be used to make a forensic diagnosis of exogenous insulin overdosage | journal = Forensic Science International | volume = 115 | issue = 1–2 | pages = 123–27 | date = January 2001 | pmid = 11056282 | doi = 10.1016/S0379-0738(00)00298-X }}</ref> |
|||
=== Signal transduction === |
|||
The effects of insulin are initiated by its binding to a receptor present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer. Insulin binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin.<ref name="diabetesincontrol.com">{{Cite news|url=http://www.diabetesincontrol.com/handbook-of-diabetes-4th-edition-excerpt-4-normal-physiology-of-insulin-secretion-and-action/|title=Handbook of Diabetes, 4th Edition, Excerpt #4: Normal Physiology of Insulin Secretion and Action|date=2014-07-28|work=Diabetes In Control. A free weekly diabetes newsletter for Medical Professionals.|access-date=2017-06-01|language=en-US}}</ref> |
|||
The cascade that leads to the insertion of GLUT4 glucose transporters into the cell membranes of muscle and fat cells, and to the synthesis of glycogen in liver and muscle tissue, as well as the conversion of glucose into triglycerides in liver, adipose, and lactating mammary gland tissue, operates via the activation, by IRS-1, of phosphoinositol 3 kinase ([[phosphoinositide 3-kinase|PI3K]]). This enzyme converts a [[phospholipid]] in the cell membrane by the name of [[phosphatidylinositol 4,5-bisphosphate]] (PIP2), into [[Phosphatidylinositol (3,4,5)-trisphosphate|phosphatidylinositol 3,4,5-triphosphate]] (PIP3), which, in turn, activates [[AKT|protein kinase B]] (PKB). Activated PKB facilitates the fusion of GLUT4 containing [[endosome]]s with the cell membrane, resulting in an increase in GLUT4 transporters in the plasma membrane.<ref name="pmid15791206">{{cite journal | vauthors = McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR | title = Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis | journal = The EMBO Journal | volume = 24 | issue = 8 | pages = 1571–83 | date = April 2005 | pmid = 15791206 | pmc = 1142569 | doi = 10.1038/sj.emboj.7600633 }}</ref> PKB also phosphorylates [[GSK-3|glycogen synthase kinase]] (GSK), thereby inactivating this enzyme.<ref name="pmid11035810">{{cite journal | vauthors = Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB | title = Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 22 | pages = 11960–75 | date = October 2000 | pmid = 11035810 | pmc = 17277 | doi = 10.1073/pnas.220413597 | bibcode = 2000PNAS...9711960F }}</ref> This means that its substrate, [[glycogen synthase]] (GS), cannot be phosphorylated, and remains dephosphorylated, and therefore active. The active enzyme, glycogen synthase (GS), catalyzes the rate limiting step in the synthesis of glycogen from glucose. Similar dephosphorylations affect the enzymes controlling the rate of [[glycolysis]] leading to the synthesis of fats via [[malonyl-CoA]] in the tissues that can generate [[triglycerides]], and also the enzymes that control the rate of [[gluconeogenesis]] in the liver. The overall effect of these final enzyme dephosphorylations is that, in the tissues that can carry out these reactions, glycogen and fat synthesis from glucose are stimulated, and glucose production by the liver through [[glycogenolysis]] and [[gluconeogenesis]] are inhibited.<ref name="stryer2">{{cite book|title=Biochemistry.|publisher=W.H. Freeman and Company|isbn=0 7167 2009 4|edition=Fourth|location=New York|publication-date=1995|pages=351–56, 494–95, 505, 605–06, 773–75|last1=Stryer|first1=Lubert | name-list-format = vanc }}</ref> The breakdown of triglycerides by adipose tissue into [[free fatty acids]] and [[glycerol]] is also inhibited.<ref name=stryer2 /> |
|||
After the intracellular signal that resulted from the binding of insulin to its receptor has been produced, termination of signaling is then needed. As mentioned below in the section on degradation, endocytosis and degradation of the receptor bound to insulin is a main mechanism to end signaling.<ref name="Najjar_2001" /> In addition, the signaling pathway is also terminated by dephosphorylation of the tyrosine residues in the various signaling pathways by tyrosine phosphatases. Serine/Threonine kinases are also known to reduce the activity of insulin. |
|||
The structure of the insulin–[[insulin receptor]] complex has been determined using the techniques of [[X-ray crystallography]].<ref name = "Menting_2013">{{cite journal | vauthors = Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Záková L, Kletvíková E, Jiráček J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC | title = How insulin engages its primary binding site on the insulin receptor | journal = Nature | volume = 493 | issue = 7431 | pages = 241–45 | date = January 2013 | pmid = 23302862 | pmc = 3793637 | doi = 10.1038/nature11781 | laysummary = http://www.abc.net.au/news/2013-01-10/australian-researchers-crack-insulin-mechanism/4458974 | laysource = Australian Broadcasting Commission | bibcode = 2013Natur.493..241M }}</ref> |
|||
=== Physiological effects === |
|||
[[File:Insulin glucose metabolism ZP.svg|thumbnail|400px|'''Effect of insulin on glucose uptake and metabolism.''' Insulin binds to its receptor (1), which starts many protein activation cascades (2). These include translocation of Glut-4 transporter to the [[plasma membrane]] and influx of glucose (3), [[glycogen]] synthesis (4), [[glycolysis]] (5) and triglyceride synthesis (6).]] |
|||
[[File:Signal Transduction Diagram- Insulin.svg|thumb|400px|The insulin signal transduction pathway begins when insulin binds to the insulin receptor proteins. Once the transduction pathway is completed, the GLUT-4 storage vesicles becomes one with the cellular membrane. As a result, the GLUT-4 protein channels become embedded into the membrane, allowing glucose to be transported into the cell.]] |
|||
The actions of insulin on the global human metabolism level include: |
|||
* Increase of cellular intake of certain substances, most prominently glucose in muscle and [[adipose tissue]] (about two-thirds of body cells)<ref name="pmid21864752">{{cite journal | vauthors = Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA | title = Insulin effects in muscle and adipose tissue | journal = Diabetes Research and Clinical Practice | volume = 93 Suppl 1 | issue = | pages = S52–59 | date = August 2011 | url=https://www.researchgate.net/profile/Eirini_Maratou/publication/221930616_Insulin_effects_in_muscle_and_adipose_tissue/links/00b7d527a370a8fd76000000.pdf | pmid = 21864752 | doi = 10.1016/S0168-8227(11)70014-6 }}</ref> |
|||
* Increase of [[DNA replication]] and [[protein synthesis]] via control of amino acid uptake |
|||
* Modification of the activity of numerous [[enzymes]]. |
|||
The actions of insulin (indirect and direct) on cells include: |
|||
* '''Stimulates the uptake of glucose''' – Insulin decreases blood glucose concentration by inducing intake of glucose by the cells. This is possible because Insulin causes the insertion of the GLUT4 transporter in the cell membranes of muscle and fat tissues which allows glucose to enter the cell.<ref name="diabetesincontrol.com"/> |
|||
* '''Increased [[Fatty acid metabolism#Glycolytic endy products are used in the conversion of carbohydrates into fatty acids|fat synthesis]]''' – insulin forces fat cells to take in blood glucose, which is converted into [[triglyceride]]s; decrease of insulin causes the reverse.<ref name="pmid21864752" /> |
|||
* Increased [[esterification]] of fatty acids – forces adipose tissue to make neutral fats (i.e., [[triglycerides]]) from fatty acids; decrease of insulin causes the reverse.<ref name="pmid21864752" /> |
|||
* Decreased [[lipolysis]] – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse.<ref name="pmid21864752" /> |
|||
* Induce glycogen synthesis – When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphate group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html|title=Physiologic Effects of Insulin|website=www.vivo.colostate.edu|language=en|access-date=2017-06-01}}</ref> |
|||
* Decreased [[gluconeogenesis]] and [[glycogenolysis]] – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); increase of insulin causes glucose production by the liver from assorted substrates.<ref name="pmid21864752" /> |
|||
* Decreased [[proteolysis]] – decreasing the breakdown of protein<ref name="pmid21864752" /> |
|||
* Decreased [[Autophagy (cellular)|autophagy]] – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.<ref name="pmid17934054">{{cite journal | vauthors = Bergamini E, Cavallini G, Donati A, Gori Z | title = The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction | journal = Annals of the New York Academy of Sciences | volume = 1114 | issue = | pages = 69–78 | date = October 2007 | pmid = 17934054 | doi = 10.1196/annals.1396.020 | bibcode = 2007NYASA1114...69B }}</ref> |
|||
* Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption.<ref name="pmid21864752" /> |
|||
* Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; decrease of insulin reduces flow by allowing these muscles to contract.<ref name="Zheng">{{cite journal |last1=Zheng |first1=Chao |last2=Liu |first2=Zhenqi |title=Vascular function, insulin action, and exercise: an intricate interplay |journal=Trends in Endocrinology & Metabolism |date=June 2015 |volume=26 |issue=6 |pages=297–304 |doi=10.1016/j.tem.2015.02.002}}</ref> |
|||
* Increase in the secretion of hydrochloric acid by parietal cells in the stomach.{{Citation needed|date=March 2017}} |
|||
* Increased potassium uptake – forces cells synthesizing [[glycogen]] (a very spongy, "wet" substance, that [[Glycogen#Structure|increases the content of intracellular water, and its accompanying K<sup>+</sup> ions]])<ref name="pmid1615908">{{cite journal | vauthors = Kreitzman SN, Coxon AY, Szaz KF | 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 = 1 Suppl | pages = 292S–93S | date = July 1992 | pmid = 1615908 }}</ref> to absorb potassium from the extracellular fluids; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood plasma. This possibly occurs via insulin-induced translocation of the [[Na+/K+-ATPase]] to the surface of skeletal muscle cells.<ref>{{cite journal | vauthors = Benziane B, Chibalin AV | title = Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 3 | pages = E553–58 | date = September 2008 | pmid = 18430962 | doi = 10.1152/ajpendo.90261.2008 }}</ref><ref>{{cite journal | vauthors = Clausen T | title = Regulatory role of translocation of Na+-K+ pumps in skeletal muscle: hypothesis or reality? | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 3 | pages = E727–28; author reply 729 | date = September 2008 | pmid = 18775888 | doi = 10.1152/ajpendo.90494.2008 }}</ref> |
|||
* Decreased renal sodium excretion.<ref>{{cite journal | vauthors = Gupta AK, Clark RV, Kirchner KA | title = Effects of insulin on renal sodium excretion | journal = Hypertension | volume = 19 | issue = 1 Suppl | pages = I78–82 | date = January 1992 | pmid = 1730458 | doi = 10.1161/01.HYP.19.1_Suppl.I78 }}</ref> |
|||
Insulin also influences other body functions, such as [[compliance (physiology)#Blood vessels|vascular compliance]] and [[cognition]]. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular.<ref name="pmid15288712">{{cite journal | vauthors = Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W | title = Intranasal insulin improves memory in humans | journal = Psychoneuroendocrinology | volume = 29 | issue = 10 | pages = 1326–34 | date = November 2004 | pmid = 15288712 | doi = 10.1016/j.psyneuen.2004.04.003 }}</ref> Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the co-ordination of a wide variety of [[Homeostasis|homeostatic or regulatory processes]] in the human body.<ref name="pmid20876713">{{cite journal | vauthors = Benedict C, Brede S, Schiöth HB, Lehnert H, Schultes B, Born J, Hallschmid M | title = Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men | journal = Diabetes | volume = 60 | issue = 1 | pages = 114–18 | date = January 2011 | pmid = 20876713 | pmc = 3012162 | doi = 10.2337/db10-0329 | postscript = [Epub'd ahead of print] }}</ref> Insulin also has stimulatory effects on [[gonadotropin-releasing hormone]] from the [[hypothalamus]], thus favoring [[fertility]].<ref name="pmid24173881">{{cite journal | vauthors = Comninos AN, Jayasena CN, Dhillo WS | title = The relationship between gut and adipose hormones, and reproduction | journal = Human Reproduction Update | volume = 20 | issue = 2 | pages = 153–74 | year = 2014 | pmid = 24173881 | doi = 10.1093/humupd/dmt033 }}</ref> |
|||
=== Degradation === |
|||
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment, or it may be degraded by the cell. The two primary sites for insulin clearance are the liver and the kidney. 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).<ref name="pmid">{{cite journal | vauthors = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocrine Reviews | volume = 19 | issue = 5 | pages = 608–24 | date = October 1998 | pmid = 9793760 | doi = 10.1210/er.19.5.608 }}</ref><ref name="urlCarbohydrate and insulin metabolism in chronic kidney disease">{{cite web | url = http://www.uptodate.com/contents/carbohydrate-and-insulin-metabolism-in-chronic-kidney-disease | title = Carbohydrate and insulin metabolism in chronic kidney disease |vauthors=Palmer BF, Henrich WL | work = UpToDate, Inc }}</ref> |
|||
=== Regulator of endocannabinoid metabolism === |
|||
Insulin is a major regulator of [[Endocannabinoids|endocannabinoid]] (EC) [[metabolism]] and insulin treatment has been shown to reduce [[intracellular]] ECs, the [[2-Arachidonoylglycerol|2-arachidonylglycerol]] (2-AG) and [[anandamide]] (AEA), which correspond with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant [[adipocyte]]s, patterns of insulin-induced enzyme expression is disturbed in a manner consistent with elevated EC [[Biosynthesis|synthesis]] and reduced EC degradation. Findings suggest that [[Insulin resistance|insulin-resistant]] adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation, whereby [[Obesity|obese]] insulin-resistant individuals exhibit increased concentrations of ECs.<ref>{{cite journal | vauthors = D'Eon TM, Pierce KA, Roix JJ, Tyler A, Chen H, Teixeira SR | title = The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids |language=en | journal = Diabetes | volume = 57 | issue = 5 | pages = 1262–68 | date = May 2008 | pmid = 18276766 | doi = 10.2337/db07-1186 | url = http://diabetes.diabetesjournals.org/content/57/5/1262 }}</ref><ref name="pmid26374449">{{cite journal | vauthors = Gatta-Cherifi B, Cota D | title = New insights on the role of the endocannabinoid system in the regulation of energy balance | journal = International Journal of Obesity | volume = 40 | issue = 2 | pages = 210–19 | date = February 2016 | pmid = 26374449 | doi = 10.1038/ijo.2015.179 }}</ref> This dysregulation contributes to excessive [[Adipose tissue|visceral fat]] accumulation and reduced [[adiponectin]] release from abdominal adipose tissue, and further to the onset of several cardiometabolic risk factors that are associated with obesity and [[Diabetes mellitus type 2|type 2 diabetes]].<ref>{{cite journal | vauthors = Di Marzo V | title = The endocannabinoid system in obesity and type 2 diabetes | journal = Diabetologia | volume = 51 | issue = 8 | pages = 1356–67 | date = August 2008 | pmid = 18563385 | doi = 10.1007/s00125-008-1048-2 }}</ref> |
|||
== Hypoglycemia == |
|||
{{Main|Hypoglycemia}} |
|||
[[Hypoglycemia]], also known as "low blood sugar", is when [[blood sugar]] decreases to below normal levels.<ref name=NIH2008/> This may result in a variety of [[symptoms]] including clumsiness, trouble talking, confusion, [[loss of consciousness]], [[seizures]] or death.<ref name=NIH2008/> A feeling of hunger, sweating, shakiness and weakness may also be present.<ref name=NIH2008/> Symptoms typically come on quickly.<ref name=NIH2008>{{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|accessdate=28 June 2015|date=October 2008|deadurl=no|archiveurl=https://web.archive.org/web/20150701034430/http://www.niddk.nih.gov/health-information/health-topics/Diabetes/hypoglycemia/Pages/index.aspx|archivedate=1 July 2015|df=dmy-all}}</ref> |
|||
The most common cause of hypoglycemia is [[Anti-diabetic medication|medications]] used to treat [[diabetes mellitus]] such as insulin and [[sulfonylurea]]s.<ref>{{cite journal|last1=Yanai|first1=H|last2=Adachi|first2=H|last3=Katsuyama|first3=H|last4=Moriyama|first4=S|last5=Hamasaki|first5=H|last6=Sako|first6=A|title=Causative anti-diabetic drugs and the underlying clinical factors for hypoglycemia in patients with diabetes.|journal=World Journal of Diabetes|date=15 February 2015|volume=6|issue=1|pages=30–6|pmid=25685276|doi=10.4239/wjd.v6.i1.30|pmc=4317315}}</ref><ref name=Sch2007>{{cite book|last1=Schrier|first1=Robert W.|title=The internal medicine casebook real patients, real answers|date=2007|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=9780781765299|page=119|edition=3rd|url=https://books.google.ca/books?id=zbuKcQwh2b0C&pg=PA119|deadurl=no|archiveurl=https://web.archive.org/web/20150701020033/https://books.google.ca/books?id=zbuKcQwh2b0C&pg=PA119|archivedate=1 July 2015|df=dmy-all}}</ref> Risk is greater in diabetics who have eaten less than usual, exercised more than usual or have drunk [[ethanol|alcohol]].<ref name=NIH2008/> 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.<ref name=NIH2008/><ref name=Sch2007/> Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.<ref name=Perk2008>{{cite book|last1=Perkin|first1=Ronald M.|title=Pediatric hospital medicine : textbook of inpatient management|date=2008|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=9780781770323|page=105|edition=2nd|url=https://books.google.ca/books?id=sV6-ifUGoMYC&pg=PA105|deadurl=no|archiveurl=https://web.archive.org/web/20150701020159/https://books.google.ca/books?id=sV6-ifUGoMYC&pg=PA105|archivedate=1 July 2015|df=dmy-all}}</ref> |
|||
== Diseases and syndromes == |
|||
{{unreferenced section|date=July 2018}} |
|||
There are several conditions in which insulin disturbance is pathologic: |
|||
* [[Diabetes mellitus]] – general term referring to all states characterized by hyperglycemia |
|||
** [[Diabetes mellitus type 1|Type 1]] – autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency |
|||
** [[Diabetes mellitus type 2|Type 2]] – either inadequate insulin production by the β-cells or [[insulin resistance]] or both because of reasons not completely understood. |
|||
*** 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. |
|||
*** it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions |
|||
** Other types of impaired glucose tolerance (see the [[Diabetes]]) |
|||
* [[Insulinoma]] – a tumor of beta cells producing excess insulin or [[reactive hypoglycemia]]. |
|||
* [[Metabolic syndrome]] – a poorly understood condition first called Syndrome X by [[Gerald Reaven]]. It is currently 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 [[Insulin#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. |
|||
* [[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. |
|||
== Medical uses == |
|||
{{Main|Insulin (medication)}} |
|||
[[File:Inzulín.jpg|thumb|right|A vial of insulin. It has been given a trade name, Actrapid, by the manufacturer.]] |
|||
Biosynthetic [[human insulin]] (insulin human rDNA, INN) for clinical use is manufactured by [[Recombinant DNA#Synthetic insulin production using recombinant DNA|recombinant DNA]] technology.<ref name=recombination /> 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]].<ref>{{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 | dead-url = yes}}</ref> This technique is anticipated to reduce production costs. |
|||
Several analogs of human insulin are available. These insulin analogs 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).<ref>[[Insulin analog]]</ref> The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), [[Humalog]] (insulin lispro),{{citation needed|reason=Humulin first introduced in 1982 per humulin.com, I don't have any peer-reviewed lit though|date=April 2015}} 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. 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. |
|||
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 now. |
|||
Synthetic insulin can trigger adverse effects, so some people with diabetes rely on animal-source insulin.<ref>[http://www.iddt.org/diabetic-commonsense/the-great-debate-natural-animal-or-artificial-human-insulin The Great Debate: Natural Animal or Artificial ‘Human’ Insulin? - IDDT<!-- Bot generated title -->]</ref> |
|||
Unlike many medicines, insulin currently cannot be taken orally 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.<ref name="pmid27364922">{{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 }}</ref><ref name="pmid27014614">{{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 }}</ref> |
|||
== History of study == |
|||
=== Discovery === |
|||
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.<ref>{{cite journal|last=Sakula|first=A|title=Paul Langerhans (1847–1888): a centenary tribute|journal=Journal of the Royal Society of Medicine|date=July 1988|volume=81|pmc=1291675|pmid=3045317|issue=7|pages=414–15}}</ref> 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.<ref>{{Cite web |url=http://musee.chru-lille.fr/Memoire/Medecins/48029.html |title=Edouard Laguesse (1861–1927) |last=Petit |first=Henri |language=fr |website=Museum of the Regional Hospital of Lille |access-date=2018-07-25 |df=dmy-all}}</ref> Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term "insulin" originates from ''insula'', the Latin word for islet/island. |
|||
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".<ref name="Johns Hopkins Hosp. Bull. p.264)">{{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 }}</ref><ref name="J. Exp. Med. 5(4)">{{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 }}</ref><ref name="J. Exp. Med. 5(5)">{{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 }}</ref> |
|||
[[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.]] |
|||
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, 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.<ref name="J. Nutrition 92">{{cite journal | url = http://jn.nutrition.org/cgi/reprint/92/4/507.pdf | 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 | year = 1967 | page = 509 | format = PDF }}</ref> |
|||
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|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".<ref name="nrjs">{{Cite journal | author = Paulesco NC | journal = Archives Internationales de Physiologie | title= Recherche sur le rôle du pancréas dans l'assimilation nutritive|volume= 17|issue=|pages= 85–103| date=August 31, 1921 }} |
|||
</ref><ref name="nrps"> |
|||
{{Cite journal | author = 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 }} |
|||
</ref> |
|||
=== Extraction and purification === |
|||
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 certain arteries could be tied off that 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 the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosuria."<ref name="rosenfeld2002">{{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 | url = http://clinchem.aaccjnls.org/content/48/12/2270 }}</ref> |
|||
In the spring of 1921, Banting traveled to [[Toronto]] to explain his idea to [[John James Rickard Macleod|J.J.R. 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 Herbert Best|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.<ref name="pmid12473641">{{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 }}</ref> On 30 July 1921, Banting and Best successfully isolated an extract ("isleton") 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.<ref name="Krishnamurthy2002">{{cite book | vauthors = Krishnamurthy K | title = Pioneers in scientific discoveries | url = https://books.google.com/books?id=dAXYzzDL_9oC&pg=PA266 | accessdate = 26 July 2011 | year = 2002 | publisher = Mittal Publications | isbn = 978-81-7099-844-0 | page=266 }}</ref><ref name="rosenfeld2002"/> |
|||
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.<ref name="rosenfeld2002"/> |
|||
On January 11, 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.<ref name="pmid8409364">{{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 }}</ref> However, the extract was so impure that Thompson suffered 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 January 23, completely 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]].<ref name=miracle>{{cite news |author = Zuger A | title = Rediscovering the First Miracle Drug | url = https://www.nytimes.com/2010/10/05/health/05insulin.html?_r=1&hp=&pagewanted=all | quote = Elizabeth Hughes was a cheerful, pretty little girl, five feet tall, with straight brown hair and a consuming interest in birds. On Dr. 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=October 4, 2010 |accessdate=2010-10-06 }}</ref> The first patient treated in the U.S. was future woodcut artist [[James D. Havens]]; Dr. [[John Ralston Williams]] imported insulin from Toronto to [[Rochester, New York]], to treat Havens.<ref name="Marcotte">{{cite news|author=Marcotte B |title=Rochester's John Williams a man of scientific talents |url=http://www.democratandchronicle.com/apps/pbcs.dll/article?AID=201011220301 |accessdate=November 22, 2010 |newspaper=[[Democrat and Chronicle]] |date=November 22, 2010 |agency=[[Gannett Company]] |archiveurl=https://www.webcitation.org/5uRSurOlI?url=http://www.democratandchronicle.com/apps/pbcs.dll/article?AID=201011220301 |archivedate=November 23, 2010 |location=[[Rochester, New York]] |pages=1B, 4B |deadurl=yes |df= }}</ref> |
|||
Banting and Best never worked well with Collip, regarding him as something of an interloper, 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. |
|||
=== Synthesis === |
|||
Purified animal-sourced insulin was initially the only type of insulin available to diabetics. The amino acid structure of insulin was characterized in the early 1950s by [[Frederick Sanger#Sequencing insulin|Frederick Sanger]],<ref name="Stretton_2002"/> 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 early 1960s.<ref>{{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 = 47–49 | date = January 2004 | pmid = 14992380 | doi = 10.1080/15216540310001659029 | publisher = Time Inc. }}</ref><ref name="isbn1-4020-0655-1">{{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 | pages = | isbn = 1-4020-0655-1 | url = https://books.google.com/?id=Ula72_FSwy8C&lpg=PP11&dq=Panayotis%20Katsoyannis&pg=PP11#v=onepage&q=Panayotis%20Katsoyannis }}</ref> [[Synthetic crystalline bovine insulin]] was achieved by Chinese researchers in 1965.<ref name=Zou2015>{{cite journal|last1=Tsou |first1=Chen-lu |authorlink1=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}}</ref> |
|||
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]].<ref name="urlGenentech" /><ref name="urlRecombinant DNA technology in the synthesis of human insulin" /> 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]].<ref name="urlRecombinant DNA technology in the synthesis of human insulin"/> The vast majority of insulin currently used worldwide is now biosynthetic recombinant "human" insulin or its analogues.<ref name="pmid23222785" /> |
|||
Recombinant insulin is produced either in yeast (usually ''[[baker's yeast|Saccharomyces cerevisiae]]'') or ''E. coli''.<ref name="pmid11030562">{{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 }}</ref> 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. |
|||
=== Nobel Prizes === |
|||
[[File:C. H. Best and F. G. Banting ca. 1924.png|thumb|[[Frederick Banting]] (right) joined by [[Charles Herbert Best|Charles Best]] 1924]] |
|||
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 James Rickard Macleod|J.J.R. Macleod]].<ref name="urlThe Nobel Prize in Physiology or Medicine 1923">{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1923/ | title = The Nobel Prize in Physiology or Medicine 1923 | publisher = The Nobel Foundation }}</ref> They were awarded the [[Nobel Prize in Physiology or Medicine]] in 1923 for the discovery of insulin. Banting, insisted that Best was not mentioned, 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. |
|||
Two other Nobel Prizes have been awarded for work on insulin. British molecular biologist [[Frederick Sanger]] determined the [[primary structure]] of insulin in 1955, making it the first protein to be sequenced.<ref name="Stretton_2002">{{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 | pmid = 12399368 | pmc = 1462286 }}</ref> Sanger was awarded the 1958 [[Nobel Prize in Chemistry]] for this work. [[Rosalyn Sussman Yalow]] received the 1977 Nobel Prize in Medicine for the development of the [[radioimmunoassay]] for insulin. |
|||
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 mellitus]]. Dr. [[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]].<ref>{{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 | authorlink = William Bosworth Castle }}</ref> [[Dorothy Hodgkin]] was awarded a Nobel Prize in Chemistry in 1964 for the development of [[crystallography]]. In 1969, after decades of work, Hodgkin determined the spatial conformation of insulin, the so-called [[tertiary structure]], by means of [[X-ray diffraction]] studies. |
|||
==== Controversy ==== |
|||
[[Image:Nicolae Paulescu - Foto03.jpg|thumb|100px|[[Nicolae Paulescu]]]] |
|||
The work published by Banting, Best, Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients.<ref name="pmid20314060">{{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 | doi = }}</ref> 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. Professor 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: |
|||
<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.<ref name="pmid4560502">{{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 | doi = }}</ref> |
|||
</blockquote> |
|||
In a private communication, Professor [[Arne Tiselius]], former head of the Nobel Institute, expressed his personal opinion that Paulescu was equally worthy of the award in 1923.<ref name="pmid4930788">{{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 }}</ref> |
|||
== See also == |
|||
{{div col|colwidth=30em}} |
|||
* [[Insulin analog]] |
|||
* Anatomy and physiolology |
|||
** [[Pancreas]] |
|||
** [[Islets of Langerhans]] |
|||
** [[Endocrinology]] |
|||
** [[Leptin#Adiposity signal|Leptin]] |
|||
* Forms of diabetes mellitus |
|||
** [[Diabetes mellitus]] |
|||
** [[Diabetes mellitus type 1]] |
|||
** [[Diabetes mellitus type 2]] |
|||
* Treatment |
|||
** [[Diabetic coma]] |
|||
** [[Insulin therapy]] |
|||
** [[Intensive insulinotherapy]] |
|||
** [[Insulin pump]] |
|||
** [[Conventional insulinotherapy]] |
|||
* Other medical / diagnostic uses |
|||
** [[Insulin tolerance test]] |
|||
** [[Triple bolus test]] |
|||
* Insulin Signal Transduction pathway |
|||
** [[Insulin signal transduction pathway and regulation of blood glucose]] |
|||
* Other uses |
|||
**[[Conus geographus#Insulin|Cone Snail venom]] |
|||
{{Div col end}} |
|||
== References == |
|||
{{reflist|32em}} |
|||
== Further reading == |
|||
{{refbegin|32em}} |
|||
* {{cite book | last1 = Laws | first1 = Gerald M. | last2 = Reaven | first2 = Ami | name-list-format = vanc | title = Insulin resistance : the metabolic syndrome X | date = 1999 | publisher = Humana Press | location = Totowa, NJ | isbn = 0-89603-588-3 | doi = 10.1226/0896035883 }} |
|||
* {{cite book | last1 = Leahy | first1 = Jack L. | first2 = William T. | last2 = Cefalu | name-list-format = vanc | title = Insulin Therapy |edition=1st | date = 2002-03-22 |publisher=Marcel Dekker |location=New York |isbn=0-8247-0711-7 }} |
|||
* {{cite book |last1 = Kumar | first1 = Sudhesh | first2 = Stephen | last2 = O'Rahilly | name-list-format = vanc | title = Insulin Resistance: Insulin Action and Its Disturbances in Disease | date = 2005-01-14 |publisher=Wiley |location=Chichester, England |isbn=0-470-85008-6 }} |
|||
* {{cite book |last1 = Ehrlich | first1 = Ann | first2 = Carol L. | last2 = Schroeder | name-list-format = vanc | title = Medical Terminology for Health Professions |edition=4th |date=2000-06-16 |publisher=Thomson Delmar Learning |location= |isbn=0-7668-1297-9 }} |
|||
* {{cite book | last1 = Draznin | first1 = Boris | last2 = LeRoith | first2 = Derek | name-list-format = vanc | author-link1 = Derek LeRoith | title=Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion |origyear= |url= |accessdate= |edition= |date= September 1994 |publisher=Humana Press |location=Totowa, New Jersey |isbn=0-89603-286-8 |doi=10.1226/0896032868 }} |
|||
* [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 |
|||
* {{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 }} |
|||
{{refend}} |
|||
== External links == |
|||
{{commons category|Insulin}} |
|||
{{div col|colwidth=32em}} |
|||
* [https://web.archive.org/web/20120502032744/http://nist.rcsb.org/pdb/101/motm.do?momID=14 Insulin: entry from protein databank] |
|||
* [http://www.med.uni-giessen.de/itr/history/inshist.html The History of Insulin] |
|||
* [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] |
|||
* [http://link.library.utoronto.ca/insulin/ Discovery and Early Development of Insulin, 1920–1925] |
|||
* [http://www.medbio.info/Horn/Time%203-4/secretion_of_insulin_and_glucagon_nov_2007.htm Secretion of Insulin and Glucagon] |
|||
* [http://www.genome.jp/kegg-bin/show_pathway?hsa04910+3630 Insulin signaling pathway] |
|||
* [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 |
|||
* [http://www.apollosugar.com/blogpost/types-of-insulin-for-diabetes-treatment/ Types of Insulin for Diabetes Treatment] at ApolloSugar.com |
|||
{{Div col end}} |
|||
{{PDB Gallery|geneid=3630}} |
|||
{{Hormones}} |
|||
{{Signaling peptide/protein receptor modulators}} |
|||
{{Growth factor receptor modulators}} |
|||
{{Authority control}} |
|||
[[Category:Animal products]] |
|||
[[Category:Eli Lilly and Company]] |
|||
[[Category:Genes on human chromosome 11]] |
|||
[[Category:Hormones of glucose metabolism]] |
|||
[[Category:Human hormones]] |
|||
[[Category:Insulin receptor agonists]] |
|||
[[Category:Insulin therapies]] |
|||
[[Category:Insulin-like growth factor receptor agonists]] |
|||
[[Category:Pancreatic hormones]] |
|||
[[Category:Peptide hormones]] |
|||
[[Category:Recombinant proteins]] |
|||
[[Category:Tumor markers]] |
|||
[[Category:World Anti-Doping Agency prohibited substances]] |
|||
Revision as of 16:18, 15 January 2019
| insulin | |||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | human insulin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | GeneCards: [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
INSULIN IS GAY