Insulin 14895 225506345 2008-07-14T01:31:11Z Jumbuck 116385 robot Modifying: [[ar:أنسولين]] {{confuse|inulin}} {{Protbox |Name=Insulin |Photo=Insulincrystals.jpg |Caption=Insulin crystals |Gene = HUGO/[http://www.genenames.org/data/hgnc_data.php?hgnc_id=6081 INS] |Gene_type=[[Protein]] codingp |Structure =[http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?form=6&db=t&Dopt=s&uid=34502 Solution Structure of Human pro-Insulin Polypeptide] |Review = |Type=insulin family |Functions=[[glucose]] regulation |Domains=[[INS domain]] |Motifs=[[SP motif]] |Molecular_weight= 5808 |Alternative_products= |Catalytic_activity= |Cofactors= |Enzyme_regulation= |Diseases=[[familial hyperproinsulinemia]], [[Diabetes mellitus]] |Pharmaceuticals= insulin ([[Humulin]] [[Novolin]]), insulin analogues: insulin lispro ([[Humalog]]), insulin aspart ([[NovoLog]]), insulin detemir ([[Levemir]]), insulin glargine ([[Lantus]]), etc |Taxa = ''[[Homo sapiens]]''; homologs: in [[metazoan]] [[taxa]] from invertebrates to mammals |Cells = [[pancreas]]: beta cells of the [[Islet of Langerhans|Islets of Langerhans]] |Location=[[extracellular]] fluids |Mods=[[glycation]], [[proteolytic cleavage]] |Pathways=[[Insulin signaling pathway]] ([http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04910+3630 KEGG]); [[Type II diabetes mellitus]] ([http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04930+3630 KEGG]); [[Type I diabetes mellitus]] ([http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04940+3630 KEGG]); [[Maturity onset diabetes of the young]] ([http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04950+3630 KEGG]); Regulation of [[actin]] [[cytoskeleton]] ([http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04810+3630 KEGG]) |Interactions= |Pages= |Actions= |Agonists= |Antagonists= [[glucagon]], [[steroid]]s, most stress hormomes |Codes={{EntrezGene|3630}}; {{OMIM|176730}}; {{UniProt|P01308}}; {{RefSeq|NM_000207}} | Chromosome = 11 | Arm = p | Band = 15.5 | LocusSupplementaryData = }} [[Image:Suckale08 fig3 glucose insulin day.jpg|thumbnail|300px|The idealised 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.]] '''Insulin''' is a [[hormone]] with intensive effects on both metabolism and several other body systems (eg, vascular compliance). When present, it causes most of the body's cells to take up [[glucose]] from the [[blood]] (including [[liver]], [[muscle]], and [[fat cell|fat tissue cells]]), storing it as [[glycogen]] in the liver and muscle, and stops use of fat as an energy source. When insulin is absent (or low), glucose is not taken up by most body cells and the body begins to use fat as an energy source (ie, transfer of lipids from adipose tissue to the liver for mobilization as an energy source). As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as [[amino acid]] uptake by body cells). It has several other [[anabolism|anabolic]] effects throughout the body. When control of insulin levels fail, [[diabetes mellitus]] results. Insulin is used medically to treat some forms of [[diabetes mellitus]]. Patients with [[Diabetes mellitus type 1|Type 1 diabetes mellitus]] depend on external insulin (most commonly [[Injection (medicine)#Subcutaneous injection|injected subcutaneously]]) for their survival because the hormone is no longer produced internally. Patients with [[Diabetes mellitus type 2|Type 2 diabetes mellitus]] are [[insulin resistance|insulin resistant]], have relatively low insulin production, or both; some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately. Insulin is a [[peptide hormone]] composed of 51 [[amino acid|amino acid residues]] and has a [[molecular weight]] of 5808 [[Dalton (unit)|Da]]. It is produced in the [[Islets of Langerhans]] in the [[pancreas]]. The name comes from the [[Latin]] ''insula'' for "island". Insulin's structure varies slightly between [[species]] of animal. Insulin from animal sources differs somewhat in 'strength' (i.e., in [[carbohydrate metabolism]] control effects) in humans because of those variations. Porcine ([[pig]]) insulin is especially close to the [[human]] version. == Structure == Within vertebrates, the similarity of insulins is extremely close. [[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 (eg, the ''c elegans'' nematode) is quite close to human insulin, has similar effects inside cells, and is produced very similarly. Insulin has been strongly preserved over evolutionary time, suggesting its centrality in animal metabolic control. The C-peptide of proinsulin (discussed later), however, differs much more amongst species; it is also a hormone, but a secondary one. == Mechanism == Insulin is produced in the [[pancreas]], and released when any of several stimuli are detected. These include protein ingestion, and glucose in the blood (from food which produces glucose when digested -- characteristically this is [[carbohydrate]], though not all types produce glucose and so an increase in blood glucose levels). In target cells, they initiate a [[signal transduction]] which has the effect of increasing [[glucose]] uptake and storage. Finally, insulin is degraded, terminating the response. === Production === [[Image:Insulinpath.png|right|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 cell]]s (β-cells) of the [[islets of Langerhans]]. One million to three million islets of Langerhans (pancreatic islets) form the [[endocrine]] part of the pancreas, which is primarily an [[exocrine]] [[gland]]. The endocrine portion only accounts for 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells. In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes, known as prohormone convertases (PC1 and PC2), as well as the exoprotease [[carboxypeptidase|carboxypeptidase E]]. These modifications of proinsulin remove the center portion of the molecule (ie, [[C-peptide]]), from the C- and N- terminal ends of proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by [[disulfide bond]]s/disulphide bonds. Confusingly, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others. ==== Regulation of production ==== {{See|Insulin gene}} 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 === Release === {{Seealso|Blood glucose regulation}} Beta cells in the islets of Langerhans release insulin mostly in response to increased [[blood glucose]] levels through the following mechanism (see figure to the right): * Glucose enters the [[beta cell]]s through the [[glucose transporter]] [[GLUT2]] * Glucose goes into the [[glycolysis]] and the respiratory cycle where multiple high-energy [[adenosine triphosphate|ATP]] molecules are produced by oxidation * Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled [[potassium channels]] (K<sup>+</sup>) close and the cell membrane depolarizes * On [[depolarization]], voltage controlled [[calcium channels]] (Ca<sup>2+</sup>) open and calcium flows into the cells * An increased calcium level causes activation of [[phospholipase|phospholipase C]], which cleaves the membrane phospholipid [[phosphatidyl inositol 4,5-bisphosphate]] into [[inositol 1,4,5-triphosphate]] and [[diglyceride|diacylglycerol]]. * Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of [[endoplasmic reticulum]] (ER). This allows the release of Ca<sup>2+</sup> from the ER via IP3 gated channels, and further raises the cell concentration of calcium. * Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in [[secretion|secretory]] [[vesicle (biology)|vesicles]] <!-- NOT CORRECT ABOUT CREB * The calcium level also regulates [[gene expression|expression]] of the insulin [[gene]] via the !calcium! responsive element binding protein ([[CREB]]). --> This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or [[carbohydrate]] intake, and the beta cells are also somewhat influenced by the [[autonomic nervous system]]. The signalling mechanisms controlling these linkages are not fully understood. Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings ([[parasympathetic nervous system]]), [[cholecystokinin]][''citation needed''], released by [[enteroendocrine cell]]s of [[Intestinal mucosa#Your digestive system and how it works|intestinal mucosa]] and [[glucose-dependent insulinotropic peptide]] (GIP). Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of [[adenylate cyclase]]. The [[sympathetic nervous system]] (via Alpha2-adrenergic stimulation as demonstrated by the agonists [[clonidine]] or [[methyldopa]]) inhibit the release of insulin. However, it is worth noting that circulating [[adrenaline]] will activate Beta<sub>2</sub>-Receptors on the Beta cells in the pancreatic Islets to promote insulin release. This is important since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin is present to allow for [[GLUT-4]] translocation in the tissue. Therefore, beginning with direct innervation, [[norepinephrine]] inhibits insulin release via alpha<sub>2</sub>-receptors, then subsequently, circulating adrenaline from the [[adrenal medulla]] will stimulate beta<sub>2</sub>-receptors thereby promoting insulin release. When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop 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 cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the [[stress hormone]] [[norepinephrine]] (noradrenaline), which leads to increased blood glucose levels during stress. ==== Oscillations ==== {{Main|Insulin release oscillations}} [[Image:Pancreas insulin oscillations.svg|thumb|right|250px|Insulin release from pancreas oscillates with a period of 3&ndash;6 minutes.<ref name="hellman" />]] Even during digestion, generally one or two hours following a meal, insulin release from pancreas is not continuous, but [[oscillates]] with a period of 3&ndash;6 minutes, changing from generating a blood insulin concentration more than ~800 [[pico-|p]][[unit mole|mol]]/l to less than 100 pmol/l.<ref name="hellman"> {{cite journal |author=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=Lakartidningen |volume=104 |issue=32-33 |pages=2236–9 |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 delivering insulin rhythmically to the [[portal vein]] or by [[islet cell transplantation]] to the liver.<ref name="hellman" /> Future insulin pumps may include this characteristic. (See also [[Pulsatile Insulin]].) === Signal transduction === There are special transporter proteins in [[cell membrane]]s through which [[glucose]] from the blood can enter a cell. These transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e.g., in Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e.g., the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is, characteristically, the same: elevated blood glucose levels. Activation of [[insulin receptor]]s leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified and the structure of the interior, cell membrane section, and now, finally after more than a decade, the extra-membrane structure of receptor (Australian researchers announced the work 2Q 2006). Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells ([[myocyte]]s) and fat cells ([[adipocyte]]s). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess [[food energy]] against future needs. Together, they account for about two-thirds of all cells in a typical human body. === Effects === [[Image:Insulin glucose metabolism.jpg|right|thumbnail|400px|'''Effect of insulin on glucose uptake and metabolism.''' Insulin binds to its receptor (1) which in turn 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 [[fatty acid]] synthesis (6).]] The actions of insulin on the global human metabolism level include: * Control of cellular intake of certain substances, most prominently [[glucose]] in muscle and [[adipose]] tissue (about ⅔ of body cells). * Increase of [[DNA replication]] and [[protein synthesis]] via control of amino acid uptake. * Modification of the activity of numerous [[enzymes]]. The actions of insulin on cells include: * Increased [[glycogen]] synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes. * Increased [[fatty acid]] synthesis – insulin forces fat cells to take in blood lipids which are converted to [[triglycerides]]; lack of insulin causes the reverse. * Increased [[esterification]] of fatty acids – forces [[adipose tissue]] to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse. * Decreased [[proteolysis]] – decreasing the breakdown of protein. * Decreased [[lipolysis]] – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse. * Decreased [[gluconeogenesis]] – decreases production of glucose from non-sugar substrates, primarily in the liver (remember, the vast majority of endogenous insulin arriving at the liver never leaves the liver) ; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere. * Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption. * Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood. * Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract. === 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. Degradation normally involves [[endocytosis]] of the insulin-receptor complex followed by the action of [[insulin degrading enzyme]]. Most insulin molecules are degraded by [[liver]] cells. It has been estimated that a typical insulin molecule that is produced endogenously by the pancreatic beta cells is finally degraded about 71 minutes after its initial release into circulation.<ref>{{cite journal |author=William C. Duckworth, Robert G. Bennett and Frederick G. Hamel |year=1998 |url=http://edrv.endojournals.org/cgi/content/full/19/5/608#F1 |title=Insulin Degradation: Progress and Potential |journal=Endocrine Reviews |volume=19 |issue=5 |pages=608–624 |doi=10.1210/er.19.5.608 |pmid=9793760}}</ref> == Hypoglycemia == {{Main|Hypoglycemia}} Although other cells can use other fuels for a while (most prominently fatty acids), [[neurons]] depend on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. [[Glycogen]] stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the [[glycerol]] backbone in [[triglycerides]] can also be used to produce blood glucose. Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the [[central nervous system]]; dizziness, speech problems, and even loss of consciousness, can occur. Low glucose is known as [[hypoglycemia]] or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an [[insulinoma]]) are very rare, and the overwhelming majority of insulin-excess induced hypoglycemia cases are [[Iatrogenesis|iatrogenic]] and usually accidental. There have been a few reported cases of murder, attempted murder, or suicide using insulin overdoses, but most insulin shocks appear to be due to errors in dosage of insulin (e.g., 20 units of insulin instead of 2) or other unanticipated factors (didn't eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself). Possible causes of hypoglycemia include: * External insulin (usually injected subcutaneously). * Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin release from beta cells in response to a particular blood glucose level). * Ingestion of low-carbohydrate sugar substitutes (animal studies show these can trigger insulin release (albeit in much smaller quantities than sugar) according to a report in ''Discover'' magazine, August 2004, p18). Note that this can ''never'' be a cause of hypoglycemia in [[type 1 diabetes mellitus]], as endogenous insulin production no longer exists. == Diseases and syndromes == 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 beta cells in the pancreas resulting in absolute insulin deficiency. ** [[Diabetes mellitus#Type 2|Type 2]] – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being [[obesity]], age, and physical inactivity, resulting in [[insulin resistance]] in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited. ** Other types of impaired glucose tolerance (see the [[diabetes]] article). * [[Insulinoma]] - a tumor of pancreatic beta cells producing excess of insulin or [[reactive hypoglycemia]]. * [[Metabolic syndrome]] – a poorly understood condition first called [[Syndrome X]] by [[Gerald Reaven]], [[Reaven's Syndrome]] after Reaven, CHAOS in Australia (from the signs which seem to travel together), and sometimes [[prediabetes]]. It is currently not clear whether these signs have a single, treatable cause, or are 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 of type 2 diabetes which is a diminished capacity for insulin response in some tissues (e.g., muscle, fat) to respond to insulin. Commonly, morbidities such as essential [[hypertension]], [[obesity]], Type 2 diabetes, and [[cardiovascular disease]] (CVD) develop. * [[Polycystic ovary syndrome]] – a complex syndrome in women in the reproductive years where there is [[anovulation]] and [[androgen]] excess commonly displayed as [[hirsutism]]. In many cases of PCOS [[insulin resistance]] is present. == As a medication == === Principles === Insulin is required for all animal life (excluding certain insects). Its mechanism of action is almost identical in nematode worms (e.g. ''[[Caenorhabitis elegans|C. elegans]]''), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called [[diabetes mellitus#Type 1|diabetes mellitus type 1]]. The initial sources of insulin for clinical use in humans were [[cow]], [[horse]], [[pig]] or [[fish]] pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef, pork, or fish derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to [[high-pressure liquid chromatography]] (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic "human" insulin varieties. Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore. Synthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using [[Recombinant_DNA#Synthetic_insulin_production_using_DNA|recombinant DNA]] technology, which the manufacturers claim reduces the presence of many impurities. [[Eli Lilly and Company|Eli Lilly]] marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (''E. coli'' in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of [[C-peptide]] which has in recent years been shown to have systemic effects itself. [[Genentech]] developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves. [[Novo Nordisk]] has also developed a genetically engineered insulin independently. According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin.<ref>[http://www.eatlas.idf.org/ e-atlas/ IDF (2004). Diabetes Atlas,: 2nd ed. International Diabetes Federation, Brussels.]</ref> A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Also, the International Diabetes Federation's position statement is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and "[modern, highly-purified] animal insulins remain a perfectly acceptable alternative."<ref>[http://www.idf.org/home/index.cfm?node=1385 IDF March 2005; "Position Statement." International Diabetes Federation, Brussels.]</ref> Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogs. A special [http://www.fda.gov/cder/drug/beefandporkinsulin/default.htm FDA importation process] is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier. There are several problems with insulin as a clinical treatment for diabetes: * Mode of administration. * Selecting the 'right' dose and timing. * Selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds). * Adjusting dosage and timing to fit food intake timing, amounts, and types. * Adjusting dosage and timing to fit exercise undertaken. * Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness. * Variability in absorption into the bloodstream via subcutaneous delivery * The dosage is non-physiological in that a subcutaneous [[Bolus (medicine)|bolus]] dose of insulin alone is administered instead of combination of insulin and [[C-peptide]] being released gradually and directly into the [[portal vein]]. * It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading. * It is dangerous in case of mistake (most especially 'too much' insulin). === Types === Medical preparations of insulin (from the major suppliers – [[Eli Lilly and Company|Eli Lilly]], [[Novo Nordisk]], and [[Sanofi Aventis]] – or from any other) are never just 'insulin in water'. Clinical insulins are specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on. Slight variations of the human insulin molecule are called [[insulin analog]]s, so named because they are not technically insulin, rather they are analogs which retain the hormone's glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with Lilly's ''lispro'', [[Novo Nordisk]]'s ''aspart'' and Sanofi Aventis' ''glulisine''), or steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (as with Novo Nordisk's version ''Insulin detemir'' and [[Sanofi Aventis]]'s ''Insulin glargine''), all while retaining insulin's glucose-lowering action in the human body. However, a number of [[meta-analysis|meta-analyses]], including those done by the [[Cochrane Collaboration]] in the United Kingdom in 2002,<ref>[http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003816/frame.html Richter B, Neises G. 'Human' insulin versus animal insulin in people with diabetes mellitus. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD003816. DOI: 10.1002/14651858.CD003816.pub2.]</ref> Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007,<ref>[http://www.iqwig.de/index.449.en.html Rapid-acting insulin analogues in the treatment of diabetes mellitus type 1: Superiority Not Proven]</ref> and the Canadian Agency for Drugs and Technology in Health (CADTH)<ref>[http://www.cadth.ca/index.php/en/compus/compus-communique/compus-communiqu-vol-3-no-12 CADTH: COMPUS Communiqué – Vol. 3, No. 12<!-- Bot generated title -->]</ref>, also released in 2007 have proven unequivocally that any claims of superiority for insulin analogs over regular insulin are unsupported by clinical evidence. Choosing insulin type and dosage/timing should be done by an experienced medical professional working with the diabetic patient. The commonly used types of insulin are: * Rapid-acting, are presently insulin analogs, such as the insulin analog ''aspart'' or ''lispro'' – begins to work within 5 to 15 minutes and is active for 3 to 4 hours. Newer varieties are in now in Phase II clinical trials which are designed to work rapidly, but retain the same genetic structure as regular human insulin.<ref>[http://files.shareholder.com/downloads/BIOD/233482394x0x114455/4751e305-1623-4dd5-9364-57fdbd4b6ef1/BIOD_News_2007_6_22_General_Releases.pdf Biodel Inc. Announces VIAject(TM) Data at Oral Presentation at the American Diabetes Association Meeting]</ref> * Short-acting, such as ''regular'' insulin – starts working within 30 minutes and is active about 5 to 8 hours. * Intermediate-acting, such as ''[[NPH insulin|NPH]]'', or ''lente'' insulin – starts working in 1 to 3 hours and is active 16 to 24 hours. * Long-acting, such as ''ultralente'' insulin – starts working in 4 to 6 hours, and is active 24 to 28 hours. * ''Insulin glargine'' and ''Insulin detemir'' – both insulin analogs which start working within 1 to 2 hours and continue to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals. * A mixture of NPH and regular insulin – starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins. ====Yeast-based==== In late 2003, [[Wockhardt]] commenced manufacture of a [[yeast]]-based insulin costing $3.25 in India claiming it eliminates the risk of contracting diseases such as [[Bovine spongiform encephalopathy|BSE]] and [[Creutzfeldt-Jakob disease|CJD]] associated with insulin derived from pigs and cattle.<ref>[http://news.bbc.co.uk/1/hi/world/south_asia/3126823.stm BBC NEWS | World | South Asia | Indian firm markets vegetarian insulin<!-- Bot generated title -->]</ref> However, the company continues to manufacture insulin derived from pigs in the United Kingdom. === Modes of administration === Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins introduced into the [[gastrointestinal tract]], it is reduced to fragments (even single amino acid components), whereupon all 'insulin activity' is lost. ==== Subcutaneous ==== Insulin is usually taken as [[subcutaneous]] [[Injection (medicine)|injection]]s by single-use [[syringe]]s with [[hypodermic needle|needle]]s, an [[insulin pump]], or by repeated-use [[insulin pen]]s with needles. Patients who wish to reduce repeated skin puncture of insulin injections often use an injection port such as the [[I-port]]. Administration schedules attempt to mimic the physiologic secretion of insulin by the pancreas. Hence, both a long-acting insulin and a short-acting insulin are typically used. ==== Insulin pump ==== {{main|Insulin pump}} [[Insulin pump]]s are a reasonable solution for some. Advantages to the patient are better control over background or 'basal' insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining 'bolus' infusion doages. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels. Insulin pumps may be like 'electrical injectors' attached to a temporarily implanted [[catheter]] or [[cannula]]. Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump. As with injections, if too much insulin is delivered or the patient eats less than he or she dosed for, there will be hypoglycemia. On the other hand, if too little insulin is delivered, there will be hyperglycemia. Both can be life-threatening. In addition, indwelling catheters pose the risk of infection and ulceration, and some patients may also develop [[lipodystrophy]] due to the infusion sets. These risks can often be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly. However, some patients with diabetes are capable of keeping their glucose in reasonable control only with an insulin pump. ==== Inhalation ==== {{main|Inhalable insulin}} In 2006 the U.S. [[Food and Drug Administration]] approved the use of [[Exubera]], the first inhalable insulin.<ref>[http://www.fda.gov/bbs/topics/news/2006/NEW01304.html FDA approval of ''Exubera'' inhaled insulin]</ref> It has been withdrawn from the market by its maker as of 3Q 2007, due to lack of acceptance. Inhaled insulin has similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required.<ref name="ACD" /> When patients were switched from injected to inhaled insulin, no significant difference was found in Hb<sub>A1c</sub> levels over three months. Accurate dosing is still a problem, although patients showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline.<ref>{{cite journal|author=Cefalu W, Skyler J, Kourides I, Landschulz W, Balagtas C, Cheng S, Gelfand R|title=Inhaled human insulin treatment in patients with type 2 diabetes mellitus|journal=Ann Intern Med|volume=134|issue=3|pages=203–7|year=2001|pmid=11177333}}</ref> Following its commercial launch in 2005 in the UK, it was not (as of July 2006) recommended by [[National Institute for Health and Clinical Excellence]] for routine use, except in cases where there is ''"proven injection phobia diagnosed by a psychiatrist or psychologist"''.<!-- --><ref name="ACD">{{cite web | title=Diabetes (type 1 and 2), Inhaled Insulin - Appraisal Consultation Document (second) | url=http://www.nice.org.uk/page.aspx?o=332283 | year=2006 | month=June 21 | author=[[National Institute for Health and Clinical Excellence|NICE]] | accessdate=2006-07-26}}</ref> In January 2008, the world's largest insulin manufacturer, [[Novo Nordisk]] A/S, also announced that the company was discontinuing all further development of the company's own version of inhalable insulin, known as the AERx iDMS inhaled insulin system.<ref>[http://www.novonordisk.com/press/sea/sea.asp?NewsTypeGuid=&sShowNewsItemGUID=7e91bb44-5368-4663-96c1-26a9a3e8e2c5&sShowLanguageCode=en-GB&csref=RSS_Novo_Nordisk_refocuses_its_activities_within_inhaled_insulin_and_discontinues_the_development_of_AERx%C2%AE Novo Nordisk refocuses its activities within inhaled insulin and discontinues the development of AERx]</ref> Similarly, [[Eli Lilly and Company]] ended its efforts to develop its Air inhaled insulin in March 2008.<ref>[http://www.nytimes.com/2008/03/08/business/08insulin.html?ex=1362718800&en=fa24193b62ff5b20&ei=5124&partner=permalink&exprod=permalink Lilly Ends Effort to Develop an Inhaled Insulin Product]</ref> MannKind Corp. (whose majority owner, [[Alfred E. Mann]], remained unusually bullish on the concept in spite of Pfizer's costly failure<ref>[http://www.nytimes.com/2007/11/16/business/16mannkind.html?ex=1352955600&en=4411035f40bc20ac&ei=5124&partner=permalink&exprod=permalink Pollack, Andrew. "Betting an Estate on Inhaled Insulin", The New York Times, 16 Nov 2007.]), are still proceeding with their own inhaled insulin plans.</ref> ==== Transdermal ==== There are several methods for transdermal delivery of insulin. [[Pulsatile insulin]] uses microjets to pulse insulin into the patient, mimicking the physiological secretions of insulin by the pancreas.<ref name="pmid17360511">{{cite journal |author=Arora A, Hakim I, Baxter J, ''et al'' |title=Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=11 |pages=4255–60 |year=2007 |pmid=17360511 |doi=10.1073/pnas.0700182104}}</ref> [[Jet injector|Jet injection]] had different insulin delivery peaks and durations as compared to needle injection. Some diabetics find control possible with jet injectors, but not with hypodermic injection. Both electricity using [[iontophoresis]]<ref name="pmid17269912">{{cite journal |author=Dixit N, Bali V, Baboota S, Ahuja A, Ali J |title=Iontophoresis - an approach for controlled drug delivery: a review |journal=Current drug delivery |volume=4 |issue=1 |pages=1–10 |year=2007 |pmid=17269912| doi = 10.2174/156720107779314802 <!--Retrieved from CrossRef by DOI bot-->}}</ref> and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental, but the blood glucose test aspect of 'wrist appliances' is commercially available. Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through [[sebaceous gland|pores]] in the skin. ==== Intranasal insulin ==== Intranasal insulin is being investigated.<ref name="pmid11553197">{{cite journal |author=Lalej-Bennis D, Boillot J, Bardin C, ''et al'' |title=Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic Type 2 diabetic patients with oral drug failure: a cross-over study |journal=Diabet. Med. |volume=18 |issue=8 |pages=614–8 |year=2001 |pmid=11553197| doi = 10.1046/j.1464-5491.2001.00528.x <!--Retrieved from CrossRef by DOI bot-->}}</ref> ==== Oral insulin ==== The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. However, insulin is a [[protein]], which are [[digestion|digested]] in the [[stomach]] and [[gut]] and in order to be effective at controlling blood sugar, can not be taken orally. The potential market for an oral form of insulin is assumed to be enormous, thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the [[portal vein]] to have a measurable effect on blood sugar. As of 2004, no products appear to be successful enough yet to bring to market.<ref>{{cite web |url=http://www.ias.ac.in/resonance/May2003/May2003p38-46.html |title=Oral Insulin - Fact or Fiction? - Resonance - May 2003 |accessdate=2007-09-23 |format= |work=}}</ref> A Connecticut-based biopharmaceutical company called [http://www.biodel.com Biodel, Inc.] is developing what it calls VIAtab, an oral formulation of insulin designed to be administered sublingually. This therapy is a tablet that dissolves in minutes when placed under the tongue. In a Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals. The company claims that an oral insulin therapy would be more convenient than currently available injectable or inhalable therapies, and they expect that convenience to result in increased insulin usage among the currently underserved early-stage patients with Type 2 diabetes, thus helping to create better long-term outcomes for that patient population.<ref>[http://www.biodel.com/pipeline/viatab.htm Biodel, Inc. VIAtab Product Overview]</ref> An Israeli pharmaceutical company, Oramed Pharmaceuticals, is currently conducting Phase 2A studies on an oral insulin pill<ref>[http://biz.yahoo.com/bw/080122/20080122006040.html?.v=1 Oramed Pharmaceuticals Commences Phase 1B Clinical Trials: Financial News - Yahoo! Finance<!-- Bot generated title -->]</ref>. [[Australia]]n biopharmaceutical company, Apollo Life Sciences, plans to enter the Phase I trial of its oral insulin tablet in mid-2008.<ref>{{cite web | url = http://www.apollolifesciences.com/Uploads/ASX/ASX_109.pdf | format = pdf | title = Apollo’s oral insulin - 2007 R&D update and 2008 roadmap | date = 2007-12-20 | accessdate = 2008-02-04 | publisher = Apollo Life Sciences }}</ref> ==== Pancreatic transplantation ==== {{main|Islet cell transplantation}} Another improvement would be a [[Organ transplant|transplantation]] of the pancreas or beta cell to avoid periodic insulin administration. This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual [[organ (anatomy)|organ]]) is difficult and relatively uncommon. It is often performed in conjunction with [[liver]] or [[kidney]] transplant, although it can be done by itself. It is also possible to do a transplantation of only the pancreatic beta cells. However, islet transplants had been highly experimental (for which read 'prone to failure') for many years, but some researchers in [[Alberta, Canada]], have developed techniques with a high ''initial'' success rate (about 90% in one group). Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting [[Genetic Engineering|genetically engineered]] non-beta cells to secrete insulin.<ref>{{cite journal |url=http://endo.endojournals.org/cgi/content/abstract/145/8/3840 |title=Aggregation and Lack of Secretion of Most Newly Synthesized Proinsulin in Non-β-Cell Lines |author=Yong Lian Zhu ''et al.'' |journal=Endocrinology |volume=145 |issue=8 |pages=3840–3849 |year=2003 |doi=10.1210/en.2003-1512 |pmid=15117881}}</ref> Clinically testable results are far from realization at this time. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval. ==== Artificial pancreas ==== {{main|artificial pancreas}} === Dosage and timing === The central problem for those requiring external insulin is picking the right dose of insulin and the right timing. <!-- It would be best to show this graphically. E.g., a graph of typical blood glucose levels and blood insulin levels in people without diabetes and in those with diabetes injecting themselves 1, 2, 3 or more times a day. Volunteers, with a graphical gift? --> Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage in cells, reducing glycogen to glucose conversion, reducing blood glucose levels, and so reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so, returns to the normal 'fasting' level. Even the best diabetic treatment with synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non-diabetic. Complicating matters is that the composition of the food eaten (see ''[[glycemic index]]'') affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. Fats and proteins cause delays in absorption of glucose from carbohydrate eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same, since working muscle has some ability to take up glucose without the help of insulin. It is, in principle, impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics' beta cells routinely and automatically manage this by continual glucose level monitoring and insulin release. All such decisions by a diabetic must be based on experience and training (i.e., at the direction of a physician, PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the patient. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice. For example, some patients with diabetes require more insulin after drinking [[skim milk]] than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skimmed milk is different from other people with diabetes, but the same amount of whole milk is likely to cause a still different reaction even in that person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all people with diabetes, especially for those taking insulin. Patients with insulin-dependent diabetes require some base level of insulin (basal insulin), as well as short-acting insulin to cover meals (bolus insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin-dependent diabetes must manage each day. This is normally achieved through regular blood tests, although continuous blood sugar testing equipment (Continuous Glucose Monitors or CGMs) are now becoming available. ====Strategies==== A long-acting insulin is used to approximate the basal secretion of insulin by the pancreas. NPH/isophane, lente, ultralente, glargine, and detemir may be used for this purpose. The advantage of NPH is its low cost and the fact that you can mix it with short-acting forms of insulin, thereby minimizing the number of injections that must be administered. The disadvantage is that the activity of NPH is less steady and will peak 4&ndash;6 hours after administration, and this peak has the potential of causing hypoglycemia. NPH and regular insulin in combination are available as premixed solutions, which can sometimes simplify administration. The theoretical advantage of glargine and detemir is that they only need to be administered once a day, and they also have steady activity, generally without peaks, although in practice, many patients find that neither lasts a full 24 hours. Glargine and detemir are also signifincantly more expensive, and they cannot be mixed with other forms of insulin. A short-acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating. Regular insulin, lispro, aspart and glulisine can be used for this purpose. Regular insulin should be given with about a 30 minute lead-time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia. Lispro, aspart and glulisine are approved for dosage with the first bite of the meal, and may even be effective if given after completing the meal. The short-acting insulin is also used to correct hyperglycemia. The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime. More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been 'covered' effectively. When insulin glargine or insulin detemir is used, it can be administered at any time during the day, provided that it is given at the same time every day. =====Sliding scales===== Insulin prescriptions generally specify fixed amounts of long-acting insulin to be given routinely, and fixed amounts of short-acting insulin prior to every meal (the 'sliding scale' approach). However, the amount of short-acting insulin may be varied depending on the patient's preprandial fingerstick glucose, in order to correct pre-existing hyperglycemia. The so-called "sliding-scale" is still widely taught, although it is controversial.<ref>{{cite journal | pmid = 17602924 | author = Umpierrez GE, Palacio A, Smiley D | title = Sliding scale insulin use: myth or insanity? | journal = Am J Med | volume= 120 | issue = 7 | pages = 563–7 | year = 2007 | doi = 10.1016/j.amjmed.2006.05.070 }}</ref> ''Sample regimen using insulin NPH and regular insulin'' {| class="wikitable" |- ! ! before breakfast ! before lunch ! before dinner ! at bedtime |- | NPH dose | 12 units | | 6 units | |- | regular insulin dose <br />if fingerstick glucose is (mg/dl): | | | | |- |70-100 |4 units | |4 units | |- |101-150 |5 units | |5 units | |- |151-200 |6 units | |6 units | |- |201-250 |7 units | |7 units | |- |251-300 |8 units |1 unit |8 units |1 unit |- |>300 |9 units |2 units |9 units |2 units |} ''Sample regimen using insulin glargine and insulin lispro''<br /> insulin glargine 20 units at bedtime<br /> insulin lispro to be given as follows: {| class="wikitable" |- | if fingerstick glucose is (mg/dl): ! before breakfast ! before lunch ! before dinner ! at bedtime |- | 70-100 | 5 units | 5 units | 5 units | |- | 101-150 | 6 units | 6 units | 6 units | |- | 151-200 | 7 units | 7 units | 7 units | |- | 201-250 | 8 units | 8 units | 8 units | 1 unit |- | 251-300 | 9 units | 9 units | 9 units | 2 units |- | >300 | 10 units | 10 units | 10 units | 3 units |} =====Carb counting and DAFNE===== A more complicated method that allows greater freedom with meal times and snacks is "carb counting." This approach is taught to diabetic patients in Europe as Dose Adjustment for Normal Eating, or DAFNE. The patient can use his or her total daily dose (TDD) of insulin to estimate how many grams of carbohydrates will be "covered" by 1 unit of insulin, and using this result, the patient can estimate how many units of insulin should be administered depending on the carbohydrate concentration of their meal. For example, if the patient determines that 1 unit of insulin will cover 15 grams of carbohydrates, then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates. Some alternative methods also consider the protein content of the meal (since excess dietary protein can be converted to glucose via [[gluconeogenesis]]). However, all dosages involve a fair degree of guesswork, and will seldom work consistently from one dosage to the next. === Abuse === There are reports that some patients abuse insulin by injecting large doses that lead to hypoglycemic states. This is extremely dangerous. Severe acute or prolonged hypoglycemia can result in brain damage or death. On [[July 23]], [[2004]], news reports claimed that a former spouse of a prominent international track athlete said that the ex-spouse had used insulin as a way of 'energizing' the body. There is no evidence to suggest it should act as a performance enhancer in non-diabetics. Poorly controlled diabetics are more prone than others to exhaustion and tiredness, and properly-administered insulin can relieve such symptoms. "[[Game of Shadows]]," by reporters Mark Fainaru-Wada and Lance Williams, includes allegations that [[Barry Bonds]] used insulin in the apparent belief that it would increase the effectiveness of the growth hormone he was (also alleged to be) taking. On top of this, non-prescribed insulin is a banned drug at the Olympics and other global competitions. The use and abuse of exogenous insulin is reportedly widespread amongst the bodybuilding community. Both insulin, human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is this: Since insulin and HGH act synergistically to promote growth, and since IGF-1 is the primary mediator of the musculoskeletal effects of growth hormone, the 'stacking' of insulin, HGH and IGF-1 should offer a synergistic growth effect on skeletal muscle. This theory has been borne out in recent years by the creation of top-level bodybuilders whose competition weight is in excess of {{convert|50|lb|abbr=on}} of muscle greater than the professionals of the past, yet with even lower levels of body fat. Indeed, the use of insulin, combined with HGH and/or IGF-1 has resulted in the development of such massively muscled physiques, that there has been a backlash amongst fans of the sport, with a professed disgust at the 'freakish' appearance of top-level professionals. Bodybuilders will inject up to 10 [[International unit|i.u.]] of quick-acting synthetic insulin following meals containing starchy carbohydrates and protein, but little fat, in an attempt to 'force feed' nutrients necessary for growth into skeletal muscle, whilst preventing growth of adipocytes. This may be done up to four times each day, following meals, for a total usage of 40iu of synthetic insulin per day. However there have been reports of substantially heavier usage, amongst even 'recreational' bodybuilders. The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death. Long-term risks may include development of type 2 diabetes, and potentially a lifetime dependency on exogenous insulin.{{Fact|date=February 2008}} == History == === Discovery and characterization === In 1869 [[Paul Langerhans]], a medical student in [[Berlin]], was studying the structure of the [[pancreas]] under a [[microscope]] when he identified some previously un-noticed tissue clumps scattered throughout the bulk of the pancreas. The function of the "little heaps of cells," later [[eponym|known as]] the ''[[Islets of Langerhans]]'', was unknown, but [[Edouard Laguesse]] later suggested that they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. In 1889, the [[Germany|Polish-German]] physician [[Oscar Minkowski]] in collaboration with [[Joseph von Mering]] removed the [[pancreas]] from a healthy dog to test its assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that there was sugar in the dog's urine, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by [[Eugene Opie]], when he clearly established the link between the Islets of Langerhans and diabetes: ''Diabetes mellitus … is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed.'' Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets. [[Image:InsulinMonomer.jpg|left|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 cartoon 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, several attempts were made to isolate whatever it was the islets produced as a potential treatment. In 1906 [[George Ludwig Zuelzer]] was partially successful treating dogs with pancreatic extract but was unable to continue his work. Between 1911 and 1912, [[E.L. Scott]] at the [[University of Chicago]] used 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]] demonstrated similar effects at [[Rockefeller University]] in 1919, but his work was interrupted by [[World War I]] and he did not return to it. [[Nicolae Paulescu]], a professor of physiology at the [[Carol Davila University of Medicine and Pharmacy|University of Medicine and Pharmacy in Bucharest]] was the first one to isolate insulin, which he called at that time pancrein, and published his work in 1921 that had been carried out in Bucharest. Use of his techniques was patented in [[Romania]], though no clinical use resulted.<ref>{{cite journal |url=http://jhmas.oxfordjournals.org/cgi/reprint/XXVI/2/150.pdf |author=Ian Murray |title=Paulesco and the Isolation of Insulin |journal=Journal of the History of Medicine and Allied Sciences |volume=26 |year=1971 |issue=2 |pages=150–157 |format=PDF}}</ref> In October 1920 Canadian [[Frederick Banting]] was reading one of Minkowski's papers and concluded that it is the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. 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 glycosurea.'' The idea was that the pancreas's internal secretion, which supposedly regulates sugar in the bloodstream, might hold the key to the treatment of diabetes. He travelled to [[Toronto]] to meet with [[John James Richard Macleod|J.J.R. Macleod]], who was not entirely impressed with his idea – so many before him had tried and failed. Nevertheless, he supplied Banting with a lab at the [[University of Toronto]], an assistant (medical student [[Charles Best]]), and 10 dogs, then left on vacation during the summer of 1921. Their method was tying a ligature (string) around the pancreatic duct, and, when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called ''isletin'' (what we now know as insulin), and tested this extract on the dogs. Banting and Best were then able to keep a pancreatectomized dog alive all summer because the extract lowered the level of sugar in the blood. [[Image:InsulinHexamer.jpg|300px|thumb|Computer-generated image of insulin hexamers highlighting the threefold [[symmetry]], the [[zinc]] ions holding it together, and the [[histidine]] residues involved in zinc binding.]] Macleod saw the value of the research on his return but demanded a re-run to prove the method actually worked. Several weeks later it was clear the second run was also a success, and he helped publish their results privately in [[Toronto, ON]] that November. However, they needed six weeks to extract the isletin, which forced considerable delays. Banting suggested that they try to use fetal calf pancreas, which had not yet developed digestive glands; he was relieved to find that this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the [[biochemist]] [[James Collip]], to help with this task, and, within a month, the team felt ready for a clinical test. 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. However, the extract was so impure that Thompson suffered a severe [[anaphylaxis|allergic reaction]], and further injections were canceled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on the 23rd. This was completely successful, not only in having no obvious side-effects, but in completely eliminating the glycosuria sign of diabetes. Children dying from diabetic keto-acidosis were kept in large wards, often with 50 or more patients in a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until then, inevitable) death. In one of medicine's more dramatic moments Banting, Best and Collip went from bed to bed, injecting an entire ward with the new purified extract. Before they had reached the last dying child, the first few were awakening from their coma, to the joyous exclamations of their families. However, 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 made a major breakthrough, and were able to produce large quantities of highly refined, 'pure' insulin. Insulin was offered for sale shortly thereafter. === Nobel Prizes === 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 Richard Macleod|J.J.R. Macleod]]. They were awarded the [[Nobel Prize in Physiology or Medicine]] in 1923 for the discovery of insulin. Banting, insulted that Best was not mentioned, shared his prize with Best, and Macleod immediately shared his with Collip. The patent for insulin was sold to the [[University of Toronto]] for one dollar. Surprisingly, Banting and Macleod received the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin, while [[Nicolae Paulescu|Paulescu's]] pioneering work was being completely ignored by the scientific and medical community. International recognition for Paulescu's merits as the true discoverer of insulin came only 50 years later. The [[primary structure]] of insulin was determined by British molecular biologist [[Frederick Sanger]]. It was the first protein to have its sequence be determined. He was awarded the 1958 [[Nobel Prize in Chemistry]] for this work. In 1969, after decades of work, [[Dorothy Crowfoot Hodgkin]] determined the spatial conformation of the molecule, the so-called [[tertiary structure]], by means of [[X-ray diffraction]] studies. She had been awarded a Nobel Prize in Chemistry in 1964 for the development of [[crystallography]]. [[Rosalyn Sussman Yalow]] received the 1977 Nobel Prize in Medicine for the development of the [[radioimmunoassay]] for insulin. === Timeline of insulin research === * 1922 Banting, Best, Collip use bovine insulin extract in human * 1923 [[Eli Lilly and Company|Eli Lilly]] produces commercial quantities of much purer bovine insulin than Banting et al had used * 1923 Farbwerke [[Hoechst]], one of the forerunner's of today's [[Sanofi Aventis]], produces commercial quantities of bovine insulin in Germany * 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark – forerunner of today's [[Novo Nordisk]] * 1926 [[Nordisk]] receives a Danish charter to produce insulin as a non-profit * 1936 Canadians D.M. Scott, A.M. Fisher formulate a zinc insulin mixture and license it to [[Novo Nordisk|Novo]] * 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin * 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or [[NPH insulin]] * 1946 Nordisk crystallizes a protamine and insulin mixture * 1950 Nordisk markets [[NPH insulin]] * 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin * 1955 [[Frederick Sanger]] determines the [[Protein sequence|amino acid sequence]] of insulin * 1966 Synthesized by total synthesis by [[C.L. Tsou]], [[Wang Yinglai]], and coworkers * 1969 [[Dorothy Crowfoot Hodgkin]] solves the crystal structure of insulin by [[x-ray crystallography]] * 1973 Purified monocomponent (MC) insulin is introduced * 1973 The U.S. officially "standardized" insulin sold for human use in the U.S. to U-100 (100 units per milliliter). Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so the effort to "standardize" the potency aimed to reduce dosage errors and ease doctors' job of prescribing insulin for patients. Other countries also followed suit. * 1978 [[Genentech]] produces synthetic 'human' insulin in ''Escheria coli'' bacteria using recombinant DNA techniques, licenses to Eli Lilly * 1981 [[Novo Nordisk]] chemically and enzymatically converts porcine to human insulin * 1982 [[Genentech]] synthetic 'human' insulin (above) approved * 1983 [[Eli Lilly and Company]] produces synthetic 'human' insulin with [[recombinant DNA]] technology, Humulin * 1985 [[Axel Ullrich]] sequences a human cell membrane insulin receptor. * 1988 [[Novo Nordisk]] produces recombinant human insulin * 1996 [[Eli Lilly and Company|Lilly]] Humalog "lispro" insulin analogue approved. * 2000 [[Sanofi Aventis]] Lantus "glargine" insulin analogue approved for clinical use in the US and Europe. * 2004 [[Sanofi Aventis]] insulin glulisine insulin analogue approved for clinical use in the US. * 2006 [[Novo Nordisk]] [[Levemir]] "detemir" insulin analogue approved for clinical use in the US. == See also == * [[Insulin analog]] * Anatomy and physiolology ** [[Glucagon]] ** [[Pancreas]] ** [[Islets of Langerhans]] ** [[Endocrinology]] * Forms of diabetes mellitus ** [[Diabetes mellitus]] ** [[Diabetes mellitus type 1]] ** [[Diabetes mellitus type 2]] * Treatment ** [[Diabetic coma]] ** [[Intensive insulinotherapy]] ** [[Insulin pump]] ** [[Conventional insulinotherapy]] * Other medical / diagnostic uses ** [[Insulin tolerance test]] ** [[Triple bolus test]] * [[Science and technology in Canada]] == References == <div class="references-small">* {{cite book |last = Reaven | first=Gerald M. | coauthors = Ami Laws (ed.)|title=Insulin Resistance: The Metabolic Syndrome X |url= |format= |accessdate= |accessyear= |accessmonth= |edition=1st Edition |date=1999--04-15 |publisher=Humana Press |location=Totowa, New Jersey |language= |id=ISBN 0-89603-588-3 |doi=10.1226/0896035883}} * {{cite book |last=Leahy |first=Jack L. |coauthors=William T. Cefalu (ed.) |title=Insulin Therapy |edition=1st Edition |date=2002-03-22 |publisher=Marcel Dekker |location=New York |id=ISBN 0-8247-0711-7 }} * {{cite book |last=Kumar |first=Sudhesh |coauthors=Stephen O'Rahilly (ed.) |title=Insulin Resistance: Insulin Action and Its Disturbances in Disease |origdate= |origyear= |origmonth= |url= |format= |accessdate= |accessyear= |accessmonth= |edition= |date=2005-01-14 |publisher=Wiley |location=Chichester, England |id=ISBN 0-470-85008-6 }} * {{cite book |last=Ehrlich |first=Ann |authorlink= |coauthors=Carol L. Schroeder |title=Medical Terminology for Health Professions |origdate= |edition=4th Edition |date=2000-06-16 |publisher=Thomson Delmar Learning |location= |id=ISBN 0-7668-1297-9 }} * {{cite book |last=Draznin |first=Boris |authorlink= |coauthors=Derek LeRoith |editor= |others= |title=Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion |origdate= |origyear= |origmonth= |url= |format= |accessdate= |accessyear= |accessmonth= |edition= |date= |year=1994 |month=September |publisher=Humana Press |location=Totowa, New Jersey |id=ISBN 0-89603-286-8 |doi=10.1226/0896032868 }} * [http://www.collectionscanada.ca/physicians/002032-200-e.html Famous Canadian Physicians: Sir Frederick Banting] at Library and Archives Canada * McKeage K, Goa KL. (2001) Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus. Drugs.61:1599-624</div> == Footnotes == {{reflist}} == External links == * [http://macromoleculeinsights.com/insulin.php The Insulin Protein] * [http://www.dailytimes.com.pk/default.asp?page=2006%5C07%5C15%5Cstory_15-7-2006_pg3_2 Inspired by Insulin] article by parent of a diabetic child * [http://www.vega.org.uk/video/programme/18 Frederick Sanger, Nobel Prize for sequencing Insulin] Freeview video with John Sanger and John Walker by the Vega Science Trust. * [http://nist.rcsb.org/pdb/molecules/pdb14_1.html Insulin: entry from protein databank] * [http://www.med.uni-giessen.de/itr/history/inshist.html The History of Insulin] * [http://www.rxlist.com/cgi/generic/insulinlispro.htm Insulin Lispro] * [http://archives.cbc.ca/IDD-1-75-702/science_technology/diabetes/ CBC Digital Archives - Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes] * [http://www.cosmosmagazine.com/node/663 ''Cosmos Magazine'': Insulin mystery cracked after 20 years] * [http://diabetes.niddk.nih.gov/ National Diabetes Information Clearinghouse] * [http://link.library.utoronto.ca/insulin/ Discovery and Early Development of Insulin, 1920&ndash;1925] * [http://www.medbio.info/Horn/Time%203-4/secretion_of_insulin_and_glucagon_nov_2007.htm Secretion of Insulin and Glucagon] * [http://www.northcoastmed.com/newsletter/news001.htm Insulin Types Comparison Chart] {{Hormones}} [[Category:Eli Lilly and Company]] [[Category:Recombinant proteins]] [[Category:Peptide hormones]] [[Category:Pancreatic hormones]] [[Category:Insulin therapies]] [[Category:Anti-diabetic drugs]] [[af:Insulien]] [[ar:أنسولين]] [[ast:Insulina]] [[bs:Inzulin]] [[bg:Инсулин]] [[ca:Insulina]] [[cs:Inzulín]] [[da:Insulin]] [[de:Insulin]] [[dv:އިންސިޔުލިން]] [[et:Insuliin]] [[el:Ινσουλίνη]] [[es:Insulina]] [[eo:Insulino]] [[eu:Intsulina]] [[fa:انسولین]] [[fr:Insuline]] [[gl:Insulina]] [[ko:인슐린]] [[hr:Inzulin]] [[id:Insulin]] [[is:Insúlín]] [[it:Insulina]] [[he:אינסולין]] [[pam:Insulin]] [[ku:Însulîn]] [[la:Insulinum]] [[lv:Insulīns]] [[lt:Insulinas]] [[hu:Inzulin]] [[ml:ഇന്‍സുലിന്‍]] [[ms:Insulin]] [[nl:Insuline]] [[ja:インスリン]] [[no:Insulin]] [[nn:Insulin]] [[oc:Insulina]] [[pl:Insulina]] [[pt:Insulina]] [[ro:Insulină]] [[ru:Инсулин]] [[sq:Insulina]] [[simple:Insulin]] [[sk:Inzulín]] [[sl:Insulin]] [[sr:Инсулин]] [[su:Insulin]] [[fi:Insuliini]] [[sv:Insulin]] [[th:อินซูลิน]] [[vi:Insulin]] [[tr:İnsülin]] [[uk:Інсулін]] [[yi:אינסולין]] [[zh:胰岛素]]