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Wikipedia

Insulin

February 15, 2024

This article is about the naturally occurring protein. For uses of insulin in treating diabetes, see Insulin (medication).
Not to be confused with Inulin.

Insulin (/ˈɪn.sjʊ.lɪn/,[5][6] from Latin insula, 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is considered to be the main anabolic hormone of the body.[7] It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells.[8] In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both.[8] Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood.[9] 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 reserve body fat.

INS
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesINS, IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10, insulin, PNDM4
External IDsOMIM: 176730 MGI: 96573 HomoloGene: 173 GeneCards: INS
Orthologs
SpeciesHumanMouse
Entrez

3630

16334

Ensembl

ENSG00000254647

ENSMUSG00000000215

UniProt

P01308

P01326

RefSeq (mRNA)

NM_000207
NM_001185097
NM_001185098
NM_001291897

NM_001185083
NM_001185084
NM_008387

RefSeq (protein)

NP_001172012
NP_001172013
NP_032413

Location (UCSC)Chr 11: 2.16 – 2.16 MbChr 7: 142.23 – 142.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Insulin is a peptide hormone containing two chains cross-linked by disulfide bridges.

Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose, and inhibit secretion of insulin when glucose levels are low.[10] Insulin production is also regulated by glucose: high glucose promotes insulin production while low glucose levels lead to lower production.[11] Insulin enhances glucose uptake and metabolism in the cells, thereby reducing blood sugar level. Their neighboring alpha cells, by taking their cues from the beta cells,[10] secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high. Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver.[8][10] The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis.[10]

Decreased or absent insulin activity results in diabetes mellitus, a condition of high blood sugar level (hyperglycaemia). There are two types of the disease. In diabetes mellitus type 1, the beta cells are destroyed by an autoimmune reaction so that insulin can no longer be synthesized or be secreted into the blood.[12] In diabetes mellitus type 2, the destruction of beta cells is less pronounced than in type 1, and is not due to an autoimmune process. Instead, there is an accumulation of amyloid in the pancreatic islets, which likely disrupts their anatomy and physiology.[10] The pathogenesis of type 2 diabetes is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance are known to be involved.[7] Type 2 diabetes is characterized by increased glucagon secretion which is unaffected by, and unresponsive to the concentration of blood glucose. But insulin is still secreted into the blood in response to the blood glucose.[10] As a result, glucose accumulates in the blood.

The human insulin protein is composed of 51 amino acids, and has a molecular mass of 5808 Da. It is a heterodimer of an A-chain and a B-chain, which are linked together by disulfide bonds. Insulin's structure varies slightly between species of animals. Insulin from non-human animal sources differs somewhat in effectiveness (in carbohydrate metabolism effects) from human insulin because of these variations. 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 technologies.[13][14][15][16]

Insulin was the first peptide hormone discovered.[17] Frederick Banting and Charles Best, working in the laboratory of John Macleod at the University of Toronto, were the first to isolate insulin from dog pancreas in 1921. Frederick Sanger sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced.[18] The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is also the first protein to be chemically synthesised and produced by DNA recombinant technology.[19] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[20]

Evolution and species distribution edit

Insulin may have originated more than a billion years ago.[21] The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.[22] Apart from animals, insulin-like proteins are also known to exist in fungi and protists.[21]

Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish.[23] Cone snails: 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.[24][25]

Production edit

 
Diagram of insulin regulation upon high blood glucose

Insulin is produced exclusively in the beta cells of the pancreatic islets in mammals, and the Brockmann body in some fish. Human insulin is produced from the INS gene, located on chromosome 11.[26] Rodents have two functional insulin genes; one is the homolog of most mammalian genes (Ins2), and the other is a retroposed copy that includes promoter sequence but that is missing an intron (Ins1).[27] Transcription of the insulin gene increases in response to elevated blood glucose.[28] This is primarily controlled by transcription factors that bind enhancer sequences in the ~400 base pairs before the gene's transcription start site.[26][28]

The major transcription factors influencing insulin secretion are PDX1, NeuroD1, and MafA.[29][30][31][32]

During a low-glucose state, PDX1 (pancreatic and duodenal homeobox protein 1) is located in the nuclear periphery as a result of interaction with HDAC1 and 2,[33] which results in downregulation of insulin secretion.[34] An increase in blood glucose levels causes phosphorylation of PDX1, which leads it to undergo nuclear translocation and bind the A3 element within the insulin promoter.[35] Upon translocation it interacts with coactivators HAT p300 and SETD7. PDX1 affects the histone modifications through acetylation and deacetylation as well as methylation. It is also said to suppress glucagon.[36]

NeuroD1, also known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes involved in exocytosis.[37] It is localized in the cytosol, but in response to high glucose it becomes glycosylated by OGT and/or phosphorylated by ERK, which causes translocation to the nucleus. In the nucleus β2 heterodimerizes with E47, binds to the E1 element of the insulin promoter and recruits co-activator p300 which acetylates β2. It is able to interact with other transcription factors as well in activation of the insulin gene.[37]

MafA is degraded by proteasomes upon low blood glucose levels. Increased levels of glucose make an unknown protein glycosylated. This protein works as a transcription factor for MafA in an unknown manner and MafA is transported out of the cell. MafA is then translocated back into the nucleus where it binds the C1 element of the insulin promoter.[38][39]

These transcription factors work synergistically and in a complex arrangement. Increased blood glucose can after a while destroy the binding capacities of these proteins, and therefore reduce the amount of insulin secreted, causing diabetes. The decreased binding activities can be mediated by glucose induced oxidative stress and antioxidants are said to prevent the decreased insulin secretion in glucotoxic pancreatic β cells. Stress signalling molecules and reactive oxygen species inhibits the insulin gene by interfering with the cofactors binding the transcription factors and the transcription factors itself.[40]

Several regulatory sequences in the promoter region of the human insulin gene bind to transcription factors. In general, the A-boxes bind to Pdx1 factors, E-boxes bind to NeuroD, C-boxes bind to MafA, and cAMP response elements to CREB. There are also silencers that inhibit transcription.

Synthesis edit

 
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.

Insulin is synthesized as an inactive precursor molecule, a 110 amino acid-long protein called "preproinsulin". Preproinsulin is translated directly into the rough endoplasmic reticulum (RER), where its signal peptide is removed by signal peptidase to form "proinsulin".[26] As the proinsulin folds, opposite ends of the protein, called the "A-chain" and the "B-chain", are fused together with three disulfide bonds.[26] Folded proinsulin then transits through the Golgi apparatus and is packaged into specialized secretory vesicles.[26] In the granule, proinsulin is cleaved by proprotein convertase 1/3 and proprotein convertase 2, removing the middle part of the protein, called the "C-peptide".[26] Finally, carboxypeptidase E removes two pairs of amino acids from the protein's ends, resulting in active insulin – the insulin A- and B- chains, now connected with two disulfide bonds.[26]

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.[41]

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.[42][43][44]

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.[8]

Structure edit

See also: Insulin/IGF/Relaxin family and Insulin and its analog structure
 
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.

Contrary to an initial belief that hormones would be generally small chemical molecules, as the first peptide hormone known of its structure, insulin was found to be quite large.[17] A single protein (monomer) of human insulin is composed of 51 amino acids, and has a molecular mass of 5808 Da. The molecular formula of human insulin is C257H383N65O77S6.[45] It is a combination of two peptide chains (dimer) named an A-chain and a B-chain, which are linked together by two disulfide bonds. The A-chain is composed of 21 amino acids, while the B-chain consists of 30 residues. The linking (interchain) disulfide bonds are formed at cysteine residues between the positions A7-B7 and A20-B19. There is an additional (intrachain) disulfide bond within the A-chain between cysteine residues at positions A6 and A11. The A-chain exhibits two α-helical regions at A1-A8 and A12-A19 which are antiparallel; while the B chain has a central α -helix (covering residues B9-B19) flanked by the disulfide bond on either sides and two β-sheets (covering B7-B10 and B20-B23).[17][46]

The amino acid sequence of insulin is strongly conserved and varies only slightly between species. Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one. Even insulin from some species of fish is similar enough to human to be clinically effective in humans. Insulin in some invertebrates is quite similar in sequence to human insulin, and has similar physiological effects. The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history. The C-peptide of proinsulin, however, differs much more among species; it is also a hormone, but a secondary one.[46]

Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is about 36000 Da in size. The six molecules are linked together as three dimeric units to form symmetrical molecule. An important feature is the presence of zinc atoms (Zn2+) on the axis of symmetry, which are surrounded by three water molecules and three histidine residues at position B10.[17][46]

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.[47] Insulin can aggregate and form fibrillar interdigitated beta-sheets. This can cause injection amyloidosis, and prevents the storage of insulin for long periods.[48]

Function edit

Secretion edit

See also: Blood glucose regulation

Beta cells in the islets of Langerhans release insulin in two phases. The first-phase release is rapidly triggered in response to increased blood glucose levels, and lasts about 10 minutes. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar, peaking in 2 to 3 hours. The two phases of the insulin release suggest that insulin granules are present in diverse stated populations or "pools". During the first phase of insulin exocytosis, most of the granules predispose for exocytosis are released after the calcium internalization. This pool is known as Readily Releasable Pool (RRP). The RRP granules represent 0.3-0.7% of the total insulin-containing granule population, and they are found immediately adjacent to the plasma membrane. During the second phase of exocytosis, insulin granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release.[49] Thus, the second phase of insulin release is governed by the rate at which granules get ready for release. This pool is known as a Reserve Pool (RP). The RP is released slower than the RRP (RRP: 18 granules/min; RP: 6 granules/min).[50] Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes.[51] First-phase release and insulin sensitivity are independent predictors of diabetes.[52]

The description of first phase release is as follows:

  • Glucose enters the β-cells through the glucose transporters, GLUT 2. At low blood sugar levels little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells.[53]
  • The glucose that enters the β-cell is phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase (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.[10][53]
  • Glucose-6-phosphate enters glycolytic pathway and then, via the pyruvate dehydrogenase reaction, into the Krebs cycle, where multiple, high-energy 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.[54]
  • An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/Kir6.2 potassium channel (see sulfonylurea receptor). This prevents potassium ions (K+) from leaving the cell by facilitated diffusion, leading to a buildup of intracellular potassium ions. As a result, the inside of the cell becomes less negative with respect to the outside, leading to the depolarization of the cell surface membrane.
  • Upon depolarization, voltage-gated calcium ion (Ca2+) 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.[55]
  • The calcium ion concentration in the cytosol of the beta cells can also, or additionally, be increased through the activation of 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 diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the plasma membrane of the endoplasmic reticulum (ER). This allows the release of Ca2+ ions from the ER via IP3-gated channels, which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration. Parasympathetic stimulation of the pancreatic islets operates via this pathway to increase insulin secretion into the blood.[56]
  • 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 secretory 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),[57] 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 α2-adrenergic receptors[58] and stimulated by β2-adrenergic receptors.[59] 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.[60]

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. An insulin spike is a 'first response' to blood glucose increase, this response is individual and dose specific although it was always previously assumed to be food type specific only.

Oscillations edit

Main article: Insulin oscillations
 
Insulin release from pancreas oscillates with a period of 3–6 minutes.[61]

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 p mol/l to less than 100 pmol/L (in rats).[61] This is thought to avoid downregulation of insulin receptors in target cells, and to assist the liver in extracting insulin from the blood.[61] 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.[61] This may be achieved by delivering insulin rhythmically to the portal vein, by light activated delivery, or by islet cell transplantation to the liver.[61][62][63]

Blood insulin level edit

Further information: Insulin index
 
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 sugar-rich versus a starch-rich meal is highlighted.

The blood insulin level can be measured in international units, such as µIU/mL or in molar concentration, such as pmol/L, where 1 µIU/mL equals 6.945 pmol/L.[64] A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).[65]

Signal transduction edit

The effects of insulin are initiated by its binding to a receptor, the insulin receptor (IR), present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer. Insulin binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin.[66]

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 (PI3K). This enzyme converts a phospholipid in the cell membrane by the name of phosphatidylinositol 4,5-bisphosphate (PIP2), into phosphatidylinositol 3,4,5-triphosphate (PIP3), which, in turn, activates protein kinase B (PKB). Activated PKB facilitates the fusion of GLUT4 containing endosomes with the cell membrane, resulting in an increase in GLUT4 transporters in the plasma membrane.[67] PKB also phosphorylates glycogen synthase kinase (GSK), thereby inactivating this enzyme.[68] 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.[69] The breakdown of triglycerides by adipose tissue into free fatty acids and glycerol is also inhibited.[69]

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.[41] 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.[70]

Physiological effects edit

 
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).
 
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:

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.[66]
  • Increased fat synthesis – insulin forces fat cells to take in blood glucose, which is converted into triglycerides; decrease of insulin causes the reverse.[71]
  • Increased esterification of fatty acids – forces adipose tissue to make neutral fats (i.e., triglycerides) from fatty acids; decrease of insulin causes the reverse.[71]
  • Decreased lipolysis in – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse.[71]
  • Induced glycogen synthesis – When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphate group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis.[72]
  • Decreased gluconeogenesis and glycogenolysis – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); decrease of insulin causes glucose production by the liver from assorted substrates.[71]
  • Decreased proteolysis – decreasing the breakdown of protein[71]
  • Decreased autophagy – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.[73]
  • Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption.[71]
  • 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.[74]
  • Increase in the secretion of hydrochloric acid by parietal cells in the stomach.[citation needed]
  • Increased potassium uptake – forces cells synthesizing glycogen (a very spongy, "wet" substance, that increases the content of intracellular water, and its accompanying K+ ions)[75] 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.[76][77]
  • Decreased renal sodium excretion.[78]
  • In hepatocytes, insulin binding acutely leads to activation of protein phosphatase 2A (PP2A)[citation needed], which dephosphorylates the bifunctional enzyme fructose bisphosphatase-2 (PFKB1),[79] activating the phosphofructokinase-2 (PFK-2) active site. PFK-2 increases production of fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate allosterically activates PFK-1, which favors glycolysis over gluconeogenesis. Increased glycolysis increases the formation of malonyl-CoA, a molecule that can be shunted into lipogenesis and that allosterically inhibits of carnitine palmitoyltransferase I (CPT1), a mitochondrial enzyme necessary for the translocation of fatty acids into the intermembrane space of the mitochondria for fatty acid metabolism.[80]

Insulin also influences other body functions, such as vascular compliance and cognition. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular.[81] 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 homeostatic or regulatory processes in the human body.[82] Insulin also has stimulatory effects on gonadotropin-releasing hormone from the hypothalamus, thus favoring fertility.[83]

Degradation edit

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.[84] It is broken down by the enzyme, protein-disulfide reductase (glutathione),[85] which breaks the disulphide bonds between the A and B chains. The liver clears most insulin during first-pass transit, whereas the kidney clears most of the insulin in systemic circulation. Degradation normally involves endocytosis of the insulin-receptor complex, followed by the action of insulin-degrading enzyme. An insulin molecule produced endogenously by the beta cells is estimated to be degraded within about one hour after its initial release into circulation (insulin half-life ~ 4–6 minutes).[86][87]

Regulator of endocannabinoid metabolism edit

Insulin is a major regulator of endocannabinoid (EC) metabolism and insulin treatment has been shown to reduce intracellular ECs, the 2-arachidonoylglycerol (2-AG) and anandamide (AEA), which correspond with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression is disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. Findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation, whereby obese insulin-resistant individuals exhibit increased concentrations of ECs.[88][89] This dysregulation contributes to excessive visceral fat accumulation and reduced adiponectin release from abdominal adipose tissue, and further to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes.[90]

Hypoglycemia edit

Main article: Hypoglycemia

Hypoglycemia, also known as "low blood sugar", is when blood sugar decreases to below normal levels.[91] This may result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures or death.[91] A feeling of hunger, sweating, shakiness and weakness may also be present.[91] Symptoms typically come on quickly.[91]

The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin and sulfonylureas.[92][93] Risk is greater in diabetics who have eaten less than usual, exercised more than usual or have consumed alcohol.[91] Other causes of hypoglycemia include kidney failure, certain tumors, such as insulinoma, liver disease, hypothyroidism, starvation, inborn error of metabolism, severe infections, reactive hypoglycemia and a number of drugs including alcohol.[91][93] Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.[94]

Diseases and syndromes edit

There are several conditions in which insulin disturbance is pathologic:

  • Diabetes mellitus – general term referring to all states characterized by hyperglycemia. It can be of the following types:[95]
    • Type 1 – autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency
    • 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, with sedentary lifestyle, with obesity, with age and with metabolic syndrome. Causality has been demonstrated in multiple model organisms including mice and monkeys; importantly, non-obese people do get Type 2 diabetes due to diet, sedentary lifestyle and unknown risk factors, though it is important to note that this may not be a causal relationship.
      • it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions
    • Other types of impaired glucose tolerance (see Diabetes)
  • Insulinoma – a tumor of beta cells producing excess insulin or reactive hypoglycemia.[96]
  • Metabolic syndrome – a poorly understood condition first called syndrome X by Gerald Reaven. It is not clear whether the syndrome has a single, treatable cause, or is the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance that precedes type 2 diabetes, which is a diminished capacity for 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.[97]
  • 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.[98]

Medical uses edit

Main article: Insulin (medication)
 
Two vials of insulin. They have been given trade names, Actrapid (left) and NovoRapid (right) by the manufacturers.

Biosynthetic human insulin (insulin human rDNA, INN) for clinical use is manufactured by recombinant DNA technology.[13] 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.[99] 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).[100] The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), Humalog (insulin lispro),[101] 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.[102] 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.[103][104] Insulin is also used in many cell lines, such as CHO-s, HEK 293 or Sf9, for the manufacturing of monoclonal antibodies, virus vaccines, and gene therapy products.[105]

Insulin is usually taken as subcutaneous injections by single-use syringes with needles, via an insulin pump, or by repeated-use insulin pens with disposable needles. Inhaled insulin is also available in the U.S. market.

The Dispovan Single-Use Pen Needle by HMD[106] is India’s first insulin pen needle that makes self-administration easy. Featuring extra-thin walls and a multi-bevel tapered point, these pen needles prioritise patient comfort by minimising pain and ensuring seamless medication delivery. The product aims to provide affordable Pen Needles to the developing part of the country through its wide distribution channel. Additionally, the universal design of these needles guarantees compatibility with all insulin pens.

Unlike many medicines, insulin cannot be taken by mouth because, like nearly all other proteins introduced into the 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.[107][108]

In 2021, the World Health Organization added insulin to its model list of essential medicines.[109]

Insulin, and all other medications, are supplied free of charge to people with diabetes by the National Health Service in the countries of the United Kingdom.[110]

History of study edit

Discovery edit

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.[111] The function of the "little heaps of cells", later 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.[112] Paul Langerhans' son, Archibald, also helped to understand this regulatory role.

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".[113][114][115]

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 demonstrated similar effects at Rockefeller University in 1915, but World War I interrupted his work and he did not return to it.[116]

In 1916, Nicolae Paulescu developed an aqueous pancreatic extract which, when injected into a diabetic dog, had a normalizing effect on blood sugar levels. He had to interrupt his experiments because of World War I, and in 1921 he wrote four papers about his work carried out in Bucharest and his tests on a diabetic dog. Later that year, he published "Research on the Role of the Pancreas in Food Assimilation".[117][118]

The name "insulin" was coined by Edward Albert Sharpey-Schafer in 1916 for a hypothetical molecule produced by pancreatic islets of Langerhans (Latin insula for islet or island) that controls glucose metabolism. Unbeknown to Sharpey-Schafer, Jean de Meyer had introduced the very similar word "insuline" in 1909 for the same molecule.[119][120]

Extraction and purification edit

In October 1920, Canadian Frederick Banting concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion, thereby making it impossible to extract successfully. A surgeon by training, Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. He jotted a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these + relieve glycosurea[sic]."[121][122]

 
Charles Best and Clark Noble ca. 1920

In the spring of 1921, Banting traveled to Toronto to explain his idea to John Macleod, Professor of Physiology at the University of Toronto. Macleod was initially skeptical, since Banting had no background in research and was not familiar with the latest literature, but he agreed to provide lab space for Banting to test out his ideas. Macleod also arranged for two undergraduates to be Banting's lab assistants that summer, but Banting required only one lab assistant. Charles Best 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.[123] On 30 July 1921, Banting and Best successfully isolated an extract ("isletin") from the islets of a duct-tied dog and injected it into a diabetic dog, finding that the extract reduced its blood sugar by 40% in 1 hour.[124][122]

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.[122]

 
Chart for Elizabeth Hughes, used to track blood, urine, diet in grams, and dietary prescriptions in grams

On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin.[125][126][127][128] However, the extract was so impure that Thompson had a severe 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, eliminating the glycosuria that was typical of diabetes without causing any obvious side-effects. The first American patient was Elizabeth Hughes, the daughter of U.S. Secretary of State Charles Evans Hughes.[129][130] The first patient treated in the U.S. was future woodcut artist James D. Havens;[131] John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens.[132]

Banting and Best never worked well with Collip, regarding him as something of an interloper,[citation needed] 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 isoelectric precipitation and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public.

Patent edit

Toward the end of January 1922, tensions mounted between the four "co-discoverers" of insulin and Collip briefly threatened to separately patent his purification process. John G. FitzGerald, director of the non-commercial public health institution Connaught Laboratories, therefore stepped in as peacemaker. The resulting agreement of 25 January 1922 established two key conditions: 1) that the collaborators would sign a contract agreeing not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught; and 2) that no changes in research policy would be allowed unless first discussed among FitzGerald and the four collaborators.[133] It helped contain disagreement and tied the research to Connaught's public mandate.

Initially, Macleod and Banting were particularly reluctant to patent their process for insulin on grounds of medical ethics. However, concerns remained that a private third-party would hijack and monopolize the research (as Eli Lilly and Company had hinted[134]), and that safe distribution would be difficult to guarantee without capacity for quality control. To this end, Edward Calvin Kendall gave valuable advice. He had isolated thyroxin at the Mayo Clinic in 1914 and patented the process through an arrangement between himself, the brothers Mayo, and the University of Minnesota, transferring the patent to the public university.[135] On April 12, Banting, Best, Collip, Macleod, and FitzGerald wrote jointly to the president of the University of Toronto to propose a similar arrangement with the aim of assigning a patent to the Board of Governors of the university.[136] The letter emphasized that:[137]

The patent would not be used for any other purpose than to prevent the taking out of a patent by other persons. When the details of the method of preparation are published anyone would be free to prepare the extract, but no one could secure a profitable monopoly.

The assignment to the University of Toronto Board of Governors was completed on 15 January 1923, for the token payment of $1.00.[138] The arrangement was congratulated in The World's Work in 1923 as "a step forward in medical ethics".[139] It has also received much media attention in the 2010s regarding the issue of healthcare and drug affordability.

Following further concern regarding Eli Lilly's attempts to separately patent parts of the manufacturing process, Connaught's Assistant Director and Head of the Insulin Division Robert Defries established a patent pooling policy which would require producers to freely share any improvements to the manufacturing process without compromising affordability.[140]

Structural analysis and synthesis edit

 
Richardson diagram of a porcine insulin monomer, showing its characteristic secondary structure. This is the biologically active form of insulin.
 
Richardson diagram of a porcine insulin hexamer. The sphere at the center is a stabilizing zinc atom, surrounded by coordinating histidine residues. This is the form in which insulin is stored in beta cells. PDB: 4INS​.

Purified animal-sourced insulin was initially the only type of insulin available for experiments and diabetics. John Jacob Abel was the first to produce the crystallised form in 1926.[141] Evidence of the protein nature was first given by Michael Somogyi, Edward A. Doisy, and Philip A. Shaffer in 1924.[142] It was fully proven when Hans Jensen and Earl A. Evans Jr. isolated the amino acids phenylalanine and proline in 1935.[143]

The amino acid structure of insulin was first characterized in 1951 by Frederick Sanger,[18][144] and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the mid-1960s.[145][146][147][148][149] Synthetic crystalline bovine insulin was achieved by Chinese researchers in 1965.[150] The complete 3-dimensional structure of insulin was determined by X-ray crystallography in Dorothy Hodgkin's laboratory in 1969.[151]

Hans E. Weber discovered preproinsulin while working as a research fellow at the University of California Los Angeles in 1974. In 1973–1974, Weber learned the techniques of how to isolate, purify, and translate messenger RNA. To further investigate insulin, he obtained pancreatic tissues from a slaughterhouse in Los Angeles and then later from animal stock at UCLA. He isolated and purified total messenger RNA from pancreatic islet cells which was then translated in oocytes from Xenopus laevis and precipitated using anti-insulin antibodies. When total translated protein was run on an SDS-polyacrylamide gel electrophoresis and sucrose gradient, peaks corresponding to insulin and proinsulin were isolated. However, to the surprise of Weber a third peak was isolated corresponding to a molecule larger than proinsulin. After reproducing the experiment several times, he consistently noted this large peak prior to proinsulin that he determined must be a larger precursor molecule upstream of proinsulin. In May 1975, at the American Diabetes Association meeting in New York, Weber gave an oral presentation of his work[152] where he was the first to name this precursor molecule "preproinsulin". Following this oral presentation, Weber was invited to dinner to discuss his paper and findings by Donald Steiner, a researcher who contributed to the characterization of proinsulin. A year later in April 1976, this molecule was further characterized and sequenced by Steiner, referencing the work and discovery of Hans Weber.[153] Preproinsulin became an important molecule to study the process of transcription and translation.

The first genetically engineered, synthetic "human" insulin was produced using E. coli in 1978 by Arthur Riggs and Keiichi Itakura at the Beckman Research Institute of the City of Hope in collaboration with Herbert Boyer at Genentech.[14][15] 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.[15] The vast majority of insulin used worldwide is biosynthetic recombinant "human" insulin or its analogues.[16] Recently, another approach has been used by a pioneering group of Canadian researchers, using an easily grown safflower plant, for the production of much cheaper insulin.[154]

Recombinant insulin is produced either in yeast (usually Saccharomyces cerevisiae) or E. coli.[155] 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 edit

 
Frederick Banting (right) joined by Charles Best in 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 Macleod.[156] They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin. Banting, incensed that Best was not mentioned,[157] 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, who determined the primary structure of insulin in 1955, was awarded the 1958 Nobel Prize in Chemistry.[18] 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. 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.[158] Dorothy Hodgkin was awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography, the technique she used for deciphering the complete molecular structure of insulin in 1969.[151]

Controversy edit

 
Nicolae Paulescu

The work published by Banting, Best, Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients.[159] Although Paulescu discovered the principles of the treatment, his saline extract could not be used on humans; he was not mentioned in the 1923 Nobel Prize. Ian Murray was particularly active in working to correct "the historical wrong" against Nicolae Paulescu. Murray was a professor of physiology at the Anderson College of Medicine in Glasgow, Scotland, the head of the department of Metabolic Diseases at a leading Glasgow hospital, vice-president of the British Association of Diabetes, and a founding member of the International Diabetes Federation. Murray wrote:

Insufficient recognition has been given to Paulescu, the distinguished Romanian 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.[160]

In a private communication, Arne Tiselius, former head of the Nobel Institute, expressed his personal opinion that Paulescu was equally worthy of the award in 1923.[161]

See also edit

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Further reading edit

  • Laws GM, Reaven A (1999). Insulin resistance : the metabolic syndrome X. Totowa, NJ: Humana Press. ISBN 978-0-89603-588-1.
  • Leahy JL, Cefalu WT (2002-03-22). Insulin Therapy (1st ed.). New York: Marcel Dekker. ISBN 978-0-8247-0711-8.
  • Kumar S, O'Rahilly S (2005-01-14). Insulin Resistance: Insulin Action and Its Disturbances in Disease. Chichester, England: Wiley. ISBN 978-0-470-85008-4.
  • Ehrlich A, Schroeder CL (2000-06-16). Medical Terminology for Health Professions (4th ed.). Thomson Delmar Learning. ISBN 978-0-7668-1297-0.
  • Draznin B, LeRoith D (September 1994). Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion. Totowa, New Jersey: Humana Press. ISBN 978-0-89603-286-6.
  • Misbin RI (February 2022). INSULIN - History from an FDA Insider. Washington, DC: Politics and Prose Publishing. ISBN 978-1-62429-391-7.
  • 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 (11): 1599–624. doi:10.2165/00003495-200161110-00007. PMID 11577797. S2CID 46972328.
  • de Leiva A, Brugués E, de Leiva-Pérez A (November 2011). "[The discovery of insulin: continued controversies after ninety years]". Endocrinologia y Nutricion (in Spanish). 58 (9): 449–56. doi:10.1016/j.endonu.2011.10.001. PMID 22036099.
  • Vecchio I, Tornali C, Bragazzi NL, Martini M (2018). "The Discovery of Insulin: An Important Milestone in the History of Medicine". Frontiers in Endocrinology. 9: 613. doi:10.3389/fendo.2018.00613. PMC 6205949. PMID 30405529.

External links edit

 
Wikimedia Commons has media related to Insulin.
  • University of Toronto Libraries Collection: Discovery and Early Development of Insulin, 1920–1925
  • CBC Digital Archives – Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes
  • at AboutKidsHealth.ca (archived 9 March 2011)
  • Overview of all the structural information available in the PDB for UniProt: P01308 (Insulin) at the PDBe-KB.

February 15, 2024
insulin, this, article, about, naturally, occurring, protein, uses, insulin, treating, diabetes, medication, confused, with, inulin, from, latin, insula, island, peptide, hormone, produced, beta, cells, pancreatic, islets, encoded, humans, insulin, gene, consi. This article is about the naturally occurring protein For uses of insulin in treating diabetes see Insulin medication Not to be confused with Inulin Insulin ˈ ɪ n sj ʊ l ɪ n 5 6 from Latin insula island is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin INS gene It is considered to be the main anabolic hormone of the body 7 It regulates the metabolism of carbohydrates fats and protein by promoting the absorption of glucose from the blood into liver fat and skeletal muscle cells 8 In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats triglycerides via lipogenesis or in the case of the liver into both 8 Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood 9 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 reserve body fat INSAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes1A7F 1AI0 1AIY 1B9E 1BEN 1EV3 1EV6 1EVR 1FU2 1FUB 1G7A 1G7B 1GUJ 1HIQ 1HIS 1HIT 1HLS 1HTV 1HUI 1IOG 1IOH 1J73 1JCA 1JCO 1K3M 1KMF 1LKQ 1LPH 1MHI 1MHJ 1MSO 1OS3 1OS4 1Q4V 1QIY 1QIZ 1QJ0 1RWE 1SF1 1T1K 1T1P 1T1Q 1TRZ 1TYL 1TYM 1UZ9 1VKT 1W8P 1XDA 1XGL 1XW7 1ZEG 1ZEH 1ZNJ 2AIY 2C8Q 2C8R 2CEU 2H67 2HH4 2HHO 2HIU 2JMN 2JUM 2JUU 2JUV 2JV1 2JZQ 2K91 2K9R 2KJJ 2KJU 2KQQ 2KXK 2L1Y 2L1Z 2LGB 2M1D 2M1E 2M2M 2M2N 2M2O 2M2P 2OLY 2OLZ 2OM0 2OM1 2OMG 2OMH 2OMI 2QIU 2R34 2R35 2R36 2RN5 2VJZ 2VK0 2W44 2WBY 2WC0 2WRU 2WRV 2WRW 2WRX 2WS0 2WS1 2WS4 2WS6 2WS7 3AIY 3BXQ 3E7Y 3E7Z 3EXX 3FQ9 3I3Z 3I40 3ILG 3INC 3IR0 3Q6E 3ROV 3TT8 3U4N 3UTQ 3UTS 3UTT 3V19 3V1G 3W11 3W12 3W13 3W7Y 3W7Z 3W80 3ZI3 3ZQR 3ZS2 3ZU1 4AIY 4AJX 4AJZ 4AK0 4AKJ 4EFX 4EWW 4EWX 4EWZ 4EX0 4EX1 4EXX 4EY1 4EY9 4EYD 4EYN 4EYP 4F0N 4F0O 4F1A 4F1B 4F1C 4F1D 4F1F 4F1G 4F4T 4F4V 4F51 4F8F 4FG3 4FKA 4GBC 4GBI 4GBK 4GBL 4GBN 4IUZ 5AIY 2LWZ 3JSD 3KQ6 3P2X 3P33 1JK8 2MLI 2MPG 2MPI 2MVC 2MVD 4CXL 4CXN 4CY7 4NIB 4OGA 4P65 4Q5Z 4RXW 4UNE 4UNG 4UNH 4XC4 4WDI 4Z76 4Z77 4Z78 2N2W 5CO6 5ENA 4Y19 5BQQ 5BOQ 2N2V 5CNY 5CO9 5EN9 4Y1A 2N2X 5BPO 5CO2 5BTS 5HYJ 5C0D s1EFE 1SJT 1SJU 2KQP s1T0C s2G54 2G56 3HYD 2OMQIdentifiersAliasesINS IDDM IDDM1 IDDM2 ILPR IRDN MODY10 insulin PNDM4External IDsOMIM 176730 MGI 96573 HomoloGene 173 GeneCards INSGene location Human Chr Chromosome 11 human 1 Band11p15 5Start2 159 779 bp 1 End2 161 221 bp 1 Gene location Mouse Chr Chromosome 7 mouse 2 Band7 F5 7 88 0 cMStart142 232 393 bp 2 End142 297 118 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inbeta cellbody of pancreasright lobe of liverright adrenal glandleft adrenal glandleft uterine tuberight coronary arterycanal of the cervixfundussubstantia nigraTop expressed inislet of Langerhanspyloric antrumyolk sacretinal pigment epitheliumsecondary oocytequadriceps femoris muscleanklesexually immature organismneuronspermatidMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functioninsulin receptor binding identical protein binding protease binding insulin like growth factor receptor binding protein binding hormone activityCellular componentendoplasmic reticulum lumen transport vesicle Golgi membrane secretory granule lumen Golgi lumen endoplasmic reticulum Golgi intermediate compartment membrane endosome lumen extracellular region extracellular spaceBiological processnegative regulation of NAD P H oxidase activity positive regulation of DNA replication positive regulation of MAPK cascade positive regulation of brown fat cell differentiation positive regulation of cell differentiation MAPK cascade positive regulation of respiratory burst positive regulation of phosphatidylinositol 3 kinase signaling negative regulation of protein oligomerization positive regulation of NF kappaB transcription factor activity negative regulation of respiratory burst involved in inflammatory response cell cell signaling positive regulation of nitric oxide biosynthetic process positive regulation of glycolytic process positive regulation of nitric oxide synthase activity positive regulation of protein autophosphorylation activation of protein kinase B activity wound healing positive regulation of mitotic nuclear division negative regulation of feeding behavior positive regulation of peptide hormone secretion negative regulation of protein catabolic process positive regulation of cell migration acute phase response regulation of protein secretion positive regulation of glycogen biosynthetic process positive regulation of protein kinase B signaling G protein coupled receptor signaling pathway regulation of cellular amino acid metabolic process negative regulation of oxidative stress induced intrinsic apoptotic signaling pathway endoplasmic reticulum to Golgi vesicle mediated transport negative regulation of lipid catabolic process positive regulation of cell growth negative regulation of glycogen catabolic process positive regulation of insulin receptor signaling pathway glucose metabolic process negative regulation of acute inflammatory response negative regulation of protein secretion positive regulation of peptidyl tyrosine phosphorylation glucose homeostasis positive regulation of cell population proliferation fatty acid homeostasis positive regulation of protein metabolic process regulation of transmembrane transporter activity negative regulation of gluconeogenesis negative regulation of fatty acid metabolic process regulation of protein localization regulation of transcription DNA templated positive regulation of lipid biosynthetic process carbohydrate metabolic process negative regulation of proteolysis alpha beta T cell activation positive regulation of protein localization to nucleus positive regulation of glucose import insulin receptor signaling pathway positive regulation of gene expression regulation of signaling receptor activity positive regulation of nitric oxide mediated signal transduction regulation of synaptic plasticity cognition positive regulation of long term synaptic potentiation positive regulation of dendritic spine maintenance regulation of protein localization to plasma membrane negative regulation of reactive oxygen species biosynthetic process neuron projection maintenance response to L arginine signal transductionSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez363016334EnsemblENSG00000254647ENSMUSG00000000215UniProtP01308P01326RefSeq mRNA NM 000207NM 001185097NM 001185098NM 001291897NM 001185083NM 001185084NM 008387RefSeq protein NP 000198NP 001172026NP 001172027NP 001278826NP 000198 1NP 001172026 1NP 001172027 1NP 001278826 1NP 000198NP 000198NP 000198NP 000198NP 001172012NP 001172013NP 032413Location UCSC Chr 11 2 16 2 16 MbChr 7 142 23 142 3 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseInsulin is a peptide hormone containing two chains cross linked by disulfide bridges Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose and inhibit secretion of insulin when glucose levels are low 10 Insulin production is also regulated by glucose high glucose promotes insulin production while low glucose levels lead to lower production 11 Insulin enhances glucose uptake and metabolism in the cells thereby reducing blood sugar level Their neighboring alpha cells by taking their cues from the beta cells 10 secrete glucagon into the blood in the opposite manner increased secretion when blood glucose is low and decreased secretion when glucose concentrations are high Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver 8 10 The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis 10 Decreased or absent insulin activity results in diabetes mellitus a condition of high blood sugar level hyperglycaemia There are two types of the disease In diabetes mellitus type 1 the beta cells are destroyed by an autoimmune reaction so that insulin can no longer be synthesized or be secreted into the blood 12 In diabetes mellitus type 2 the destruction of beta cells is less pronounced than in type 1 and is not due to an autoimmune process Instead there is an accumulation of amyloid in the pancreatic islets which likely disrupts their anatomy and physiology 10 The pathogenesis of type 2 diabetes is not well understood but reduced population of islet beta cells reduced secretory function of islet beta cells that survive and peripheral tissue insulin resistance are known to be involved 7 Type 2 diabetes is characterized by increased glucagon secretion which is unaffected by and unresponsive to the concentration of blood glucose But insulin is still secreted into the blood in response to the blood glucose 10 As a result glucose accumulates in the blood The human insulin protein is composed of 51 amino acids and has a molecular mass of 5808 Da It is a heterodimer of an A chain and a B chain which are linked together by disulfide bonds Insulin s structure varies slightly between species of animals Insulin from non human animal sources differs somewhat in effectiveness in carbohydrate metabolism effects from human insulin because of these variations 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 technologies 13 14 15 16 Insulin was the first peptide hormone discovered 17 Frederick Banting and Charles Best working in the laboratory of John Macleod at the University of Toronto were the first to isolate insulin from dog pancreas in 1921 Frederick Sanger sequenced the amino acid structure in 1951 which made insulin the first protein to be fully sequenced 18 The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969 Insulin is also the first protein to be chemically synthesised and produced by DNA recombinant technology 19 It is on the WHO Model List of Essential Medicines the most important medications needed in a basic health system 20 Contents 1 Evolution and species distribution 2 Production 2 1 Synthesis 3 Structure 4 Function 4 1 Secretion 4 2 Oscillations 4 3 Blood insulin level 4 4 Signal transduction 4 5 Physiological effects 4 6 Degradation 4 7 Regulator of endocannabinoid metabolism 5 Hypoglycemia 6 Diseases and syndromes 7 Medical uses 8 History of study 8 1 Discovery 8 2 Extraction and purification 8 3 Patent 8 4 Structural analysis and synthesis 8 5 Nobel Prizes 8 5 1 Controversy 9 See also 10 References 11 Further reading 12 External linksEvolution and species distribution editInsulin may have originated more than a billion years ago 21 The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes 22 Apart from animals insulin like proteins are also known to exist in fungi and protists 21 Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish 23 Cone snails 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 24 25 Production edit nbsp Diagram of insulin regulation upon high blood glucoseInsulin is produced exclusively in the beta cells of the pancreatic islets in mammals and the Brockmann body in some fish Human insulin is produced from the INS gene located on chromosome 11 26 Rodents have two functional insulin genes one is the homolog of most mammalian genes Ins2 and the other is a retroposed copy that includes promoter sequence but that is missing an intron Ins1 27 Transcription of the insulin gene increases in response to elevated blood glucose 28 This is primarily controlled by transcription factors that bind enhancer sequences in the 400 base pairs before the gene s transcription start site 26 28 The major transcription factors influencing insulin secretion are PDX1 NeuroD1 and MafA 29 30 31 32 During a low glucose state PDX1 pancreatic and duodenal homeobox protein 1 is located in the nuclear periphery as a result of interaction with HDAC1 and 2 33 which results in downregulation of insulin secretion 34 An increase in blood glucose levels causes phosphorylation of PDX1 which leads it to undergo nuclear translocation and bind the A3 element within the insulin promoter 35 Upon translocation it interacts with coactivators HAT p300 and SETD7 PDX1 affects the histone modifications through acetylation and deacetylation as well as methylation It is also said to suppress glucagon 36 NeuroD1 also known as b2 regulates insulin exocytosis in pancreatic b cells by directly inducing the expression of genes involved in exocytosis 37 It is localized in the cytosol but in response to high glucose it becomes glycosylated by OGT and or phosphorylated by ERK which causes translocation to the nucleus In the nucleus b2 heterodimerizes with E47 binds to the E1 element of the insulin promoter and recruits co activator p300 which acetylates b2 It is able to interact with other transcription factors as well in activation of the insulin gene 37 MafA is degraded by proteasomes upon low blood glucose levels Increased levels of glucose make an unknown protein glycosylated This protein works as a transcription factor for MafA in an unknown manner and MafA is transported out of the cell MafA is then translocated back into the nucleus where it binds the C1 element of the insulin promoter 38 39 These transcription factors work synergistically and in a complex arrangement Increased blood glucose can after a while destroy the binding capacities of these proteins and therefore reduce the amount of insulin secreted causing diabetes The decreased binding activities can be mediated by glucose induced oxidative stress and antioxidants are said to prevent the decreased insulin secretion in glucotoxic pancreatic b cells Stress signalling molecules and reactive oxygen species inhibits the insulin gene by interfering with the cofactors binding the transcription factors and the transcription factors itself 40 Several regulatory sequences in the promoter region of the human insulin gene bind to transcription factors In general the A boxes bind to Pdx1 factors E boxes bind to NeuroD C boxes bind to MafA and cAMP response elements to CREB There are also silencers that inhibit transcription Synthesis edit nbsp 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 Insulin is synthesized as an inactive precursor molecule a 110 amino acid long protein called preproinsulin Preproinsulin is translated directly into the rough endoplasmic reticulum RER where its signal peptide is removed by signal peptidase to form proinsulin 26 As the proinsulin folds opposite ends of the protein called the A chain and the B chain are fused together with three disulfide bonds 26 Folded proinsulin then transits through the Golgi apparatus and is packaged into specialized secretory vesicles 26 In the granule proinsulin is cleaved by proprotein convertase 1 3 and proprotein convertase 2 removing the middle part of the protein called the C peptide 26 Finally carboxypeptidase E removes two pairs of amino acids from the protein s ends resulting in active insulin the insulin A and B chains now connected with two disulfide bonds 26 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 41 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 42 43 44 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 8 Structure editSee also Insulin IGF Relaxin family and Insulin and its analog structure nbsp 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 Contrary to an initial belief that hormones would be generally small chemical molecules as the first peptide hormone known of its structure insulin was found to be quite large 17 A single protein monomer of human insulin is composed of 51 amino acids and has a molecular mass of 5808 Da The molecular formula of human insulin is C257H383N65O77S6 45 It is a combination of two peptide chains dimer named an A chain and a B chain which are linked together by two disulfide bonds The A chain is composed of 21 amino acids while the B chain consists of 30 residues The linking interchain disulfide bonds are formed at cysteine residues between the positions A7 B7 and A20 B19 There is an additional intrachain disulfide bond within the A chain between cysteine residues at positions A6 and A11 The A chain exhibits two a helical regions at A1 A8 and A12 A19 which are antiparallel while the B chain has a central a helix covering residues B9 B19 flanked by the disulfide bond on either sides and two b sheets covering B7 B10 and B20 B23 17 46 The amino acid sequence of insulin is strongly conserved and varies only slightly between species Bovine insulin differs from human in only three amino acid residues and porcine insulin in one Even insulin from some species of fish is similar enough to human to be clinically effective in humans Insulin in some invertebrates is quite similar in sequence to human insulin and has similar physiological effects The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history The C peptide of proinsulin however differs much more among species it is also a hormone but a secondary one 46 Insulin is produced and stored in the body as a hexamer a unit of six insulin molecules while the active form is the monomer The hexamer is about 36000 Da in size The six molecules are linked together as three dimeric units to form symmetrical molecule An important feature is the presence of zinc atoms Zn2 on the axis of symmetry which are surrounded by three water molecules and three histidine residues at position B10 17 46 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 47 Insulin can aggregate and form fibrillar interdigitated beta sheets This can cause injection amyloidosis and prevents the storage of insulin for long periods 48 Function editSecretion edit See also Blood glucose regulation Beta cells in the islets of Langerhans release insulin in two phases The first phase release is rapidly triggered in response to increased blood glucose levels and lasts about 10 minutes The second phase is a sustained slow release of newly formed vesicles triggered independently of sugar peaking in 2 to 3 hours The two phases of the insulin release suggest that insulin granules are present in diverse stated populations or pools During the first phase of insulin exocytosis most of the granules predispose for exocytosis are released after the calcium internalization This pool is known as Readily Releasable Pool RRP The RRP granules represent 0 3 0 7 of the total insulin containing granule population and they are found immediately adjacent to the plasma membrane During the second phase of exocytosis insulin granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release 49 Thus the second phase of insulin release is governed by the rate at which granules get ready for release This pool is known as a Reserve Pool RP The RP is released slower than the RRP RRP 18 granules min RP 6 granules min 50 Reduced first phase insulin release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes 51 First phase release and insulin sensitivity are independent predictors of diabetes 52 The description of first phase release is as follows Glucose enters the b cells through the glucose transporters GLUT 2 At low blood sugar levels little glucose enters the b cells at high blood glucose concentrations large quantities of glucose enter these cells 53 The glucose that enters the b cell is phosphorylated to glucose 6 phosphate G 6 P by glucokinase 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 10 53 Glucose 6 phosphate enters glycolytic pathway and then via the pyruvate dehydrogenase reaction into the Krebs cycle where multiple high energy 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 54 An increased intracellular ATP ADP ratio closes the ATP sensitive SUR1 Kir6 2 potassium channel see sulfonylurea receptor This prevents potassium ions K from leaving the cell by facilitated diffusion leading to a buildup of intracellular potassium ions As a result the inside of the cell becomes less negative with respect to the outside leading to the depolarization of the cell surface membrane Upon depolarization voltage gated calcium ion Ca2 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 55 The calcium ion concentration in the cytosol of the beta cells can also or additionally be increased through the activation of 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 diacylglycerol Inositol 1 4 5 trisphosphate IP3 then binds to receptor proteins in the plasma membrane of the endoplasmic reticulum ER This allows the release of Ca2 ions from the ER via IP3 gated channels which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration Parasympathetic stimulation of the pancreatic islets operates via this pathway to increase insulin secretion into the blood 56 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 secretory 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 57 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 a2 adrenergic receptors 58 and stimulated by b2 adrenergic receptors 59 The net effect of norepinephrine from sympathetic nerves and epinephrine from adrenal glands on insulin release is inhibition due to dominance of the a adrenergic receptors 60 When the glucose level comes down to the usual physiologic value insulin release from the b 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 An insulin spike is a first response to blood glucose increase this response is individual and dose specific although it was always previously assumed to be food type specific only Oscillations edit Main article Insulin oscillations nbsp Insulin release from pancreas oscillates with a period of 3 6 minutes 61 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 p mol l to less than 100 pmol L in rats 61 This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood 61 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 61 This may be achieved by delivering insulin rhythmically to the portal vein by light activated delivery or by islet cell transplantation to the liver 61 62 63 Blood insulin level edit Further information Insulin index nbsp 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 sugar rich versus a starch rich meal is highlighted The blood insulin level can be measured in international units such as µIU mL or in molar concentration such as pmol L where 1 µIU mL equals 6 945 pmol L 64 A typical blood level between meals is 8 11 mIU mL 57 79 pmol L 65 Signal transduction edit The effects of insulin are initiated by its binding to a receptor the insulin receptor IR present in the cell membrane The receptor molecule contains an a and b subunits Two molecules are joined to form what is known as a homodimer Insulin binds to the a subunits of the homodimer which faces the extracellular side of the cells The b subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding This activity provokes the autophosphorylation of the b 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 66 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 PI3K This enzyme converts a phospholipid in the cell membrane by the name of phosphatidylinositol 4 5 bisphosphate PIP2 into phosphatidylinositol 3 4 5 triphosphate PIP3 which in turn activates protein kinase B PKB Activated PKB facilitates the fusion of GLUT4 containing endosomes with the cell membrane resulting in an increase in GLUT4 transporters in the plasma membrane 67 PKB also phosphorylates glycogen synthase kinase GSK thereby inactivating this enzyme 68 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 69 The breakdown of triglycerides by adipose tissue into free fatty acids and glycerol is also inhibited 69 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 41 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 70 Physiological effects edit nbsp 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 nbsp 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 71 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 66 Increased fat synthesis insulin forces fat cells to take in blood glucose which is converted into triglycerides decrease of insulin causes the reverse 71 Increased esterification of fatty acids forces adipose tissue to make neutral fats i e triglycerides from fatty acids decrease of insulin causes the reverse 71 Decreased lipolysis in forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol decrease of insulin causes the reverse 71 Induced glycogen synthesis When glucose levels are high insulin induces the formation of glycogen by the activation of the hexokinase enzyme which adds a phosphate group in glucose thus resulting in a molecule that cannot exit the cell At the same time insulin inhibits the enzyme glucose 6 phosphatase which removes the phosphate group These two enzymes are key for the formation of glycogen Also insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis 72 Decreased gluconeogenesis and glycogenolysis decreases production of glucose from noncarbohydrate substrates primarily in the liver the vast majority of endogenous insulin arriving at the liver never leaves the liver decrease of insulin causes glucose production by the liver from assorted substrates 71 Decreased proteolysis decreasing the breakdown of protein 71 Decreased autophagy decreased level of degradation of damaged organelles Postprandial levels inhibit autophagy completely 73 Increased amino acid uptake forces cells to absorb circulating amino acids decrease of insulin inhibits absorption 71 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 74 Increase in the secretion of hydrochloric acid by parietal cells in the stomach citation needed Increased potassium uptake forces cells synthesizing glycogen a very spongy wet substance that increases the content of intracellular water and its accompanying K ions 75 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 76 77 Decreased renal sodium excretion 78 In hepatocytes insulin binding acutely leads to activation of protein phosphatase 2A PP2A citation needed which dephosphorylates the bifunctional enzyme fructose bisphosphatase 2 PFKB1 79 activating the phosphofructokinase 2 PFK 2 active site PFK 2 increases production of fructose 2 6 bisphosphate Fructose 2 6 bisphosphate allosterically activates PFK 1 which favors glycolysis over gluconeogenesis Increased glycolysis increases the formation of malonyl CoA a molecule that can be shunted into lipogenesis and that allosterically inhibits of carnitine palmitoyltransferase I CPT1 a mitochondrial enzyme necessary for the translocation of fatty acids into the intermembrane space of the mitochondria for fatty acid metabolism 80 Insulin also influences other body functions such as vascular compliance and cognition Once insulin enters the human brain it enhances learning and memory and benefits verbal memory in particular 81 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 homeostatic or regulatory processes in the human body 82 Insulin also has stimulatory effects on gonadotropin releasing hormone from the hypothalamus thus favoring fertility 83 Degradation edit 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 84 It is broken down by the enzyme protein disulfide reductase glutathione 85 which breaks the disulphide bonds between the A and B chains The liver clears most insulin during first pass transit whereas the kidney clears most of the insulin in systemic circulation Degradation normally involves endocytosis of the insulin receptor complex followed by the action of insulin degrading enzyme An insulin molecule produced endogenously by the beta cells is estimated to be degraded within about one hour after its initial release into circulation insulin half life 4 6 minutes 86 87 Regulator of endocannabinoid metabolism edit Insulin is a major regulator of endocannabinoid EC metabolism and insulin treatment has been shown to reduce intracellular ECs the 2 arachidonoylglycerol 2 AG and anandamide AEA which correspond with insulin sensitive expression changes in enzymes of EC metabolism In insulin resistant adipocytes patterns of insulin induced enzyme expression is disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation Findings suggest that insulin resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation whereby obese insulin resistant individuals exhibit increased concentrations of ECs 88 89 This dysregulation contributes to excessive visceral fat accumulation and reduced adiponectin release from abdominal adipose tissue and further to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes 90 Hypoglycemia editMain article Hypoglycemia Hypoglycemia also known as low blood sugar is when blood sugar decreases to below normal levels 91 This may result in a variety of symptoms including clumsiness trouble talking confusion loss of consciousness seizures or death 91 A feeling of hunger sweating shakiness and weakness may also be present 91 Symptoms typically come on quickly 91 The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin and sulfonylureas 92 93 Risk is greater in diabetics who have eaten less than usual exercised more than usual or have consumed alcohol 91 Other causes of hypoglycemia include kidney failure certain tumors such as insulinoma liver disease hypothyroidism starvation inborn error of metabolism severe infections reactive hypoglycemia and a number of drugs including alcohol 91 93 Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours 94 Diseases and syndromes editThere are several conditions in which insulin disturbance is pathologic Diabetes mellitus general term referring to all states characterized by hyperglycemia It can be of the following types 95 Type 1 autoimmune mediated destruction of insulin producing b cells in the pancreas resulting in absolute insulin deficiency Type 2 either inadequate insulin production by the b cells or insulin resistance or both because of reasons not completely understood there is correlation with diet with sedentary lifestyle with obesity with age and with metabolic syndrome Causality has been demonstrated in multiple model organisms including mice and monkeys importantly non obese people do get Type 2 diabetes due to diet sedentary lifestyle and unknown risk factors though it is important to note that this may not be a causal relationship it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions Other types of impaired glucose tolerance see Diabetes Insulinoma a tumor of beta cells producing excess insulin or reactive hypoglycemia 96 Metabolic syndrome a poorly understood condition first called syndrome X by Gerald Reaven It is not clear whether the syndrome has a single treatable cause or is the result of body changes leading to type 2 diabetes It is characterized by elevated blood pressure dyslipidemia disturbances in blood cholesterol forms and other blood lipids and increased waist circumference at least in populations in much of the developed world The basic underlying cause may be the insulin resistance that precedes type 2 diabetes which is a diminished capacity for 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 97 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 98 Medical uses editMain article Insulin medication nbsp Two vials of insulin They have been given trade names Actrapid left and NovoRapid right by the manufacturers Biosynthetic human insulin insulin human rDNA INN for clinical use is manufactured by recombinant DNA technology 13 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 99 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 100 The first biosynthetic insulin analog was developed for clinical use at mealtime prandial insulin Humalog insulin lispro 101 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 102 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 103 104 Insulin is also used in many cell lines such as CHO s HEK 293 or Sf9 for the manufacturing of monoclonal antibodies virus vaccines and gene therapy products 105 Insulin is usually taken as subcutaneous injections by single use syringes with needles via an insulin pump or by repeated use insulin pens with disposable needles Inhaled insulin is also available in the U S market The Dispovan Single Use Pen Needle by HMD 106 is India s first insulin pen needle that makes self administration easy Featuring extra thin walls and a multi bevel tapered point these pen needles prioritise patient comfort by minimising pain and ensuring seamless medication delivery The product aims to provide affordable Pen Needles to the developing part of the country through its wide distribution channel Additionally the universal design of these needles guarantees compatibility with all insulin pens Unlike many medicines insulin cannot be taken by mouth because like nearly all other proteins introduced into the 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 107 108 In 2021 the World Health Organization added insulin to its model list of essential medicines 109 Insulin and all other medications are supplied free of charge to people with diabetes by the National Health Service in the countries of the United Kingdom 110 History of study editDiscovery edit 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 111 The function of the little heaps of cells later known as the islets of Langerhans initially remained unknown but Edouard Laguesse later suggested they might produce secretions that play a regulatory role in digestion 112 Paul Langerhans son Archibald also helped to understand this regulatory role 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 113 114 115 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 demonstrated similar effects at Rockefeller University in 1915 but World War I interrupted his work and he did not return to it 116 In 1916 Nicolae Paulescu developed an aqueous pancreatic extract which when injected into a diabetic dog had a normalizing effect on blood sugar levels He had to interrupt his experiments because of World War I and in 1921 he wrote four papers about his work carried out in Bucharest and his tests on a diabetic dog Later that year he published Research on the Role of the Pancreas in Food Assimilation 117 118 The name insulin was coined by Edward Albert Sharpey Schafer in 1916 for a hypothetical molecule produced by pancreatic islets of Langerhans Latin insula for islet or island that controls glucose metabolism Unbeknown to Sharpey Schafer Jean de Meyer had introduced the very similar word insuline in 1909 for the same molecule 119 120 Extraction and purification edit In October 1920 Canadian Frederick Banting concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion thereby making it impossible to extract successfully A surgeon by training Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy while leaving the islets of Langerhans intact He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone He jotted a note to himself Ligate pancreatic ducts of dog Keep dogs alive till acini degenerate leaving Islets Try to isolate the internal secretion of these relieve glycosurea sic 121 122 nbsp Charles Best and Clark Noble ca 1920In the spring of 1921 Banting traveled to Toronto to explain his idea to John Macleod Professor of Physiology at the University of Toronto Macleod was initially skeptical since Banting had no background in research and was not familiar with the latest literature but he agreed to provide lab space for Banting to test out his ideas Macleod also arranged for two undergraduates to be Banting s lab assistants that summer but Banting required only one lab assistant Charles Best 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 123 On 30 July 1921 Banting and Best successfully isolated an extract isletin from the islets of a duct tied dog and injected it into a diabetic dog finding that the extract reduced its blood sugar by 40 in 1 hour 124 122 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 122 nbsp Chart for Elizabeth Hughes used to track blood urine diet in grams and dietary prescriptions in gramsOn January 11 1922 Leonard Thompson a 14 year old diabetic who lay dying at the Toronto General Hospital was given the first injection of insulin 125 126 127 128 However the extract was so impure that Thompson had a severe 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 eliminating the glycosuria that was typical of diabetes without causing any obvious side effects The first American patient was Elizabeth Hughes the daughter of U S Secretary of State Charles Evans Hughes 129 130 The first patient treated in the U S was future woodcut artist James D Havens 131 John Ralston Williams imported insulin from Toronto to Rochester New York to treat Havens 132 Banting and Best never worked well with Collip regarding him as something of an interloper citation needed 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 isoelectric precipitation and was able to produce large quantities of highly refined insulin Shortly thereafter insulin was offered for sale to the general public Patent edit Toward the end of January 1922 tensions mounted between the four co discoverers of insulin and Collip briefly threatened to separately patent his purification process John G FitzGerald director of the non commercial public health institution Connaught Laboratories therefore stepped in as peacemaker The resulting agreement of 25 January 1922 established two key conditions 1 that the collaborators would sign a contract agreeing not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught and 2 that no changes in research policy would be allowed unless first discussed among FitzGerald and the four collaborators 133 It helped contain disagreement and tied the research to Connaught s public mandate Initially Macleod and Banting were particularly reluctant to patent their process for insulin on grounds of medical ethics However concerns remained that a private third party would hijack and monopolize the research as Eli Lilly and Company had hinted 134 and that safe distribution would be difficult to guarantee without capacity for quality control To this end Edward Calvin Kendall gave valuable advice He had isolated thyroxin at the Mayo Clinic in 1914 and patented the process through an arrangement between himself the brothers Mayo and the University of Minnesota transferring the patent to the public university 135 On April 12 Banting Best Collip Macleod and FitzGerald wrote jointly to the president of the University of Toronto to propose a similar arrangement with the aim of assigning a patent to the Board of Governors of the university 136 The letter emphasized that 137 The patent would not be used for any other purpose than to prevent the taking out of a patent by other persons When the details of the method of preparation are published anyone would be free to prepare the extract but no one could secure a profitable monopoly The assignment to the University of Toronto Board of Governors was completed on 15 January 1923 for the token payment of 1 00 138 The arrangement was congratulated in The World s Work in 1923 as a step forward in medical ethics 139 It has also received much media attention in the 2010s regarding the issue of healthcare and drug affordability Following further concern regarding Eli Lilly s attempts to separately patent parts of the manufacturing process Connaught s Assistant Director and Head of the Insulin Division Robert Defries established a patent pooling policy which would require producers to freely share any improvements to the manufacturing process without compromising affordability 140 Structural analysis and synthesis edit nbsp Richardson diagram of a porcine insulin monomer showing its characteristic secondary structure This is the biologically active form of insulin nbsp Richardson diagram of a porcine insulin hexamer The sphere at the center is a stabilizing zinc atom surrounded by coordinating histidine residues This is the form in which insulin is stored in beta cells PDB 4INS Purified animal sourced insulin was initially the only type of insulin available for experiments and diabetics John Jacob Abel was the first to produce the crystallised form in 1926 141 Evidence of the protein nature was first given by Michael Somogyi Edward A Doisy and Philip A Shaffer in 1924 142 It was fully proven when Hans Jensen and Earl A Evans Jr isolated the amino acids phenylalanine and proline in 1935 143 The amino acid structure of insulin was first characterized in 1951 by Frederick Sanger 18 144 and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the mid 1960s 145 146 147 148 149 Synthetic crystalline bovine insulin was achieved by Chinese researchers in 1965 150 The complete 3 dimensional structure of insulin was determined by X ray crystallography in Dorothy Hodgkin s laboratory in 1969 151 Hans E Weber discovered preproinsulin while working as a research fellow at the University of California Los Angeles in 1974 In 1973 1974 Weber learned the techniques of how to isolate purify and translate messenger RNA To further investigate insulin he obtained pancreatic tissues from a slaughterhouse in Los Angeles and then later from animal stock at UCLA He isolated and purified total messenger RNA from pancreatic islet cells which was then translated in oocytes from Xenopus laevis and precipitated using anti insulin antibodies When total translated protein was run on an SDS polyacrylamide gel electrophoresis and sucrose gradient peaks corresponding to insulin and proinsulin were isolated However to the surprise of Weber a third peak was isolated corresponding to a molecule larger than proinsulin After reproducing the experiment several times he consistently noted this large peak prior to proinsulin that he determined must be a larger precursor molecule upstream of proinsulin In May 1975 at the American Diabetes Association meeting in New York Weber gave an oral presentation of his work 152 where he was the first to name this precursor molecule preproinsulin Following this oral presentation Weber was invited to dinner to discuss his paper and findings by Donald Steiner a researcher who contributed to the characterization of proinsulin A year later in April 1976 this molecule was further characterized and sequenced by Steiner referencing the work and discovery of Hans Weber 153 Preproinsulin became an important molecule to study the process of transcription and translation The first genetically engineered synthetic human insulin was produced using E coli in 1978 by Arthur Riggs and Keiichi Itakura at the Beckman Research Institute of the City of Hope in collaboration with Herbert Boyer at Genentech 14 15 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 15 The vast majority of insulin used worldwide is biosynthetic recombinant human insulin or its analogues 16 Recently another approach has been used by a pioneering group of Canadian researchers using an easily grown safflower plant for the production of much cheaper insulin 154 Recombinant insulin is produced either in yeast usually Saccharomyces cerevisiae or E coli 155 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 edit nbsp Frederick Banting right joined by Charles Best in 1924The Nobel Prize committee in 1923 credited the practical extraction of insulin to a team at the University of Toronto and awarded the Nobel Prize to two men Frederick Banting and John Macleod 156 They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin Banting incensed that Best was not mentioned 157 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 who determined the primary structure of insulin in 1955 was awarded the 1958 Nobel Prize in Chemistry 18 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 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 158 Dorothy Hodgkin was awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography the technique she used for deciphering the complete molecular structure of insulin in 1969 151 Controversy edit nbsp Nicolae PaulescuThe work published by Banting Best Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients 159 Although Paulescu discovered the principles of the treatment his saline extract could not be used on humans he was not mentioned in the 1923 Nobel Prize Ian Murray was particularly active in working to correct the historical wrong against Nicolae Paulescu Murray was a professor of physiology at the Anderson College of Medicine in Glasgow Scotland the head of the department of Metabolic Diseases at a leading Glasgow hospital vice president of the British Association of Diabetes and a founding member of the International Diabetes Federation Murray wrote Insufficient recognition has been given to Paulescu the distinguished Romanian 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 160 In a private communication Arne Tiselius former head of the Nobel Institute expressed his personal opinion that Paulescu was equally worthy of the award in 1923 161 See also editTreatment Conventional insulinotherapy Diabetic coma Insulin therapy Intensive insulinotherapy Insulin pump Anatomy and physiology Leptin 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 Cone Snail venom List of Canadian inventions and discoveriesReferences edit a b c GRCh38 Ensembl release 89 ENSG00000254647 Ensembl May 2017 a b c GRCm38 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Retrieved 25 July 2018 Opie EL 1901 Diabetes Mellitus Associated with Hyaline Degeneration of the islands of Langerhans of the Pancreas Bulletin of the Johns Hopkins Hospital 12 125 263 64 hdl 2027 coo 31924069247447 Opie EL 1901 On the Relation of Chronic Interstitial Pancreatitis to the Islands of Langerhans and to Diabetes Mellitus Journal of Experimental Medicine 5 4 397 428 doi 10 1084 jem 5 4 397 PMC 2118050 PMID 19866952 Opie EL 1901 The Relation of Diabetes Mellitus to Lesions of the Pancreas Hyaline Degeneration of the Islands of Langerhans Journal of Experimental Medicine 5 5 527 40 doi 10 1084 jem 5 5 527 PMC 2118021 PMID 19866956 The American Institute of Nutrition 1967 Proceedings of the Thirty First Annual Meeting of the American Institute of Nutrition Journal of Nutrition 92 4 509 doi 10 1093 jn 92 4 507 Paulesco NC August 31 1921 Recherche sur le role du pancreas dans l assimilation nutritive Archives Internationales de Physiologie 17 85 109 Lestradet H 1997 Le 75e anniversaire de la decouverte de l insuline Diabetes amp Metabolism 23 1 112 de Leiva A Brugues E de Leiva Perez A 2011 The discovery of insulin Continued controversies after ninety years Endocrinologia y Nutricion English Edition 58 9 449 456 doi 10 1016 j endoen 2011 10 001 Vecchio I Tornali C Bragazzi NL Martini M 2018 10 23 The Discovery of Insulin An Important Milestone in the History of Medicine Frontiers in Endocrinology 9 613 doi 10 3389 fendo 2018 00613 PMC 6205949 PMID 30405529 Banting FG 31 October 1920 Note dated Oct 31 20 from loose leaf notebook 1920 21 University of Toronto Libraries a b c Rosenfeld L December 2002 Insulin discovery and controversy Clinical Chemistry 48 12 2270 88 doi 10 1093 clinchem 48 12 2270 PMID 12446492 Wright JR December 2002 Almost famous E Clark Noble the common thread in the discovery of insulin and vinblastine CMAJ 167 12 1391 96 PMC 137361 PMID 12473641 Krishnamurthy K 2002 Pioneers in scientific discoveries Mittal Publications p 266 ISBN 978 81 7099 844 0 Retrieved 26 July 2011 Bliss M July 1993 Rewriting medical history Charles Best and the Banting and Best myth PDF Journal of the History of Medicine and Allied Sciences 48 3 253 74 doi 10 1093 jhmas 48 3 253 PMID 8409364 Work on diabetes shows progress against disease Toronto Star Weekly University of Toronto Libraries 14 Jan 1922 Fletcher AA November 1962 Early clinical experiences with insulin Canadian Medical Association Journal 87 20 1052 5 PMC 1849803 PMID 13945508 Banting FG Dec 1921 Jan 1922 Patient records for Leonard Thompson University of Toronto Libraries Zuger A October 4 2010 Rediscovering the First Miracle Drug The New York Times Retrieved 2010 10 06 Elizabeth Hughes was a cheerful pretty little girl five feet tall with straight brown hair and a consuming interest in birds On Allen s diet her weight fell to 65 pounds then 52 pounds and then after an episode of diarrhea that almost killed her in the spring of 1922 45 pounds By then she had survived three years far longer than expected And then her mother heard the news Insulin had finally been isolated in Canada Banting FG 16 August 1922 Chart for Elizabeth Hughes University of Toronto Libraries Woodbury DO February 1963 Please save my son University of Toronto Libraries Marcotte B November 22 2010 Rochester s John Williams a man of scientific talents Democrat and Chronicle Rochester New York Gannett Company pp 1B 4B Archived from the original on November 23 2010 Retrieved November 22 2010 University of Toronto Board of Governors Insulin Committee 25 Jan 1922 Memorandum in reference to the co operation of the Connaught Antitoxin Laboratories in the researches conducted by Dr Banting Mr Best and Dr Collip under the general direction of Professor J J R Macleod to obtain an extract of pancreas having a specific effect on blood sugar concentration University of Toronto Libraries Bliss M 2007 The discovery of insulin 25th anniversary ed Chicago University of Chicago Press p 132 ISBN 9780226058993 OCLC 74987867 The Lilly company would be delighted to work with Toronto Clowes wrote and hinted perhaps intentionally perhaps not that Toronto could be bypassed I have thus far refrained from starting work in our laboratories on the field of this question as I was anxious to avoid in any way intruding on the field of yourself and your associates until you had published your results I feel however that the matter is now one of such immediate importance that we should take up the experimental end of the question without delay preferably cooperating with you and your associates Kendall EC 10 April 1922 Letter to Dr J J R Macleod 10 04 1922 University of Toronto Libraries Discovery and Early Development of Insulin Macleod JJ 28 April 1924 Statement read by J J R Macleod at the Insulin Committee meeting regarding patents and royalties 28 04 1924 University of Toronto Libraries The Discovery and Early Development of Insulin Bliss M 2007 The discovery of insulin 25th anniversary ed Chicago University of Chicago Press pp 131 133 ISBN 9780226058993 OCLC 74987867 Banting FG Best C Collip JS 15 January 1923 Assignment to the Governors of the University of Toronto University of Toronto Libraries Discovery and Early Development of Insulin Copy of the article A step forward in medical ethics University of Toronto Libraries The Discovery and Early Development of Insulin The World s Work February 1923 Bliss M 2007 The discovery of insulin 25th anniversary ed Chicago University of Chicago Press p 181 ISBN 9780226058993 OCLC 74987867 Abel JJ February 1926 Crystalline Insulin Proceedings of the National Academy of Sciences of the United States of America 12 2 132 6 Bibcode 1926PNAS 12 132A doi 10 1073 pnas 12 2 132 PMC 1084434 PMID 16587069 Somogyi M Doisy EA Shaffer PA May 1924 On the Preparation of Insulin PDF Journal of Biological Chemistry 60 1 31 58 doi 10 1016 S0021 9258 18 85220 6 Jensen H Evans EA 1935 01 01 Studies on Crystalline Insulin Xviii the Nature of the Free Amino Groups in Insulin and the Isolation of Phenylalanine and Proline from Crystalline Insulin PDF Journal of Biological Chemistry 108 1 1 9 doi 10 1016 S0021 9258 18 75301 5 Sanger F Tuppy H September 1951 The amino acid sequence in the phenylalanyl chain of insulin I The identification of lower peptides from partial hydrolysates The Biochemical Journal 49 4 463 81 doi 10 1042 bj0490463 PMC 1197535 PMID 14886310 Sanger F Tuppy H September 1951 The amino acid sequence in the phenylalanyl chain of insulin 2 The investigation of peptides from enzymic hydrolysates The Biochemical Journal 49 4 481 90 doi 10 1042 bj0490481 PMC 1197536 PMID 14886311 Sanger F Thompson EO February 1953 The amino acid sequence in the glycyl chain of insulin I The identification of lower peptides from partial hydrolysates The Biochemical Journal 53 3 353 66 doi 10 1042 bj0530353 PMC 1198157 PMID 13032078 Sanger F Thompson EO February 1953 The amino acid sequence in the glycyl chain of insulin II The investigation of peptides from enzymic hydrolysates The Biochemical Journal 53 3 366 74 doi 10 1042 bj0530366 PMC 1198158 PMID 13032079 Katsoyannis PG Fukuda K Tometsko A Suzuki K Tilak M 1964 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 of the American Chemical Society 86 5 930 32 doi 10 1021 ja01059a043 Kung YT Du YC Huang WT Chen CC Ke LT November 1965 Total synthesis of crystalline bovine insulin Scientia Sinica 14 11 1710 6 PMID 5881570 nbsp Marglin A Merrifield RB November 1966 The synthesis of bovine insulin by the solid phase method Journal of the American Chemical Society 88 21 5051 2 doi 10 1021 ja00973a068 PMID 5978833 Costin GE January 2004 What is the advantage of having melanin in parts of the central nervous system e g substantia nigra IUBMB Life Time Inc 56 1 47 9 doi 10 1080 15216540310001659029 PMID 14992380 S2CID 85423381 Wollmer A Dieken ML Federwisch M De Meyts P 2002 Insulin amp related proteins structure to function and pharmacology Boston Kluwer Academic Publishers ISBN 978 1 4020 0655 5 Tsou CL 2015 对人工合成结晶牛胰岛素的回忆 Memory on the research of synthesizing bovine insulin 生命科学 Chinese Bulletin of Life Science in Simplified Chinese 27 6 777 79 a b Blundell TL Cutfield JF Cutfield SM Dodson EJ Dodson GG Hodgkin DC et al June 1971 Atomic positions in rhombohedral 2 zinc insulin crystals Nature 231 5304 506 11 Bibcode 1971Natur 231 506B doi 10 1038 231506a0 PMID 4932997 S2CID 4158731 Weber H E 1975 Diabetes 24 405 see figure Chan SJ Keim P Steiner DF Cell free synthesis of rat preproinsulins Characterization and partial amino acid sequence determination Proc Natl Acad Sci USA 1976 73 1964 1968 Safflowers may provide new insulin source CTV News www ctvnews ca February 2010 Retrieved 2019 11 12 Kjeldsen T September 2000 Yeast secretory expression of insulin precursors PDF Applied Microbiology and Biotechnology 54 3 277 86 doi 10 1007 s002530000402 PMID 11030562 S2CID 9246671 Archived from the original PDF on 2017 09 27 The Nobel Prize in Physiology or Medicine 1923 The Nobel Foundation Felman A 22 November 2018 Who discovered insulin Medical News Today Castle WB 1962 The Gordon Wilson Lecture A Century of Curiosity About Pernicious Anemia Transactions of the American Clinical and Climatological Association 73 54 80 PMC 2249021 PMID 21408623 Banting FG Best CH Collip JB Campbell WR Fletcher AA March 1922 Pancreatic Extracts in the Treatment of Diabetes Mellitus Canadian Medical Association Journal 12 3 141 46 PMC 1524425 PMID 20314060 Drury MI July 1972 The golden jubile of insulin Journal of the Irish Medical Association 65 14 355 63 PMID 4560502 Murray I April 1971 Paulesco and the isolation of insulin Journal of the History of Medicine and Allied Sciences 26 2 150 57 doi 10 1093 jhmas XXVI 2 150 PMID 4930788 Further reading editLaws GM Reaven A 1999 Insulin resistance the metabolic syndrome X Totowa NJ Humana Press ISBN 978 0 89603 588 1 Leahy JL Cefalu WT 2002 03 22 Insulin Therapy 1st ed New York Marcel Dekker ISBN 978 0 8247 0711 8 Kumar S O Rahilly S 2005 01 14 Insulin Resistance Insulin Action and Its Disturbances in Disease Chichester England Wiley ISBN 978 0 470 85008 4 Ehrlich A Schroeder CL 2000 06 16 Medical Terminology for Health Professions 4th ed Thomson Delmar Learning ISBN 978 0 7668 1297 0 Draznin B LeRoith D September 1994 Molecular Biology of Diabetes Autoimmunity and Genetics Insulin Synthesis and Secretion Totowa New Jersey Humana Press ISBN 978 0 89603 286 6 Misbin RI February 2022 INSULIN History from an FDA Insider Washington DC Politics and Prose Publishing ISBN 978 1 62429 391 7 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 11 1599 624 doi 10 2165 00003495 200161110 00007 PMID 11577797 S2CID 46972328 de Leiva A Brugues E de Leiva Perez A November 2011 The discovery of insulin continued controversies after ninety years Endocrinologia y Nutricion in Spanish 58 9 449 56 doi 10 1016 j endonu 2011 10 001 PMID 22036099 Vecchio I Tornali C Bragazzi NL Martini M 2018 The Discovery of Insulin An Important Milestone in the History of Medicine Frontiers in Endocrinology 9 613 doi 10 3389 fendo 2018 00613 PMC 6205949 PMID 30405529 External links edit nbsp Wikimedia Commons has media related to Insulin University of Toronto Libraries Collection Discovery and Early Development of Insulin 1920 1925 CBC Digital Archives Banting Best Macleod Collip Chasing a Cure for Diabetes Animations of insulin s action in the body at AboutKidsHealth ca archived 9 March 2011 Overview of all the structural information available in the PDB for UniProt P01308 Insulin at the PDBe KB Retrieved from https en wikipedia org w index php title Insulin amp oldid 1206500691, wikipedia, wiki, book, books, library,

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