text:
Insulin
From Wikipedia, the free encyclopedia
Jump to: navigation, search
This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin (medication).
Not to be confused with Inulin.
INS
Available structures
PDB
Ortholog search: PDBe RCSB
[show]List of PDB id codes
1A7F, 1AI0, 1AIY, 1B9E, 1BEN, 1EFE, 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, 1SJT, 1SJU, 1T0C, 1T1K, 1T1P, 1T1Q, 1TRZ, 1TYL, 1TYM, 1UZ9, 1VKT, 1W8P, 1XDA, 1XGL, 1XW7, 1ZEG, 1ZEH, 1ZNJ, 2AIY, 2C8Q, 2C8R, 2CEU, 2G54, 2G56, 2H67, 2HH4, 2HHO, 2HIU, 2JMN, 2JUM, 2JUU, 2JUV, 2JV1, 2JZQ, 2K91, 2K9R, 2KJJ, 2KJU, 2KQP, 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, 3HYD, 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, 2OMQ, 4CXL, 4CXN, 4CY7, 4IYD, 4IYF, 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
Identifiers
Aliases
INS, IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10, insulin
External IDs
MGI: 96573 HomoloGene: 173 GeneCards: INS
[hide]Gene location (Human)
Chr.
Chromosome 11 (human)[1]
Band
11p15.5
Start
2,159,779 bp[1]
End
2,161,341 bp[1]
[show]Gene location (Mouse)
Chr.
Chromosome 7 (mouse)[2]
Band
7 F5|7 88.0 cM
Start
142,678,656 bp[2]
End
142,743,381 bp[2]
[hide]RNA expression pattern
More reference expression data
[show]Gene ontology
Molecular function
• insulin receptor binding
• identical protein binding
• protease binding
• insulin-like growth factor receptor binding
• protein binding
• hormone activity
Cellular component
• endoplasmic reticulum lumen
• transport vesicle
• Golgi membrane
• secretory granule lumen
• Golgi lumen
• endoplasmic reticulum-Golgi intermediate compartment membrane
• endosome lumen
• extracellular region
• extracellular space
Biological process
• negative 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 cytokine secretion
• 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
• cellular protein metabolic process
• 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
• glucose transport
• regulation of cellular amino acid metabolic process
• negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
• ER 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 proliferation
• fatty acid homeostasis
• positive regulation of cellular 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
• positive regulation of blood vessel diameter
• negative regulation of blood vessel diameter
• regulation of receptor activity
• response to L-arginine
Sources:Amigo / QuickGO
Orthologs
Species
Human Mouse
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)
[show]NP_000198
NP_001172026
NP_001172027
NP_001278826
NP_000198.1
NP_001172026.1
NP_001172027.1
NP_001278826.1
NP_001172012
NP_001172013
NP_032413
Location (UCSC)
Chr 11: 2.16 – 2.16 Mb Chr 11: 142.68 – 142.74 Mb
PubMed search
[3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Insulin (from Latin insula, island) is a peptide hormone produced by beta cells of the pancreatic islets, and it is considered to be the main anabolic hormone of the body.[5] It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells.[6] 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.[6] Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood.[7] 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.
Beta cells are sensitive to glucose concentrations, also known as blood sugar levels. When the glucose level is high, the beta cells secrete insulin into the blood; when glucose levels are low, secretion of insulin is inhibited.[8] Their neighboring alpha cells, by taking their cues from the beta cells,[8] secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high.[6][8] Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin.[6][8] The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis.[8]
If beta cells are destroyed by an autoimmune reaction, insulin can no longer be synthesized or be secreted into the blood. This results in type 1 diabetes mellitus, which is characterized by abnormally high blood glucose concentrations, and generalized body wasting.[9] In type 2 diabetes mellitus the destruction of beta cells is less pronounced than in type 1 diabetes, and is not due to an autoimmune process. Instead there is an accumulation of amyloid in the pancreatic islets, which likely disrupts their anatomy and physiology.[8] The pathogenesis of type 2 diabetes is not well understood but patients exhibit a reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive and peripheral tissue insulin resistance.[5] Type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, and unresponsive to the concentration of glucose in the blood glucose. Insulin is still secreted into the blood in response to the blood glucose.[8] As a result, the insulin levels, even when the blood sugar level is normal, are much higher than they are in healthy persons. There are a variety of treatment regimens, none of which is entirely satisfactory. When the pancreas’s capacity to secrete insulin can no longer keep the blood sugar level within normal bounds, insulin injections are given.[10]
The human insulin protein is composed of 51 amino acids, and has a molecular mass of 5808 Da. It is a dimer 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 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.[11][12][13][14]
The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[15]
Contents
[hide]
1 Evolution and species distribution
2 Gene
2.1 Alleles
2.2 Regulation
3 Protein structure
4 Synthesis, physiological effects, and degradation
4.1 Synthesis
4.2 Release
4.3 Oscillations
4.4 Blood insulin level
4.5 Signal transduction
4.6 Physiological effects
4.7 Degradation
4.8 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 Synthesis
8.4 Nobel Prize
8.4.1 Controversy
9 See also
10 References
11 Further reading
12 External links
Evolution and species distribution[edit]
Insulin may have originated more than a billion years ago.[16] The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.[17] Apart from animals, insulin-like proteins are also known to exist in the Fungi and Protista kingdoms.[16]
Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish.[18] 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.[19][20]
Gene[edit]
The preproinsulin precursor of insulin is encoded by the INS gene.[21][22]
Alleles[edit]
A variety of mutant alleles with changes in the coding region have been identified. A read-through gene, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.[21]
Regulation[edit]
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.
Regulatory sequences and their transcription factors for the insulin gene.[23]
Regulatory sequence
binding transcription factors
ILPR Par1
A5 Pdx1
negative regulatory element (NRE)[24] glucocorticoid receptor, Oct1
Z (overlapping NRE and C2) ISF
C2 Pax4, MafA(?)
E2 USF1/USF2
A3 Pdx1
CREB RE –
CREB RE CREB, CREM
A2 –
CAAT enhancer binding (CEB) (partly overlapping A2 and C1) –
C1 –
E1 E2A, NeuroD1, HEB
A1 Pdx1
G1 –
Protein structure[edit]
See also: Insulin/IGF/Relaxin family and Insulin and its analog structure
Within vertebrates, the amino acid sequence of insulin is strongly conserved. 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 (discussed later), however, differs much more among species; it is also a hormone, but a secondary one.
SS-linked insulin monomer
The primary structure of bovine insulin was first determined by Frederick Sanger in 1951.[25] After that, this polypeptide was synthesized independently by several groups.[26][27][28] The 3-dimensional structure of insulin was determined by X-ray crystallography in Dorothy Hodgkin's laboratory in 1969 (PDB file 1ins).[29]
Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is an inactive form with long-term stability, which serves as a way to keep the highly reactive insulin protected, yet readily available. The hexamer-monomer conversion is one of the central aspects of insulin formulations for injection. The hexamer is far more stable than the monomer, which is desirable for practical reasons; however, the monomer is a much faster-reacting drug because diffusion rate is inversely related to particle size. A fast-reacting drug means insulin injections do not have to precede mealtimes by hours, which in turn gives people with diabetes more flexibility in their daily schedules.[30] Insulin can aggregate and form fibrillar interdigitated beta-sheets. This can cause injection amyloidosis, and prevents the storage of insulin for long periods.[31]
Synthesis, physiological effects, and degradation[edit]
Synthesis[edit]
Insulin is produced in the pancreas and the Brockmann body (in some fish), and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food.[32] Carbohydrates can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response.
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
In mammals, insulin is synthesized in the pancreas within the beta cells. One million to three million pancreatic islets form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the pancreatic islets, beta cells constitute 65–80% of all the cells.
Insulin consists of two polypeptide chains, the A- and B- chains, linked together by disulfide bonds. It is however first synthesized as a single polypeptide called preproinsulin in beta cells. Preproinsulin contains a 24-residue signal peptide which directs the nascent polypeptide chain to the rough endoplasmic reticulum (RER). The signal peptide is cleaved as the polypeptide is translocated into lumen of the RER, forming proinsulin.[33] In the RER the proinsulin folds into the correct conformation and 3 disulfide bonds are formed. About 5–10 min after its assembly in the endoplasmic reticulum, proinsulin is transported to the trans-Golgi network (TGN) where immature granules are formed. Transport to the TGN may take about 30 min.
Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E.[34] The endopeptidases cleave at 2 positions, releasing a fragment called the C-peptide, and leaving 2 peptide chains, the B- and A- chains, linked by 2 disulfide bonds. The cleavage sites are each located after a pair of basic residues (lysine-64 and arginine-65, and arginine-31 and −32). After cleavage of the C-peptide, these 2 pairs of basic residues are removed by the carboxypeptidase.[35] The C-peptide is the central portion of proinsulin, and the primary sequence of proinsulin goes in the order "B-C-A" (the B and A chains were identified on the basis of mass and the C-peptide was discovered later).
The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the cell into the circulation.[36]
The endogenous production of insulin is regulated in several steps along the synthesis pathway:
At transcription from the insulin gene
In mRNA stability
At the mRNA translation
In the posttranslational modifications
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.[37][38][39]
Release[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. Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes.[40] First-phase release and insulin sensitivity are independent predictors of diabetes.[41]
The description of first phase release is as follows:
Glucose enters the β-cells through the glucose transporters, GLUT2. These glucose transporters have a relatively low affinity for glucose, ensuring that the rate of glucose entry into the β-cells is proportional to the extracellular glucose concentration (within the physiological range). At low blood sugar levels very little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells.[42]
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.[8][42]
Glucose-6-phosphate enters glycolytic pathway and then, via the pyruvate carboxylase 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.[43]
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.[44]
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.[45]
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),[46] 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[47] and stimulated by β2-adrenergic receptors.[48] 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.[49]
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 a slow drop over the next 100 minutes, to remain above 120 mg/100 ml after two hours after the start of the test. In a normal person the blood glucose level is corrected (and may even be slightly over-corrected) by the end of the test.
Oscillations[edit]
Main article: Insulin oscillations
Insulin release from pancreas oscillates with a period of 3–6 minutes.[50]
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 pmol/l to less than 100 pmol/l.[50] This is thought to avoid downregulation of insulin receptors in target cells, and to assist the liver in extracting insulin from the blood.[50] 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.[50] This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver.[50]
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.[51] A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).[52]
Signal transduction[edit]
The effects of insulin are initiated by its binding to a receptor present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer. Insulin binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin.[53]
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.[54] PKB also phosphorylates glycogen synthase kinase (GSK), thereby inactivating this enzyme.[55] 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.[56] The breakdown of triglycerides by adipose tissue into free fatty acids and glycerol is also inhibited.[56]
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.[36] 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.[57]
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:
Increase of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells)[58]
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 cell. 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.[53]
Induce glycogen synthesis – When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphate group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis.[59]
Increased potassium uptake – forces cells synthesizing glycogen (a very spongy, "wet" substance, that increases the content of intracellular water, and its accompanying K+ ions)[60] 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.[61][62]
Decreased gluconeogenesis and glycogenolysis – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); increase of insulin causes glucose production by the liver from assorted substrates.[58]
Increased lipid synthesis – insulin forces fat cells to take in blood glucose, which is converted into triglycerides; decrease of insulin causes the reverse.[58]
Increased esterification of fatty acids – forces adipose tissue to make neutral fats (i.e., triglycerides) from fatty acids; decrease of insulin causes the reverse.[58]
Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease of insulin causes the reverse.[58]
Decreased proteolysis – decreasing the breakdown of protein[58]
Decreased autophagy – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.[63]
Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption.[58]
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.[citation needed]
Increase in the secretion of hydrochloric acid by parietal cells in the stomach.[citation needed]
Decreased renal sodium excretion.[64]
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.[65] 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.[66] Insulin also has stimulatory effects on gonadotropin-releasing hormone from the hypothalamus, thus favoring fertility.[67]
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. 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).[68][69]
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-arachidonylglycerol (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.[70][71] 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.[72]
Hypoglycemia[edit]
Main article: Hypoglycemia
Although other cells can use other fuels (most prominently fatty acids), neurons depend on glucose as a source of energy, unless the person is in ketosis. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in triglycerides can also be used to produce blood glucose.
Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the central nervous system: dizziness, speech problems, and even loss of consciousness. Low blood glucose level is known as hypoglycemia or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an insulinoma) are very rare, and the overwhelming majority of insulin excess-induced hypoglycemia cases are iatrogenic and usually accidental. A few cases of murder, attempted murder, or suicide using insulin overdoses have been reported, but most insulin shocks appear to be due to errors in dosage of insulin (e.g., 20 units instead of 2) or other unanticipated factors (did not eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself).
Possible causes of hypoglycemia include:
External insulin (usually injected subcutaneously)
Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin release from β-cells in response to a particular blood glucose level)
Ingestion of low-carbohydrate sugar substitutes in people without diabetes or with type 2 diabetes. Animal studies show these can trigger insulin release, albeit in much smaller quantities than sugar, according to a report in Discover magazine, August 2004, p 18. (This can never be a cause of hypoglycemia in patients with mature type 1 diabetes, since there is no endogenous insulin production to stimulate. It can occur during the honeymoon period, a period up to several years after a type 1 diabetes diagnosis during which endogenous insulin production still occurs.)
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
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.
it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions
Other types of impaired glucose tolerance (see the Diabetes)
Insulinoma – a tumor of beta cells producing excess insulin or reactive hypoglycemia.
Metabolic syndrome – a poorly understood condition first called Syndrome X by Gerald Reaven. It is currently not clear whether the syndrome has a single, treatable cause, or is the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance that precedes type 2 diabetes, which is a diminished capacity for insulin response in some tissues (e.g., muscle, fat). It is common for morbidities such as essential hypertension, obesity, type 2 diabetes, and cardiovascular disease (CVD) to develop.
Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where anovulation and androgen excess are commonly displayed as hirsutism. In many cases of PCOS, insulin resistance is present.
Medical uses[edit]
Main article: Insulin (medication)
A vial of insulin. It has been given a trade name, Actrapid, by the manufacturer.
Biosynthetic human insulin (insulin human rDNA, INN) for clinical use is manufactured by recombinant DNA technology.[11] 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.[73] 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).[74] The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), Humalog (insulin lispro),[citation needed] it is more rapidly absorbed after subcutaneous injection than regular insulin, with an effect 15 minutes after injection. Other rapid-acting analogues are NovoRapid and Apidra, with similar profiles. All are rapidly absorbed due to amino acid sequences that will reduce formation of dimers and hexamers (monomeric insulins are more rapidly absorbed). Fast acting insulins do not require the injection-to-meal interval previously recommended for human insulin and animal insulins. The other type is long acting insulin; the first of these was Lantus (insulin glargine). These have a steady effect for an extended period from 18 to 24 hours. Likewise, another protracted insulin analogue (Levemir) is based on a fatty acid acylation approach. A myristyric acid molecule is attached to this analogue, which associates the insulin molecule to the abundant serum albumin, which in turn extends the effect and reduces the risk of hypoglycemia. Both protracted analogues need to be taken only once daily, and are used for type 1 diabetics as the basal insulin. A combination of a rapid acting and a protracted insulin is also available, making it more likely for patients to achieve an insulin profile that mimics that of the body´s own insulin release.
Insulin is usually taken as subcutaneous 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 now.
Synthetic insulin can trigger adverse effects, so some people with diabetes rely on animal-source insulin.[75]
Unlike many medicines, insulin currently cannot be taken orally 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.[76][77]
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. 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. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term "insulin" originates from insula, the Latin word for islet/island.
In 1889, the physician Oskar Minkowski, in collaboration with Joseph von Mering, removed the pancreas from a healthy dog to test its assumed role in digestion. On testing the urine, they found sugar, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by the American physician and scientist Eugene Lindsay Opie, when he established the link between the islets of Langerhans and diabetes: "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".[78][79][80] Before Opie's work, medical science had clearly established the link between the pancreas and diabetes, but not the specific role of the islets.
The structure of insulin. The left side is a space-filling model of the insulin monomer, believed to be biologically active. Carbon is green, hydrogen white, oxygen red, and nitrogen blue. On the right side is a ribbon diagram of the insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions.
Over the next two decades researchers made several attempts to isolate – as a potential treatment – whatever the islets produced. 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 used aqueous pancreatic extracts, and noted "a slight diminution of glycosuria", but was unable to convince his director of his work's value; it was shut down. Israel Kleiner demonstrated similar effects at Rockefeller University in 1915, but World War I interrupted his work and he did not return to it.[81]
In 1916, Nicolae Paulescu, a Romanian professor of physiology at the University of Medicine and Pharmacy in Bucharest, 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".[82][83]
Extraction and purification[edit]
This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2017) (Learn how and when to remove this template message)
In October 1920, Canadian Frederick Banting concluded that it was the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. He jotted a note to himself: "Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea."
The idea was the pancreas's internal secretion, which, it was supposed, regulates sugar in the bloodstream, might hold the key to the treatment of diabetes. A surgeon by training, Banting knew certain arteries could be tied off that would lead to atrophy of most of the pancreas, while leaving the islets of Langerhans intact. He theorized a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone.
In the spring of 1921, Banting traveled to Toronto to explain his idea to J.J.R. Macleod, Professor of Physiology at the University of Toronto, and asked Macleod if he could use his lab space to test the idea. Initially skeptical, Macleod eventually agreed and supplied Banting with ten test animals (dogs) and two medical students, Charles Best and Clark Noble, as lab assistants. Since Banting required only one lab assistant, Best and Noble flipped a coin to see which would assist Banting for the first half of the summer. Best won the coin toss and took the first shift. This may have proved unfortunate for Noble, as Banting decided to keep Best for the entire summer and eventually shared half his Nobel Prize money and a large part of the credit for the discovery.[84] Banting's method was to tie a ligature around the pancreatic duct; when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called "isletin" (what we now know as insulin), and tested this extract on the dogs starting July 27.[85] Banting and Best were then able to keep a pancreatectomized dog named Marjorie alive for the rest of the summer by injecting her with the crude extract they had prepared. Removal of the pancreas in test animals in essence mimics diabetes, leading to elevated blood glucose levels. Marjorie was able to remain alive because the extracts, containing isletin, were able to lower her blood glucose levels.
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 then supplied Banting and Best with 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. However, six weeks required to extract the isletin forced considerable delays. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands; he was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the biochemist James Collip to help with this task, and, within a month, the team felt ready for a clinical test.
On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin.[86] However, the extract was so impure, Thompson suffered a severe allergic reaction, and further injections were canceled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on January 23. This was completely successful, not only in having no obvious side-effects but also in completely eliminating the glycosuria sign of diabetes. The first American patient was Elizabeth Hughes Gossett, the daughter of U.S. Secretary of State Charles Evans Hughes.[87] The first patient treated in the U.S. was future woodcut artist James D. Havens; Dr. John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens.[88]
Children dying from diabetic ketoacidosis were kept in large wards, often with 50 or more patients in a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until then, inevitable) death.
Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after.
Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly's head chemist, George B. Walden discovered isoelectric precipitation and was able to produce large quantities of highly refined insulin. Insulin was offered for sale shortly thereafter.
Synthesis[edit]
Purified animal-sourced insulin was the only type of insulin available to diabetics until genetic advances occurred later with medical research. The amino acid structure of insulin was characterized in the early 1950s by Frederick Sanger,[89] and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the early 1960s.[90][91]
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.[12][13] 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.[13] The vast majority of insulin currently used worldwide is now biosynthetic recombinant "human" insulin or its analogues.[14]
Recombinant insulin is produced either in yeast (usually Saccharomyces cerevisiae) or E. coli.[92] 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 Prize[edit]
Frederick Banting joined by Charles Best in office, 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 J.J.R. Macleod.[93] They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin. Banting, insulted that Best was not mentioned, shared his prize with him, and Macleod immediately shared his with James Collip. The patent for insulin was sold to the University of Toronto for one half-dollar.
The primary structure of insulin was determined by British molecular biologist Frederick Sanger.[89] It was the first protein to have its sequence be determined. He was awarded the 1958 Nobel Prize in Chemistry for this work.
In 1969, after decades of work, Dorothy Hodgkin determined the spatial conformation of the molecule, the so-called tertiary structure, by means of X-ray diffraction studies. She had been awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography.
Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for insulin.
George Minot, co-recipient of the 1934 Nobel Prize for the development of the first effective treatment for pernicious anemia, had diabetes mellitus. Dr. William 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.[94]
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.[95] Although Paulescu discovered the principles of the treatment, his saline extract could not be used on humans; he was not mentioned in the 1923 Nobel Prize. Professor Ian Murray was particularly active in working to correct "the historical wrong" against Nicolae Paulescu. Murray was a professor of physiology at the Anderson College of Medicine in Glasgow, Scotland, the head of the department of Metabolic Diseases at a leading Glasgow hospital, vice-president of the British Association of Diabetes, and a founding member of the International Diabetes Federation. Murray wrote:
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.[96]
In a private communication Professor Tiselius, former head of the Nobel Institute, expressed his personal opinion that Paulescu was equally worthy of the award in 1923.[97]
See also[edit]
Insulin analog
Anatomy and physiolology
Pancreas
Islets of Langerhans
Endocrinology
Leptin
Forms of diabetes mellitus
Diabetes mellitus
Diabetes mellitus type 1
Diabetes mellitus type 2
Treatment
Diabetic coma
Insulin therapy
Intensive insulinotherapy
Insulin pump
Conventional insulinotherapy
Other medical / diagnostic uses
Insulin tolerance test
Triple bolus test
Insulin Signal Transduction pathway
Insulin signal transduction pathway and regulation of blood glucose
References[edit]
^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000254647 - Ensembl, May 2017
^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000000215 - Ensembl, May 2017
Jump up ^ "Human PubMed Reference:".
Jump up ^ "Mouse PubMed Reference:".
^ Jump up to: a b Voet D, Voet JG. (2011). Biochemistry (4th ed.). New York: Wiley.
^ Jump up to: a b c d Stryer, Lubert (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. pp. 773–774. ISBN 0 7167 2009 4.
Jump up ^ Sonksen P, Sonksen J (July 2000). "Insulin: understanding its action in health and disease". British Journal of Anaesthesia. 85 (1): 69–79. doi:10.1093/bja/85.1.69. PMID 10927996.
^ Jump up to: a b c d e f g h Koeslag JH, Saunders PT, Terblanche E (June 2003). "A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex". The Journal of Physiology (published 2003). 549 (Pt 2): 333–46. doi:10.1113/jphysiol.2002.037895. PMC 2342944  . PMID 12717005.
Jump up ^ American Society of Health-System Pharmacists (2009-02-01). "Insulin Injection". PubMed Health. National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 2012-10-12.
Jump up ^ "Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus" – via PMID 20091571.
^ Jump up to: a b Drug Information Portal NLM – Insulin human USAN http://druginfo.nlm.nih.gov/drugportal/
^ Jump up to: a b "First Successful Laboratory Production of Human Insulin Announced". News Release. Genentech. 1978-09-06. Retrieved 2016-09-26.
^ Jump up to: a b c Tof I (1994). "Recombinant DNA technology in the synthesis of human insulin". Little Tree Publishing. Retrieved 2009-11-03.
^ Jump up to: a b Aggarwal SR (December 2012). "What's fueling the biotech engine-2011 to 2012". Nature Biotechnology. 30 (12): 1191–7. doi:10.1038/nbt.2437. PMID 23222785.
Jump up ^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
^ Jump up to: a b de Souza AM, López JA (2004). "Insulin or insulin-like studies on unicellular organisms: a review". Braz. arch. biol. technol. 47 (6): 973–981. doi:10.1590/S1516-89132004000600017.
Jump up ^ LeRoith D, Shiloach J, Heffron R, Rubinovitz C, Tanenbaum R, Roth J (August 1985). "Insulin-related material in microbes: similarities and differences from mammalian insulins". Canadian Journal of Biochemistry and Cell Biology = Revue Canadienne de Biochimie et Biologie Cellulaire. 63 (8): 839–49. doi:10.1139/o85-106. PMID 3933801.
Jump up ^ Wright JR, Yang H, Hyrtsenko O, Xu BY, Yu W, Pohajdak B (2014). "A review of piscine islet xenotransplantation using wild-type tilapia donors and the production of transgenic tilapia expressing a "humanized" tilapia insulin". Xenotransplantation. 21 (6): 485–95. doi:10.1111/xen.12115. PMC 4283710  . PMID 25040337.
Jump up ^ "Deadly sea snail uses weaponised insulin to make its prey sluggish". The Guardian. 19 January 2015.
Jump up ^ Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM (February 2015). "Specialized insulin is used for chemical warfare by fish-hunting cone snails". Proceedings of the National Academy of Sciences of the United States of America. 112 (6): 1743–8. doi:10.1073/pnas.1423857112. PMC 4330763  . PMID 25605914.
^ Jump up to: a b "Entrez Gene: INS insulin".
Jump up ^ Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". Nature. 284 (5751): 26–32. doi:10.1038/284026a0. PMID 6243748.
Jump up ^ Melloul D, Marshak S, Cerasi E (March 2002). "Regulation of insulin gene transcription". Diabetologia. 45 (3): 309–26. doi:10.1007/s00125-001-0728-y. PMID 11914736.
Jump up ^ Jang WG, Kim EJ, Park KG, Park YB, Choi HS, Kim HJ, Kim YD, Kim KS, Lee KU, Lee IK (January 2007). "Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha". Biochemical and Biophysical Research Communications. 352 (3): 716–21. doi:10.1016/j.bbrc.2006.11.074. PMID 17150186.
Jump up ^ 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.
Jump up ^ 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): 930–932. doi:10.1021/ja01059a043.
Jump up ^ 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.
Jump up ^ 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.
Jump up ^ Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DC, Mercola DA, Vijayan M (June 1971). "Atomic positions in rhombohedral 2-zinc insulin crystals". Nature. 231 (5304): 506–11. doi:10.1038/231506a0. PMID 4932997.
Jump up ^ Dunn MF (August 2005). "Zinc-ligand interactions modulate assembly and stability of the insulin hexamer – a review". Biometals. 18 (4): 295–303. doi:10.1007/s10534-005-3685-y. PMID 16158220.
Jump up ^ Ivanova MI, Sievers SA, Sawaya MR, Wall JS, Eisenberg D (November 2009). "Molecular basis for insulin fibril assembly". Proceedings of the National Academy of Sciences of the United States of America. 106 (45): 18990–5. doi:10.1073/pnas.0910080106. PMC 2776439  . PMID 19864624.
Jump up ^ Rhoades RA, Bell DR (2009). Medical physiology : principles for clinical medicine (3rd ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 644–647. ISBN 978-0-7817-6852-8.
Jump up ^ C. Ronald Kahn; et al. (2005). Joslin's Diabetes Mellitus (14th ed.). Lippincott Williams & Wilkins. ISBN 978-8493531836.
Jump up ^ Steiner DF, Oyer PE (February 1967). "The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma". Proceedings of the National Academy of Sciences of the United States of America. 57 (2): 473–80. doi:10.1073/pnas.57.2.473. PMC 335530  . PMID 16591494.
Jump up ^ Thomas E Creighton (1993). Proteins: Structures and Molecular Properties (2nd ed.). W H Freeman and Company. pp. 81–83. ISBN 0-7167-2317-4.
^ Jump up to: a b Najjar S (2001). "Insulin Action: Molecular Basis of Diabetes". Encyclopedia of Life Sciences. John Wiley & Sons. doi:10.1038/npg.els.0001402. ISBN 0470016175.
Jump up ^ Gustin N (2005-03-07). "Researchers discover link between insulin and Alzheimer's". EurekAlert!. American Association for the Advancement of Science. Retrieved 2009-01-01.
Jump up ^ de la Monte SM, Wands JR (February 2005). "Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease". Journal of Alzheimer's Disease. 7 (1): 45–61. PMID 15750214.
Jump up ^ Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (February 2005). "Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes?". Journal of Alzheimer's Disease. 7 (1): 63–80. PMID 15750215.
Jump up ^ Gerich JE (February 2002). "Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?". Diabetes. 51 (Suppl 1): S117–21. doi:10.2337/diabetes.51.2007.s117. PMID 11815469.
Jump up ^ Lorenzo C, Wagenknecht LE, Rewers MJ, Karter AJ, Bergman RN, Hanley AJ, Haffner SM (September 2010). "Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS)". Diabetes Care. 33 (9): 2098–103. doi:10.2337/dc10-0165. PMC 2928371  . PMID 20805282.
^ Jump up to: a b Schuit F, Moens K, Heimberg H, Pipeleers D (November 1999). "Cellular origin of hexokinase in pancreatic islets". The Journal of Biological Chemistry (published 1999). 274 (46): 32803–9. doi:10.1074/jbc.274.46.32803. PMID 10551841.
Jump up ^ Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T, Prentki M (July 1997). "Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells". The Journal of Biological Chemistry (published 1997). 272 (30): 18572–9. doi:10.1074/jbc.272.30.18572. PMID 9228023.
Jump up ^ Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR (May 2015). "Calcium release channel RyR2 regulates insulin release and glucose homeostasis". The Journal of Clinical Investigation. 125 (5): 1968–78. doi:10.1172/JCI79273. PMC 4463204  . PMID 25844899.
Jump up ^ Stryer L (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. pp. 343–344. ISBN 0 7167 2009 4.
Jump up ^ Cawston EE, Miller LJ (March 2010). "Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor". British Journal of Pharmacology. 159 (5): 1009–21. doi:10.1111/j.1476-5381.2009.00489.x. PMC 2839260  . PMID 19922535.
Jump up ^ Nakaki T, Nakadate T, Kato R (August 1980). "Alpha 2-adrenoceptors modulating insulin release from isolated pancreatic islets". Naunyn-Schmiedeberg's Archives of Pharmacology. 313 (2): 151–3. doi:10.1007/BF00498572. PMID 6252481.
Jump up ^ Layden BT, Durai V, Lowe WL Jr (2010). "G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes". Nature Education. 3 (9): 13.
Jump up ^ Sircar S (2007). Medical Physiology. Stuttgart: Thieme Publishing Group. pp. 537–538. ISBN 3-13-144061-9.
^ Jump up to: a b c d e Hellman B, Gylfe E, Grapengiesser E, Dansk H, Salehi A (2007). "[Insulin oscillations—clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release]". Läkartidningen (in Swedish). 104 (32–33): 2236–9. PMID 17822201.
Jump up ^ A Dictionary of Units of Measurement Archived 2013-10-28 at the Wayback Machine. By Russ Rowlett, the University of North Carolina at Chapel Hill. June 13, 2001
Jump up ^ Iwase H, Kobayashi M, Nakajima M, Takatori T (January 2001). "The ratio of insulin to C-peptide can be used to make a forensic diagnosis of exogenous insulin overdosage". Forensic Science International. 115 (1–2): 123–7. doi:10.1016/S0379-0738(00)00298-X. PMID 11056282.
^ Jump up to: a b "Handbook of Diabetes, 4th Edition, Excerpt #4: Normal Physiology of Insulin Secretion and Action". Diabetes In Control. A free weekly diabetes newsletter for Medical Professionals. 2014-07-28. Retrieved 2017-06-01.
Jump up ^ McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR (April 2005). "Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis". The EMBO Journal. 24 (8): 1571–83. doi:10.1038/sj.emboj.7600633. PMC 1142569  . PMID 15791206.
Jump up ^ Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB (October 2000). "Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A". Proceedings of the National Academy of Sciences of the United States of America. 97 (22): 11960–5. doi:10.1073/pnas.220413597. PMC 17277  . PMID 11035810.
^ Jump up to: a b Stryer, Lubert (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. pp. 351–356, 494–495, 505, 605–606, 773–775. ISBN 0 7167 2009 4.
Jump up ^ Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Záková L, Kletvíková E, Jiráček J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC (January 2013). "How insulin engages its primary binding site on the insulin receptor". Nature. 493 (7431): 241–5. doi:10.1038/nature11781. PMC 3793637  . PMID 23302862. Lay summary – Australian Broadcasting Commission.
^ Jump up to: a b c d e f g Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA (August 2011). "Insulin effects in muscle and adipose tissue" (PDF). Diabetes Research and Clinical Practice. 93 Suppl 1: S52–9. doi:10.1016/S0168-8227(11)70014-6. PMID 21864752.
Jump up ^ "Physiologic Effects of Insulin". www.vivo.colostate.edu. Retrieved 2017-06-01.
Jump up ^ Kreitzman SN, Coxon AY, Szaz KF (July 1992). "Glycogen storage: illusions of easy weight loss, excessive weight regain, and distortions in estimates of body composition". The American Journal of Clinical Nutrition. 56 (1 Suppl): 292S–293S. PMID 1615908.
Jump up ^ Benziane B, Chibalin AV (September 2008). "Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm". American Journal of Physiology. Endocrinology and Metabolism. 295 (3): E553–8. doi:10.1152/ajpendo.90261.2008. PMID 18430962.
Jump up ^ Clausen T (September 2008). "Regulatory role of translocation of Na+-K+ pumps in skeletal muscle: hypothesis or reality?". American Journal of Physiology. Endocrinology and Metabolism. 295 (3): E727–8; author reply 729. doi:10.1152/ajpendo.90494.2008. PMID 18775888.
Jump up ^ Bergamini E, Cavallini G, Donati A, Gori Z (October 2007). "The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction". Annals of the New York Academy of Sciences. 1114: 69–78. doi:10.1196/annals.1396.020. PMID 17934054.
Jump up ^ Gupta AK, Clark RV, Kirchner KA (January 1992). "Effects of insulin on renal sodium excretion". Hypertension. 19 (1 Suppl): I78–82. doi:10.1161/01.HYP.19.1_Suppl.I78. PMID 1730458.
Jump up ^ Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (November 2004). "Intranasal insulin improves memory in humans". Psychoneuroendocrinology. 29 (10): 1326–34. doi:10.1016/j.psyneuen.2004.04.003. PMID 15288712.
Jump up ^ Benedict C, Brede S, Schiöth HB, Lehnert H, Schultes B, Born J, Hallschmid M (January 2011). "Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men". Diabetes. 60 (1): 114–8. doi:10.2337/db10-0329. PMC 3012162  . PMID 20876713[Epub'd ahead of print]
Jump up ^ Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Human Reproduction Update. 20 (2): 153–74. doi:10.1093/humupd/dmt033. PMID 24173881.
Jump up ^ Duckworth WC, Bennett RG, Hamel FG (October 1998). "Insulin degradation: progress and potential". Endocrine Reviews. 19 (5): 608–24. doi:10.1210/er.19.5.608. PMID 9793760.
Jump up ^ Palmer BF, Henrich WL. "Carbohydrate and insulin metabolism in chronic kidney disease". UpToDate, Inc.
Jump up ^ D'Eon TM, Pierce KA, Roix JJ, Tyler A, Chen H, Teixeira SR (May 2008). "The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids". Diabetes. 57 (5): 1262–8. doi:10.2337/db07-1186. PMID 18276766.
Jump up ^ Gatta-Cherifi B, Cota D (February 2016). "New insights on the role of the endocannabinoid system in the regulation of energy balance". International Journal of Obesity. 40 (2): 210–9. doi:10.1038/ijo.2015.179. PMID 26374449.
Jump up ^ Di Marzo V (August 2008). "The endocannabinoid system in obesity and type 2 diabetes". Diabetologia. 51 (8): 1356–67. doi:10.1007/s00125-008-1048-2. PMID 18563385.
Jump up ^ Marcial GG (13 August 2007). "From SemBiosys, A New Kind Of Insulin". Inside Wall Street. Archived from the original on 17 November 2007.
Jump up ^ Insulin analog
Jump up ^ http://www.iddt.org/diabetic-commonsense/the-great-debate-natural-animal-or-artificial-human-insulin
Jump up ^ Wong CY, Martinez J, Dass CR (2016). "Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities". The Journal of Pharmacy and Pharmacology. 68 (9): 1093–108. doi:10.1111/jphp.12607. PMID 27364922.
Jump up ^ Shah RB, Patel M, Maahs DM, Shah VN (2016). "Insulin delivery methods: Past, present and future". International Journal of Pharmaceutical Investigation. 6 (1): 1–9. doi:10.4103/2230-973X.176456. PMC 4787057  . PMID 27014614.
Jump up ^ 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): 263–264.
Jump up ^ 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.
Jump up ^ 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.
Jump up ^ The American Institute of Nutrition (1967). "Proceedings of the Thirty-first Annual Meeting of the American Institute of Nutrition" (PDF). Journal of Nutrition. 92: 509.
Jump up ^ Paulesco NC (August 31, 1921). "Recherche sur le rôle du pancréas dans l'assimilation nutritive". Archives Internationales de Physiologie. 17: 85–103.
Jump up ^ Lestradet H (1997). "Le 75e anniversaire de la découverte de l'insuline". Diabetes & Metabolism. 23 (1): 112.
Jump up ^ Wright JR (December 2002). "Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine". CMAJ. 167 (12): 1391–6. PMC 137361  . PMID 12473641.
Jump up ^ Krishnamurthy K (2002). Pioneers in scientific discoveries. Mittal Publications. p. 266. ISBN 978-81-7099-844-0. Retrieved 26 July 2011.
Jump up ^ Bliss M (July 1993). "Rewriting medical history: Charles Best and the Banting and Best myth". Journal of the History of Medicine and Allied Sciences. 48 (3): 253–74. doi:10.1093/jhmas/48.3.253. PMID 8409364.
Jump up ^ Zuger A (October 4, 2010). "Rediscovering the First Miracle Drug". 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 Dr. Allen’s diet her weight fell to 65 pounds, then 52 pounds, and then, after an episode of diarrhea that almost killed her in the spring of 1922, 45 pounds. By then she had survived three years, far longer than expected. And then her mother heard the news: Insulin had finally been isolated in Canada.
Jump up ^ 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.
^ Jump up to: a b Stretton AO (October 2002). "The first sequence. Fred Sanger and insulin". Genetics. 162 (2): 527–32. PMC 1462286  . PMID 12399368.
Jump up ^ 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.
Jump up ^ Wollmer A, Dieken ML, Federwisch M, De Meyts P (2002). Insulin & related proteins structure to function and pharmacology. Boston: Kluwer Academic Publishers. ISBN 1-4020-0655-1.
Jump up ^ Kjeldsen T (September 2000). "Yeast secretory expression of insulin precursors". Applied Microbiology and Biotechnology. 54 (3): 277–86. doi:10.1007/s002530000402. PMID 11030562.
Jump up ^ "The Nobel Prize in Physiology or Medicine 1923". The Nobel Foundation.
Jump up ^ 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.
Jump up ^ 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): 141–6. PMC 1524425  . PMID 20314060.
Jump up ^ Drury MI (July 1972). "The golden jubile of insulin". Journal of the Irish Medical Association. 65 (14): 355–63. PMID 4560502.
Jump up ^ Murray I (April 1971). "Paulesco and the isolation of insulin". Journal of the History of Medicine and Allied Sciences. 26 (2): 150–7. doi:10.1093/jhmas/XXVI.2.150. PMID 4930788.
Further reading[edit]
Laws GM, Reaven A (1999). Insulin resistance : the metabolic syndrome X. Totowa, NJ: Humana Press. doi:10.1226/0896035883. ISBN 0-89603-588-3.
Leahy JL, Cefalu WT (2002-03-22). Insulin Therapy (1st ed.). New York: Marcel Dekker. ISBN 0-8247-0711-7.
Kumar S, O'Rahilly S (2005-01-14). Insulin Resistance: Insulin Action and Its Disturbances in Disease. Chichester, England: Wiley. ISBN 0-470-85008-6.
Ehrlich A, Schroeder CL (2000-06-16). Medical Terminology for Health Professions (4th ed.). Thomson Delmar Learning. ISBN 0-7668-1297-9.
Draznin, Boris; LeRoith, Derek (September 1994). Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion. Totowa, New Jersey: Humana Press. doi:10.1226/0896032868. ISBN 0-89603-286-8.
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.
External links[edit]
Wikimedia Commons has media related to Insulin.
Insulin: entry from protein databank
The History of Insulin
CBC Digital Archives – Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes
Discovery and Early Development of Insulin, 1920–1925
Secretion of Insulin and Glucagon
Insulin signaling pathway
Animations of insulin's action in the body at AboutKidsHealth.ca
Types of Insulin for Diabetes Treatment at ApolloSugar.com
[show]
v
t
e
PDB gallery
1ai0: R6 HUMAN INSULIN HEXAMER (NON-SYMMETRIC), NMR, 10 STRUCTURES
1aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 10 STRUCTURES
1aph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11
1b17: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 5.00 COORDINATES)
1b18: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 5.53 COORDINATES)
1b19: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 5.80 COORDINATES)
1b2a: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.00 COORDINATES)
1b2b: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.16 COORDINATES)
1b2c: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.26 COORDINATES)
1b2d: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.35 COORDINATES)
1b2e: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.50 COORDINATES)
1b2f: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 6.98 COORDINATES)
1b2g: PH AFFECTS GLU B13 SWITCHING AND SULFATE BINDING IN CUBIC INSULIN CRYSTALS (PH 9.00 COORDINATES)
1b9e: HUMAN INSULIN MUTANT SERB9GLU
1ben: INSULIN COMPLEXED WITH 4-HYDROXYBENZAMIDE
1bph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11
1cph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11
1dph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11
1ev3: Structure of the rhombohedral form of the M-cresol/insulin R6 hexamer
1ev6: Structure of the monoclinic form of the M-cresol/insulin R6 hexamer
1evr: The structure of the resorcinol/insulin R6 hexamer
1fu2: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA
1fub: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA
1g7a: 1.2 A structure of T3R3 human insulin at 100 K
1g7b: 1.3 A STRUCTURE OF T3R3 HUMAN INSULIN AT 100 K
1guj: INSULIN AT PH 2: STRUCTURAL ANALYSIS OF THE CONDITIONS PROMOTING INSULIN FIBRE FORMATION.
1hiq: PARADOXICAL STRUCTURE AND FUNCTION IN A MUTANT HUMAN INSULIN ASSOCIATED WITH DIABETES MELLITUS
1hit: RECEPTOR BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN
1hls: NMR STRUCTURE OF THE HUMAN INSULIN-HIS(B16)
1htv: CRYSTAL STRUCTURE OF DESTRIPEPTIDE (B28-B30) INSULIN
1iza: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-> GLN) INSULIN
1izb: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-> GLN) INSULIN
1j73: Crystal structure of an unstable insulin analog with native activity.
1jca: Non-standard Design of Unstable Insulin Analogues with Enhanced Activity
1jco: Solution structure of the monomeric [Thr(B27)->Pro,Pro(B28)->Thr] insulin mutant (PT insulin)
1lph: LYS(B28)PRO(B29)-HUMAN INSULIN
1m5a: Crystal Structure of 2-Co(2+)-Insulin at 1.2A Resolution
1mhi: THREE-DIMENSIONAL SOLUTION STRUCTURE OF AN INSULIN DIMER. A STUDY OF THE B9(ASP) MUTANT OF HUMAN INSULIN USING NUCLEAR MAGNETIC RESONANCE DISTANCE GEOMETRY AND RESTRAINED MOLECULAR DYNAMICS
1mhj: SOLUTION STRUCTURE OF THE SUPERACTIVE MONOMERIC DES-[PHE(B25)] HUMAN INSULIN MUTANT. ELUCIDATION OF THE STRUCTURAL BASIS FOR THE MONOMERIZATION OF THE DES-[PHE(B25)] INSULIN AND THE DIMERIZATION OF NATIVE INSULIN
1mpj: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL
1mso: T6 Human Insulin at 1.0 A Resolution
1os3: Dehydrated T6 human insulin at 100 K
1os4: Dehydrated T6 human insulin at 295 K
1q4v: CRYSTAL STRUCTURE OF ALLO-ILEA2-INSULIN, AN INACTIVE CHIRAL ANALOGUE: IMPLICATIONS FOR THE MECHANISM OF RECEPTOR
1qiy: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR COMPLEXED WITH PHENOL
1qiz: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR COMPLEXED WITH RESORCINOL
1qj0: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR
1rwe: Enhancing the activity of insulin at receptor edge: crystal structure and photo-cross-linking of A8 analogues
1sf1: NMR STRUCTURE OF HUMAN INSULIN under Amyloidogenic Condition, 15 STRUCTURES
1t0c: Solution Structure of Human Proinsulin C-Peptide
1trz: CRYSTALLOGRAPHIC EVIDENCE FOR DUAL COORDINATION AROUND ZINC IN THE T3R3 HUMAN INSULIN HEXAMER
1tyl: THE STRUCTURE OF A COMPLEX OF HEXAMERIC INSULIN AND 4'-HYDROXYACETANILIDE
1tym: THE STRUCTURE OF A COMPLEX OF HEXAMERIC INSULIN AND 4'-HYDROXYACETANILIDE
1uz9: CRYSTALLOGRAPHIC AND SOLUTION STUDIES OF N-LITHOCHOLYL INSULIN: A NEW GENERATION OF PROLONGED-ACTING INSULINS.
1w8p: STRUCTURAL PROPERTIES OF THE B25TYR-NME-B26PHE INSULIN MUTANT.
1wav: CRYSTAL STRUCTURE OF FORM B MONOCLINIC CRYSTAL OF INSULIN
1xda: STRUCTURE OF INSULIN
1xgl: HUMAN INSULIN DISULFIDE ISOMER, NMR, 10 STRUCTURES
1xw7: Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama
1zeg: STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL
1zeh: STRUCTURE OF INSULIN
1zni: INSULIN
1znj: INSULIN, MONOCLINIC CRYSTAL FORM
2a3g: The structure of T6 bovine insulin
2aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 20 STRUCTURES
2bn1: INSULIN AFTER A HIGH DOSE X-RAY BURN
2bn3: INSULIN BEFORE A HIGH DOSE X-RAY BURN
2c8q: INSULINE(1SEC) AND UV LASER EXCITED FLUORESCENCE
2c8r: INSULINE(60SEC) AND UV LASER EXCITED FLUORESCENCE
2g4m: Insulin collected at 2.0 A wavelength
2g54: Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain
2g56: crystal structure of human insulin-degrading enzyme in complex with insulin B chain
2hiu: NMR STRUCTURE OF HUMAN INSULIN IN 20% ACETIC ACID, ZINC-FREE, 10 STRUCTURES
2ins: THE STRUCTURE OF DES-PHE B1 BOVINE INSULIN
2omg: Structure of human insulin cocrystallized with protamine and urea
2omh: Structure of human insulin cocrystallized with ARG-12 peptide in presence of urea
2omi: Structure of human insulin cocrystallized with protamine
2tci: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL
3aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, REFINED AVERAGE STRUCTURE
3ins: STRUCTURE OF INSULIN. RESULTS OF JOINT NEUTRON AND X-RAY REFINEMENT
3mth: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL
4aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'GREEN' SUBSTATE, AVERAGE STRUCTURE
4ins: THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION
5aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'RED' SUBSTATE, AVERAGE STRUCTURE
6ins: X-RAY ANALYSIS OF THE SINGLE CHAIN /B29-A1$ PEPTIDE-LINKED INSULIN MOLECULE. A COMPLETELY INACTIVE ANALOGUE
7ins: STRUCTURE OF PORCINE INSULIN COCRYSTALLIZED WITH CLUPEINE Z
9ins: MONOVALENT CATION BINDING IN CUBIC INSULIN CRYSTALS
[show]
v
t
e
Hormones
Endocrine
glands
Hypothalamic-
pituitary
Hypothalamus
GnRH
TRH
Dopamine
CRH
GHRH
Somatostatin (GHIH)
MCH
Posterior pituitary
Oxytocin
Vasopressin
Anterior pituitary
FSH
LH
TSH
Prolactin
POMC
CLIP
ACTH
MSH
Endorphins
Lipotropin
GH
Adrenal axis
Adrenal cortex
aldosterone
cortisol
cortisone
DHEA
DHEA-S
androstenedione
Adrenal medulla
epinephrine
norepinephrine
Thyroid
Thyroid hormone
T3
T4
Calcitonin
Thyroid axis
Parathyroid
PTH
Gonadal axis
Testis
testosterone
AMH
inhibin
Ovary
estradiol
progesterone
activin and inhibin
relaxin
Placenta
hCG
HPL
estrogen
progesterone
Pancreas
glucagon
insulin
amylin
somatostatin
pancreatic polypeptide
Pineal gland
melatonin
N,N-dimethyltryptamine
5-methoxy-N,N-dimethyltryptamine
Other
Thymus
Thymosins
Thymosin α1
Beta thymosins
Thymopoietin
Thymulin
Digestive system
Stomach
gastrin
ghrelin
Duodenum
CCK
Incretins
GIP
GLP-1
secretin
motilin
VIP
Ileum
enteroglucagon
peptide YY
Liver/other
Insulin-like growth factor
IGF-1
IGF-2
Adipose tissue
leptin
adiponectin
resistin
Skeleton
Osteocalcin
Kidney
renin
EPO
calcitriol
prostaglandin
Heart
Natriuretic peptide
ANP
BNP
[show]
v
t
e
Signaling peptide/protein receptor modulators
Adiponectin
AdipoR1
Agonists: Peptide: Adiponectin
ADP-355
ADP-399; Non-peptide: AdipoRon
(–)-Arctigenin
Arctiin
Gramine
Matairesinol
Antagonists: Peptide: ADP-400
AdipoR2
Agonists: Peptide: Adiponectin
ADP-355
ADP-399; Non-peptide: AdipoRon
Deoxyschizandrin
Parthenolide
Syringing
Taxifoliol
Antagonists: Peptide: ADP-400
Angiotensin
See here instead.
Bradykinin
Agonists: Bradykinin
Kallidin
Antagonists: FR-173657
Icatibant
LF22-0542
CGRP
Agonists: Amylin
CGRP
Pramlintide
Antagonists: Atogepant
BI 44370 TA
CGRP (8-37)
MK-3207
Olcegepant
Rimegepant
SB-268262
Telcagepant
Ubrogepant
Antibodies: Eptinezumab
Erenumab
Fremanezumab
Galcanezumab
Cholecystokinin
CCKA
Agonists: Cholecystokinin
Antagonists: Amiglumide
Asperlicin
Devazepide
Dexloxiglumide
Lintitript
Lorglumide
Loxiglumide
Pranazepide
Proglumide
Tarazepide
Tomoglumide
CCKB
Agonists: Cholecystokinin
CCK-4
Gastrin
Pentagastrin (CCK-5)
Antagonists: Ceclazepide
CI-988 (PD-134308)
Itriglumide
L-365,360
Netazepide
Proglumide
Spiroglumide
Unsorted
Antagonists: Nastorazepide
CRH
CRF1
Agonists: Cortagine
Corticorelin
Corticotropin releasing hormone
Sauvagine
Stressin I
Urocortin
Antagonists: Antalarmin
Astressin-B
CP-154,526
Emicerfont
Hypericin
LWH-234
NBI-27914
Pexacerfont
R-121919
TS-041
Verucerfont
CRF2
Agonists: Corticorelin
Corticotropin releasing hormone
Sauvagine
Urocortin
Antagonists: Astressin-B
Cytokine
See here instead.
Endothelin
Agonists: Endothelin 1
Endothelin 2
Endothelin 3
IRL-1620
Antagonists: A-192621
ACT-132577
Ambrisentan
Aprocitentan
Atrasentan
Avosentan
Bosentan
BQ-123
BQ-788
Clazosentan
Darusentan
Edonentan
Enrasentan
Fandosentan
Feloprentan
Macitentan
Nebentan
Sitaxentan
Sparsentan
Tezosentan
Zibotentan
Galanin
GAL1
Agonists: Galanin
Galanin (1-15)
Galanin-like peptide
Galmic
Galnon
NAX 810-2
Antagonists: C7
Dithiepine-1,1,4,4-tetroxide
Galantide (M15)
M32
M35
M40
SCH-202596
GAL2
Agonists: Galanin
Galanin (1-15)
Galanin (2-11)
Galanin-like peptide
Galmic
Galnon
J18
NAX 810-2
Antagonists: C7
Galantide (M15)
M32
M35
M40
M871
GAL3
Agonists: Galanin
Galanin (1-15)
Galmic
Galnon
Antagonists: C7
Galantide (M15)
GalR3ant
HT-2157
M32
M35
M40
SNAP-37889
SNAP-398299
Ghrelin/GHS
See here instead.
GH
See here instead.
GHRH
See here instead.
GLP
GLP-1
Agonists: Albiglutide
Beinaglutide
Dulaglutide
Efpeglenatide
Exenatide
GLP-1
Langlenatide
Liraglutide
Lixisenatide
Oxyntomodulin
Semaglutide
Taspoglutide
GLP-2
Agonists: Elsiglutide
Glepaglutide
GLP-2
Teduglutide
Others
Propeptides: Preproglucagon
Proglucagon
Glucagon
Agonists: Dasiglucagon
Glucagon
Oxyntomodulin
Antagonists: Adomeglivant
L-168,049
LGD-6972
Propeptides: Preproglucagon
Proglucagon
GnRH
Agonists: Peptide: Avorelin
Buserelin (buserelin acetate)
Deslorelin
Fertirelin (fertirelin acetate)
GnRH (LHRH, gonadorelin)
Gonadorelin
Goserelin (goserelin acetate)
Histrelin
Leuprorelin (leuprolide acetate)
Lutrelin
Nafarelin
Peforelin
Triptorelin
Zoptarelin doxorubicin
Antagonists: Peptide: Abarelix
Acyline
Cetrorelix
Degarelix
Detirelix
Ganirelix
Iturelix
Ozarelix
Prazarelix
Ramorelix
Teverelix (antarelix); Non-peptide: ASP-1707
Elagolix
KLH-2109 (OBE-2109)
Relugolix
Sufugolix
Gonadotropin
LH/CG
Agonists: Choriogonadotropin alfa
Human chorionic gonadotropin
Luteinizing hormone
Lutropin alfa
Menotropin (human menopausal gonadotropin)
FSH
Agonists: Corifollitropin alfa
Follicle-stimulating hormone
Follitropin alfa
Follitropin beta
Follitropin epsilon
Menotropin (human menopausal gonadotropin)
Urofollitropin
Varfollitropin alfa
NAMs: ADX-61623
Growth factor
See here instead.
Insulin
Agonists: Chaetochromin (4548-G05)
Insulin-like growth factor 1
Insulin-like growth factor 2
Insulin
Insulin aspart
Insulin degludec
Insulin detemir
Insulin glargine
Insulin glulisine
Insulin lispro
Mecasermin
Mecasermin rinfabate
Antagonists: BMS-754807
S661
S961
Kinase inhibitors: Linsitinib
Antibodies: Xentuzumab (against IGF-1 and IGF-2)
Kisspeptin
Agonists: Kisspeptin
Kisspeptin-10
Antagonists: Kisspeptin-234
Leptin
Agonists: Leptin
Metreleptin
MCH
MCH1
Agonists: Melanin concentrating hormone
Antagonists: ATC-0065
ATC-0175
GW-803430
NGD-4715
SNAP-7941
SNAP-94847
MCH2
Agonists: Melanin concentrating hormone
Melanocortin
See here instead.
Neuropeptide FF
Agonists: Neuropeptide AF
Neuropeptide FF
Neuropeptide SF (RFRP-1)
Neuropeptide VF (RFRP-3)
Antagonists: BIBP-3226
RF9
Neuropeptide S
Agonists: Neuropeptide S
Antagonists: ML-154
SHA-68
Neuropeptide Y
Y1
Agonists: Neuropeptide Y
Peptide YY
Antagonists: BIBO-3304
BIBP-3226
BVD-10
GR-231118
PD-160170
Y2
Agonists: 2-Thiouridine 5'-triphosphate
Neuropeptide Y
Neuropeptide Y (13-36)
Peptide YY
Peptide YY (3-36)
Antagonists: BIIE-0246
JNJ-5207787
SF-11
Y4
Agonists: GR-231118
Neuropeptide Y
Pancreatic polypeptide
Peptide YY
Antagonists: UR-AK49
Y5
Agonists: BWX-46
Neuropeptide Y
Peptide YY
Antagonists: CGP-71683
FMS-586
L-152,804
Lu AA-33810
MK-0557
NTNCB
Velneperit (S-2367)
Neurotensin
NTS1
Agonists: Neurotensin
Neuromedin N
Antagonists: Meclinertant
SR-142948
NTS2
Agonists: Neurotensin
Antagonists: Levocabastine
SR-142948
Opioid
See here instead.
Orexin
OX1
Agonists: Orexin (A, B)
Antagonists: ACT-335827
ACT-462206
Almorexant
Filorexant
Lemborexant
SB-334867
SB-408124
SB-649868
Suvorexant
TCS-1102
OX2
Agonists: Orexin (A, B)
SB-668875
Antagonists: ACT-335827
ACT-462206
Almorexant
EMPA
Filorexant
JNJ-10397049
Lemborexant
MK-1064
SB-649868
Seltorexant
Suvorexant
TCS-1102
TCS-OX2-29
Oxytocin
See here instead.
Prolactin
Agonists: Growth hormone
Human placental lactogen
Placental growth hormone (growth hormone variant)
Prolactin
S179D-hPRL
Somatotropin
Antagonists: Δ1–9-G129R-hPRL
Δ1–14-G129R-hPRL
G120K-hGH
G129R-hPRL
Prolactin modulators: Prolactin inhibitors: D2 receptor agonists (e.g., bromocriptine, cabergoline); Prolactin releasers: D2 receptor antagonists (e.g., domperidone, metoclopramide, risperidone)
Estrogens (e.g., estradiol)
Progestogens (e.g., progesterone)
PTH
Agonists: Abaloparatide
Parathyroid hormone
Parathyroid hormone-related protein (PTHrP)
Semparatide
Teriparatide
Relaxin
Agonists: Insulin-like factor 3
Relaxin (1, 2, 3)
Serelaxin
Somatostatin
See here instead.
Tachykinin
See here instead.
TRH
Agonists: Azetirelin
Fertirelin
Montirelin
Orotirelin
Posatirelin
Protirelin
Rovatirelin
Taltirelin
TRH (TRF)
TSH
Agonists: Thyrotropin alfa
TSH (thyrotropin)
Vasopressin
See here instead.
VIP/PACAP
VIPR1
Agonists: Peptide: Bay 55-9837
LBT-3393
PACAP
VIP
VIPR2
Agonists: Peptide: LBT-3627
PACAP
VIP
PAC1
Agonists: PACAP
PACAP (1-27)
PACAP (1-38)
Antagonists: PACAP (6-38)
Unsorted
PHI
PHM
PHV
Others
Endogenous: Adrenomedullin
Apelin
Asprosin
Bombesin
Calcitonin
Carnosine
CART
CLIP
DSIP
Enteroglucagon
Formyl peptide
GALP
GIP
GRP
Integrin ligands (collagens, fibrinogen, fibronectin, laminins, ICAM-1, ICAM-2, osteopontin, VCAM-1, vitronectin)
Kininogens
Motilin
Natriuretic peptides (ANP, BNP, CNP, urodilatin)
Nesfatin-1
Neuromedin B
Neuromedin N
Neuromedin S
Neuromedin U
Obestatin
Osteocalcin
Resistin
Secretin
Thymopoietin
Thymosins
Thymulin
Urotensin-II
VGF
Exogenous: Lifitegrast (LFA-1 antagonist)
See also
Receptor/signaling modulators
[show]
v
t
e
Growth factor receptor modulators
Angiopoietin
Agonists: Angiopoietin 1
Angiopoietin 4
Antagonists: Angiopoietin 2
Angiopoietin 3
Kinase inhibitors: Altiratinib
CE-245677
Rebastinib
Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)
CNTF
Agonists: Axokine
CNTF
Dapiclermin
EGF (ErbB)
EGF
(ErbB1/HER1)
Agonists: Amphiregulin
Betacellulin
EGF (urogastrone)
Epigen
Epiregulin
Heparin-binding EGF-like growth factor (HB-EGF)
Murodermin
Nepidermin
Transforming growth factor alpha (TGFα)
Kinase inhibitors: Afatinib
AG-490
Agerafenib
Brigatinib
Canertinib
Dacomitinib
Erlotinib
Gefitinib
Grandinin
Icotinib
Lapatinib
Neratinib
Osimertinib
Vandetanib
WHI-P 154
Antibodies: Cetuximab
Depatuxizumab
Depatuxizumab mafodotin
Futuximab
Imgatuzumab
Matuzumab
Necitumumab
Nimotuzumab
Panitumumab
Zalutumumab
ErbB2/HER2
Agonists: Unknown/none
Antibodies: Ertumaxomab
Pertuzumab
Trastuzumab
Trastuzumab duocarmazine
Trastuzumab emtansine
Kinase inhibitors: Afatinib
AG-490
Lapatinib
Mubritinib
Neratinib
ErbB3/HER3
Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C))
Antibodies: Duligotumab
Patritumab
Seribantumab
ErbB4/HER4
Agonists: Betacellulin
Epigen
Heparin-binding EGF-like growth factor (HB-EGF)
Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))
FGF
FGFR1
Agonists: Ersofermin
FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20)
Repifermin
Trafermin
Velafermin
FGFR2
Agonists: Ersofermin
FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22)
Palifermin
Repifermin
Sprifermin
Trafermin
Antibodies: Aprutumab
Aprutumab ixadotin
FGFR3
Agonists: Ersofermin
FGF (1, 2 (bFGF), 4, 8, 9, 18, 23)
Sprifermin
Trafermin
Antibodies: Burosumab (against FGF23)
FGFR4
Agonists: Ersofermin
FGF (1, 2 (bFGF), 4, 6, 8, 9, 19)
Trafermin
Unsorted
Agonists: FGF15/19
HGF (c-Met)
Agonists: Hepatocyte growth factor
Potentiators: Dihexa (PNB-0408)
Kinase inhibitors: Altiratinib
AM7
AMG-458
Amuvatinib
BMS-777607
Cabozantinib
Crizotinib
Foretinib
Golvatinib
INCB28060
JNJ-38877605
K252a
MK-2461
PF-04217903
PF-2341066
PHA-665752
SU-11274
Tivantinib
Volitinib
Antibodies: Emibetuzumab
Ficlatuzumab
Flanvotumab
Onartuzumab
Rilotumumab
Telisotuzumab
Telisotuzumab vedotin
IGF
IGF-1
Agonists: des(1-3)IGF-1
Insulin-like growth factor-1 (somatomedin C)
IGF-1 LR3
Insulin-like growth factor-2 (somatomedin A)
Insulin
Mecasermin
Mecasermin rinfabate
Kinase inhibitors: BMS-754807
Linsitinib
NVP-ADW742
NVP-AEW541
OSl-906
Antibodies: AVE-1642
Cixutumumab
Dalotuzumab
Figitumumab
Ganitumab
Robatumumab
R1507
Teprotumumab
Xentuzumab (against IGF-1 and IGF-2)
IGF-2
Agonists: Insulin-like growth factor-2 (somatomedin A)
Antibodies: Dusigitumab
Xentuzumab (against IGF-1 and IGF-2)
Others
Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7)
Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1)
Trofinetide
LNGF (p75NTR)
Agonists: BDNF
BNN-20
BNN-27
Cenegermin
DHEA
DHEA-S
NGF
NT-3
NT-4
Antagonists: ALE-0540
Dexamethasone
EVT-901 (SAR-127963)
Testosterone
Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab
Aptamers: Against NGF: RBM-004
Decoy receptors: LEVI-04 (p75NTR-Fc)
PDGF
Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)
Kinase inhibitors: Agerafenib
Axitinib
Crenolanib
Imatinib
Lenvatinib
Masitinib
Motesanib
Nintedanib
Pazopanib
Radotinib
Quizartinib
Sunitinib
Sorafenib
Toceranib
Antibodies: Olaratumab
Ramucirumab
Tovetumab
RET (GFL)
GFRα1
Agonists: Glial cell line-derived neurotrophic factor (GDNF)
Liatermin
Kinase inhibitors: Vandetanib
GFRα2
Agonists: Neurturin (NRTN)
Kinase inhibitors: Vandetanib
GFRα3
Agonists: Artemin (ARTN)
Kinase inhibitors: Vandetanib
GFRα4
Agonists: Persephin (PSPN)
Kinase inhibitors: Vandetanib
Unsorted
Kinase inhibitors: Agerafenib
SCF (c-Kit)
Agonists: Ancestim
Stem cell factor
Kinase inhibitors: Agerafenib
Axitinib
Dasatinib
Imatinib
Masitinib
Nilotinib
Pazopanib
Quizartinib
Sorafenib
Sunitinib
Toceranib
TGFβ
See here instead.
Trk
TrkA
Agonists: Amitriptyline
BNN-20
BNN-27
Cenegermin
DHEA
DHEA-S
Gambogic amide
NGF
Tavilermide
Antagonists: ALE-0540
Dexamethasone
FX007
Testosterone
Negative allosteric modulators: VM-902A
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
Milciclib
ONO-4474
ONO-5390556
PLX-7486
Rebastinib
SNA-120 (pegylated K252a))
Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab
Aptamers: Against NGF: RBM-004
Decoy receptors: ReN-1820 (TrkAd5)
TrkB
Agonists: 3,7-DHF
3,7,8,2'-THF
4'-DMA-7,8-DHF
7,3'-DHF
7,8-DHF
7,8,2'-THF
7,8,3'-THF
Amitriptyline
BDNF
BNN-20
Deoxygedunin
Deprenyl
Diosmetin
DMAQ-B1
HIOC
LM22A-4
N-Acetylserotonin
NT-3
NT-4
Norwogonin (5,7,8-THF)
R7
TDP6
Antagonists: ANA-12
Cyclotraxin B
Gossypetin (3,5,7,8,3',4'-HHF)
Ligands: DHEA
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
ONO-4474
ONO-5390556
PLX-7486
TrkC
Agonists: BNN-20
DHEA
NT-3
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
ONO-4474
ONO-5390556
PLX-7486
VEGF
Agonists: Placental growth factor (PGF)
Telbermin
VEGF (A, B, C, D (FIGF))
Allosteric modulators: Cyclotraxin B
Kinase inhibitors: Agerafenib
Altiratinib
Axitinib
Cabozantinib
Cediranib
Lapatinib
Lenvatinib
Motesanib
Nintedanib
Pazopanib
Pegaptanib
Rebastinib
Regorafenib
Semaxanib
Sorafenib
Sunitinib
Toceranib
Tivozanib
Vandetanib
WHI-P 154
Antibodies: Alacizumab pegol
Bevacizumab
Icrucumab
Ramucirumab
Ranibizumab
Decoy receptors: Aflibercept
Others
Additional growth factors: Adrenomedullin
Colony-stimulating factors (see here instead)
Connective tissue growth factor (CTGF)
Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)
Erythropoietin (see here instead)
Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
Glia maturation factor (GMF)
Hepatoma-derived growth factor (HDGF)
Interleukins/T-cell growth factors (see here instead)
Leukemia inhibitory factor (LIF)
Macrophage-stimulating protein (MSP; HLP, HGFLP)
Midkine (NEGF2)
Migration-stimulating factor (MSF; PRG4)
Oncomodulin
Pituitary adenylate cyclase-activating peptide (PACAP)
Pleiotrophin
Renalase
Thrombopoietin (see here instead)
Wnt signaling proteins
Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)
See also
Receptor/signaling modulators
Signaling peptide/protein receptor modulators
Cytokine receptor modulators
Retrieved from "https://en.wikipedia.org/w/index.php?title=Insulin&oldid=815723797"
Categories:
Genes on human chromosome 11
Animal products
Eli Lilly and Company
Hormones of glucose metabolism
Human hormones
Insulin receptor agonists
Insulin therapies
Insulin-like growth factor receptor agonists
Pancreatic hormones
Peptide hormones
Recombinant proteins
Tumor markers
World Anti-Doping Agency prohibited substances
Hidden categories:
CS1 Swedish-language sources (sv)
Webarchive template wayback links
Pages using PMID magic links
All articles with unsourced statements
Articles with unsourced statements from March 2017
Articles with unsourced statements from April 2015
Articles needing additional references from July 2017
All articles needing additional references
Navigation menu
Personal tools
Not logged in
Talk
Contributions
Create account
Log in
Namespaces
Article
Talk
Variants
Views
Read
Edit
View history
More
Search
Navigation
Main page
Contents
Featured content
Current events
Random article
Donate to Wikipedia
Wikipedia store
Interaction
Help
About Wikipedia
Community portal
Recent changes
Contact page
Tools
What links here
Related changes
Upload file
Special pages
Permanent link
Page information
Wikidata item
Cite this page
Print/export
Create a book
Download as PDF
Printable version
In other projects
Wikimedia Commons
Languages
Afrikaans
العربية
Asturianu
Azərbaycanca
বাংলা
Беларуская
Беларуская (тарашкевіца)
Български
Boarisch
Bosanski
Català
Čeština
Dansk
Deutsch
ދިވެހިބަސް
Eesti
Ελληνικά
Español
Esperanto
Euskara
فارسی
Français
Gaeilge
Galego
한국어
Հայերեն
हिन्दी
Hrvatski
Ido
Bahasa Indonesia
Interlingua
Íslenska
Italiano
עברית
Basa Jawa
ಕನ್ನಡ
Kapampangan
Қазақша
Kurdî
Кыргызча
Latina
Latviešu
Lietuvių
Magyar
Македонски
മലയാളം
Bahasa Melayu
မြန်မာဘာသာ
Nederlands
日本語
Norsk
Norsk nynorsk
Occitan
Oʻzbekcha/ўзбекча
ਪੰਜਾਬੀ
پنجابی
پښتو
Polski
Português
Română
Русский
Scots
Shqip
Simple English
Slovenčina
Slovenščina
کوردی
Српски / srpski
Srpskohrvatski / српскохрватски
Basa Sunda
Suomi
Svenska
தமிழ்
ไทย
Türkçe
Українська
اردو
Tiếng Việt
Winaray
ייִדיש
中文
Edit links
This page was last edited on 16 December 2017, at 18:18.
Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.
Privacy policy
About Wikipedia
Disclaimers
Contact Wikipedia
Developers
Cookie statement
Mobile view
Enable previews

key: html

type: local

value: div

attrs: id class

values: mw-page-base noprint

values: mw-head-base noprint

value: a

attrs: id class lang

values: firstHeading firstHeading en

values: siteSub noprint

values: jump-to-nav mw-jump

attrs: href title

attrs: role class

values:
note
hatnote navigation-not-searchable

value: th

attrs: colspan style

value: tr

value: img

attrs: alt src width height srcset data-file-width data-file-height

attrs: href class

value: td

attrs: rowspan style

values:
/wiki/File:HSR_1996_II_3.5e.svg
image
Genomic location for INS

values: position: absolute; left: -0.69566720091646px; top: 2px; padding: 0;

attrs: alt src width height data-file-width data-file-height

values:
/wiki/File:Red_rectangle_2x18.png
image
Genomic location for INS

values: position: absolute; left: 5.3px; top: 19px; padding: 0;

values:
center
position: relative; width: 300px;

values: position: absolute; left: 283.21129993659px; top: 2px; padding: 0;

values: position: absolute; left: 289.2px; top: 19px; padding: 0;

values:
nofollow
http://biogps.org/gene/3630/
external text

values:
nofollow
http://amigo.geneontology.org/
external text

values:
nofollow
https://www.ebi.ac.uk/QuickGO/
external text

values:
nofollow
external text
http://www.uniprot.org/uniprot/P01308

values:
nofollow
external text
http://www.uniprot.org/uniprot/P01326

values:
/wiki/Dalton_(unit)
mw-redirect
Dalton (unit)

values:
/wiki/Disulfide_bond
mw-redirect
Disulfide bond

values: Edit section: Evolution and species distribution

values:
/wiki/Teleost_fish
mw-redirect
Teleost fish

values:
/wiki/Promoter_(biology)
mw-redirect
Promoter (biology)

values:
/wiki/CAMP_response_element
mw-redirect
CAMP response element

values:
/wiki/Transcription_factors
mw-redirect
Transcription factors

values: ISF (transcription factor) (page does not exist)

values:
/wiki/C2_regulatory_sequence
mw-redirect
C2 regulatory sequence

values:
/wiki/Insulin_and_its_analog_structure
mw-redirect
Insulin and its analog structure

attrs: alt src width height class srcset data-file-width data-file-height

values: Edit section: Synthesis, physiological effects, and degradation

values:
/wiki/Prohormone_convertase
mw-redirect
Prohormone convertase

values:
/wiki/DNA_transcription
mw-redirect
DNA transcription

values:
/wiki/Insulin_gene
mw-redirect
Insulin gene

values:
/wiki/MRNA_translation
mw-redirect
MRNA translation

values:
/wiki/Posttranslational_modification
mw-redirect
Posttranslational modification

values:
/wiki/Blood_glucose_regulation
mw-redirect
Blood glucose regulation

values:
/wiki/Islets_of_Langerhans
mw-redirect
Islets of Langerhans

values:
/wiki/Glucose_transporters
mw-redirect
Glucose transporters

values:
/wiki/Krebs_cycle
mw-redirect
Krebs cycle

values:
/wiki/Calcium_channels
mw-redirect
Calcium channels

values:
/wiki/Inositol_1,4,5-trisphosphate
mw-redirect
Inositol 1,4,5-trisphosphate

values:
/wiki/Vesicle_(biology)
mw-redirect
Vesicle (biology)

values:
/wiki/Insulin_oscillations
mw-redirect
Insulin oscillations

values:
/wiki/Receptor_downregulation
mw-redirect
Receptor downregulation

values:
/wiki/Blood_sugar
mw-redirect
Blood sugar

values:
/wiki/Free_fatty_acids
mw-redirect
Free fatty acids

values:
/wiki/Plasma_membrane
mw-redirect
Plasma membrane

values:
/wiki/Protein_synthesis
mw-redirect
Protein synthesis

values:
/wiki/Autophagy_(cellular)
mw-redirect
Autophagy (cellular)

values: This claim needs references to reliable sources. (March 2017)

values:
noprint Inline-Template Template-Fact
white-space:nowrap;

values: Edit section: Regulator of endocannabinoid metabolism

values:
/wiki/Human_insulin
mw-redirect
Human insulin

values: Humulin first introduced in 1982 per humulin.com, I don't have any peer-reviewed lit though (April 2015)

values:
/wiki/Inhaled_insulin
mw-redirect
Inhaled insulin

values:
/wiki/Human_gastrointestinal_tract
mw-redirect
Human gastrointestinal tract

values:
/wiki/Edouard_Laguesse
mw-redirect
Edouard Laguesse

values: Carol Davila University of Medicine and Pharmacy

values: Edit section: Extraction and purification

values: Help:Introduction to referencing with Wiki Markup/1

values: plainlinks metadata ambox ambox-content ambox-Refimprove

values:
/wiki/John_James_Rickard_Macleod
mw-redirect
John James Rickard Macleod

values:
/wiki/Charles_Herbert_Best
mw-redirect
Charles Herbert Best

values:
/wiki/Bruce_Merrifield
mw-redirect
Bruce Merrifield

values:
/wiki/Primary_structure
mw-redirect
Primary structure

values:
/wiki/Tertiary_structure
mw-redirect
Tertiary structure

values:
/wiki/X-ray_diffraction
mw-redirect
X-ray diffraction

values:
/wiki/Pernicious_anemia
mw-redirect
Pernicious anemia

values:
/wiki/Insulin_therapy
mw-redirect
Insulin therapy

values:
/wiki/Triple_bolus_test
mw-redirect
Triple bolus test

values: Insulin signal transduction pathway and regulation of blood glucose

values: -moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em;

values:
nofollow
external text
//doi.org/10.1093%2Fbja%2F85.1.69

values:
/wiki/PubMed_Identifier
mw-redirect
PubMed Identifier

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/10927996

attrs: alt src title width height srcset data-file-width data-file-height

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12717005

values:
nofollow
http://druginfo.nlm.nih.gov/drugportal/
external free

values:
nofollow
external text
http://www.littletree.com.au/dna.htm

values:
nofollow
external text
//doi.org/10.1038%2Fnbt.2437

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/23222785

values:
nofollow
external text
//doi.org/10.1139%2Fo85-106

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/3933801

values:
nofollow
external text
//doi.org/10.1111%2Fxen.12115

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/25040337

values:
nofollow
external text
//doi.org/10.1073%2Fpnas.1423857112

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/25605914

values:
nofollow
external text
//doi.org/10.1038%2F284026a0

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/6243748

values:
nofollow
external text
//doi.org/10.1007%2Fs00125-001-0728-y

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11914736

values:
nofollow
external text
//doi.org/10.1016%2Fj.bbrc.2006.11.074

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/17150186

values:
nofollow
external text
//doi.org/10.1042%2Fbj0490463

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/14886310

values:
nofollow
external text
//doi.org/10.1042%2Fbj0490481

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/14886311

values:
nofollow
external text
//doi.org/10.1042%2Fbj0530353

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/13032078

values:
nofollow
external text
//doi.org/10.1042%2Fbj0530366

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/13032079

values:
nofollow
external text
//doi.org/10.1021%2Fja01059a043

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/5881570

values:
nofollow
external text
//doi.org/10.1021%2Fja00973a068

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/5978833

values:
nofollow
external text
//doi.org/10.1038%2F231506a0

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/4932997

values:
nofollow
external text
//doi.org/10.1007%2Fs10534-005-3685-y

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/16158220

values:
nofollow
external text
//doi.org/10.1073%2Fpnas.0910080106

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/19864624

values:
nofollow
external text
//doi.org/10.1073%2Fpnas.57.2.473

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/16591494

values:
nofollow
external text
//doi.org/10.1038%2Fnpg.els.0001402

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/15750214

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/15750215

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11815469

values:
nofollow
external text
//doi.org/10.2337%2Fdc10-0165

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/20805282

values:
nofollow
external text
//doi.org/10.1074%2Fjbc.274.46.32803

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/10551841

values:
nofollow
external text
//doi.org/10.1074%2Fjbc.272.30.18572

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/9228023

values:
nofollow
external text
//doi.org/10.1172%2FJCI79273

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/25844899

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/19922535

values:
nofollow
external text
//doi.org/10.1007%2FBF00498572

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/6252481

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/17822201

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11056282

values:
nofollow
external text
//doi.org/10.1038%2Fsj.emboj.7600633

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/15791206

values:
nofollow
external text
//doi.org/10.1073%2Fpnas.220413597

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11035810

values:
nofollow
external text
//doi.org/10.1038%2Fnature11781

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/23302862

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/21864752

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/1615908

values:
nofollow
external text
//doi.org/10.1152%2Fajpendo.90261.2008

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/18430962

values:
nofollow
external text
//doi.org/10.1152%2Fajpendo.90494.2008

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/18775888

values:
nofollow
external text
//doi.org/10.1196%2Fannals.1396.020

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/17934054

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/1730458

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/15288712

values:
nofollow
external text
//doi.org/10.2337%2Fdb10-0329

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/20876713

values:
nofollow
external text
//doi.org/10.1093%2Fhumupd%2Fdmt033

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/24173881

values:
nofollow
external text
//doi.org/10.1210%2Fer.19.5.608

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/9793760

values:
nofollow
external text
//doi.org/10.2337%2Fdb07-1186

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/18276766

values:
nofollow
external text
//doi.org/10.1038%2Fijo.2015.179

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/26374449

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/18563385

values:
nofollow
external text
//doi.org/10.1111%2Fjphp.12607

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/27364922

values:
nofollow
external text
//doi.org/10.4103%2F2230-973X.176456

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/27014614

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12473641

values:
nofollow
external text
//doi.org/10.1093%2Fjhmas%2F48.3.253

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/8409364

values:
/wiki/New_York_Times
mw-redirect
New York Times

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/12399368

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/14992380

values:
nofollow
external text
//doi.org/10.1007%2Fs002530000402

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11030562

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/21408623

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/20314060

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/4560502

values:
nofollow
external text
//doi.org/10.1093%2Fjhmas%2FXXVI.2.150

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/4930788

values: -moz-column-width: 32em; -webkit-column-width: 32em; column-width: 32em; list-style-type: decimal;

values:
nofollow
external text
//doi.org/10.1226%2F0896035883

values:
nofollow
external text
//doi.org/10.1226%2F0896032868

values:
nofollow
external text
//www.ncbi.nlm.nih.gov/pubmed/11577797

values: -moz-column-width: 35em; -webkit-column-width: 35em; column-width: 35em;

values: 1ai0: R6 HUMAN INSULIN HEXAMER (NON-SYMMETRIC), NMR, 10 STRUCTURES

values: min-height:6.1em;width:187px;line-height:1.3em;padding:2px 6px 1px 6px;margin:0px;border:none;border-width:0px

values: 1aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 10 STRUCTURES

values: 1aph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11

values:
/wiki/File:PDB_1b9e_EBI.jpg
image
1b9e: HUMAN INSULIN MUTANT SERB9GLU

values: 1ben: INSULIN COMPLEXED WITH 4-HYDROXYBENZAMIDE

values: 1bph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11

values: 1cph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11

values: 1dph: CONFORMATIONAL CHANGES IN CUBIC INSULIN CRYSTALS IN THE PH RANGE 7-11

values: 1ev3: Structure of the rhombohedral form of the M-cresol/insulin R6 hexamer

values: 1ev6: Structure of the monoclinic form of the M-cresol/insulin R6 hexamer

values: 1evr: The structure of the resorcinol/insulin R6 hexamer

values: 1fu2: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA

values: 1fub: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA

values: 1g7a: 1.2 A structure of T3R3 human insulin at 100 K

values: 1g7b: 1.3 A STRUCTURE OF T3R3 HUMAN INSULIN AT 100 K

values: 1hit: RECEPTOR BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN

values: 1hls: NMR STRUCTURE OF THE HUMAN INSULIN-HIS(B16)

values: 1htv: CRYSTAL STRUCTURE OF DESTRIPEPTIDE (B28-B30) INSULIN

values: 1j73: Crystal structure of an unstable insulin analog with native activity.

values: 1jca: Non-standard Design of Unstable Insulin Analogues with Enhanced Activity

values:
/wiki/File:PDB_1lph_EBI.jpg
image
1lph: LYS(B28)PRO(B29)-HUMAN INSULIN

values: 1m5a: Crystal Structure of 2-Co(2+)-Insulin at 1.2A Resolution

values: 1mso: T6 Human Insulin at 1.0 A Resolution

values: 1os3: Dehydrated T6 human insulin at 100 K

values: 1os4: Dehydrated T6 human insulin at 295 K

values: 1qiy: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR COMPLEXED WITH PHENOL

values: 1qiz: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR COMPLEXED WITH RESORCINOL

values: 1qj0: HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR

values: 1sf1: NMR STRUCTURE OF HUMAN INSULIN under Amyloidogenic Condition, 15 STRUCTURES

values: 1t0c: Solution Structure of Human Proinsulin C-Peptide

values: 1tyl: THE STRUCTURE OF A COMPLEX OF HEXAMERIC INSULIN AND 4'-HYDROXYACETANILIDE

values: 1tym: THE STRUCTURE OF A COMPLEX OF HEXAMERIC INSULIN AND 4'-HYDROXYACETANILIDE

values: 1w8p: STRUCTURAL PROPERTIES OF THE B25TYR-NME-B26PHE INSULIN MUTANT.

values: 1wav: CRYSTAL STRUCTURE OF FORM B MONOCLINIC CRYSTAL OF INSULIN

values:
/wiki/File:PDB_1xda_EBI.jpg
image
1xda: STRUCTURE OF INSULIN

values: 1xgl: HUMAN INSULIN DISULFIDE ISOMER, NMR, 10 STRUCTURES

values: 1zeg: STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL

values:
/wiki/File:PDB_1zeh_EBI.jpg
image
1zeh: STRUCTURE OF INSULIN

values:
/wiki/File:PDB_1zni_EBI.jpg
image
1zni: INSULIN

values:
/wiki/File:PDB_1znj_EBI.jpg
image
1znj: INSULIN, MONOCLINIC CRYSTAL FORM

values: 2a3g: The structure of T6 bovine insulin

values: 2aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 20 STRUCTURES

values: 2bn1: INSULIN AFTER A HIGH DOSE X-RAY BURN

values: 2bn3: INSULIN BEFORE A HIGH DOSE X-RAY BURN

values: 2c8q: INSULINE(1SEC) AND UV LASER EXCITED FLUORESCENCE

values: 2c8r: INSULINE(60SEC) AND UV LASER EXCITED FLUORESCENCE

values: 2g4m: Insulin collected at 2.0 A wavelength

values: 2hiu: NMR STRUCTURE OF HUMAN INSULIN IN 20% ACETIC ACID, ZINC-FREE, 10 STRUCTURES

values: 2ins: THE STRUCTURE OF DES-PHE B1 BOVINE INSULIN

values: 2omg: Structure of human insulin cocrystallized with protamine and urea

values: 2omh: Structure of human insulin cocrystallized with ARG-12 peptide in presence of urea

values: 2omi: Structure of human insulin cocrystallized with protamine

values: 3aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, REFINED AVERAGE STRUCTURE

values: 3ins: STRUCTURE OF INSULIN. RESULTS OF JOINT NEUTRON AND X-RAY REFINEMENT

values: 4aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'GREEN' SUBSTATE, AVERAGE STRUCTURE

values: 4ins: THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION

values: 5aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'RED' SUBSTATE, AVERAGE STRUCTURE

values: 7ins: STRUCTURE OF PORCINE INSULIN COCRYSTALLIZED WITH CLUPEINE Z

values: 9ins: MONOVALENT CATION BINDING IN CUBIC INSULIN CRYSTALS

values: nowraplinks collapsible collapsed navbox-inner

values:
/wiki/Hypothalamic-pituitary_hormone
mw-redirect
Hypothalamic-pituitary hormone

values:
/wiki/Growth_hormone_releasing_hormone
mw-redirect
Growth hormone releasing hormone

values:
/wiki/Melanin_concentrating_hormone
mw-redirect
Melanin concentrating hormone

values:
/wiki/Thyroid_hormone
mw-redirect
Thyroid hormone

values: nowraplinks hlist collapsible collapsed navbox-inner

values: Template:Signaling peptide/protein receptor modulators

values: Template talk:Signaling peptide/protein receptor modulators

values:
/wiki/Peptide_receptor
mw-redirect
Peptide receptor

values:
/wiki/Angiotensin_receptor
mw-redirect
Angiotensin receptor

values: Calcitonin gene-related peptide receptor

values: Corticotropin releasing hormone receptor 1

values:
/wiki/Corticotropin_releasing_hormone
mw-redirect
Corticotropin releasing hormone

values: Corticotropin releasing hormone receptor 2

values: Dithiepine-1,1,4,4-tetroxide (page does not exist)

values: Template:GH/IGF-1 axis signaling modulators

values:
/wiki/Glucagon-like_peptide_1
mw-redirect
Glucagon-like peptide 1

values:
/wiki/Glucagon-like_peptide_2
mw-redirect
Glucagon-like peptide 2

values:
/wiki/Choriogonadotropin_alfa
mw-redirect
Choriogonadotropin alfa

values:
/wiki/Lutropin_alfa
mw-redirect
Lutropin alfa

values:
/wiki/Corifollitropin_alfa
mw-redirect
Corifollitropin alfa

values:
/wiki/Follitropin_alfa
mw-redirect
Follitropin alfa

values:
/wiki/Follitropin_beta
mw-redirect
Follitropin beta

values: Follitropin epsilon (page does not exist)

values: Varfollitropin alfa (page does not exist)

values: Template:Growth factor receptor modulators

values: Melanin-concentrating hormone receptor 1

values: Melanin-concentrating hormone receptor 2

values: 2-Thiouridine 5'-triphosphate (page does not exist)

values: Neuropeptide Y (13-36) (page does not exist)

values: Template:Oxytocin and vasopressin receptor modulators

values:
/wiki/Placental_growth_hormone
mw-redirect
Placental growth hormone

values:
/wiki/D2_receptor
mw-redirect
D2 receptor

values:
/wiki/Thyrotropin_alfa
mw-redirect
Thyrotropin alfa

values: Pituitary adenylate cyclase-activating peptide

values: Peptide histidine isoleucineamide (page does not exist)

values: Peptide histidine methionineamide (page does not exist)

values: Peptide histidine valine (page does not exist)

values: Cocaine and amphetamine regulated transcript

values:
/wiki/Formyl_peptide
mw-redirect
Formyl peptide

values:
/wiki/C-type_natriuretic_peptide
mw-redirect
C-type natriuretic peptide

values: Template talk:Growth factor receptor modulators

values:
/wiki/Angiopoietin_4
mw-redirect
Angiopoietin 4

values:
/wiki/Angiopoietin_2
mw-redirect
Angiopoietin 2

values:
/wiki/Transforming_growth_factor_alpha
mw-redirect
Transforming growth factor alpha

values: Trastuzumab duocarmazine (page does not exist)

values: Aprutumab ixadotin (page does not exist)

values:
/wiki/Hepatocyte_growth_factor_receptor
mw-redirect
Hepatocyte growth factor receptor

values: Telisotuzumab vedotin (page does not exist)

values: Insulin-like growth factor-binding protein

values: Low-affinity nerve growth factor receptor

values: Glial cell line-derived neurotrophic factor

values: Transforming growth factor beta receptor

values: Template:TGFβ receptor superfamily modulators

values:
/wiki/TrkA_receptor
mw-redirect
TrkA receptor

values:
/wiki/TrkB_receptor
mw-redirect
TrkB receptor

values: 3,7-Dihydroxyflavone (page does not exist)

values: 3,7,8,2'-Tetrahydroxyflavone (page does not exist)

values: 7,3′-Dihydroxyflavone (page does not exist)

values: 7,8,2'-Trihydroxyflavone (page does not exist)

values:
/wiki/TrkC_receptor
mw-redirect
TrkC receptor

values: Vascular endothelial growth factor receptor

values:
/wiki/Connective_tissue_growth_factor
mw-redirect
Connective tissue growth factor

values:
/wiki/Macrophage-stimulating_protein
mw-redirect
Macrophage-stimulating protein

values:
/wiki/Migration-stimulating_factor
mw-redirect
Migration-stimulating factor

values: Category:Insulin-like growth factor receptor agonists

values: Category:World Anti-Doping Agency prohibited substances

values: Category:CS1 Swedish-language sources (sv)

values: Category:Webarchive template wayback links

values: Category:All articles with unsourced statements

values: Category:Articles with unsourced statements from March 2017

values: Category:Articles with unsourced statements from April 2015

values: Category:Articles needing additional references from July 2017

values: Category:All articles needing additional references

values: Discussion about edits from this IP address [ctrl-alt-n]

values: A list of edits made from this IP address [ctrl-alt-y]

values: You are encouraged to create an account and log in; however, it is not mandatory

values: You're encouraged to log in; however, it's not mandatory. [ctrl-alt-o]

values:
/wiki/Insulin
View the content page [ctrl-alt-c]
c

values: Discussion about the content page [ctrl-alt-t]

values: p-namespaces navigation vectorTabs p-namespaces-label

values:
p-variants
navigation
vectorMenu emptyPortlet
p-variants-label

values:
/w/index.php?title=Insulin&action=edit
Edit this page [ctrl-alt-e]
e

values: Past revisions of this page [ctrl-alt-h]

values: p-views navigation vectorTabs p-views-label

values:
p-cactions
navigation
vectorMenu emptyPortlet
p-cactions-label

values:
mw-wiki-logo
/wiki/Main_Page
Visit the main page

values:
/wiki/Main_Page
Visit the main page [ctrl-alt-z]
z

values: Featured content – the best of Wikipedia

values: portal navigation p-wikibase-otherprojects p-wikibase-otherprojects-label

values:
uls-settings-trigger
Language settings
0
button
true

values:
https://af.wikipedia.org/wiki/Insulien
Insulien – Afrikaans
af
af
interlanguage-link-target

values: إنسولين – Arabic

values:
https://ast.wikipedia.org/wiki/Insulina
Insulina – Asturian
ast
ast
interlanguage-link-target

values: ইনসুলিন – Bangla

values: Інсулін – Belarusian (Taraškievica orthography)

values:
https://bar.wikipedia.org/wiki/Insulin
Insulin – Bavarian
bar
bar
interlanguage-link-target

values:
https://bs.wikipedia.org/wiki/Inzulin
Inzulin – Bosnian
bs
bs
interlanguage-link-target

values:
https://ca.wikipedia.org/wiki/Insulina
Insulina – Catalan
ca
ca
interlanguage-link-target

values:
https://cs.wikipedia.org/wiki/Inzulin
Inzulin – Czech
cs
cs
interlanguage-link-target

values:
https://da.wikipedia.org/wiki/Insulin
Insulin – Danish
da
da
interlanguage-link-target

values:
https://de.wikipedia.org/wiki/Insulin
Insulin – German
de
de
interlanguage-link-target

values: އިންސިޔުލިން – Divehi

values:
https://et.wikipedia.org/wiki/Insuliin
Insuliin – Estonian
et
et
interlanguage-link-target

values: Ινσουλίνη – Greek

values:
https://es.wikipedia.org/wiki/Insulina
Insulina – Spanish
es
es
interlanguage-link-target

values:
https://eo.wikipedia.org/wiki/Insulino
Insulino – Esperanto
eo
eo
interlanguage-link-target

values:
https://eu.wikipedia.org/wiki/Intsulina
Intsulina – Basque
eu
eu
interlanguage-link-target

values: انسولین – Persian

values:
https://fr.wikipedia.org/wiki/Insuline
Insuline – French
fr
fr
interlanguage-link-target

values:
https://ga.wikipedia.org/wiki/Inslin
Inslin – Irish
ga
ga
interlanguage-link-target

values:
https://gl.wikipedia.org/wiki/Insulina
Insulina – Galician
gl
gl
interlanguage-link-target

values: Ինսուլին – Armenian

values: इन्सुलिन – Hindi

values:
https://hr.wikipedia.org/wiki/Inzulin
Inzulin – Croatian
hr
hr
interlanguage-link-target

values:
https://io.wikipedia.org/wiki/Insulino
Insulino – Ido
io
io
interlanguage-link-target

values:
https://id.wikipedia.org/wiki/Insulin
Insulin – Indonesian
id
id
interlanguage-link-target

values:
https://ia.wikipedia.org/wiki/Insulina
Insulina – Interlingua
ia
ia
interlanguage-link-target

values:
https://it.wikipedia.org/wiki/Insulina
Insulina – Italian
it
it
interlanguage-link-target

values: אינסולין – Hebrew

values:
https://jv.wikipedia.org/wiki/Insulin
Insulin – Javanese
jv
jv
interlanguage-link-target

values: ಇನ್ಸುಲಿನ್ – Kannada

values:
https://pam.wikipedia.org/wiki/Insulin
Insulin – Pampanga
pam
pam
interlanguage-link-target

values: Инсулин – Kazakh

values: Инсулин – Kyrgyz

values:
https://la.wikipedia.org/wiki/Insulinum
Insulinum – Latin
la
la
interlanguage-link-target

values:
https://lt.wikipedia.org/wiki/Insulinas
Insulinas – Lithuanian
lt
lt
interlanguage-link-target

values:
https://hu.wikipedia.org/wiki/Inzulin
Inzulin – Hungarian
hu
hu
interlanguage-link-target

values:
https://ms.wikipedia.org/wiki/Insulin
Insulin – Malay
ms
ms
interlanguage-link-target

values: အင်ဆူလင် – Burmese

values:
https://nl.wikipedia.org/wiki/Insuline
Insuline – Dutch
nl
nl
interlanguage-link-target

values:
https://no.wikipedia.org/wiki/Insulin
Insulin – Norwegian
no
no
interlanguage-link-target

values: interlanguage-link interwiki-no badge-Q17437798 badge-goodarticle

values:
https://nn.wikipedia.org/wiki/Insulin
Insulin – Norwegian Nynorsk
nn
nn
interlanguage-link-target

values:
https://oc.wikipedia.org/wiki/Insulina
Insulina – Occitan
oc
oc
interlanguage-link-target

values:
https://uz.wikipedia.org/wiki/Insulin
Insulin – Uzbek
uz
uz
interlanguage-link-target

values: ਇੰਸੂਲਿਨ – Punjabi

values: انسولين – Pashto

values:
https://pl.wikipedia.org/wiki/Insulina
Insulina – Polish
pl
pl
interlanguage-link-target

values:
https://pt.wikipedia.org/wiki/Insulina
Insulina – Portuguese
pt
pt
interlanguage-link-target

values: Инсулин – Russian

values:
https://sco.wikipedia.org/wiki/Insulin
Insulin – Scots
sco
sco
interlanguage-link-target

values:
https://sq.wikipedia.org/wiki/Insulina
Insulina – Albanian
sq
sq
interlanguage-link-target

values:
https://sl.wikipedia.org/wiki/Insulin
Insulin – Slovenian
sl
sl
interlanguage-link-target

values: Инсулин – Serbian

values:
https://sh.wikipedia.org/wiki/Inzulin
Inzulin – Serbo-Croatian
sh
sh
interlanguage-link-target

values:
https://su.wikipedia.org/wiki/Insulin
Insulin – Sundanese
su
su
interlanguage-link-target

values:
https://fi.wikipedia.org/wiki/Insuliini
Insuliini – Finnish
fi
fi
interlanguage-link-target

values:
https://sv.wikipedia.org/wiki/Insulin
Insulin – Swedish
sv
sv
interlanguage-link-target

values: இன்சுலின் – Tamil

values: อินซูลิน – Thai

values: انسولین – Urdu

values:
https://vi.wikipedia.org/wiki/Insulin
Insulin – Vietnamese
vi
vi
interlanguage-link-target

values:
https://war.wikipedia.org/wiki/Insulin
Insulin – Waray
war
war
interlanguage-link-target

values: אינסולין – Yiddish

values: /static/images/wikimedia-button-1.5x.png 1.5x, /static/images/wikimedia-button-2x.png 2x

values: /static/images/poweredby_mediawiki_132x47.png 1.5x, /static/images/poweredby_mediawiki_176x62.png 2x

values:
suggestions
display: none; font-size: 13px;

values: mediawiki ltr sitedir-ltr mw-hide-empty-elt ns-0 ns-subject page-Insulin rootpage-Insulin skin-vector action-view