Insulin (/n.sj.ln/,[5][6] from Latin insula, 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is considered to be the main anabolic hormone of the body.[7] It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells.[8] In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both.[8] Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood.[9] Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.
Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose, and inhibit secretion of insulin when glucose levels are low.[10] Insulin production is also regulated by glucose: high glucose promotes insulin production while low glucose levels lead to lower production.[11] Insulin enhances glucose uptake and metabolism in the cells, thereby reducing blood sugar level. Their neighboring alpha cells, by taking their cues from the beta cells,[10] secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high. Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver.[8][10] The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis.[10]
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Decreased or absent insulin activity results in diabetes mellitus, a condition of high blood sugar level (hyperglycaemia). There are two types of the disease. In diabetes mellitus type 1, the beta cells are destroyed by an autoimmune reaction so that insulin can no longer be synthesized or be secreted into the blood.[12] In diabetes mellitus type 2, the destruction of beta cells is less pronounced than in type 1, and is not due to an autoimmune process. Instead, there is an accumulation of amyloid in the pancreatic islets, which likely disrupts their anatomy and physiology.[10] The pathogenesis of type 2 diabetes is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance are known to be involved.[7] Type 2 diabetes is characterized by increased glucagon secretion which is unaffected by, and unresponsive to the concentration of blood glucose. But insulin is still secreted into the blood in response to the blood glucose.[10] As a result, glucose accumulates in the blood.
The human insulin protein is composed of 51 amino acids, and has a molecular mass of 5808 Da. It is a heterodimer of an A-chain and a B-chain, which are linked together by disulfide bonds. Insulin's structure varies slightly between species of animals. Insulin from non-human animal sources differs somewhat in effectiveness (in carbohydrate metabolism effects) from human insulin because of these variations. Porcine insulin is especially close to the human version, and was widely used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies.[13][14][15][16]
Insulin was the first peptide hormone discovered.[17] Frederick Banting and Charles Best, working in the laboratory of John Macleod at the University of Toronto, were the first to isolate insulin from dog pancreas in 1921. Frederick Sanger sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced.[18] The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is also the first protein to be chemically synthesised and produced by DNA recombinant technology.[19] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[20]
Insulin may have originated more than a billion years ago.[21] The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.[22] Apart from animals, insulin-like proteins are also known to exist in fungi and protists.[21]
Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish.[23] Cone snails: Conus geographus and Conus tulipa, venomous sea snails that hunt small fish, use modified forms of insulin in their venom cocktails. The insulin toxin, closer in structure to fishes' than to snails' native insulin, slows down the prey fishes by lowering their blood glucose levels.[24][25]
Insulin is produced exclusively in the beta cells of the pancreatic islets in mammals, and the Brockmann body in some fish. Human insulin is produced from the INS gene, located on chromosome 11.[26] Rodents have two functional insulin genes; one is the homolog of most mammalian genes (Ins2), and the other is a retroposed copy that includes promoter sequence but that is missing an intron (Ins1).[27] Transcription of the insulin gene increases in response to elevated blood glucose.[28] This is primarily controlled by transcription factors that bind enhancer sequences in the ~400 base pairs before the gene's transcription start site.[26][28]
During a low-glucose state, PDX1 (pancreatic and duodenal homeobox protein 1) is located in the nuclear periphery as a result of interaction with HDAC1 and 2,[33] which results in downregulation of insulin secretion.[34] An increase in blood glucose levels causes phosphorylation of PDX1, which leads it to undergo nuclear translocation and bind the A3 element within the insulin promoter.[35] Upon translocation it interacts with coactivators HAT p300 and SETD7. PDX1 affects the histone modifications through acetylation and deacetylation as well as methylation. It is also said to suppress glucagon.[36]
NeuroD1, also known as 2, regulates insulin exocytosis in pancreatic cells by directly inducing the expression of genes involved in exocytosis.[37] It is localized in the cytosol, but in response to high glucose it becomes glycosylated by OGT and/or phosphorylated by ERK, which causes translocation to the nucleus. In the nucleus 2 heterodimerizes with E47, binds to the E1 element of the insulin promoter and recruits co-activator p300 which acetylates 2. It is able to interact with other transcription factors as well in activation of the insulin gene.[37]
MafA is degraded by proteasomes upon low blood glucose levels. Increased levels of glucose make an unknown protein glycosylated. This protein works as a transcription factor for MafA in an unknown manner and MafA is transported out of the cell. MafA is then translocated back into the nucleus where it binds the C1 element of the insulin promoter.[38][39]
These transcription factors work synergistically and in a complex arrangement. Increased blood glucose can after a while destroy the binding capacities of these proteins, and therefore reduce the amount of insulin secreted, causing diabetes. The decreased binding activities can be mediated by glucose induced oxidative stress and antioxidants are said to prevent the decreased insulin secretion in glucotoxic pancreatic cells. Stress signalling molecules and reactive oxygen species inhibits the insulin gene by interfering with the cofactors binding the transcription factors and the transcription factors itself.[40]
Several regulatory sequences in the promoter region of the human insulin gene bind to transcription factors. In general, the A-boxes bind to Pdx1 factors, E-boxes bind to NeuroD, C-boxes bind to MafA, and cAMP response elements to CREB. There are also silencers that inhibit transcription.
The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the cell into the circulation.[41]
Insulin release is stimulated also by beta-2 receptor stimulation and inhibited by alpha-1 receptor stimulation. In addition, cortisol, glucagon and growth hormone antagonize the actions of insulin during times of stress. Insulin also inhibits fatty acid release by hormone-sensitive lipase in adipose tissue.[8]
Contrary to an initial belief that hormones would be generally small chemical molecules, as the first peptide hormone known of its structure, insulin was found to be quite large.[17] A single protein (monomer) of human insulin is composed of 51 amino acids, and has a molecular mass of 5808 Da. The molecular formula of human insulin is C257H383N65O77S6.[45] It is a combination of two peptide chains (dimer) named an A-chain and a B-chain, which are linked together by two disulfide bonds. The A-chain is composed of 21 amino acids, while the B-chain consists of 30 residues. The linking (interchain) disulfide bonds are formed at cysteine residues between the positions A7-B7 and A20-B19. There is an additional (intrachain) disulfide bond within the A-chain between cysteine residues at positions A6 and A11. The A-chain exhibits two -helical regions at A1-A8 and A12-A19 which are antiparallel; while the B chain has a central -helix (covering residues B9-B19) flanked by the disulfide bond on either sides and two -sheets (covering B7-B10 and B20-B23).[17][46]
The amino acid sequence of insulin is strongly conserved and varies only slightly between species. Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one. Even insulin from some species of fish is similar enough to human to be clinically effective in humans. Insulin in some invertebrates is quite similar in sequence to human insulin, and has similar physiological effects. The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history. The C-peptide of proinsulin, however, differs much more among species; it is also a hormone, but a secondary one.[46] 2351a5e196
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