Carbon is a chemical element with symbol C and atomic number 6. It is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds, it belongs to group 14 of the periodic table. Three isotopes occur 12C and 13C being stable, while 14C is a radionuclide, decaying with a half-life of about 5,730 years. Carbon is one of the few elements known since antiquity. Carbon is the 15th most abundant element in the Earth's crust, the fourth most abundant element in the universe by mass after hydrogen and oxygen. Carbon's abundance, its unique diversity of organic compounds, its unusual ability to form polymers at the temperatures encountered on Earth enables this element to serve as a common element of all known life, it is the second most abundant element in the human body by mass after oxygen. The atoms of carbon can bond together in different ways, termed allotropes of carbon; the best known are graphite and amorphous carbon. The physical properties of carbon vary with the allotropic form.
For example, graphite is opaque and black while diamond is transparent. Graphite is soft enough to form a streak on paper, while diamond is the hardest occurring material known. Graphite is a good electrical conductor. Under normal conditions, carbon nanotubes, graphene have the highest thermal conductivities of all known materials. All carbon allotropes are solids under normal conditions, with graphite being the most thermodynamically stable form at standard temperature and pressure, they are chemically resistant and require high temperature to react with oxygen. The most common oxidation state of carbon in inorganic compounds is +4, while +2 is found in carbon monoxide and transition metal carbonyl complexes; the largest sources of inorganic carbon are limestones and carbon dioxide, but significant quantities occur in organic deposits of coal, peat and methane clathrates. Carbon forms a vast number of compounds, more than any other element, with ten million compounds described to date, yet that number is but a fraction of the number of theoretically possible compounds under standard conditions.
For this reason, carbon has been referred to as the "king of the elements". The allotropes of carbon include graphite, one of the softest known substances, diamond, the hardest occurring substance, it bonds with other small atoms, including other carbon atoms, is capable of forming multiple stable covalent bonds with suitable multivalent atoms. Carbon is known to form ten million different compounds, a large majority of all chemical compounds. Carbon has the highest sublimation point of all elements. At atmospheric pressure it has no melting point, as its triple point is at 10.8±0.2 MPa and 4,600 ± 300 K, so it sublimes at about 3,900 K. Graphite is much more reactive than diamond at standard conditions, despite being more thermodynamically stable, as its delocalised pi system is much more vulnerable to attack. For example, graphite can be oxidised by hot concentrated nitric acid at standard conditions to mellitic acid, C66, which preserves the hexagonal units of graphite while breaking up the larger structure.
Carbon sublimes in a carbon arc, which has a temperature of about 5800 K. Thus, irrespective of its allotropic form, carbon remains solid at higher temperatures than the highest-melting-point metals such as tungsten or rhenium. Although thermodynamically prone to oxidation, carbon resists oxidation more than elements such as iron and copper, which are weaker reducing agents at room temperature. Carbon is the sixth element, with a ground-state electron configuration of 1s22s22p2, of which the four outer electrons are valence electrons, its first four ionisation energies, 1086.5, 2352.6, 4620.5 and 6222.7 kJ/mol, are much higher than those of the heavier group-14 elements. The electronegativity of carbon is 2.5 higher than the heavier group-14 elements, but close to most of the nearby nonmetals, as well as some of the second- and third-row transition metals. Carbon's covalent radii are taken as 77.2 pm, 66.7 pm and 60.3 pm, although these may vary depending on coordination number and what the carbon is bonded to.
In general, covalent radius decreases with higher bond order. Carbon compounds form the basis of all known life on Earth, the carbon–nitrogen cycle provides some of the energy produced by the Sun and other stars. Although it forms an extraordinary variety of compounds, most forms of carbon are comparatively unreactive under normal conditions. At standard temperature and pressure, it resists all but the strongest oxidizers, it does not react with hydrochloric acid, chlorine or any alkalis. At elevated temperatures, carbon reacts with oxygen to form carbon oxides and will rob oxygen from metal oxides to leave the elemental metal; this exothermic reaction is used in the iron and steel industry to smelt iron and to control the carbon content of steel: Fe3O4 + 4 C → 3 Fe + 4 COCarbon monoxide can be recycled to smelt more iron: Fe3O4 + 4 CO → 3 Fe + 4 CO2with sulfur to form carbon disulfide and with steam in the coal-gas reaction: C + H2O → CO + H2. Carbon combines with some metals at high temperatures to form metallic carbides, such as the iron carbide cementite in steel and tungsten carbide used as an abrasive and for making hard tips for cutting tools.
The system of carbon allotropes spans a range of extremes: Atomic carbon is a ver
International Standard Serial Number
An International Standard Serial Number is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is helpful in distinguishing between serials with the same title. ISSN are used in ordering, interlibrary loans, other practices in connection with serial literature; the ISSN system was first drafted as an International Organization for Standardization international standard in 1971 and published as ISO 3297 in 1975. ISO subcommittee TC 46/SC 9 is responsible for maintaining the standard; when a serial with the same content is published in more than one media type, a different ISSN is assigned to each media type. For example, many serials are published both in electronic media; the ISSN system refers to these types as electronic ISSN, respectively. Conversely, as defined in ISO 3297:2007, every serial in the ISSN system is assigned a linking ISSN the same as the ISSN assigned to the serial in its first published medium, which links together all ISSNs assigned to the serial in every medium.
The format of the ISSN is an eight digit code, divided by a hyphen into two four-digit numbers. As an integer number, it can be represented by the first seven digits; the last code digit, which may be 0-9 or an X, is a check digit. Formally, the general form of the ISSN code can be expressed as follows: NNNN-NNNC where N is in the set, a digit character, C is in; the ISSN of the journal Hearing Research, for example, is 0378-5955, where the final 5 is the check digit, C=5. To calculate the check digit, the following algorithm may be used: Calculate the sum of the first seven digits of the ISSN multiplied by its position in the number, counting from the right—that is, 8, 7, 6, 5, 4, 3, 2, respectively: 0 ⋅ 8 + 3 ⋅ 7 + 7 ⋅ 6 + 8 ⋅ 5 + 5 ⋅ 4 + 9 ⋅ 3 + 5 ⋅ 2 = 0 + 21 + 42 + 40 + 20 + 27 + 10 = 160 The modulus 11 of this sum is calculated. For calculations, an upper case X in the check digit position indicates a check digit of 10. To confirm the check digit, calculate the sum of all eight digits of the ISSN multiplied by its position in the number, counting from the right.
The modulus 11 of the sum must be 0. There is an online ISSN checker. ISSN codes are assigned by a network of ISSN National Centres located at national libraries and coordinated by the ISSN International Centre based in Paris; the International Centre is an intergovernmental organization created in 1974 through an agreement between UNESCO and the French government. The International Centre maintains a database of all ISSNs assigned worldwide, the ISDS Register otherwise known as the ISSN Register. At the end of 2016, the ISSN Register contained records for 1,943,572 items. ISSN and ISBN codes are similar in concept. An ISBN might be assigned for particular issues of a serial, in addition to the ISSN code for the serial as a whole. An ISSN, unlike the ISBN code, is an anonymous identifier associated with a serial title, containing no information as to the publisher or its location. For this reason a new ISSN is assigned to a serial each time it undergoes a major title change. Since the ISSN applies to an entire serial a new identifier, the Serial Item and Contribution Identifier, was built on top of it to allow references to specific volumes, articles, or other identifiable components.
Separate ISSNs are needed for serials in different media. Thus, the print and electronic media versions of a serial need separate ISSNs. A CD-ROM version and a web version of a serial require different ISSNs since two different media are involved. However, the same ISSN can be used for different file formats of the same online serial; this "media-oriented identification" of serials made sense in the 1970s. In the 1990s and onward, with personal computers, better screens, the Web, it makes sense to consider only content, independent of media; this "content-oriented identification" of serials was a repressed demand during a decade, but no ISSN update or initiative occurred. A natural extension for ISSN, the unique-identification of the articles in the serials, was the main demand application. An alternative serials' contents model arrived with the indecs Content Model and its application, the digital object identifier, as ISSN-independent initiative, consolidated in the 2000s. Only in 2007, ISSN-L was defined in the
In enzymology, a 3-methyl-2-oxobutanoate dehydrogenase is an enzyme that catalyzes the chemical reaction 3-methyl-2-oxobutanoate + lipoyllysine ⇌ S-dihydrolipoyllysine + CO2The 3 substrates of this enzyme are 3-methyl-2-oxobutanoate, dihydrolipoyllysine-residue transferase, lipoyllysine, whereas its 3 products are dihydrolipoyllysine-residue transferase, S-dihydrolipoyllysine, CO2. This enzyme belongs to the family of oxidoreductases those acting on the aldehyde or oxo group of donor with a disulfide as acceptor; this enzyme participates in valine and isoleucine degradation. It employs thiamin diphosphate; as of late 2007, twenty-nine structures have been solved for this class of enzymes, with PDB accession codes 1DTW, 1OLS, 1OLU, 1OLX, 1U5B, 1UM9, 1UMB, 1UMC, 1UMD, 1V11, 1V16, 1V1M, 1V1R, 1WCI, 1X7W, 1X7X, 1X7Y, 1X7Z, 1X80, 2BEU, 2BEV, 2BEW, 2BFB, 2BFC, 2BFD, 2BFE, 2BFF, 2BP7, 2J9F. Bowden JA, Connelly JL. "Branched chain alpha-keto acid metabolism. II. Evidence for the common identity of alpha-ketoisocaproic acid and alpha-keto-beta-methyl-valeric acid dehydrogenases".
J. Biol. Chem. 243: 3526–31. PMID 5656388. Connelly JL, Danner DJ, Bowden JA. "Branched chain alpha-keto acid metabolism. I. Isolation and partial characterization of bovine liver alpha-ketoisocaproic:alpha-keto-beta-methylvaleric acid dehydrogenase". J. Biol. Chem. 243: 1198–203. PMID 5689906. Danner DJ, Lemmon SK, Besharse JC, Elsas LJ II. "Purification and characterization of branched chain alpha-ketoacid dehydrogenase from bovine liver mitochondria". J. Biol. Chem. 254: 5522–6. PMID 447664. Pettit FH, Yeaman SJ, Reed LJ. "Purification and characterization of branched chain alpha-keto acid dehydrogenase complex of bovine kidney". Proc. Natl. Acad. Sci. U. S. A. 75: 4881–5. Doi:10.1073/pnas.75.10.4881. PMC 336225. PMID 283398. Perham RN. "Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions". Annu. Rev. Biochem. 69: 961–1004. Doi:10.1146/annurev.biochem.69.1.961. PMID 10966480
Amino acids are organic compounds containing amine and carboxyl functional groups, along with a side chain specific to each amino acid. The key elements of an amino acid are carbon, hydrogen and nitrogen, although other elements are found in the side chains of certain amino acids. About 500 occurring amino acids are known and can be classified in many ways, they can be classified according to the core structural functional groups' locations as alpha-, beta-, gamma- or delta- amino acids. In the form of proteins, amino acid residues form the second-largest component of human muscles and other tissues. Beyond their role as residues in proteins, amino acids participate in a number of processes such as neurotransmitter transport and biosynthesis. In biochemistry, amino acids having both the amine and the carboxylic acid groups attached to the first carbon atom have particular importance, they are known as α-amino acids. They include the 22 proteinogenic amino acids, which combine into peptide chains to form the building-blocks of a vast array of proteins.
These are all L-stereoisomers, although a few D-amino acids occur in bacterial envelopes, as a neuromodulator, in some antibiotics. Twenty of the proteinogenic amino acids are encoded directly by triplet codons in the genetic code and are known as "standard" amino acids; the other two are selenocysteine, pyrrolysine. Pyrrolysine and selenocysteine are encoded via variant codons. N-formylmethionine is considered as a form of methionine rather than as a separate proteinogenic amino acid. Codon–tRNA combinations not found in nature can be used to "expand" the genetic code and form novel proteins known as alloproteins incorporating non-proteinogenic amino acids. Many important proteinogenic and non-proteinogenic amino acids have biological functions. For example, in the human brain and gamma-amino-butyric acid are the main excitatory and inhibitory neurotransmitters. Hydroxyproline, a major component of the connective tissue collagen, is synthesised from proline. Glycine is a biosynthetic precursor to porphyrins used in red blood cells.
Carnitine is used in lipid transport. Nine proteinogenic amino acids are called "essential" for humans because they cannot be produced from other compounds by the human body and so must be taken in as food. Others may be conditionally essential for medical conditions. Essential amino acids may differ between species; because of their biological significance, amino acids are important in nutrition and are used in nutritional supplements, fertilizers and food technology. Industrial uses include the production of drugs, biodegradable plastics, chiral catalysts; the first few amino acids were discovered in the early 19th century. In 1806, French chemists Louis-Nicolas Vauquelin and Pierre Jean Robiquet isolated a compound in asparagus, subsequently named asparagine, the first amino acid to be discovered. Cystine was discovered in 1810, although its monomer, remained undiscovered until 1884. Glycine and leucine were discovered in 1820; the last of the 20 common amino acids to be discovered was threonine in 1935 by William Cumming Rose, who determined the essential amino acids and established the minimum daily requirements of all amino acids for optimal growth.
The unity of the chemical category was recognized by Wurtz in 1865, but he gave no particular name to it. Usage of the term "amino acid" in the English language is from 1898, while the German term, Aminosäure, was used earlier. Proteins were found to yield amino acids after enzymatic acid hydrolysis. In 1902, Emil Fischer and Franz Hofmeister independently proposed that proteins are formed from many amino acids, whereby bonds are formed between the amino group of one amino acid with the carboxyl group of another, resulting in a linear structure that Fischer termed "peptide". In the structure shown at the top of the page, R represents a side chain specific to each amino acid; the carbon atom next to the carboxyl group is called the α–carbon. Amino acids containing an amino group bonded directly to the alpha carbon are referred to as alpha amino acids; these include amino acids such as proline which contain secondary amines, which used to be referred to as "imino acids". The alpha amino acids are the most common form found in nature, but only when occurring in the L-isomer.
The alpha carbon is a chiral carbon atom, with the exception of glycine which has two indistinguishable hydrogen atoms on the alpha carbon. Therefore, all alpha amino acids but glycine can exist in either of two enantiomers, called L or D amino acids, which are mirror images of each other. While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amin
Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue, under the voluntary control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons. A skeletal muscle refers to multiple bundles of cells joined together called muscle fibers; the fibers and muscles are surrounded by connective tissue layers called fasciae. Muscle fibers, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibers have more than one nucleus, they have multiple mitochondria to meet energy needs. Muscle fibers are in turn composed of myofibrils; the myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, which are the basic functional units of the muscle fiber. The sarcomere is responsible for the striated appearance of skeletal muscle and forms the basic machinery necessary for muscle contraction.
Connective tissue is present in all muscles as fascia. Enclosing each muscle is a layer of connective tissue known as the epimysium. Muscle fibers are the individual contractile units within a muscle. A single muscle such as the biceps brachii contains many muscle fibers. Another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers; these cells are quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair. DevelopmentIndividual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. MicroanatomySkeletal muscle exhibits a distinctive banding pattern when viewed under the microscope due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers; the principal cytoplasmic proteins are myosin and actin which are arranged in a repeating unit called a sarcomere.
The interaction of myosin and actin is responsible for muscle contraction. Every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function; the cell membrane is called the sarcolemma with the cytoplasm known as the sarcoplasm. In the sarcoplasm are the myofibrils; the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei. Between the myofibrils are the mitochondria. While the muscle fiber does not have smooth endoplasmic cisternae, it contains a sarcoplasmic reticulum; the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae; these cross the muscle fiber from one side to the other. In between two terminal cisternae is a tubular infolding called a transverse tubule. T tubules are the pathways for action potentials to signal the sarcoplasmic reticulum to release calcium, causing a muscle contraction.
Together, two terminal cisternae and a transverse tubule form a triad. Muscle architecture refers to the arrangement of muscle fibers relative to the axis of force generation of the muscle; this axis is a hypothetical line from the muscle's origin to insertion. For some longitudinal muscles, such as the biceps brachii, this is a simple concept. For others, such as the rectus femoris or deltoid muscle, it becomes more complicated. While the muscle fibers of a fascicle lie parallel to one another, the fascicles themselves can vary in their relationship to one another and to their tendons; the different fiber arrangements produce broad categories of skeletal muscle architectures including longitudinal, unipennate and multipennate. Because of these different architectures, the tension a muscle can create between its tendons varies by more than its size and fiber-type makeup. Longitudinal architectureThe fascicles of longitudinally arranged, parallel, or fusiform muscles run parallel to the axis of force generation, thus these muscles on a whole function to a single, large muscle fiber.
Variations exist, the different terms are used more specifically. For instance, fusiform refers to a longitudinal architecture with a widened muscle belly, while parallel may refer to a more ribbon-shaped longitudinal architecture. A less common example would be a circular muscle such as the orbicularis oculi, in which the fibers are longitudinally arranged, but create a circle from origin to insertion. Unipennate architectureThe fibers in unipennate muscles are all oriented at the same angle relative to the axis of force generation; this angle reduces the effective force of any individual fiber, as it is pulling off-axis. However, because of this angle, more fibers can be packed into the same muscle volume, increasing the Physiological cross-sectional area; this effect is known as fiber packing, and—in terms of force generation—it more than overcomes the efficiency loss of the off-axis orientation. The trade-off comes in the total excursion. Overall muscle shortening speed is reduced compared to fiber shortening speed, as is the total distance of shortening.
All of these effects scale with pennation angle.
Leucine is an essential amino acid, used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group, an α-carboxylic acid group, a side chain isobutyl group, making it a non-polar aliphatic amino acid, it is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, beans and other legumes, it is encoded by the codons UUA, UUG, CUU, CUC, CUA, CUG. Like valine and isoleucine, leucine is a branched-chain amino acid; the primary metabolic end products of leucine metabolism are acetoacetate. It is the most important ketogenic amino acid in humans.p. 101Leucine and β-hydroxy β-methylbutyric acid, a minor leucine metabolite, exhibit pharmacological activity in humans and have been demonstrated to promote protein biosynthesis via the phosphorylation of the mechanistic target of rapamycin. As a food additive, L-leucine is classified as a flavor enhancer.
The Food and Nutrition Board of the U. S. Institute of Medicine set Recommended Dietary Allowances for essential amino acids in 2002. For leucine, for adults 19 years and older, 42 mg/kg body weight/day; as a dietary supplement, leucine has been found to slow the degradation of muscle tissue by increasing the synthesis of muscle proteins in aged rats. However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle strength in healthy elderly men. More studies are needed, preferably ones based on an random sample of society. Factors such as lifestyle choices, gender, exercise, etc. must be factored into the analyses to isolate the effects of supplemental leucine as a standalone, or if taken with other branched chain amino acids. Until dietary supplemental leucine cannot be associated as the prime reason for muscular growth or optimal maintenance for the entire population. Both L-leucine and D-leucine protect mice against seizures. D-leucine terminates seizures in mice after the onset of seizure activity, at least as as diazepam and without sedative effects.
Decreased dietary intake of L-leucine promotes adiposity in mice. High blood levels of leucine are associated with insulin resistance in humans and rodents; this might be due to the effect of leucine to stimulate mTOR signaling. Dietary restriction of leucine and the other BCAAs can reverse diet-induced obesity in wild-type mice by increasing energy expenditure, can restrict fat mass gain of hyperphagic rats. Leucine toxicity, as seen in decompensated maple syrup urine disease, causes delirium and neurologic compromise, can be life-threatening. A high intake of leucine may cause or exacerbate symptoms of pellagra in people with low niacin status because it interferes with the conversion of L-tryptophan to niacin. Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia; as such, unofficially, a tolerable upper intake level for leucine in healthy adult men can be suggested at 500 mg/kg/d or 35 g/d under acute dietary conditions. Leucine is a dietary amino acid with the capacity to directly stimulate myofibrillar muscle protein synthesis.
This effect of leucine arises results from its role as an activator of the mechanistic target of rapamycin, a serine-threonine protein kinase that regulates protein biosynthesis and cell growth. The activation of mTOR by leucine is mediated through Rag GTPases, leucine binding to leucyl-tRNA synthetase, leucine binding to sestrin 2, other mechanisms. Leucine metabolism occurs in many tissues in the human body. Adipose and muscle tissue use leucine in the formation of other compounds. Combined leucine use in these two tissues is seven times greater than in the liver. In healthy individuals 60% of dietary L-leucine is metabolized after several hours, with 5% of dietary L-leucine being converted to β-hydroxy β-methylbutyric acid. Around 40% of dietary L-leucine is converted to acetyl-CoA, subsequently used in the synthesis of other compounds; the vast majority of L-leucine metabolism is catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate. Α-KIC is metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.
Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to MC-CoA, used in the synthesis of acetyl-CoA and other compounds. During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert MC-CoA into HMB-CoA and HMB-CoA into HMB respectively. A small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase, which converts α-KIC to HMB. In healthy individuals, this minor pathway – which involves the conversion of L-leucine to α-KIC and HMB – is the predominant route of HMB synthesis. A small fraction of L-leucine metabolism – less than 5% in all tissues except the testes where it accounts for about 33% – is catalyzed by leucine aminomutase, producing β-leucine, subsequently metabolized into β-ketoisocaproate, β-ketoisocaproyl-CoA, acetyl-CoA by a series of uncharacterized enzymes; the metabolism o
Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It regulates the metabolism of carbohydrates and protein by promoting the absorption of carbohydrates glucose from the blood into liver and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is inhibited by high concentrations of insulin in the blood. Circulating insulin 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 of reserve body fat. Beta cells are sensitive to glucose concentrations known as blood sugar levels; when the glucose level is high, the beta cells secrete insulin into the blood. Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, decreased secretion when glucose concentrations are high.
Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin. The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis. 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, characterized by abnormally high blood glucose concentrations, generalized body wasting. In type 2 diabetes mellitus the destruction of beta cells is less pronounced than in type 1 diabetes, is not due to an autoimmune process. Instead there is an accumulation of amyloid in the pancreatic islets, which disrupts their anatomy and physiology; 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, peripheral tissue insulin resistance.
Type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, unresponsive to the concentration of glucose in the blood. Insulin is still secreted into the blood in response to the blood glucose; as a result, the insulin levels when the blood sugar level is normal, are much higher than they are in healthy persons. The human insulin protein is composed of 51 amino acids, has a molecular mass of 5808 Da, it is a dimer of a B-chain, which are linked together by disulfide bonds. Insulin's structure varies between species of animals. Insulin from animal sources differs somewhat in effectiveness from human insulin because of these variations. Porcine insulin is close to the human version, was used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies; 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.
Insulin may have originated more than a billion years ago. The molecular origins of insulin go at least as far back. Apart from animals, insulin-like proteins are known to exist in the Fungi and Protista kingdoms. Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish. 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. The preproinsulin precursor of insulin is encoded by the INS gene. 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. In the pancreatic β cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis.
Insulin is regulated through the transcription factors PDX1, NeuroD1, MafA. PDX1 is in the nuclear periphery upon low blood glucose levels interacting with corepressors HDAC1 and 2, downregulating the insulin secretion. An increase in blood glucose levels causes phosphorylation of PDX1 and it translocates centrally and binds the A3 element within the insulin promoter. Upon translocation it interacts with coactivators HAT p300 and acetyltransferase set 7/9. PDX1 affects the histone modifications through deacetylation as well as methylation, it is said to suppress glucagon. NeuroD1 known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes involved in exocytosis, it is localized in the cytosol, but in response to high glucose it becomes glycosylated by OGT and/or phosphorylated by ERK, which causes translocation to the nucleus. In the nucleus β2 heterodimerizes with E47, binds to the E1 element of the insulin promoter and recruits co-activator p300 which acetylates β2.
It is able to interact with other transcription factors as well in activation of the insulin gene. MafA is degraded by proteasomes upon low blood glucose levels