{"id":362,"date":"2019-05-13T07:40:42","date_gmt":"2019-05-13T07:40:42","guid":{"rendered":"https:\/\/www.diabetesasia.org\/magazine\/?p=362"},"modified":"2025-04-16T10:13:14","modified_gmt":"2025-04-16T04:43:14","slug":"what-is-insulinhow-it-is-effected","status":"publish","type":"post","link":"https:\/\/www.diabetesasia.org\/magazine\/what-is-insulinhow-it-is-effected\/","title":{"rendered":"what is insulin? how does it works ?"},"content":{"rendered":"

INSULIN<\/strong><\/h2>\n

Insulin<\/b>\u00a0(\/\u02c8<\/span>\u026a<\/span>n<\/span>.<\/span>sj<\/span>\u028a<\/span>.<\/span>l<\/span>\u026a<\/span>n<\/span>\/<\/span><\/span>,<\/sup><\/sup>\u00a0from\u00a0Latin\u00a0insula<\/i>, ‘island’) is a\u00a0peptide hormone\u00a0produced by\u00a0beta cells\u00a0of the\u00a0pancreatic islets; it is considered to be the main\u00a0anabolic\u00a0hormone\u00a0of the body.<\/sup>\u00a0It regulates the\u00a0metabolism\u00a0of\u00a0carbohydrates,\u00a0fats,\u00a0and\u00a0protein\u00a0by promoting the absorption of\u00a0glucose from the blood into the\u00a0liver,\u00a0fat,\u00a0and\u00a0skeletal muscle cells.<\/sup> In these tissues, the absorbed glucose is converted into either\u00a0glycogen\u00a0via\u00a0glycogenesis\u00a0or\u00a0fats\u00a0(triglycerides) via\u00a0lipogenesis, or, in the case of the liver, into both.<\/sup>\u00a0Glucose\u00a0production and\u00a0secretion by the liver are strongly inhibited by high concentrations of insulin in the blood.<\/sup>\u00a0Circulating 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\u00a0catabolism, especially of\u00a0reserve body fat.<\/p>\n

Beta cells<\/a>\u00a0are sensitive to\u00a0blood sugar levels<\/a> so they secrete insulin into the blood in response to a high level of glucose, and inhibit the secretion of insulin when glucose levels are low.<\/sup> Insulin enhances glucose uptake and metabolism in the cells, thereby reducing blood sugar levels. Their neighboring\u00a0alpha cells<\/a>, by taking their cues from the beta cells,<\/sup>\u00a0secrete\u00a0glucagon<\/a>\u00a0into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high.\u00a0Glucagon<\/a> increases blood glucose levels by stimulating\u00a0glycogenolysis<\/a>\u00a0and\u00a0gluconeogenesis<\/a>\u00a0in the liver.<\/sup><\/sup>\u00a0The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of\u00a0glucose homeostasis<\/a>.<\/sup><\/p>\n

Decreased or loss of insulin activity results in diabetes mellitus, a condition of high blood sugar level (hyperglycemia). There are two types of the disease. In type 1 diabetes mellitus, the beta cells are destroyed by an\u00a0autoimmune reaction so that insulin can no longer be synthesized or secreted into the blood In\u00a0type 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\u00a0amyloid\u00a0in the pancreatic islets, which likely disrupts their anatomy and physiology.<\/sup>\u00a0The\u00a0pathogenesis of type 2 diabetes is not well understood but a reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance is known to be involved.[7]<\/sup>\u00a0Type 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.<\/sup>\u00a0As a result, glucose accumulates in the blood.<\/p>\n

The human insulin protein is composed of 51\u00a0amino acids\u00a0and has a\u00a0molecular mass\u00a0of 5808\u00a0Da. It is a heterodimer\u00a0of an A-chain and a B-chain, which are linked together by\u00a0disulfide bonds. Insulin’s structure varies slightly between\u00a0species\u00a0of animals. Insulin from animal sources differs somewhat in effectiveness (in\u00a0carbohydrate metabolism\u00a0effects) from human insulin because of these variations.\u00a0Porcine\u00a0insulin is especially close to the\u00a0human version and was widely used to treat type 1 diabetics before human insulin could be produced in large quantities by\u00a0recombinant DNA\u00a0technologies.<\/sup><\/sup><\/sup><\/sup><\/p>\n

Insulin was the first peptide hormone discovered.<\/sup>\u00a0Frederick Banting\u00a0and\u00a0Charles Herbert Best, working in the laboratory of\u00a0J<\/a>.J.R. Macleod\u00a0at the\u00a0University of Toronto, were the first to isolate insulin from dog pancreas in 1921.\u00a0Frederick Sanger\u00a0sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced.<\/sup>\u00a0The\u00a0crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is also the first protein to be chemically synthesized and produced by\u00a0DNA recombinant technology.<\/sup>\u00a0It is on the\u00a0WHO Model List of Essential Medicines, the most important medications needed in a basic\u00a0health system.<\/p>\n

Gene<\/span><\/h2>\n

The\u00a0preproinsulin<\/a>\u00a0precursor of insulin is encoded by the\u00a0INS<\/i>\u00a0gene<\/a>, which is located on chromosome 11p15.5.<\/sup><\/sup><\/p>\n

Alleles<\/span><\/h3>\n

A variety of mutant\u00a0alleles<\/a>\u00a0with changes in the coding region have been identified. A\u00a0read-through gene<\/a>, INS-IGF2, overlaps with this gene at the 5′ region and with the IGF2 gene at the 3′ region.<\/sup><\/p>\n

Structure<\/span><\/h2>\n
See also:\u00a0Insulin\/IGF\/Relaxin family<\/a>\u00a0and\u00a0Insulin and its analog structure.<\/a><\/div>\n
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The structure of <\/b>insulin<\/a><\/span><\/strong>.<\/b>\u00a0The left side is a space-filling model of the insulin monomer, believed to be biologically active.\u00a0Carbon\u00a0is green,\u00a0hydrogen\u00a0white,\u00a0oxygen\u00a0red, and\u00a0nitrogen\u00a0blue. On the right side is a\u00a0ribbon diagram\u00a0of 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.<\/p>\n<\/div>\n<\/div>\n<\/div>\n

Contrary to an initial belief that hormones would be generally small chemical molecules, as the first peptide hormone known for its structure, insulin was found to be quite large. <\/sup>A single protein (monomer) of human insulin is composed of 51\u00a0amino acids\u00a0and has a\u00a0molecular mass\u00a0of 5808\u00a0Da. The\u00a0molecular formula\u00a0of human insulin is C257<\/sub>H383<\/sub>N65<\/sub>O77<\/sub>S6<\/sub>.<\/sup>\u00a0It is a combination of two peptide chains (dimer) named an A-chain and a B-chain, which are linked together by two\u00a0disulfide 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 A4 and A11. The A-chain exhibits two \u03b1-helical regions at A1-A8 and A12-A19 which are antiparallel; while the B chain has a central \u03b1 -helix (covering residues B9-B19) flanked by the disulfide bond on either side and two \u03b2-sheets (covering B7-B10 and B20-B23).<\/sup><\/sup><\/p>\n

The amino acid sequence of insulin is\u00a0strongly conserved<\/a>\u00a0and varies only slightly between species.\u00a0Bovine<\/a> insulin differs from humans in only three amino acid<\/a> residues and\u00a0porcine<\/a> insulin in one. Even insulin from some species of fish is similar enough to humans 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<\/a>, however, differs much more among species; it is also a hormone, but a secondary one.<\/sup><\/p>\n

Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer.<\/p>\n

Synthesis<\/span><\/h3>\n

Insulin is produced in the\u00a0pancreas<\/a>\u00a0and the Brockmann body (in some fish), and released when any of several stimuli are detected. These stimuli include the rise in plasma concentrations of amino acids and glucose resulting from the digestion of food.<\/sup>\u00a0Carbohydrates<\/a> 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 the blood glucose level will begin to rise. In target cells, insulin initiates signal transduction<\/a>, which has the effect of increasing\u00a0glucose<\/a>\u00a0uptake and storage. Finally, insulin is degraded, terminating the response.<\/p>\n

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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.<\/p>\n<\/div>\n<\/div>\n<\/div>\n

In mammals, insulin is synthesized in the pancreas within the beta cells. One million to three million pancreatic islets form the\u00a0endocrine\u00a0part of the pancreas, which is primarily an\u00a0exocrine\u00a0gland. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the pancreatic islets, beta cells constitute 65\u201380% of all the cells.[<\/i><\/sup><\/p>\n

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\u00a0preproinsulin\u00a0in beta cells. Preproinsulin contains a 24-residue\u00a0signal peptide\u00a0which directs the nascent polypeptide chain to the rough\u00a0endoplasmic reticulum (RER). The signal peptide is cleaved as the polypeptide is translocated into the lumen of the RER, forming\u00a0proinsulin.<\/sup> In the RER the proinsulin folds into the correct conformation and 3 disulfide bonds are formed. About 5\u201310 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 minutes.<\/p>\n

Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases known as\u00a0prohormone convertases\u00a0(PC1\u00a0and\u00a0PC2), as well as the exoprotease\u00a0carboxypeptidase E. <\/sup>The endopeptidases cleave at 2 positions, releasing a fragment called the\u00a0C-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 \u221232). After cleavage of the C-peptide, these 2 pairs of basic residues are removed by the carboxypeptidase.<\/sup>\u00a0The\u00a0C-peptide<\/a> 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).<\/p>\n

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.<\/sup><\/p>\n

The endogenous production of insulin is regulated in several steps along the synthesis pathway:<\/p>\n