Table of contents
Insulin consists of two Peptidketten, the A-chain with 21 and the B-chainwith 30 amino acids, which are held together by two disulphide bridges. The third disulphide bridge connects the Cysteinreste of the positions 6 and 11 the A-Kette.Die radioactive half-life lies approximately at a half hour.
is generated forAnimals and humans a vitally necessary hormone.
Additionally it stands in addition, on the list of the forbidden Dopingsubstanzen.
1921 succeeded it to Frederick Banting and Charles Best for the first time to win insulin from Pankreasgewebe. Already for some decadesit was clear that secretions of the pancreas can lower the blood sugar mirror. Earlier attempts of other scientists were not successful however, since they used the complete gemahlene pancreas, whereby other digesting juices of the Pankreas destroyed the insulin. The first attempts of Banting and Bestat dogs were accomplished, for which the pancreas had been operationally removed.1922 succeeded to them the first rescue of a Diabetikers, a 13 years old boy, who suffered for one and a half years at the illness and in coma was fallen already. 1923Banting and John MacLeod, the director/conductor of the institute received, the Nobelpreis for medicine. They divided the price voluntarily with Best and James Collip, which had invented an improved excerpt.
In the following decades insulin became from the pancreasesof cattle and pigs industrially won. Cattle and pig insulin differ from the human insulin only slightly, with the pig are only one, with the cattle are replaced three amino acids by other amino acids. Although also animal insulin works with humans, nevertheless one tried,to produce human insulin, since the treatment with unmodified animal insulin often led to serious immunological secondary reactions.1963 succeeded to professor Helmut Zahn and its team at German Wollforschungsinstitut in Aachen those world-wide first chemical synthesis of the insulin. Due to thatover 200 synthesis stages, this insulin synthesis could be used however not yet industrially. It cleared up however with the prejudice that one could not synthesize proteins.1982 succeeded it for the first time to manufacture human insulin through genetically changed bacteria. In the meantime also yeast mushrooms take over theseTask. Since 1996 is also artificial Insuline (insulin analogues) available, which exhibits a changed effect profile as natural insulin.
biosynthesis of insulin
- mRNA first into an inactive Präproinsulin translated (Peptid from 107 amino acids), consisting of a signal sequence (more leader), to first the 30 amino acids of the B-chain to close and to a C Peptid (connecting peptide) the A-chain from 21Follows amino acids.
- From splitting off of the signal sequence and education from three disulphide bridges (two between A-and B-Peptid, one within the A-Peptids) the pro insulin ( 84 amino acids) results. In the process of further maturing the C-chain becomes by specific Peptidasen abgespalten. The insulin molecule lies thenas Hexamer by a Zinkion stabilizes in Granula at the cell membrane of the beta cell stored forwards.
- A rising blood sugar mirror (off approx. 4 mmol glucose/L blood) as secretion attraction finally leads by merging the diaphragms (Exocytose) to the emptying of the Granulainhaltes inthe extracellular area.
biochemical effects of insulin
the metabolic and mitogenen effects of insulin are initiated over the connection at its receptor on the cell surface of the goal fabrics liver, muscle and fat. One of the most important biological effects of the insulinthe rapid acceleration of the glucose admission is in muscle and fat cells. Insulin induces further the Glykogensynthese and - storage in liver and muscle, the Triglyceridsynthese in liver and fatty tissue as well as the storage of amino acids in the muscle. At the same time insulin restrains the hepatische Gluconeogeneseand ranks therefore altogether among the most important modulators of the Glucosemetabolismus. A further central function of the Peptidhormons insulin exists those in the regularization of cell growth and pro running ration by the activation of the Transkription of genes, for control and expiration of the cell cycle ofgreat importance are.
The insulin receptor almost in all cells one exprimiert. Its number reaches from few hundred receptors on Erythrocyten up to several hundredthousand on Adipocyten and Hepatocyten. The insulin receptor is a heterotetrameres Glykoprotein and sits down from twoextracellular alpha subunits and two the cell membrane through-exciting beta subunits together, which are kovalent connected by disulphide bridges with one another. To the connection of insulin to the alpha subunits it comes in the cell inside to car the phosphorylation of the beta subunits of the receptor. Intrazelluläre Adaptorproteine bind thereupon onthe receptor and at specific amino acid residues are phosphoryliert. The insulin signal is then coupled over this Adaptorproteine by the education by signal complexes to different intrazelluläre signal cascades. Two main cascades publicise the signal generated by the insulin receptor, the pi 3-Kinase-Signalweg and the Map Kinase signal path.These signal paths coordinate concentrated the various processes in the cell, as for example the rapid glucose admission by Translokation of the glucose transporter GLUT4 at the cell surface, glucose, lipid and Proteinmetabolismus and the Genexpression. The more exact molecular signal paths in the cell become activeworked on.
cellular effects of insulin
- in the liver and the musculature are stored coal hydrates taken up with the food as Glykogen. This entails a dropping of the glucose concentration in the blood.
- In the liver, the fatty tissue and the musculature under insulin influence the Triacylglycerinsynthese is stimulated. Substrates for it are beside coal hydrates with the food taken up Lipide.
- In the three fabrics mentioned amino acids are strengthened taken up and used for the protein synthesis
by insulinreleased signal paths
the organism signals by payment of the insulin a too high blood sugar mirror. This signal is answered by turning glucose-using ways on, in particular in the liver. Three of these ways are schematically represented in the following:
Illustration: Three important signal paths released by insulin
- PLC/IP 3 - Away: Phospholipase C (PLC) reacted not only to signals of 7-Transmembranhelix receptors (7TMR) separate insulin of the receptor (InsR) on such. From Phosphatidylinositol-4,5-bisphosphat (BEEP to 2) thereby second the measuringclose Inositol-1,4,5-triphosphat (IP 3) and Diacylglycerin are set free,those together protein kinase C activate. A substrate of the Kurdish worker's party is the sodium protons anti-haven, which with well + - influx H + from the cell pumps at the same time and so that easily raises the pH value of the Cytosols. This change of environment has the activation of theKey enzyme Phosphofructokinase and thus increased glucose consumption to the consequence.
- Map Kinasekaskade: as under blood sugars discussed, activate this way the insulin-stimulated protein kinase (ISPK). This phosphoryliert and activates the Proteinphosphatase PP1G. PP1G dephosphoryliert Glykogen Synthase, which is thereby activated. By this procedure glucose becomes(with high energy charge) the Glykogenspeicher supplied.
- PI3K-Weg. Phosphatidylinosit-3-kinase (PI3K) phosphoryliert diaphragm components, i.e. Phosphatidylinosite to the 3-Position, whereby way becomes closed 1. This group of Phospholipiden serves instead as diaphragm anchors for protein kinase B (PKB), then by anotherPhosphatidylinosit dependent protein kinase (PDK) to be activated can. PKB causes the fact that vesicles with which otherwise on the cell surface with the cell membrane in muscle and fat cells does not merge existing glucose transporter 4 (GLUT4). Thus GLOW 4 functionally and it can is increased glucosefor the power production to be consulted. Over this mechanism the blood glucose mirror rapidly and effectively lowered
the three described ways to cause thus sinking the blood glucose mirror by
- promotion of the glucose admission (GLUT4-Translokation to the cell surface);
- Promotion of glucose storage (Glykogen synthesis);
- Supporting measuresexist in switching off glucose-supplying ways, so for example by dismantling second more measuringclosely cAMP over a Phosphodiesterase.
opponent of the insulin
drops the blood sugar mirror in the body under a value of 80 mg/dl, becomes insulin production alreadystrongly reduces. If the blood sugar continues to drop, different opponents of the insulin arise:
the mirrors of these against-adjusting hormones rise already clearly, if the blood sugar drops under 60 mg /dl. With the genuine lack of insulin type of the IDiabetikers is supplied from the outside the insulin. Since the blood sugar sensor is missing up to now, the insulin release from the injected subkutanen insulin depot is not throttled. In addition often also the Glukagonproduktion is decreased by the auto+immune destruction of the beta cells of the Pankreas. Thisleads to a decreased counterregulation and a substantial Hypoglykämiegefahr (= Unterzuckerung).
insulin should subkutan and can intravenously (i. v.) to be squirted. With i. v. - Gift is absolute on thoseTo respect Stimmigkeit of the Korrekturfaktoren with insulin (see insulin therapy). It can be also squirted intramuskulär. The 3 kinds of administration have different effect entrances. The standard statements about the effect (old) of the insulin always proceed from the subkutanen administration. The intramuskuläre administration bringsusually an effect acceleration of approx. 30-50 %. If into not regenerated yet, vernarbte muscle areas is squirted, can the effect be missing.
Intravenously insulin should be squirted only with extreme caution (or by Infusor or pump, which delivers Kleinstmengen), because a directEffect entrance takes place. The blood sugar mirror begins to sink. Fast dropping leads however just like a too high blood sugar to cell damages. Therefore insulin is given intravenously only in emergency and also only in small doses.
Over with high Hyperglykämien deposits onthe Aterien (late damage) to avoid, a substantial acceleration of the insulin effect can be achieved by the intravenous insulin delivery in place of subkutaner insulin injection. A further advantage of the intravenous insulin delivery is that here the complete effect already after approximately. 30 minutes final is.Since no insulin effect in the fatty tissue is absorbed, small doses with intravenous delivery (max. are sufficient. 5 - 7 i.e.).
To the danger of Hypoglykämien as consequence of the rapid insulin effect is to be prevented by premature supply of liquid or gelformiger Dextrose. However are thoseTo adjust Hypoglykämien due to the small given doses with few coal hydrates. Persons, who react a little sensitively to own Hypoglykämien, should i.v. Insulinierung only under medical observation and never without trained safeguard person accomplish.
The intravenous Insulinierung can with usual insulin syringesare accomplished. After delivery of the insulin the patient feels briefly “putrefies” to taste at the tongue point, which is to be led on the preservative in the insulin back.
a large progress represents the inhalational gift of insulin:so far the difficulties were particularly in the badly controllable and therefore varying absorption of the insulin because of the lung fabric. A condition for a constant admission is among other things a defined pellet size of the active substance. One of the technical difficulties lies in the fact that conventional Inhaler(D. h. Apparatuses, which deliver a defined quantity of a Arzneimitels in the Atemtrakt on pressure) for a such application by insulin are not suitable. The companies Pfizer, Aventis and Nektar placed a request for European permission in March 2004 of thefirst inhalational insulin (Exubera®) which they in January 2006 received. Few days later the American permission followed by the FDA.
Advantages of inhalational application are above all the better acceptance with the patient (it are void squirting) as well as the reducedRate at late complications diabetes its, makes possible by an earlier conversion to insulin with a simultaneous passing on of the oral antidiabetischen medicines. Both Typ-1 and Typ-2-Diabetiker could profit from the new Darreichungsform.
A disadvantage of inhalational application however is thata 10-10-fach higher quantity of insulin to be supplied must, so that a comparable effect is obtained. Since insulin is also a growth hormone, the danger of cancer of the lungs exists. Thus a study is necessary, which might take several years. Further disadvantages of the inhalationalAdministration of insulin is the not yet sufficiently investigated effects on lung and respiratory system. Critical voices fear deposits at the lung, which could possibly lead in the final stage after application of several years to pulmonary embolisms.
under insulin resistance one understands a decreased effect of the Peptidhormons insulin in peripheral fabrics. See also: Metabolic syndrome.
The insulin resistance is the main cause type 2 diabetes. The exact mechanisms, which lead to the insulin resistance in humans, are unverstanden as far as possible at present, are however intensivst investigated.
In this connection a set of secondary factors due to environmental factors becomes beside a polygenetischen Prädispositiondiscussed. For this count adiposity (Fettleibigkeit), metabolic factors, age and lack of physical activity. Not of all scientists the influence is accepted by char-hydrate-rich food with a high Glykämi index.
Improvements with the patient with a reduction of the insulin resistance become in generalare reached through:
- (e.g. .ärztlich) a cared for Diät (with weight acceptance)
- certain one oral Antidiabetika
insulin analogues are from the human insulin derived structure variations, therefore modified Insuline. Individual that altogether 51 amino acids with the goal were exchanged by towards-technological methods,a changed and/or. to reach more favourable effect profile. Like that today meanwhile short and long-working Insuline for diabetes patients is available. For example Lysin and Prolin at the positions 28 and 29 of the B-chain of the insulin became that by the exchange of the amino acidsshorteffective analogue reading pro (Humalog) generates, which itself by a more rapid effect entrance and shorter duration of effect, under the fact that the individual molecules in the subcutaneous fatty tissue are present freely (normal insulin: Hexamere), distinguishes. Further insulin analogues are Glargine (Lantus), Aspart (NovoRapid), (glulisin) Apidra, (insulin December me) Levemir.
risks of the insulin analogues of the general agents of the Analoginsuline - reading pro - in the diabetes therapy. In the permission study, that becamedid not increase Retinopathierisiko in principle impossible. For this reason various Fomulierenungen arose, which taught patient being afraid Analoginsulinen. Meanwhile exist scientifically clean studies, which a increased Retinopathierisiko excludes by reading pro.
With the opponents of the competitive companies is this stillnot the case, however points also here nothing on the fact that patients should not profit from the clear advantages of these shorteffective Insuline.
Lantus (insulin glargin) is discussed as a promoter of eye injuries. Can snap with (with Lantus easily possible)Arise to attitude of before bad on very good blood sugar values a Retinopathie.
In the German health service momentarily efforts exist to only order the Analoginsuline due to the higher costs under special circumstances (and naturally gotten to all, it today already).Artuse 21:16,23. February 2006 (CET)
Web on the left of
- articles: 80 years insulin on the diabetes portal DiabSite
- portal for parents of children with hyperinsulinism
- http://www.pro-tierisches-insulin.info network for the receipt animalInsuline
- The Discovery OF insulin: A Canadian medical miracle OF the 20th century (English)
- http://www.diabetes-world.net/68924/datenbanken/insulin-datenbank insulin data base after effect profiles
- http://www.diabeti-kuss.de website for concerning of insulin incompatibilities