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German: Insulin

1 Definition

The peptide hormone insulin regulates the absorption of glucose in body cells. It has a glucose-lowering effect and plays an essential role in the treatment of diabetes mellitus. Insulin is the natural antagonist of the hormone glucagon.

The name insulin comes from the islet cells of the pancreas, which produces the insulin.

2 History

In the 1920s, Frederick Banting and Charles Best succeeded for the first time in extracting insulin from pancreatic tissues. It was already known for some years that secretions of the pancreas can lower blood sugar levelss. Earlier attempts by other scientists were not successful however, since they used the complete ground pancreas, whereby other digestive juices destroyed the insulin. The first trials of Banting and Best were conducted on dogs, whose pancreases were surgically removed. In 1922 they succeeded for the first time in saving a 13-year old diabetic, who had been suffering from the disease for one and a half years and was already in a coma. In 1923 Banting and John MacLeod, the director of the institute, received the Nobel Prize for medicine. They shared the prize voluntarily with Best and James Collip, who had invented an improved extract.

In the following decades, insulin was produced in large scale from the pancreases of cows and pigs. Cowand pig insulin differ from the human insulin only marginally; in the case of pigs only one amino acid, and in the case of cows three amino acids, are replaced by other amino acids. Even though animal insulin is effective in humans, attempts were made nevertheless to produce human insulin. In 1982 the human insulin was produced for the first time through genetically modified bacteria. In the meantime, this task has been taken over by yeasts. Artificial insulins (analog insulins) have been available since 1996, which works faster than natural insulin.

3 Biochemistry

3.1 Structure

Insulin is a macromolecule with a molecular weight of approximately 5,700 daltons. It consists of 2 longer polypeptides, an A chain of 21 amino acids and a B chain of 30 amino acids. The two chains are linked by 2 disulfide bridges, which forms between the cystein components of the polypeptide. A third disulphide bridge exists within the A chain. It serves to stabilize the spatial structure.

Through the formation of hydrogen bonds between the oxygen atoms of the carbonyl groups and the hydrogen atoms of the amide groups of both the polypeptide chains, the secondary structure of the insulin is formed: The molecular chains shorten themselves into a spiral. The A chain forms 2 α-helices, which separate from each other through an amino acid component. The B chain coils by about 40% to form an a-helix.

In solution, insulin has the tendency to form dimers during the formation of hydrogen bonds, i.e. to combine into molecular pairs. The so-called hexamers are formed from the dimers in the presence of zinc.

3.2 Biosynthesis

Insulin is synthesized in the so-called beta cells of the islets of langerhans of the pancreas. The genetic information for the synthesis of insulin is coded only by a gen locus in the short arm of chromosome 11. The gene consists of around 300 nucleotidess and contains 2 introns and 3 extrons.

The transcribed mRNA from the gene is translated initially in the ribosomes of the rough endoplasmatic reticulum (RER) in an inactive preproinsulin, a peptide of 107 amino acids. It consists of a signal sequence (leader), to which initially the 30 amino acids of the B chain, later a C peptide (connecting peptide) and finally, the A chain of 21 amino acids attach:

  • Signal sequence --- B chain --- C peptide --- A chain

The signal sequence makes sure that the preproinsulin is transported into the interiors of the endoplasmatic reticulum. The further “maturation�? of the peptide hormone takes place there: The proinsulin (84 amino acids) results from the splitting of the signal sequence and formation of three disulfide bridges. In the course of further maturation, the C chain is split off through specific peptidases. The insulin molecule is then stored as hexamer stabilized by a zinc ion in vesicles on the cell membrane of the beta cells.

An increasing blood sugar level (from approximately 4 mmol glucose/l blood) as secretion stimulus eventually leads to the release of the vesicle contents into the extracellular space through fusion of the membranes (exocytosis).

4 Physiology

The effect of insulin is conveyed by a linkage to insulin receptors on the cell surfaces of the liver, [[muscle tissues|muscle ] and fatty tissues. Insulin influences the glucose metabolism through several mechanisms. The most important biological effects of insulin are:

Plasma glucose level and insulin secretion mutually influence each other thus forming a feedback control. Thereby the healthy organism can keep the blood sugar level constant also during dysfunctions. The performance and reliability of the carbohydrate homeostasis are increased by the antagonistic redundancy of insulin with antagonist hormones such as glucagon, catecholamine and glucocorticoids.

5 Reference range

After 12 h fasting 6 - 25 mU/l (µU/ml) 36 - 150 pmol/l
After 72 h fasting < 6 mU/l (µU/ml) < 36 pmol/l
After maximum stimulation by glucose or glucagon up to 200 mU/l (µU/ml) up to 1200 pmol/l

The determination of insulation level in the serum as an individual test doesn’t make much sense. Normally it takes place in the scope of an Oral Clucose Tolerance Test (OGTT) or together with the determination of C peptides.

6 Insulin preparation

The treatment of diabetes mellitus takes place today basically with human insulin, i.e. with insulins whose amino acid sequences correspond to the insulin produced by the human body or with insulin analogs. The formerly used animal insulins (pig insulin and cow insulin) are not normally used today.

The insulins are classified according to their duration of action:

6.1 Rapid-acting insulins

Rapid-acting insulins, also called short-acting insulins, are used in case of metabolic derailments, for the first adjustment, in the intensive conventional therapy (ICT), in the use of an insulin pump and in perioperative diabetes management.

  • Normal insulin (old insulin): Effect appears after 30-45 minutes, duration of action 4-6 hours
    • Insuman Rapid Höchst®
    • Actrapid® HM
    • Huminsulin®
  • Rapid-acting insulin analog: Effect appears after 15 minutes, duration of action approximately 3 hours
    • Insulin Lispro (Humalog®)
    • Insulin Aspartat (NovoRapid®)

6.2 Slow-acting insulins

In slow-acting insulins, the action is delayed by the combination of insulin with protamine, zinc, surfen or by use of proinsulin. Slow-acting insulins can only be administered through subcutaneous injections. It is used, among other things, for providing the basic insulin requirement in case of ICT.

  • Intermediate-acting insulins: Duration of action 8-12 hours
    • NPH insulins
      • Insuman® Basal
      • Insulin Protaphane®
      • Huminsulin® Basal
      • Insulin Insulatard® Human
      • And many others
  • Long-lasting insulins: Duration of action 12-36 hours
    • Ultratard® HM
  • Long-acting insulin analogs: Duration of action 16-30 hours
    • Insulin Glargin (Lantus®)
    • Insulin Detemir (Levemir®)

6.3 Mixed insulins

Fixed mixtures of regular insulin and NPH insulins are used for 2-3 x daily injections in the scope of conventional insulin therapy.

  • Actraphane®
  • Insuman® Comb
  • NovoMix®
  • Humalog® Mix
  • And many others.

7 Administration

7.1 Parenteral

Insulin can be applied subcutaneously, intravenously or (rarely) intramuscularly. The 3 application types exhibit a very different pharmacokinetics.

  • The standard application is the subcutaneous injection, to which the specifications of appearance of effect and duration of action refer. </br>
  • Intravenous administration of insulin should be undertaken only with utmost attention (or by infuser or pump, which dispense minute quantities), because of an immediate appearance of effect.</br>
  • The intramuscular administration mostly brings about an acceleration of action by about 30-50%. But if injected in scarred muscle area, the action can even fail to appear.

7.2 Inhalational

A new pharmaceutical form constitutes the inhalation of insulin with subsequent resorption by the lung capillaries. This pharmaceutical form is at present (2004) not licensed in Germany. A drawback of this method is that the bioavailability of insulin can be very different after inhalation.

Orally administered insulin has no action.

See also: Insulin therapy, Insulin analogs, Insulin resistance, Minimal model, HOMA

8 Links

Discovery of Insulin

The Endocrine Pancreas: Introduction and Index

Considerably presentation of the insulin structure

Insulin resistance syndrom

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