Insulin

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Insulin (Latin insula, "island") is a polypeptide hormone primarily playing a pivotal role in the regulation of carbohydrate metabolism; it also takes active part in metabolisms of fat and proteins. Its general characteristic is that it has anabolic properties.

Insulin structure and production

Insulin is synthesized by beta cells (B cells) in islets of Langerhans. 1-3 million of islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is esentially an exocrine gland. The endocrine part accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans beta cells constitute 60-80% of the all cells.

Insulin is a relatively small protein with molecular weight of 5734 that comprises 2 polypeptide chains linked with 3 sulphide bonds. Chain A consists of 21 and chain B of 30 amino acids. Insulin is produced as a prohormone - proinsulin that subsequently is by proteolytic action transformed into the active hormone. The remaining part is called peptide C. This peptide is released in equimolar quantities, and therefore it is a good indicator of insulin production. Human insulin consists of 51 amino acids. After production and before final release from the cell, insulin molecules are joined into polymeric form.

The exact structure of insulin was established by a British molecular biologist Frederic Sanger. For this discovery he was awarded a Nobel Prize in Chemistry in 1958.


Actions of insulin on cell level and global metabolism level

The actions of insulin on the global metabolism level are :

The actions of insulin on cell level are :

Regulatory actions of insulin on blood glucose levels

Despite long intervals between meals and the occasional consumption of meals with substantial carbohydrate load (e.g half a birthday cake), blood glucose levels normally remain within certain boundaries. This homeostatic process involves many actions but hormone regulation is the most important. There are two groups of antagonistic (contradictory) hormones :

  • hyperglycemic hormones (such as glucagon, growth hormone, and adrenaline), which increase blood sugar,
  • and only one hypoglycemic hormone (insulin), which decreases blood sugar.

This is because, at least in the short term, it is less harmful to have too much glucose in the blood than too little.

Beta cells in the islets of Langerhans have receptors that are sensitive to variations in blood glucose. If the level increases, more insulin from the stores is released and production intensified. When the level comes down to the physiologic value, the release stops. If the level of glucose drops dangerously low, hyperglycemic hormones come into play.

Actions of insulin on neurons

Insulin acts on all cells of the body. Although other cells can live on other fuels for a while, neurons are totally dependent on glucose as a source of energy. Thus, a lack of glucose first and most dramatically manifests itself in the functioning of the central nervous system. The phenomenon was once known as insulin shock, and is now called hypoglycemia or hypoglycemic coma. Because internal causes of insulin excess are extremly rare (insulinoma), the overwhelming majority of hypoglycemia cases are iatrogenic (caused by medical intervention). Two general classes of medication can cause hypoglycemia :

  • oral hypoglycemic agents
  • insulin in form of injection (subcutaneous, rarely intramuscular or intravenous)

Intracellular transformation of the insulin signal

There is a special channel in the cell membrane through which glucose can enter the cell. This channel is under the glucose's control. Most commonly it is a lack of circulating insulin that prevents glucose from entering cells. However, sometimes there is a defect in the insulin or the cell channels. Either way, the effect is the same: elevated blood glucose levels.

The insulin receptors interact between insulin and intracellular metabolism mechanisms.

There are two other tissues whose metabolisms are strongly influenced by insulin: muscle cells (myocytes) and fat cells (adipocytes).The former are important because of their enormous needs for glucose and the latter because they can accumulate excess glucose.

Insulin disturbances

There are two states where insulin disturbance can be pathologic:

These need further elaboration but perhaps elsewhere.

Insulin as a medication

Insulin is necessary for human life. Insulin deprivation due to the removal of the pancreas leads to death in days or weeks. Insulin must be administered to patients in whom there is a total lack of the hormone, clinically called diabetes mellitus type 1.

Insulin was discovered at the University of Toronto in 1921 by Frederick Banting, Charles Best, James Collip, and J.J.R. MacLeod. For this breakthrough discovery, MacLeod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923.

Harvesting pancreases from human corpses is hardly imaginable, so originally insulin from cows or pigs was used instead. Now, human insulin can be manufactured in the laboratory in sufficient quantity for all patients. Eli Lilly produced the first such synthetic insulin, Humulin, using molecular biology techniques.

There are two problems with insulin treatment :

  • way of administration
  • picking of the right dose and the timing of the dose

Diabetics have to inject themselves with insulin subcutaneously. This mode is both :

  • not physiologic (insulin is released into portal vein bloodstream)
  • and simply a fuss for a patient to inject oneself several times a day

There have been several attempts to amend this cumbersome way of insulin administration. Obviously insulin can not be administered orally like other medicines. Remember it is a polypeptide hormone (a protein) so it would be digested in the stomach and the duodenum.

Insulin pump could theoretically prove to be almost the ideal solution. However there are two major limitations - cost and potential hypoglycemic treat. Hypoglycemia can be lethal to neurons if it is too pronounced and too long. Diabetics can not risk leave themselves in vegetative state (endless coma) if the pump malfunctions.

Another viable solution that went under scrutiny was pancreatic transplantation. It is rather difficult technically so transplantation of the pancreas as an organ was rejected. However pancreatic B cells producing insulin transplantation was another option. Again this procedure was rather experimental.

Another thing is picking the right dose of insulin and the right timing. It would be here best to see a graph of blood glucose levels and blood insulin levels in people without diabetes and in diabetics injecting themselves 1, 2, 3 or four times a day. Physiologically regulation of blood glucose is ideal. Raised glucose level afer a meal is a stimulus for prompt release of an sufficient amount of insulin from the pancreas that brings soon blood glucose down. Just the right amount we do not expierience hypoglycemia in our lives do we? Even the best diabetic treatment with human insulin injected subcutanously fall sort of the control of a nondiabetic person. It is impossible to know how much insulin would be needed for a certain meal to achive blood glucose balance in an hour like it is in healthy persons. Most insulins are a specially prepared mixtures of rapid acting and slow acting components. These mixtures must be administred about half an hour before meals to interact the height of its action with the peak of blood glucose after the meal.

Letting the glucose levels be just good enough not to produce symptoms is not the way to go. Long term studies showed that the better control of diabetes the lower risk of diabetic complications like cerebrovascular accidents (CVA), blindness or renal insufficiency. It is especially important in diabetes mellitus type 1 (insulin dependent diabetes mellitus = IDDM) where patientsare subject to unphysiological blood glucose control for decades. After one important study, carried out in the UK, it was ascertained that so-called intensive insulinotherapy is superior to conventional insulinotherapy. However intensive insulinotherapy is linked with higher incidence of untowards side-effects, most notably, hypoglycemia.

Work is progressing now on delivering insulin by inhalation instead of injection.

Insulin abuse

There are reports that some patients abuse insulin by injecting larger doses that lead to mild hypoglycemic states.

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