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Insulin

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 is used medicinally in some forms of diabetes. Type 1 diabetics depend on exteranl insulin (typically injected) for their survival because of an essentially absolute deficiency of the hormone. The first successful treatment with insulin happened in Toronto, Canada, on January 11, 1922.

  1. Preproinsulin (Leader, B chain, C chain, A chain); proinsulin consists of BCA, without L
  2. spontaneous folding
  3. A and B chains linked by sulphide bonds
  4. Leader and C chain are cut off
  5. Insulin remains

Table of contents

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 essentially 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 all the cells.

Insulin is a small protein built from 51 amino acids. In humans it has a molecular weight of 5734. Insulin is structured as 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 is later transformed by proteolytic action into the active hormone. The remaining part is called peptide C[?]. This peptide is released in equimolar quantities, and is a good indicator of internal insulin production since clinical insulins contain no C-peptide component. It has recently been discovered to have biological activity itself; the activity is apparently confined to an effect on the muscular layer of the arteries. Human insulin consists of 51 amino acids; beef insulin differs in two amino acids, pork insulin in one. Fish insulin is also close enough to human insulin to have 'insulin activity' in humans. After its production, and before final release from a beta cell into the blood, insulin molecules are joined into polymeric form.

The exact structure of insulin was established by a British molecular biologist Frederick Sanger. It was the first protein whose structure was completely determined. 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 human metabolism level include :

The actions of insulin at the cellular level include :

  • increase in glycogen synthesis -- forces storage of glucose in liver (and muscle) cells in the form of glycogen
  • increase in synthesis of fatty acids[?] -- forces fat cells to take in triglycerides and store them internally
  • increase in esterification of fatty acids into glycerides[?] -- forces the liver to prepare triglycerides for transport to fat cells
  • decrease in proteinolysis[?] -- forces reduction of protein degradation
  • decrease in lipolysis[?] -- forces reduction in conversion of fat cell lipid stores into blood triglycerides
  • decrease in gluconeogenesis -- decreases production of glucose from degraded protein

Regulatory actions of insulin on blood glucose levels

Despite long intervals between meals and the occasional consumption of meals with a substantial carbohydrate load (eg, half a birthday cake[?]), human blood glucose levels normally remain within a strictly limited range. In normal humans this varies from person to person from about 70 mg/dl to perhaps 110 mg/dl except shortly after eating when the blood glucose level rises temporarily. This homeostatic process is the result of many things, but hormone regulation is the most important. There are two groups of antagonistic (opposing action) 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 far less harmful to have too much glucose in the blood than too little. Too little glucose (hypoglycemia) can be quickly fatal. If insufficiently low to produce death, hypoglycemia typically produces any of a variety of symptoms, many of which can indirectly cause death through accident or increased vulnerability to, for instance, predators.

Beta cells in the Islets of Langerhans have receptors sensitive to variations in blood glucose levels. If that level increases, more insulin from beta cell stores is released into the blood, and internal insulin production increases. When the glucose 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 use other fuels for a while (most prominently fatty acids), neurons are totally dependent on glucose as a source of energy in the normal human. They do not require insulin to absorb glucose, however, as about 2/3 of all body cells do. Thus, a sufficiently low glucose level first and most dramatically manifests itself in impaired functioning of the functioning of the central nervous system. This phenomenon is known as hypoglycemia or hypoglycemic coma, formerly insulin shock. Because internal causes of insulin excess are extremly rare (insulinoma[?]), the overwhelming majority of hypoglycemia cases are iatrogenic (caused by medical intervention). Misuse of any of three classes of medication are the usual causes of iatrogenic hypoglycemia :

  • oral hypoglycemic agents (eg, any of the sulfonylureas which increase insulin release from beta cells in response to a particular blood glucose level)
  • external insulin (usually injected subcutaneously, rarely intramuscularly or intravenously)
  • insulin resistance reducers (eg, one of a new class of drugs (troglitazone (Rezulin) was the first) which increase celular sensitivity to insulin)

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, indirectly, under insulin control. A lack of circulating insulin will prevent glucose from entering cells (eg, in untreated Type I diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (eg, the reduced insulin sensitivity characteristic of Type II diabetes), resulting in decreased glucose absorption and 'cell starvation'. Sometimes there is a defect in the insulin itself. Either way, one effect is the same: elevated blood glucose levels.

The insulin receptors[?] control internal cellular mechanisms which directly control glucose absorption by opening or closing the glucose absorption channels in the cell membrane.

Two tissues are most strongly influenced by insulin: muscle cells (myocytes[?]) and fat cells (adipocytes[?]). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess calories (from glucose and fats) against future need. Together, they are about 2/3 of all cells in a typical human bodies.

Insulin disturbances There are several conditions in which insulin disturbance is pathologic:

These need further elaboration but perhaps elsewhere.

Insulin as a medication Insulin is absolutely required for all mammalian (including human) life. Insulin deprivation due to the removal of the pancreas leads to death in days or at most weeks. Insulin must be administered to patients in whom there is a lack of the hormone. Clinically, this is 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 was not possible in practice, so insulin from cows or pigs or fish pancreases was used instead. All have 'insulin activity' in humans. Insulin is a protein which has been very strongly conserved across evolutionary time. Differences in suitability of beef, pork, or fish insulin preparations for particular patients have been primarily the result of preparation purity and allergic reactions. Human insulin can now manufactured, using genetic engineering molecular biology techniques, in sufficient quantity for widespread clinical use. Eli Lilly produced the first such synthetic insulin, Humulin, in 1982.

There are several problems with the use of insulin as a clinical treatment for diabetes :

  • mode of administration
  • selecting the 'right' dose and 'timing'
  • selecting an appropriate insulin preparation
  • adjusting dosage and timing to fit the food eaten
  • adjusting dosage and timing to fit exercise undertaken

Diabetics give themselves insulin, usuall via subcutaneously[?] hypodermic injection. This mode is both :

  • not physiologic (the pancreas releases insulin gradually directly into the portal vein), and
  • simply a nuisance for patients to inject themselves once or several times a day

There have been several attempts to improve this awkward mode of administering insulin. There are jet injectors (also used for some vaccinations by some clinics) which have different insulin delivery peaks and durations as compared to injection of the same amount and type of insulin. Some diabetics find control possible with jet injectors, but not with hypodermic injection.

Unlike many medicines, insulin cannot be taken orally. It is a polypeptide hormone (ie, a protein), so it is treated like any other protein in the stomach and the duodenum. It is reduced to its amino acid components and loses all 'insulin activity'. There are research efforts underway to develop methods of protecting insulin from the digestive tract so that it can be taken orally, but none have yet proven both safe and effective.

Inhaled insulin is under active investigation as are several other, more exotic, techniques.

An insulin pump could theoretically be the ideal solution. However there are several major limitations - cost, the potential for hypoglycemic episodes, and thus far no means of controlling insulin delivery based on blood glucose levels. Hypoglycemia can be dangerous if it is too severe or lasts too long. Except under starvation conditions, neurons (including the brain) requie glucose to function and survive. Pump failure in the other direction can lead to hyperglycemia, and possibly diabetic ketoacidosis (DKA). This can also be fatal. In addition, indwelling catheters pose considerable risk of infection and ulceration. Thus far, insulin pumps require considerable care and effort to use correctly. Some diabetics are able to keep their glucose in reasonable onctol only on a pump.

As well, researchers have produced a watch like device that tests for insulin levels in the blood through the skin and administers corrective doses through pours in the mechanical device to be absorbed by the skin of the patient. The insulin injection aspect remains experimental. The blood glucose test aspect is commercially available essentially as described.

Another 'solution' to diabetes would be to avoid periodic insulin entirely by installing a self-regulating insulin source. For instance, pancreatic, or beta cell, transplantation. It is rather difficult technically so transplantation of the pancreas as an individual organ is not common, unless performed in conjunction with liver or kidney transplant surgery. However, transplantation of pancreatic beta cells alone is a possibility. It has been highly experimental (eg, prone to failure) for many years. Some researchers in Alberta, Canada, have developed techniques which have produced a much higher success rate. Beta cell transplant may become practical, and common, in the near future.

The central problem for those requiring external insulin is picking the right dose of insulin and the right timing. ***It would be best to show this graphically. Eg, a graph of typical blood glucose levels and blood insulin levels in people without diabetes and in those with diabetes injecting themselves 1, 2, 3 or four times a day. *** Physiological regulation of blood glucose, as in the non-diabetic, is ideal. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage, reducing blood glucose levels and reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so returns to the normal 'fasting' level. Even the best diabetic treatment with human insulin, however administered, falls short of the glucose control in a non-diabetic.

Complicating matters is that the composition of the food eaten affects intestinal absorption rates. Fats and proteins both cause delays in absorption of carbohydrate eaten at the same time. And, exercise reduces the need for insulin even when all other factors remain the same.

It is impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal in order to achieve a reasonable blood glucose level within an hour or two after eating, as non-diabetics' beta cells routinely and automatically do. All such decisions must be made based on general experience and training (ie, at the direction of a physician or PA) and specifically, based on the individual experience of the patient. Thus, some diabetics require more insulin after drinking skim milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skim milk is different than other diabetics'. But, the same amount of whole milk is likely to cause a different reactiion even in that same person. Whole milk contains considerable fat while skim milk has much less. It's a continual balancing act for all diabetics, especially for those taking insulin.

Clinically used insulins (from the major suppliers -- Eli Lilly and Novo Nordisk -- or from any other) are never just 'insulin in solution'. Clinical insulins are a specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on. Some recent insulins are not even exactly insulin at all. They are insulin which has been slightly changed (one amino acid or perhaps two) so that they are

  • absorbed rapidly enough to mimic real beta cell insulin (Lilly's is 'lispro', Novo Nordisk's is 'aspart') or
  • steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (Adventis' is 'glargine').

Choosing an insulin type and dosage cannot be done casually.

Letting the glucose levels go, so long as they don't go high enough to cause acute symptoms is not reasonable. Several large, well designed, long term studies have conclusively shown (in a way that most such studies do not) that diabetic complications decrease markedly and consistently as blood glucose levels approach 'normal' patterns. In short, if a diabetic closely controls blood gluxose levels (on average over days and weeks, and avoiding too high peaks after meals) the rate of diabetic complications goes down. If very closely controlled, that rate can approach 'normal'. The chronic diabetic complications include cerebrovascular accidents (CVA or stroke), heart attack, blindness (from proliferative diabetic retinopathy), nerve damage from diabetic neuropathy[?], or kidney failure from diabetic nephropathy[?]. These studies have demonstrated beyond doubt that, if it is possible for a patient, so-called intensive insulinotherapy is superior to conventional insulinotherapy. However, close control of blood glucose levels (as in intensive insulinotherapy) does require care and considerable effort, for a mistake in the direction of lower glucose can lead to hypoglycemia which can be fatal and is always dangerous.

Insulin abuse There are reports that some patients abuse insulin by injecting larger doses that lead to mild hypoglycemic states. This is EXTREMELY dangerous and is eseentially equivalent to suffocation experimentation with pastic bags.

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