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Insulin
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Insulin

Insulin (Latin insula, "island") is a polypeptide hormone which is the primary control mechanism for carbohydrate metabolism; it also takes an active part in the metabolism of fat (triglycerides) and proteins – it has anabolic properties. It also affects other tissues. Insulin is used medically in some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on exogenous insulin (typically injected) for their survival because of an absolute deficiency of the hormone while patients with Type 2 diabetes mellitus have either relatively low insulin production or insulin resistance.

Insulin has the molecular formula C254H377N65O75S6.

Table of contents
1 Discovery and characterization of Insulin
2 Insulin structure and production
3 Actions of insulin on cell level and global metabolism level
4 Regulatory actions of insulin on blood glucose levels
5 Insulin and the brain
6 Intracellular transformation of the insulin signal
7 Diseases and syndromes caused by an insulin disturbance
8 Insulin as a medication
9 Types of medical insulin
10 Insulin abuse
11 Related wikipedia articles
12 External Links

Discovery and characterization of Insulin

In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a new microscope when he noticed some previously unidentified cells scattered in the exocrine tissue. The function of the "little heaps of cells", later known as the Islets of Langerhans, was unknown, but Edouard Laguesse later argued that they may produce a secretion that plays a regulatory role in digestion.

In 1889, the German physician Oscar Minkowski removed the pancreas from a healthy dog to demonstrate this assumed role in digestion. Several days after the dog's pancreas was removed, Bernardo Houssay, Minkowski's animal keeper, noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that the dog was secreting sugar in its urine, demonstrating for the first time the relationship between the pancreas and diabetes. In 1901 another major step was taken by Eugene Opie, when he clearly identified that Diabetes mellitus.... is caused by destruction of the islands of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before this demonstration the link between the pancreas and diabetes was clear, but not the specific nature of the islets.

Over the next two decades several attempts were made to isolate the secretion of the islets as a potential treatment. In 1906 Georg Ludwig Zuelzer was partially successful treating dogs with pancreatic extract, but unable to continue his work. Between 1911 and 1912 E.L. Scott at the University of Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria, but was unable to convince his director and the research was shut down. Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he was unable to return to it. Nicolae Paulescu, a professor of physiology at the Romanian School of Medicine published similar work in 1921 that was carried out in France, and it has been argued ever since by Romanians that he is the rightful discoverer.

However the practical extraction of insulin is rightfully credited to a team at the University of Toronto. In October 1920 Frederick Banting was reading one of Minkowski's papers and concluded that it was the very digestive secretions that Minkowski had originally studied that were breaking down the secretion, thereby making it impossible to extract successfully. He jotted a note to himself Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea.

He travelled to Toronto to meet with J.J.R. Macleod, who was not entirely impressed with his idea. Nevertheless he supplied Banting with a lab at the University, an assistant, Charles Best, and ten dogs, while he left on vacation during the summer of 1921. Using his idea, Banting and Best were able to keep a pancretized dog alive all summer. Their method worked by tying a ligature (string) around the pancreatic duct, and when examined several weeks later the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated the protein from these islets to produce what they called isletin.

Macleod saw the value of the research on his return from Europe, but demanded a re-run to prove the method actually worked. Several weeks later it was clear the second run was also a success, and he helped publish their results privately in Toronto that November. However the needed six weeks to extract the isletin, dramatically slowing testing. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands, and was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the protein. In December 1921 Macleod invited the brilliant biochemist, James Collip, to help with this task, and within a month he felt ready to test.

On January 11, 1922, Leonard Thompson, a fourteen year old diabetic was given the first injection of insulin. Unfortunately the extract was so impure that he suffered a severe allergic reaction and further injections were cancelled. Over the next 12 days Collip worked day and night to improve the extract, and a second dose injected on the 23rd. This was completely successful, not only in not having obvious side-effects, but in completely eliminating the symptoms of diabetes. However Banting and Best never worked well with Collip, apparently seeing him as something of an interloper, and Collip left soon after.

Over the spring of 1922 Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the extract remained impure. However they had been approached by Eli Lilly with an offer of help shortly after their first publications in 1921, and they took them up on their offer in April. In November Lily made a major breakthrough, and were able to produce large quantities of very pure insulin. Insulin was offered for sale shortly thereafter.

For this breakthrough discovery, Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923. Banting, apparently insulted that Best was not mentioned, shared half of his price with Best, and MacLeod immediately shared some of his with Collip.

The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein whose structure was completely determined. For this he was awarded the Nobel Prize in Chemistry in 1958. In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of x-ray diffraction studies. She also was awarded a Nobel Prize.

  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 molecule remains

Insulin structure and production

Insulin is synthesized in humans and other mammals within the beta cells (B-cells) of the islets of Langerhans in the pancreas. One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily 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 built from 51 amino acids and is one of the smallest proteins known; shorter 'proteins' are usually referred to as a polypeptide. Beef insulin differs from human insulin in two amino acid residues, and pork insulin in one residue. Fish insulin is also close enough to human insulin to be effective. In humans, insulin has a molecular weight of 5734. Insulin is structured as 2 polypeptide chains linked by 2 sulfur bridges (see figure shown above). Chain A consists of 21, and chain B of 30 amino acids. Insulin is produced as a prohormone molecule – proinsulin – that is later transformed by proteolytic action into the active hormone.

The remaining part is called C-peptide. This polypeptide is released into the blood in equal amounts to the insulin protein. Since external insulins currently contain no C-peptide component, serum amounts of peptide C are good indicators of internal insulin production. C-peptide has recently been discovered to have biological activity itself; the activity is apparently confined to an effect on the muscular layer of the arteries.

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 on cells include:

Regulatory actions of insulin on blood glucose levels

Despite long intervals between meals or the occasional consumption of meals with a substantial carbohydrate load (e.g., half a
birthday cake or a bag of potato chips), human blood glucose levels normally remain within a narrow range. In most humans this varies from person to person from about 70 milligrams per deciliter (mg/dl) to perhaps 110 mg/dl except shortly after eating when the blood glucose level rises temporarily; this is a total of about 5 g (1/5 of an ounce) of glucose in the 5 liters (1.25 gallons) of blood in the average adult male. This homeostatic process is the result of many factors, but hormone regulation is the most important.

There are two groups of antagonistic hormones affecting blood glucose levels:

This is because, at least in the short term, it is far less dangerous to have too much glucose in the blood than too little. Mechanisms which restore too low blood glucose (hypoglycemia) must be quick and effective because of serious consequences of insufficient glucose. They are mostly efficient, and symptomatic hypoglycemia is found almost entirely in diabetics on pharmacologic treatment. Such hypoglycemic episodes vary greatly in severity and swiftness of onset. In severe cases prompt medical assistance is essential, as death will result from sufficiently low blood glucose levels.

Beta cells in the islets of Langerhans are sensitive to variations in blood glucose levels because of the presence of glucokinase, which responds to glucose concentrations. If that level increases, more insulin from beta cell stores is released into the blood, and beta cell insulin production increases. When the glucose level comes down to the physiologic value, insulin release slows or stops. And, before the level of glucose drops dangerously low, hyperglycemic hormones come into play, forcing release of glucose into the blood from cellular stores.

Insulin and the brain

Though other cells can use other fuels for a while (most prominently fatty acids), neurons are dependent on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue and they have very small internal stores of glycogen. Thus, a sufficiently low glucose level first and most dramatically manifests itself in impaired functioning of the central nervous system – dizzness, speech problems, even loss of consciousness, are common. This phenomenon is known as hypoglycemia or, in cases producing unconsciousness, hypoglycemic coma (formerly termed insulin shock from the most common causative agent). Because endogenous causes of insulin excess (such as an insulinoma) are extremely rare naturally, the overwhelming majority of hypoglycemia cases are caused by human action (eg, iatrogenic (meaning caused by medicine)), and are usually accidental. There have been a few cases reported of murder or attempted murder using insulin overdoses, but most insulin shock appears to be due to mismangement of insulin (didn't eat as much as anticipated, or exercised more than expected), or a mistake (eg, 200 units of insulin instead of 20).

Misuse of any of three classes of medication are the usual causes of iatrogenic hypoglycemia:

Intracellular transformation of the insulin signal

There are special transport channels in cell membranes through which
glucose from the blood can enter a cell. These channels are, indirectly, under insulin control in certain body cell types. A lack of circulating insulin will prevent glucose from entering those cells (eg, in untreated Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (eg, the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is the same: elevated blood glucose levels.

Activation of insulin receptors leads to internal cellular mechanisms which directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane which transport glucose into the cell.

Two types of 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 against future needs. Together, they account for about 2/3 of all cells in a typical human body.

Diseases and syndromes caused by an insulin disturbance

There are several conditions in which insulin disturbance is pathologic:

Insulin as a medication

Insulin is absolutely required for all animal (including human) life. The mechanism is almost identical in nematode worms (ie,
C. elegans), fish, and in mammals. In humans, insulin deprivation due to the removal or destruction 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 for this, or any other, reason. Clinically, this is called diabetes mellitus type 1.

Although it was evident to researchers in the late 1800s that there was some connection between the pancreas and diabetic symptoms, efforts to isolate the active principle (secretion or whatever) were unsuccessful. Progress was only made when it was realised that the digestive enzymes also produced by the pancreas destroyed the active material during the attempts at extraction. Many around the world came close, but the announcement of isolation of insulin from the pancreases of foetal calves (which had not yet begun the production of digestive enzymes) was made on 27 July 1921 at the University of Toronto (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. Banting and MacLeod shared some of the Prize money with the others.

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 as they are nearly identical to human insulin (2 amino acid difference for bovine insulin, 1 amino acid difference for porcine). 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 of allergic reactions to assorted non-insulin substances remaining in those preparations. Human insulin can now be manufactured, using genetic engineering molecular biology techniques, in sufficient quantity for widespread clinical use, much reducing impurity reaction problems. Eli Lilly marketed the first such synthetic insulin, Humulin, in 1982. Genentech Inc developed the technique Lilly used.

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

Diabetics give themselves insulin, usually via subcutaneously hypodermic injection. This is both: There have been several attempts to improve upon this mode of administering insulin as many people find injection awkward and painful. One alternative is jet injection (also sometimes used for some vaccinations) which has different insulin delivery peaks and durations as compared to needle injection of the same amount and type of insulin. Some diabetics find control possible with jet injectors, but not with hypodermic injection. There are also 'insulin pumps' of various types which are 'electrical injectors' attached to a semi-permanently implanted needle (a catheter). Some who cannot achieve adequate glucose control by conventional injection (or sometimes jet injection) are able to with the appropriate pump.

Unlike many medicines, insulin cannot be taken orally. It is treated in the gastrointestinal tract precisely as any other protein; that is, reduced to its amino acid components, whereupon all 'insulin activity' is lost. There are research efforts underway to develop methods of protecting insulin from the digestive tract so that it can be taken orally, but none has yet reached clinical use.

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

An insulin pump is a reasonable solution for some. However there are several major limitations - cost, the potential for hypoglycemic episodes, catheter problems, and, thus far, no approvable means of controlling insulin delivery in the field based on blood glucose levels. If too much insulin is delivered or the patient eats less than normal, there will be hypoglycemia. On the other hand, if too little insulin is delivered by the pump, there will be hyperglycemia. Both of these can lead to potentially life-threatening conditions. In addition, indwelling catheters pose considerable risk of infection and ulceration. Thus far, insulin pumps require considerable care and effort to use correctly. However, some diabetics are able to keep their glucose in reasonable control only on a pump.

Researchers have produced a watch-like device that tests for insulin levels in the blood through the skin and administers corrective doses through pores in the skin of the patient. Both electricity and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental at this writing. The blood glucose test aspect of such 'wrist appliances' is, at this writing, commercially available essentially as described.

Another 'improvement' would be to avoid periodic insulin administration entirely by installing a self-regulating insulin source. For instance, pancreatic, or beta cell, transplantation. Transplantation of an entire pancreas (as an individual organ) is technically difficult, and is not common. Generally, it is performed in conjunction with liver or kidney transplant surgery. However, transplantation of only pancreatic beta cells is a possibility. It has been highly experimental (for which read 'prone to failure') for many years, but some researchers in Alberta, Canada, have developed techniques which have produced a much higher success rate (about 90% in one group). Beta cell transplant may become practical, and common, in the near future. Several other non-transplant methods of automatic insulin delivery are being developed in the research labs as this is written. None is currently close to clinical approval.

The central problem for those requiring external insulin is picking the right dose of insulin and the right timing.

 

Physiological regulation of blood glucose, as in the non-diabetic, would be best. 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 glycogen to glucose conversion, reducing blood glucose levels, and so 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 normal glucose control in the non-diabetic.

Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. And, fats and proteins both cause delays in absorption of glucose from carbohydrate eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same.

It is in principle 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. Non-diabetics' beta cells routinely and automatically manage this by continual glucose level monitoring and adjustment of insulin release. All such decisions by a diabetic must be based on general experience and training (ie, at the direction of a physician or PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the patient. It is not straightforward and should never be done by habit or routine, but with care can be done quite successfully in practice.

For example, 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 still different reaction even in that same person. Whole milk contains considerable fat while skim milk has much less. It is a continual balancing act for all diabetics, especially for those taking insulin.

Types of medical insulin

Medical preparations of insulin (from the major suppliers – Eli Lilly and Novo Nordisk -- or from any other) are never just 'insulin in water'. Clinical insulins are 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 precisely insulin, but so called insulin analogs. The insulin molecule in an insulin analog is slightly modified 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 (Aventis' version is 'Insulin glargine')
  • all while retaining insulin action in the human body.

  • The management of choosing insulin type and dosage / timing should be done by an experienced medical professional working with the diabetic.

    Allowing blood glucose levels to rise, though not to levels which cause acute hyperglycemic symptoms, is not a sensible choice. Several large, well designed, long term studies have conclusively shown that diabetic complications decrease markedly, linearly, and consistently as blood glucose levels approach 'normal' patterns over long periods. In short, if a diabetic closely controls blood glucose levels (ie, on average, both over days and weeks, and avoiding too high peaks after meals) the rate of diabetic complications goes down. If glucose levels are very closely controlled, that rate can even approach 'normal'. The chronic diabetic complications include cerebrovascular accidents (CVA or stroke), heart attack, blindness (from proliferative diabetic retinopathy), toehr vascular damage, 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 hypoglycemia is dangerous and can be fatal.

    A good measure of long term diabetic control (over approximately 90 days in most people) is the serum level of glycosylated hemoglobin (HbA1c). A shorter term integrated measure (over two weeks or so) is the so-called 'fructosamine' level, which is a measure of similarly glyclosylated proteins (chiefly albumin) with a shorter half life in the blood. There is a commercial meter available which measures this level in the field.

    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 essentially equivalent to suffocation experimentation. Severe acute or prolonged hypoglycemia can result in brain damage or death.

    On July 23, 2004, news reports claim that a former spouse of a prominent international track athlete said that, among other drugs, the ex-spouse had used insulin as a way of 'energizing' the body. The intended implication would seem to be that insulin has effects similar to those alleged for some steroids. This is not so; eighty years of insulin use has given no reason to believe it to be in any respect a performance enhancer for non diabetics. Improperly treated diabetics are, to be sure, more prone than others to exhaustion and tiredness, and in some of these cases, proper administration of insulin can relieve such symptoms. However, insulin is not, chemically or clinically, a steroid, and its use in non diabetics is dangerous and alwasy an abuse outside of a well-equipped medical facility. Its use in athletes, very few of whom are diabetic, is at best simply foolish, and can be, at worst, quickly fatal. Between these cases lies permanent brain damage.

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