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Insulin (from Latin insula, "island", as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary effector in carbohydrate homeostasis, it has effects on fat metabolism and it can change the liver's ability to release fat stores. Insulin's concentration has extremely widespread effects throughout the body. Insulin is used medically in some forms of diabetes mellitus. Patients with type 1 diabetes mellitus depend on exogenous insulin (commonly injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with type 2 diabetes mellitus have either relatively low insulin production or insulin resistance or both, and a non-trivial fraction of type 2 diabetics eventually require insulin administration when other medications become inadequate in controlling blood glucose levels. Insulin has a molecular weight of 5808 Da. It has the molecular formula C257H383N65O77S6. Insulin structure varies slightly between species of animal. Its carbohydrate metabolism regulatory function strength in humans also varies. Porcine (pig) insulin is particularly close to humans'. Discovery and characterization
Nobel Prizes Structure and production Insulin is synthesized in humans, and other mammals, within the beta cells (β-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. In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications of proinsulin remove the center portion of the molecule, or C-peptide, from the C- and N- terminal ends of the proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds. Confusingly, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others. Amongst vertebrates, insulin has been highly conserved. Bovine insulin differs from human insulin in only three amino acid residues, and porcine insulin in one residue. Even insulin from some species of fish is also close enough to human insulin to be effective in humans. Actions on cellular and metabolic level
Regulatory action on blood glucose
Signal transduction There are special transporter proteins in cell membranes through which glucose from the blood can enter a cell. These transporters are, indirectly, under insulin control in certain body cell types (eg, muscle cells). Low levels of circulating insulin, or its absence, 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, characteristically, 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. The genes which specify the proteins which make up the insulin receptor in cell membranes have been identified and the structure of the interior, cell membrane section, and now, finally after more than a decade, the extra-membrane structure of receptor (Australian researchers announced the work 2Q 2006). Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: 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 food energy against future needs. Together, they account for about ⅔ of all cells in a typical human body. Hypoglycemia Although other cells can use other fuels for a while (most prominently fatty acids), neurons depend 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. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in triglycerides can also be used to produce blood glucose. Exhaustion of these sources can, either temporarily or on a sustained basis, if reducing blood glucose to a sufficiently low level, first and most dramatically manifest itself in impaired functioning of the central nervous system – dizziness, speech problems, even loss of consciousness, are not unknown. This is known as hypoglycemia or, in cases producing unconsciousness, "hypoglycemic coma" (formerly termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an insulinoma) are very rare, and the overwhelming majority of hypoglycemia cases are caused by human action (e.g. iatrogenic, caused by medicine), and are usually accidental. There have been a few reported cases of murder, attempted murder or suicide using insulin overdoses, but most insulin shocks appear to be due to mismanagement of insulin (didn't eat as much as anticipated, or exercised more than expected), or a mistake (e.g. 20 units of insulin instead of 2). Possible causes of hypoglycemia include: Diseases and syndromes There are several conditions in which insulin disturbance is pathologic: Principles Insulin is absolutely required for all animal (including human) life. The mechanism is almost identical in nematode worms (e.g. 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. The initial source of insulin for clinical use in humans was from cow, horse, pig or fish pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference for bovine insulin, one amino acid difference for porcine). Insulin is obviously 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. Purity has improved more or less steadily since the 1920s, but allergic reactions have continued though slowly reducing in severity. Insulin production from animal pancreases was widespread for decades, but there are very few patients today relying on insulin from these sources. Human insulin is now manufactured for widespread clinical use using genetic engineering techniques, which significantly reduces impurity reaction problems. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques, in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce actual human insulin. Genentech developed the technique Lilly used to produce Humulin. Novo Nordisk has also developed a genetically engineered insulin independently. Most insulins used clinically are produced this way, for they avoid most of the allergic reaction problem. Since January 2006, all insulins distributed in the U.S. and some other countries are human insulins or their analogs. A special FDA importation process is required to obtain beef or pork insulin for use in the U.S., though there may be some remaining stocks of pork insulin made by Lilly in 2005 or earlier. Modes of administration Unlike many medicines, insulin cannot be taken orally; like other proteins in the gastrointestinal tract, it is reduced to its amino acid components, whereupon all 'insulin activity' is lost. There is research underway to develop methods of protecting insulin so that it can be taken orally, but none has yet reached clinical use (see oral insulin). Instead insulin is usually taken as subcutaneous injections by single-use syringes with needles, an insulin pump or by repeated-use insulin pens with needles. There are several problems with insulin as a clinical treatment for diabetes: There have been 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 vaccinations), which has different insulin delivery peaks and durations as compared to needle injection. 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 (i.e. a catheter). Some who cannot achieve adequate glucose control by conventional injection (or sometimes jet injection) are able to do so with the appropriate pump. An insulin pump is a reasonable solution for some. However there are limitations - cost, the potential for hypoglycemic episodes, catheter problems, and, so far, no approvable means of controlling insulin delivery in the field based on current 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, there will be hyperglycemia. Both of these can lead to life-threatening conditions. In addition, indwelling catheters pose the risk of infection and ulceration. However, that risk can be minimized by keeping catheter sites clean. Thus far, insulin pumps require 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 blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin. Both electricity and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental, but the blood glucose test aspect of 'wrist appliances' is commercially available. Another 'improvement' would be to avoid periodic insulin administration by a self-regulating insulin source, for instance, pancreatic, or beta cell, transplantation. Transplantation of an entire pancreas (as an individual organ) is difficult, and is not common. Generally, it is performed in conjunction with liver or kidney transplant. 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 with a high initial success rate (about 90% in one group). Beta cell transplant may become practical and common in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered non-beta cells to secrete insulin.* Clinically testable results are far from realization. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval. Inhaled insulin is under investigation, as are several other insulin administration techniques. Currently the only inhalable insulin approved by the Food and Drug Administration is Exubera. Inhaled insulin has been shown to have similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. When patients were switched from injected to inhaled insulin, no significant difference was found in HBA1c levels over three months. Patients showed no significant weight gain or pulmonary function over the length of the trial, when compared to the baseline.• However following its commercial launch in 2005 into the UK, it has not (as of July 2006) been recommended by National Institute for Health and Clinical Excellence for routine use, except in cases where there is "proven injection phobia diagnosed by a psychiatrist or psychologist".• An additional method of administration of insulin to diabetics is pulsatile insulin. In this method insulin is pulsed into the patient, mimicking the physiological secretions of insulin by the pancreas. Dosage and timing 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 in cells, 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, since working muscle has some ability to take up glucose without the help of insulin. 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 insulin release. All such decisions by a diabetic must be based on 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 skimmed milk is different from other diabetics', but the same amount of whole milk is likely to cause a still different reaction even in that person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all diabetics, especially for those taking insulin. Insulin dependent diabetics require a base level of insulin (Basal Insulin), as well as extra short acting insulin to cope with meals (Bolus Insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that all insulin diabetics have to manage each day. This is normally achieved through regular blood tests, although there is work being undertaken on continuous blood sugar testing equipment. It is important to notice that diabetics generally need more insulin than the usual -- not less -- during physical stress like infections or surgeries. Types 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. The insulin molecules in an insulin analog is slightly modified so that they are: 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), other 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. The commonly used types of insulin are: Abuse There are reports that some patients abuse insulin by injecting larger doses that lead to mild hypoglycemic states. This is extremely dangerous. 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 always an abuse outside of a well-equipped medical facility. "Game of Shadows," by reporters Mark Fainaru-Wada and Lance Williams, includes allegations that San Francisco Giant, Barry Bonds, used insulin in the apparent belief that it would increase the effectiveness of the growth hormone he was (also alleged to be) taking. On top of this, non-prescribed insulin is a banned drug at the Olympics and other global competitions. 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