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Page: As a Medication
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Principles
Insulin is 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 nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (even single 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. 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:
* Mode of administration.
* Selecting the 'right' dose and timing.
* Selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds).
* Adjusting dosage and timing to fit food intake timing, amounts, and types.
* Adjusting dosage and timing to fit exercise undertaken.
* Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness.
* The dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C-peptide being released gradually and directly into the portal vein.
* It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading.
* It is dangerous in case of mistake (most especially 'too much' insulin).
There have been attempts to improve upon this mode of administering insulin, as many people find injection inconvenient, awkward, and generally 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 that are 'electrical injectors' attached to a semi-permanently implanted catheter or cannula. Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump.
Insulin pumps are a reasonable solution for some. Advantages to the patient are better control over background or 'basal' insulin dose, bolus doses calculated to fractions of a unit, and calculators in the pump that help with dosing 'bolus' infusions. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels.
As with injections, if too much insulin is delivered or the patient eats less than he or she dosed for, there will be hypoglycemia. On the other hand, if too little insulin is delivered, there will be hyperglycemia. Both can be life-threatening. In addition, indwelling catheters pose the risk of infection and ulceration. These risks can be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly. However, some diabetics are capable 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 a transplantation of the pancreas or beta cell to avoid periodic insulin administration. This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual organ) is difficult and uncommon. Generally, it is performed in conjunction with liver or kidney transplant. However, it is possible to do a transplantation of only the pancreatic beta cells. 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). Nearly half of those who got an islet cell transplant are insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. Beta cell transplant may become practical 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.
Inhalable insulin is under investigation, as are several other insulin administration techniques. The only inhalable insulin approved by the Food and Drug Administration is Exubera. Inhaled insulin has similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required. When patients were switched from injected to inhaled insulin, no significant difference was found in HbA1c levels over three months. Accurate dosing is still a problem, but patients showed no significant weight gain or pulmonary function over the length of the trial, when compared to the baseline. Following its commercial launch in 2005 in 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". Several clinical studies reported greater patient satisfaction compared with subcutaneous insulin in both type 1 and type 2 diabetes.
Pulsatile insulin is an additional method of administration of insulin to diabetics. 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. Fats and proteins 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 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 (i.e., at the direction of a physician, 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. With care it 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 short-acting insulin to cover meals (bolus insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that insulin-dependent diabetics have to manage each day. This is normally achieved through regular blood tests, although there is work being done 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.
[edit] 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.
Slight variations of the human insulin molecule are called insulin analogs. They have absorption and activity characteristics not possible with insulin proper. They are:
* Absorbed rapidly enough to mimic real beta cell insulin (Lilly's is lispro, Novo Nordisk's is aspart).
* Steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (Novo Nordisk' version is Insulin detemir and Aventis' version is Insulin glargine).
* All while retaining insulin action in the human body.
Choosing insulin type and dosage / timing should be done by an experienced medical professional working with the diabetic patient.
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 approaches '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:
* Quick-acting, such as the insulin analog lispro -- begins to work within 5 to 15 minutes and is active for 3 to 4 hours.
* Short-acting, such as regular insulin -- starts working within 30 minutes and is active about 5 to 8 hours.
* Intermediate-acting, such as NPH, or lente insulin -- starts working in 1 to 3 hours and is active 16 to 24 hours.
* Long-acting, such as ultralente insulin -- starts working in 4 to 6 hours, and is active 24 to 28 hours.
* Insulin glargine and Insulin detemir -- both insulin analogs which start working within 1 to 2 hours and continue to be active, without peaks or dips, for about 24 hours.
* A mixture of NPH and regular insulin -- starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins.
[edit] Abuse
There are reports that some patients abuse insulin by injecting large doses that lead to hypoglycemic states. This is extremely dangerous. Severe acute or prolonged hypoglycemia can result in brain damage or death.
On July 23, 2004, news reports claimed 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: 80 years of injected insulin use has given no reason to believe it could 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 cases, proper administration of insulin can relieve such symptoms. 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.
The use/abuse of exogenous insulin is widespread amongst the bodybuilding community. Both insulin, growth hormone (GH) and insulin-like growth factor 1 (IGF1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is this: Since insulin and GH act synergistically to promote growth, and since IGF1 is the primary mediator of the musculoskeletal effects of growth hormone, the 'stacking' of insulin, GH and IGF1 should offer a synergistic growth effect on skeletal muscle. This theory has been borne out in recent years by the creation of top-level bodybuilders whose competition weight is in excess of 50lbs of muscle greater than the professionals of the past, yet with even lower levels of body fat. Indeed, the use of insulin, combined with GH and/or IGF1 has resulted in the development of such massively muscled physiques, that there has been a backlash amongst fans of the sport, with a professed disgust at the 'freakish' appearence of top-level professionals.
Bodybuilders will inject up to 10 i.u. of quick-acting synthetic insulin following meals containing starchy carbohydrates and protein, but little fat, in an attempt to 'force feed' nutrients necessary for growth into skeletal muscle, whilst preventing growth of adipocytes. This may be done up to 4 times each day, following meals, for a total usage of 40iu of synthetic insulin / day. However there have been reports of substantially heavier usage, amongst even 'recreational' bodybuilders.
The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death. Long term risks include development of type II diabetes, and a lifetime dependancy on synthetic insulin.
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Important notice:
The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other
qualified health provider with any questions you may have regarding a medical condition.
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