Insulin

Insulin (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 also has a substantial effect on small vessel muscle tone, controls storage and release of fat (triglycerides) and cellular uptake of both amino acids and some electrolytes. In this last sense, it has anabolic properties. Its concentration (more or less, prsence or absence) has extremely widespread effects throughout the body.

Insulin as a medication

Principles

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.

Related Topics:
C. elegans - Diabetes mellitus type 1

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

Harvesting pancreases from human corpses is not practical on a large scale, so insulin from cows, pigs or fish pancreases is 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. Purity has improved more or less steadily since the 1920s, but allergic reactions have continued.

Related Topics:
Cows - Pigs - Fish

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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 developed the technique Lilly used. NovoNordisk has also developed a genetically engineered insulin independently. Most insulins used clinically is produced this way, for it avoids the allergic reaction problem.

Related Topics:
Genetic engineering - Molecular biology - Eli Lilly - 1982 - Genentech

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

Modes of administration

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. Instead insulin is usually taken as subcutaneous injections by single-use syringes with needles, or by repeated-use insulin pens with needles.

Related Topics:
Gastrointestinal tract - Subcutaneous - Injection - Syringe - Needle - Insulin pen

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

There are several difficulties 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 (typically on 'speed of onset and duration of action' grounds)
• adjusting dosage and timing to fit food amounts and types
• adjusting dosage and timing to fit exercise undertaken
• adjusting dosage, type, and timing to fit other conditions as for instance the increased stress of illness
• the dosage is non-physiologic in that a subcutaneous bolus dosage of only insulin is given instead of the pancreas releasing insulin and C-peptide gradually and directly into the portal vein
• it is simply a nuisance for patients to inject themselves once or several times a day
• it may be dangerous in the case of mistake (most especially 'too much' insulin)

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 (ie, a catheter). Some who cannot achieve adequate glucose control by conventional injection (or sometimes jet injection) are able to with the appropriate pump.

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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 the risk of infection and ulceration. However, that risk can be minimized by keeping catheter sites clean. 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 blood glucose levels through the skin and administers corrective doses of insulin 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.

Related Topics:
Transplantation - Organ - Liver - Kidney - Alberta, Canada

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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, 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 skimmed 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 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 skimmed milk has much less. It is a continual balancing act for all diabetics, especially for those taking insulin.

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

It is important to notice that diabetics 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. 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

Related Topics:
Eli Lilly - Novo Nordisk - Insulin analog

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

• 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 (Novo Nordisk version is 'Insulin detemir' and 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.

Related Topics:
Long term studies - Cerebrovascular accident - Retinopathy - Diabetic neuropathy - Diabetic nephropathy - Intensive insulinotherapy - Conventional insulinotherapy - Hypoglycemia

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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.

Related Topics:
Glycosylated hemoglobin - HbA1c

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

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 always an abuse outside of a well-equipped medical facility.

Related Topics:
July 23 - 2004 - Steroid

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

However, when properly administered, insulin can restore body metabolism to something sufficiently close to normal to allow ahtletes to return to their former performance levels. Examples include Bill Talbert, the best male tennis player in the world for an extended time, Gary Hall Jr. the Olympic champion swimmer, at least one young professional Tour golfer, etc. Performace in other fields can also be maintained. Examples include Jerry Garcia of the Grateful Dead, and David Crosby, of Crosby, Stills & Nash.

Related Topics:
Bill Talbert - Gary Hall Jr. - Jerry Garcia - Grateful Dead - David Crosby - Crosby, Stills & Nash

~ ~ ~ ~ ~ ~ ~ ~ ~ ~