Insulin

Insulin is a hormone that performs a variety of tasks in the human body, and is key to regulating blood sugar levels. Insulin is produced in the pancreas by the Beta cells (or "B cells").

One of insulin's many functions is to store glucose in liver and muscle cells. Those cells can use the glucose for immediate energy, store it in the form of glycogen for later use, or convert into fat for long-term use.

When insulin is functioning properly in the body, the hormone keeps the blood glucose level steady at 60 to 100 mg/dL.

Type 1 diabetes is caused by an insufficient amount of insulin in the blood. Patients with type 1 diabetes inject insulin in order to move the glucose in their blood into the cells that need it.

Patients with type 2 diabetes are insulin-resistant; their cells block the normal functioning of insulin. Some type 2 diabetics eventually require insulin if other medications are insufficient in controlling blood glucose levels.

Principles
Insulin is required for all animal (including human) life. 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.

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. 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, although very few patients today rely on insulin from these sources because most manufacturers have stopped producing it.

Human insulin is now manufactured for widespread clinical use using genetic engineering techniques, which reduced many of the 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 synthetic "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 today.

Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogs.

Modes of administration
Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins introduced into the digestive process, it is reduced to fragments, 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 hypodermic syringe, 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 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).

Alternatives to injections
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. Both electricity and ultrasound have been found to make the skin temporarily porous. Called the "Glucowatch" this device was found to be extremely inaccurate, ineffective, expensive, unreliable, and irritating and has since been discontinued.

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. Insulin pumpers can accommodate these differences in absorption by using dual/combo boluses or extended/square wave boluses. 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. Insulin pumpers can adjust for this using temporary basal rates.

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, NP, 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 people with diabetes 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 people with diabetes, especially for those taking insulin.

People with insulin-dependent (type 1) diabetes generally require a base level of insulin (basal insulin), as well as short or rapid-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 glucose monitoring equipment.

It is important to notice that people with diabetes generally need more insulin than the usual &mdash; not less &mdash; during physical stress like infections or surgeries.

Types
Medical preparations of insulin (from the major suppliers &mdash; Eli Lilly, Novo Nordisk and Sanofi-Aventis &mdash; 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 in an effort to better mimic beta cell insulin (Lilly's is insulin lisipro, Novo Nordisk's is insulin aspart and Sanofi-Aventis' is insulin glulisine). While it is an improvement over regular insulin, it remains far less than an ideal physiological match.
 * Steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (Novo Nordisk's version is Insulin detemir and Sanofi-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 stroke, heart attack, blindness (from proliferative diabetic retinopathy), other vascular damage, nerve damage from neuropathy, or kidney failure from nephropathy. These studies have demonstrated that, if it is possible for a patient, so-called intensive insulin therapy is superior to conventional insulinotherapy. However, close control of blood glucose levels (as in intensive insulin therapy) 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:


 * Rapid-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 insulin, 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.


 * Premixed insulin -- a mixture of NPH and regular insulin that starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins.

Link to graphical example of insulin types by onset, duration, and peak