Insulin Therapy is the treatment of diabetes by administration of exogenous insulin.
Insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant, have relatively low insulin production, or both; certain patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately.
The initial sources of insulin for clinical use in humans were 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- derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions in the presence of non- insulin substances.
Bio synthetic “human” insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities, although there is no clinical evidence to substantiate this claim. However, the clinical preparations prepared from such insulin differ from endogenous human insulin in several important respects; an example is the absence of C- peptide which has in recent years been shown to have systemic effects itself. Adverse reactions have been reported, these include loss of warning signs that sufferers may slip in to a coma through hypoglycemia, convulsions, memory lapse and loss of concentration.
There are several problems with insulin as a clinical treatment for diabetes:
- Mode of administration
- Selecting the ‘right’ dose and timing: Usually one unit of insulin is ~15 grams of CHO.
- 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.
- Variability in absorption into the blood stream via subcutaneous delivery.
- The dose 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).
Types: Medical preparations of insulin are never just ‘insulin in water’. Clinical insulin is specially prepared mixtures of insulin plus other substances including preservatives. 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 analogues, so named because they are not technically insulin; rather they are analogues which retain the hormone’s glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin, or steadily absorbed after injection instead of having a ‘peak’ followed by more or less rapid decline in insulin action, all while retaining insulin’s glucose- lowering action in the human body. However, a number of meta– analyses have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types.
Choosing insulin type and dosage/timing should be done by an experienced medical professional working closely with the diabetic patient.
The commonly used types of insulin are:
- Fast- acting: Includes the insulin analogues aspart, lispro, and glulisine. These begin to work within 5 to 15 minutes and are active for 3 to 4 hours.
- Short – acting: Includes regular insulin which begins working within 30 minutes and is active about 5 to 8 hours.
- Intermediate- acting: Includes NPH insulin which begins working in 1 to 3 hours and is active 16 to 24 hours.
- Long- acting: Includes the analogues glargine and detemer, each of which begins working with 1 to 2 hours and continue to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals.
- Ultra- long acting: Currently only includes the analogue degludec, which begins working within 30 to 90 minutes, and continues to be active for greater than 24 hours.
- Combination insulin products – Includes a combination of either fast – acting or short – acting insulin with a lager acting insulin, typically an NPH insulin. The combination products begin to work with the shorter acting insulin ( 5 – 15 minutes for fast acting, and 30 minutes for short acting ), and remain active for 16 to 24 hours. There are several variations with different proportions of the mixed insulin.
Modes of administration:
Unlike many medicines, insulin cannot be taken orally at the present time. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments, whereupon all ‘insulin activity’ is lost.
Insulin is usually taken as subcutaneous injections by single- use syringes with needles, an insulin pump, or by repeated- use insulin pens with needles.
Administration schedules often attempt to mimic the physiological secretion of insulin by the pancreas. Hence, both long- acting insulin and short- acting insulin are typically used.
Insulin pumps are a reasonable solution for some. Advantages to the patient are better control over background or “basal” insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining “bolus” infusion dosages. 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, in dwelling catheters pose the risk of infection and ulceration, and some patients may also develop lipodystrophy due to the infusion sets. These risks can often be minimized by keeping infusion sets clean. Insulin pumps require care and effort to use correctly. However, some patients with diabetes are capable of keeping their glucose in reasonable control only with an insulin pump.
Inhaled insulin claimed to have 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 observed in HbA1C levels over three months.
There are several methods for transdermal delivery of insulin. Pulsatilla insulin uses micro jets to pulse insulin into the patient, mimicking the physiological secretions of insulin by the pancreas. Jet injections had different insulin delivery peaks and durations as compared to needle injection. Some diabetics find control with jet injections, but not with hypodermic injection.
Intranasal insulin is being investigated.
The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. However, insulin is a protein, which is digested in the stomach and gut and in order to be effective at controlling blood sugar, cannot be taken orally in its current form.
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 relatively uncommon. It is often performed in conjunction with liver or kidney transplant, although it can be done by itself. It is also possible to do a transplantation of only the pancreatic beta cells.
Dosages and timing:
The dosage units:
One international unit of insulin (1IU) is defined as the “biological equivalent” of 34.7 microgram pure crystalline insulin. This corresponds to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/ dl (2.5 mmol/ L).
The unit of measurement used in insulin therapy is not part of the International system of units (abbreviated SI) which is the modern form of the metric system.
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, reduces 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 synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non- diabetic.
Complicating matters is that the composition of the food eaten affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. In addition, fats and proteins cause delays in absorption of glucose from carbohydrates eaten at the same time. As well, exercise reduces the need for insulin even when all the factors remain the same, since working muscle has some ability to take up glucose without the help of insulin.
Because of the complex and interacting factors, 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 lbe based on experience and training (I.e., at the direction of a physician) and further, especially based on the individual experience of the patient. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice.
For example, some patients 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 people with diabetes, 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.
Patients with insulin- dependent diabetes typically require some 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 people with insulin dependent diabetes must manage each day.
Dr. A.K.M. Aminul Hoque
Associate Prof. (Medicine)
Dhaka Medical College & Hospital,