Types of Insulin
Insulin can be classified according to its source, namely bovine, porcine, and human; action profile; the degree of purity; strength.
Source
The earliest insulin preparations were bovine (from cow, bull). Subsequently porcine insulin (from pork) and human insulin were introduced. The human insulin is not obtained from cadavers but is prepared by bioengineering technique. Bovine insulin differs from human insulin by three amino acids, while porcine insulin differs from human insulin by one amino acid. Allergic reactions are most likely to occur with bovine insulin and least with the human, pork insulin, being in between the two.
ACTION PROFILE
Regular
Till 1935, only one type of insulin, that is plain, regular, soluble or crystalline was available. As the duration of the action of this insulin is approximately eight hours, multiple injections per day were necessary to achieve normoglycaemia over 24 hours.
PZI and NPH insulin
Protein insulin complexes were introduced to prolong the action of regular insulin Thus, protamine zinc insulin, produced by adding protamine, a fish protein and zinc to insulin, was introduced in 1936 and isophane or neutral protamine Hagedorn ( NPH ) insulin was introduced in 1946. Hans Christian Hagedorn, a scientist from Denmark had made notable contribution to introduction of long and intermediate acting insulins.
Insulin zinc suspensions
The PZ and NPH insulins gave rise to allergic reactions due to protamine, a foreign protein. In order to overcome this problem, insulin zinc suspensions were produced by adding an excess of zinc to insulin. The action of these suspensions was modified by altering the aize of the insulin zinc particles. Ultra lente with the larger crystals, has slow and prolonged action, while the amorphous or semi lente has a rapid but a short action. Lente insulin, a mixture of 30 per cent of semi lente and 70 per cent of ultra lente, shares action profile of both semi and ultra lente insulin.
Premixed insulins
Ideally, the short and intermediate acting insulins should be mixed in proportions tailored to suit the individual need. For the sake of simplification, mixtures of insulins in fixed proportion for example, 30:70, 50:50 have been introduced (premixed insulins).
Action profiles of different insulins
| Type | Action in hours | ||
| Onset | Peak | Duration | |
| Rapid analogue | 5 mixtures | 1-2 | 3-4 |
| Short-acting | 1/2 | 2-4 | 6-8 |
| Intermediate-acting | 1-3 | 6-12 | 14-18 |
| Long-acting | 4-6 | 8-30 | 24-36 |
| Pre-mixed | 1/2 | 2-10 | 20-24 |
| Long acting analogue | 4-6 | peakless | 24 |
These action profiles are not valid for extremes of insulin dosages, for example, a very large dose of intermediate-acting insulin may act longer than a very small dose. Human insulins have faster action as compared to bovine insulins.
All short-acting insulins are clear like water, whereas all other insulins are uniformly cloudy. The long acting insulin analogue, glargine is clear. Insulins are marketed with distinctly coloured cartons and labels. With the introduction of a large number of insulin preparations, colour-coding of insulin preparations has become very complex. An insulin preparation should be identified by its name rather than by the colour-scheme of its label or carton.
Broadly, insulin preparations are of two types; meal time and basal. The regular and rapid acting insulins cover the mealtime rise in blood glucose. The NPH, lente and insulin glargine are meant to replace the basal insulin requirement.
Normally, insulin is produced continuously at a low steady rale. With meals, there is a prompt and adequate increase in insulin secretion. The aim of insulin treatment is to mimic this normal process. In practice, however, exact duplication of the physiological process is currently not possible.
Purity
The conventional insulin, although much purer than initial insulins contained proinsulin, the precursor of insulin, peptides and other impurities. By recrystalisation, insulin was purified and by the 1970s, monocomponent insulins (containing component of insulin only) were introduced.
Strengths of Insulin
Insulin is available mostly in a strength of 40 units per ml(U40). Few insulins are also available in a strength of 100 units per ml(U100). In USA and UK, only U100 insulin is available. In some countries, U80 insulins are also available.
Choice of an insulin preparation
The doctor will select the most suitable insulin preparation. Multiple short-acting insulin preparations are required when diabetes is severe, when strict control is required as in pregnancy or when management of diabetes has to be flexible, for example, pre and post operatively, or for a person with an irregular lifestyle. In emergency situations such as diabetic coma or pre-coma, short-acting insulins arc absolutely essential. The rapid acting insulin analogues are given at the start of a meal or even 15 minutes later. Since their action is short, a fall in blood glucose level, a few hours after meals, is unlikely to occur. Snacks in between meals, are hence not necessary with them.
Premixed insulin preparations are convenient, since they do away drawing two insulins, i.e. short and intermediate acting insulins; in same syringe. Those who have a small breakfast should have 30:70 premixed insulin (smaller dose of short acting insulin). Those who have a larger breakfast should go for a 50:50 mixture, (larger dose of short acting insulin)
Some persons can control their diabetes with a single intermediate acting or pre-mixed insulin; others require mixtures of short-acting and intermediate-acting insulins before dinner.
Many diabetics wish to avoid insulin injections in the evening They feel that they can dispense with evening insulin by increasing the dose of morning insulin. From the action profile of intermediate-acting and pre-mixed insulins, it is obvious that a single morning dose of insulin whether short or intermediate acting cannot control the blood glucose level during the night and the following morning. Further, there is a risk of hypoglycaemia at the peak action of morning insulin if its dose is increased injudiciously.
Hypoglycaemia at night or early morning occurs very often with an intermediate acting insulin before dinner. This hazard is not encountered with insulin glargine, a long acting peakless insulin analogue.
Price of insulin is often a crucial factor in selection of an insulin preparation. The human insulin is the most and the bovine insulin is the least expensive, with pork insulin in between the two. Insulin analogues are even more expensive than the human insulins. Animal insulins are as effective as human insulin.
In view of its identity with body insulin and high degree of purity, human insulin should ideally be used in all diabetics who require it. However, as it is about three times costlier than animal insulin, its use particularly on a long-term basis, is out of reach of the many Indian diabetics.
However in certain situations, human insulins are preferred. Human insulins are absolutely indicated in insulin allergy, insulin resistance, shrinkage or lump of subcutaneous fat. They are indicated when intermittent administration of insulin is needed, to minimize long-term risk of insulin antibody formation, for instance, in pregnancy or surgery.
Factors that alter insulin requirement
| Increase | Decrease |
| Hyperglycaemia | Control of diabetes |
| Physical inactivity | Exercise |
| Obesity | Weight reduction |
| Overfeeding | Reduced diet |
| Excess of saturated fats | |
| Infection | Control of infection |
| Stroke, myocardial infarction | |
| Injury | |
| Pregnancy | Delivery |
| Overactivity of thyroid, adrenals | |
| Drugs e. g steroids | Impaired kidney function |
Hyperglycaemia by itself impairs insulin secretion and action. An unexplained increase in insulin requirement should arouse suspicion of an infection. The insulin dose has to be reduced because the person becomes more active after discharge from the hospital.
Several trials have proved that intensive control of diabetes prevents or slows chronic complications of diabetes. However, targets of control of diabetes have to be relaxed in very young children, and adults with and troublesome hypoglycaemia, in whom hypoglycaemia is hazardous.
Diet
Insulin is not a substitute for a diet. In fact it is all the more necessary, for a person on insulin, to have regular and uniform meals. (See Ch. 13)
Blood glucose tests
Persons taking insulin should check following blood samples for glucose: fasting, before lunch, before dinner and at bed time.
Adjustment of insulin dose according to blood glucose tests
| Type of insulin | Urine/blood glucose | |||
| Fasting | Before lunch/supper | Bed | ||
| Before breakfast | • | |||
| Short-acting | ||||
| Intermediate-acting | ||||
| Before supper | ||||
| Short-acting | • | |||
| Intermediate-acting * | • | |||
Note : o Indicates the blood test which guides the dose of insulin. * blood test, next morning
Note : The dose of appropriate insulin should be increased by 2 u to 4 u, if blood tests on two to three consecutive days shows elevated/glucose.
An important rule
In type 1 diabetes and also in type 2 diabetes in presence of infection, vomiting, diarrhoea and injury, omission of insulin can be dangerous. A person with diabetes should not stop taking insulin or change over to oral drugs, without consulting his or her doctor.
Insulin Analogues
By altering the cohesiveness of the insulin molecules, 'designer' insulins with different action profiles have been prepared. The action of the insulin analogue will be rapid and short if the cohesiveness of the insulin molecules is reduced. On the other hand, the action will be slow and prolonged if the cohesiveness is enhancd.
In the 'B' chain of insulin, amino acids proline and lysine are in the 28th and the 29th position. By bioengineering technique, the positions of these two amino acids, have been interchanged, producing lispro (Humalog Eli Lilly) By substituting, proline by aspartic acid in the 28th position of 'B' chain of insulin, insulin aspart (Novo Rapid; Novo Nordisk) is produced. Lispro and insulin aspart arc rapid acting insulin analogues.
By introducing arginine in two new positions, at the end of 'A'' chain, insulin glargine Lantus, Aventic Sanofi a long acting, peakless insulin analogue has been developed. Glargine cannot be mixed with a short acting insulin in the same syringe. It can be injected at any time of the day.
Premixed insulin analogues, in varying proportions, like lispro/neutral protamine lispro (Humalog mix) and aspart/neutral protamine aspart Novomix have also been introduced.
Natural insulin or insulin in the body starts its action immediately after its release, reaches its peak action 30-60 minutes later and continues to lower blood glucose for two to three hours. The action of available short-acting insulin starts about 30 minutes after its injection, reaches a peak action after 2-3 hours and lasts for about 6-8 hours. Thus people using insulin require to time their injection in relation to their meals, so that glucose and insulin end up in the same place at the same time. Compared to natural insulin, short-acting insulin is thus slow because short-acting insulin molecules are attracted to each other in a group of six molecules called hexamers (hexa=six). Hexamers are too big to move from the injection site to the blood stream. The insulin has to be broken down from a hexamer into three dimers (aggregate of two molecules; di=two) and then into six monomers (single molecules of insulin) before it can be absorbed. It takes at least S5 minutes and usually more than 30 minutes for enough hexamers to be broken down and enough of the resulting monomers to be absorbed. But not all hexamers get broken down and absorbed in the first 30 minutes. Many hexamers are still left hours after injection, waiting their turn. That is why the duration of action is 6-8 hours.
Because of the change in the sequence of amino acids, in rapid acting insulin analogues, the insulin molecules are repelled instead of getting attracted to each other. Instead of forming a hexamer, the insulin remains in monomeric form.
Since it does not need time to break down after injection, it is faster-acting. Its action starts 5 minutes after the injection, reaches its peak at 1 hour and lasts for 2-4 hours.
As the onset of action is quick, the insulin analogue is convenient and affords flexibility in meal timings. Post-meal hypoglycaemia is likely to be less frequent, since it acts for 2-4 hours only.
More frequent injections will be necessary due to the short duration of action. A mixture of short-acting insulin and this analogue could be useful.