Overview

• Patients presenting with type 1 diabetes require insulin without delay to avoid ketoacidosis

• An increasing proportion of type 2 patients will require insulin to achieve modern glycaemic control targets

• The majority of type 2 patients requiring insulin can have this treatment initiated in primary care

• A wide range of insulin types is available, but most patients can be managed using a limited selection of regimens and devices

• Familiarity with these devices and regimens overcomes the inertia that may delay the initiation of insulin in type 2 diabetes

Introduction

Insulin replacement therapy is essential for a patient with type 1 diabetes and is needed to achieve good glycaemic control in many patients with type 2 diabetes once other agents are no longer able to achieve this effectively. For patients with previously poor glycaemic control insulin has dramatic effects and can enhance wellbeing in a way that other therapies cannot match. Despite these obvious benefits, many patients who have previously taken tablets resist going onto insulin therapy, principally because it is an injectable preparation. Insulin therapy also requires much more active involvement by the patient to adjust the doses. Insulin is unusual as a drug in that the dose different patients take may range very widely from a few units to several hundred units. This often makes healthcare professionals with limited experience wary of managing patients on insulin. The optimal dose is tailored for every given patient and is one that achieves the best possible control avoiding hypoglycaemia as much as possible. In older, frail patients it might be inappropriate to provide intensive insulin therapy and here a once-daily insulin injection that alleviates the symptoms may be all that is required.

Types of insulin

1 Animal insulins: Until the 1980s, insulin was manufactured from purified extracts from pancreas of cows and pigs. Today it is manufactured by recombinant DNA technology that involves the insertion of the synthesised genes for insulin into an Escherichia coli bacteria, or yeast cells. Resulting protein is yielded in large quantities and then purified. Some patients still use animal insulin, often those individuals who experienced hypoglycaemia after commencinghuman insulin. Today the vast majority of people with diabetes in the UK use human insulin.

2 Short-acting insulins: Short-acting insulin is also known as soluble insulin and has a duration of action of about 6-8 hours and needs to be injected about 30 minutes before meals. Examples are listed in Table 8.1.

3 Very rapid-acting insulin analogues: These are newer human insulin analogues that can be taken with or just after the meal because they are absorbed more or less immediately. They are used to cover mealtime hyperglycaemia in a basal-bolus insulin regime that is discussed later.

4 Intermediate-acting insulins: These insulins usuallyhave abasic protein like protoamine or zinc added to them to delay their action. They generally tend to have a duration of action of about 8-10 hours after subcutaneous injection. Variants are also available where a duration of action that is considerably longer can be obtained.

5 Long-acting insulin zinc suspensions: These are prepared by adding excess zinc ions to insulin and examples of these include ultratard and humulin zinc. These are usually administered at bedtime.

6 Long-acting insulin analogues: These insulin analogues provide up to 24-hour basal insulin when injected subcutaneously. These preparations may be suitable for once-daily administration and carry a low-risk of hypoglycaemia because their action profile does nothave a 'peak', unlike short-acting or intermediate-acting insulins.

7 Pre-mixed insulin mixtures: Several preparations of insulin are available as pre-prepared mixtures in vials or as pre-mixed pens, eliminating the need for patients to mix insulin in a syringe. This reduces the risk of mistakes made while mixing insulin and is also more convenient. Examples of popular insulin mixtures are shown in Table 8.1. The choice of a mixture is dependent on the patient's life-style and meal patterns. Similarly, the selection of particular insulins for a patient is also made bearing in mind the patient's particular circumstances and also their preferences in terms of choice of device, and frequency of injection.

Table 8.1 Commonly used types of insulin, with examples.

Type of insulin

Examples

Comments

Soluble insulin Rapid-acting insulin analogues

Long-acting insulin analogues Isophane (NPH)

Biphasic 'pre-mixed' insulins or insulin analogues

Human Actrapid, Pork Acrapid, Humulin S Aspart (Novorapid), Lispro (Humalog), Glulisine (Apidra)

Glargine (Lantus), Detemir (Levemir)

Insulatard, Humulin I, Insuman Basal, Hypurine Porcine Isophane, Hypurin Bovine Isophane Biphasic insulin aspart (Novomix 30), Biphasic insulin Lispro (Humalog Mix25 and Mix50), Mixtard (10, 20, 30, 40, 50), Humulin M3, Insuman Comb (15, 25, 50)

Actrapid now only available in vials

Onset only takes 15 minutes so can be given immediately after, rather than before, a meal when the exact carbohydrate intake is known, if this suits the patient. Short duration of action reduces risk of nocturnal hypoglycaemia and provides flexibility for dose adjustment. Risk of overlap with subsequent injection later in the day is reduced

Have little or no 'peak' of action and are therefore useful as the basal component of the basal-bolus regimen Still used as the basal component but does 'peak' in its action. This effect may be useful, but may contribute to the risk of nocturnal hypoglycaemia. Significantly less expensive than long-acting analogues Useful for patients requiring some flexibility but wishing to avoid the more intensive basal-bolus regimen (which requires at least four injections a day). Can be given twice or three times a day before meals. The proportion of overall insulin in the soluble form is indicated by the number. A commonly used option is the '30' strength

Insulin regimens

Starting insulin in type 1 diabetes

Many type 1 patients can start treatment with a twice-daily biphasic regimen, usually about 8 units twice a day and then the dose is optimised. However, in younger patients in particular, a more flexible method is the basal-bolus regime where a long-acting insulin is given at bedtime and meals are covered by soluble insulin or a very short-acting analogue. An increasing number of people in the UK now use insulin analogues, especially if they experience hypoglycaemia on conventional insulins.

Basal-bolus regime

Here an intermediate- or long-acting acting insulin is used at bedtime and meals are covered using a short-acting insulin or a rapid-acting insulin analogue. A long-acting insulin analogue such as insulin glargine or insulin detemir is often used in the UK now as the basal insulin. The timing of the rapid-acting insulin can vary according to the timing of meals. This is convenient for those at work or at college. Rapid-acting insulin analogues have made this regimen more popular because they avoid the overlap effects that may cause problems with frequently administered soluble insulin.

Twice or three times a day biphasic regimen

Some patients opt to have twice-daily biphasic mixtures taken at breakfast and with an evening meal. This can be increased by adding in a lunchtime dose if using a biphasic with a rapid acting component, but there may in some cases be a risk of overlap between the lunchtime and evening doses. Occasionally such patients may require a short-acting or rapid-acting insulin with lunch instead of the biphasic.

Starting insulin in type 2 diabetes

For some type 2 patients where symptom control is the main aim of therapy, and particularly where assistance is required with insulin injections from others, it may be appropriate to provide once-daily insulin injection with a long-acting insulin analogue. For most patients, however, pre-mixed insulin or insulin analogue is preferred. Many patients with type 2 diabetes also elect to go on a basal bolus regimen, which involves four or more injections a day because of the flexibility it offers. For most patients with type 2 diabetes, however, a twice or three times a day regimen of pre-mixed analogues is useful. Maintaining glycaemic control in a patient with type 2 diabetes represents more of a challenge as their needs will change along with disease progression. The doses are increased usually in increments of 2 or 4 units with each dose until glucose control is satisfactory, taking care to avoid hypoglycaemia. This is important to explain to the patient and also to alter insulin doses and the regime as requirements increase. Patients should also be warned about weight gain, particularly in those with type 2 diabetes and concomitant attention to control of obesity is valuable in mitigating this. There is more discussion on insulin management of type 2 patients in Chapter 6.

Administering insulin

In the past most patients used a syringe to draw up and administer insulin. The following modes of administration are now available:

1 Insulin administered with a syringe: The patient uses a syringe to draw the appropriate dose from a vial. These plastic insulin syringes are often still preferred by patients who have been using them for years but are less likely to be chosen by patients who start insulin today.

2 Insulin 'pens': These are quite sophisticated and reliable devices and deliver metered doses of insulin either from a cartridge or as a pre-loaded disposable pen that is discarded once the insulin has been fully dispensed. Mixtard 30 is available as a 'InnoLet' device, which may be convenient for patients with visual or manual dexterity problems.

3 Insulin pumps: There are now several types of insulin pumps available and the size has reduced so that they are quite unobtrusive. These pumps deliver insulin subcutaneously over 24 hours

Figure 8.1 Injection sites.

Figure 8.1 Injection sites.

and there are facilities for prandial boosts of insulin. Corrective dose requirements based on carbohydrate intake and the current blood glucose level (entered by the patient) can be calculated by the device and delivered. Insulin pump therapy should be managed by secondary care centres that provide readily accessible expertise to handle any problems. Pump failure may rapidly lead to insulin deficiency with risk of ketosis as the formulation used is rapid acting and has a short plasma half life. Their use is restricted on the NHS to those who cannot be managed otherwise on basal-bolus therapy. 4 Inhaled insulin: Inhaled insulin was recently unsuccessfully launched and has been since withdrawn from the market as it did not prove to be as popular as anticipated. Nevertheless newer varieties of inhaled insulins are due on the market. These are of value perhaps only in those patients with severe needle-phobia.

Insulin injection sites

Insulin injection sites that can be used are shown in Figure 8.1. It is most commonly injected in the front of the thigh or on the lower abdominal wall. Patients are advised to rotate sites to reduce the risk of unsightly bruises or fat hypertrophy. Injection sites should be inspected in case lipohypertrophy develops as this can cause instability in glycaemic control, due to variable rates of absorption of insulin.

Insulin injection technique

When the patient first starts insulin he or she is shown how to inject it using the device that has been chosen. The correct dose of insulin is drawn up using the pen and any air bubbles are expelled prior to injection. The length of the needle will also have been chosen for the given patient and the needle should be inserted briskly at 90° to the skin to its whole length. Pressing the plunger rapidly will deliver the dose and the device is then removed.

Problems with insulin injections

Apart from injection site bruises, insulin injections rarely cause problems. Occasionally, insulin allergy may appear and in these cases switching the type of insulin may help. In some cases investigation by skin testing and desensitisation may be needed. Lipohypertrophy at injection sites may occur and it is important to avoid injecting into these areas as absorption is unreliable. Patients who have commenced insulin therapy sometimes experience blurring of vision due to changes in the amount of water in the lens. This usually corrects itselfin a few weeks and the patients should be advised not to change their spectacle prescription during this time or to purchase new glasses. Oedema of the feet is also a transient phenomenon and some patients with mild neuropathy may experience a worsening of pain in the feet when starting insulin. This again will improve with time.

Summary

Insulin therapy should where possible be tailored to the needs and preferences of the individual, which differ widely across different patient groups. A need for flexibility is provided for by the rapid-acting insulin analogues that have proven extremely useful for intensive insulin management where life-style patterns and schedules change from day to day. Long-acting insulin analogues have significantly improved the problem of nocturnal hypogly-caemia associated with 'peaking' of the older intermediate-acting insulins. However, for many patients the older insulins are very satisfactory particularly where glycaemic control is not the main issue. For health services there are cost implications with the newer formulations. Optimisation of glycaemic control should, however, be a health service priority given the benefits both in terms of quality of life and avoidance of longer term complications.

Further reading

Bolli GB. Physiological insulin replacement in type 1 diabetes mellitus. Exp

Clin End°crin°l Diabetes 2001; 109 (Suppl 2):S317-32. Gallichan M, O'Brien S, Dromgoole P, Nute B, Preston F, Tipson M. Starting insulin treatment in adults with type 2 diabetes. Royal College of

Nurses, 2004. http://www.rcn.org.uk/_data/assets/pdf_file/0009/78606/

002254.pdf

Pickup J, Keen H. Continuous subcutaneous insulin infusion in type 1

diabetes. BMJ 2001;322:1262-3. Richter B, Neises G. 'Human' insulin versus animal insulin in people with diabetes mellitus. Cochrane Library, 2005. http://www.mrw.interscience.wiley. com/cochrane/clsysrev/articles/CD003816/frame.html.

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