Using Insulin

The discovery of insulin in the early 1920s was undoubtedly one of the most important breakthroughs in medicine of this age. In 1922 Leonard Thompson, a young boy of fourteen, weighing just over four and a half stone, was the first to receive an injection of insulin. Hailed as a miracle cure at the time, it has since prevented the deaths of many people, myself included.




What's covered on this page


Natural Insulin in the Body

Insulin Treatment in Diabetes

Using Insulin Effectively

Insulin Pump Therapy






Natural Insulin in the Body


Insulin production

Insulin is a hormone made and secreted by the beta cells in the Islets of Langerhans, found within the pancreas. (The pancreas is a pear shaped gland that lies just behind the stomach.) Insulin is secreted throughout the day at a 'basal' or 'background' level. This allows the body's cells to use glucose from the blood. When the blood glucose level starts to rise, for example, after a meal, a large burst of insulin is produced which enables the body's cells to take up and store the glucose from the meal.

Insulin secretion is also affected by a number of other factors, including other hormones and nutrients. The nervous system also directly affects insulin secretion by beta cells.

contents

Insulin action

Insulin allows cells to take glucose from the bloodstream. If insulin is absent, or ineffective, then cells cannot access the blood glucose and its level rises; the end result is diabetes. (Not all cells require insulin to take up glucose - the brain, red blood cells, pancreas and kidney cells are notable exceptions.)

At the cellular level, insulin has many actions; amongst them it stimulates the following:

  • Utilisation of glucose for energy
  • Formation of glycogen in liver/muscle cells - this is a storage form of glucose
  • Conversion of glucose (which is surplus to requirements) to fat

contents

Glucagon

Insulin is a key player in the regulation of our body chemistry or 'metabolism'. Not so often mentioned is another hormone which acts as a partner to insulin - glucagon. You may have heard of it - it is sometimes used to treat severe episodes of hypoglycaemia.

Glucagon is produced in the alpha cells in the Islets of Langerhans, found within the pancreas. Its action contradicts that of insulin: for example, insulin stimulates the uptake of glucose by the liver; glucagon stimulates the release of glucose by the liver.

In the non-diabetic, insulin and glucagon work hand in hand to keep the blood glucose level within tight limits at all times.

contents

Insulin Treatment in Diabetes

Insulin is a natural protein and is broken down by digestive enzymes if taken by mouth; for this reason insulin needs to be injected.

Type 1 diabetes

People with Type 1 diabetes depend upon insulin injections for survival; for this reason they may be described as being insulin dependent.

Type 2 diabetes

The natural course of Type 2 diabetes follows a decline in beta cell function. If insulin production becomes inadequate, and therapy with tablets is unsuccessful, then insulin will be required.

Note: Type 2 diabetes does not progress to Type 1 diabetes. People with Type 2 diabetes may come to need insulin to keep blood glucose levels under control, but it is best to describe them as being insulin requiring, as opposed to insulin dependent, in order to distinguish them from Type 1 patients.

Prescription insulins

There are a number of different types of insulin available from a number of manufacturers. You need to know which insulin(s) you are using and when they act.

Source

Early insulin preparations were crude extractions from the pancreases of pigs or cows. These  preparations were purified, but they still contained a number of additional substances such as  proinsulin, insulin derivatives and other active peptides found in the pancreas. Improved purification  methods have reduced the content of these. Animal insulins are still available in the UK from CP Pharmaceuticals Ltd.

The insulin that humans produce differs very slightly in structure from that of pigs(porcine) and  cows (bovine). Porcine insulin differs by one amino acid molecule and can be modified to human insulin by enzyme treatment. Such 'human' insulin is called semisynthetic human insulin or enzymatically modified porcine insulin.

Human insulin produced by 'recombinant DNA technology' is referred to as biosynthetic human insulin. DNA, encoding the human insulin molecule, is inserted into bacteria or yeast and the insulin is 'manufactured' on a large scale.

The source of the insulin may be indicated on the label by a two- or three-letter code:

Abbreviation

Meaning

SP

single peak

MP or SC

 monocomponent or single component

Highly purified animal insulin.

emp

enzymatically modified porcine

Porcine insulin modified to produce 'human' insulin.

ge

genetic engineering

crb

chain recombinant bacterial

pyr

precursor yeast recombinant

prb

proinsulin recombinant bacterial

These denote different methods in recombinant DNA technology used to produce 'human' insulin.

RI

rarely immunogenic

 

Types of insulin

Short acting or 'soluble' insulins exist in solution as hexamers - clusters of six insulin molecules. After injection, these dissociate and then the insulin can be absorbed.

The new fast acting insulin analogues are derived from modifications of the natural human insulin molecule. A single change in molecular structure encourages the insulin to exist as a monomer, so that it is absorbed much more rapidly. Its biological function, in terms of lowering blood glucose, is unaltered by the subtle change in molecular structure.

Intermediate and long acting insulins are specially formulated to modify the duration of action. The insulin is complexed with zinc and/or protamine and is only released slowly from these complexes after it has been injected.

The new long acting insulin analogues are also derived from modifications of the natural insulin molecule.

GLARGINE (Lantus)

The structure of insulin glargine differs from that of native human insulin by 3 amino acids. It has a glycine in place of an asparagine at position A21 and 2 arginines added to the carboxyl terminal of the B chain at positions 831 and B32.25,27 These amino acid substitutions shift the isoelectric point of the molecule closer to neutral (from pH 5.4 to 7.0), making the molecule more soluble within the acidic environment of the vial hut insoluble at the neutral pH of the injection site. Ultimately, the formation of microprecipitates at the injection site slows absorption of insulin glargine into the circulation. The addition of small amounts of zinc (30 pg/mL) to the commercial insulin glargine formulation furhter stabilizes the molecule and helps delay absorption time. Furthermore, the substitution of glycine for asparagine at position A21 alters the association properties of this insulin, making its hexamer structure more stable. Because of these changes, absorption of insulin glargine is delayed, prolonging the duration of effect and providing a fairly constant basal insulin supply.


Insulins are broadly categorised by their action profiles*:

Insulin type

Onset*

 Peak*

Duration*

Examples

Fast acting insulin analogues

15 mins

30 - 60 mins

2 - 5 hrs

Insulin lispro

Insulin aspart

Humalog

NovoRapid

Short acting

30 mins

1 -3 hrs

6 - 8 hrs

Soluble

Actrapid

Velosulin

Humulin R

Hypurin Neutral

Intermediate acting

2 hrs

4 - 12 hrs

< 24 hrs

Isophane

NPH

Insulatard

Humulin N

Long acting insulin analogues 2 hrs no peak 12 -24 hrs

Insulin glargine

Insulin detimir

Lantus

Levemir

Long acting

2 - 4 hrs

6 - 20 hrs

< 36 hrs

Zinc suspension

Humulin L

Ultratard

Monotard

Pre-mixed insulins are mixtures of short and intermediate/long acting insulins, available in a number of pre-determined fixed proportions; Humulin Mixture 70/30, for example, is 30% soluble (short acting) and 70% isophane (intermediate acting) insulin.

* The times given are approximate guidelines only. Action profiles are affected by the insulin type, injection area, size of the dose, ambient temperature and exercise of muscle close to the injection site.

More information on insulins available in NZ

Diabetes New Zealand have introduced a useful guide to what's available here in New Zealand:

>> click here.

contents

Using Insulin Effectively

If it were just a case of 'Jab-and-Go' then I would not be writing these pages. Unfortunately, insulin therapy is far from the ideal solution. It may keep us alive, but it is often inconvenient, and frequently yields inconsistent or unpredictable results. However, it is the only option for many of us right now, so we must learn how to make the most of it.

Injecting insulin

Insulin is injected into the fat layer just beneath the skin. If injected into a muscle ('intramuscular) or a vein (intravenous) then the insulin is absorbed into the bloodstream too quickly and can cause sudden or severe hypoglycaemia.

(The use of insulin pumps is dealt with in a section below)

Injection sites

Suitable injection sites include the following:

  • Abdomen
  • Arm
  • Thigh
  • Buttock

It is important that the same area is not repeatedly used again and again - this can cause hypertrophy (sometimes called lipohypertrophy, but this is not the same as lipoatrophy (see below)). Hypertrophy refers to the accumulation of fat deposits in the area, leading to 'lumpy' skin. Often the area becomes numb and injections seem less painful - you may feel reluctant to change injection site. Insulin injected into such areas, however, is poorly or erratically absorbed and this often leads to fluctuating blood glucose levels.

A local immune reaction at the injection site can cause lipoatrophy (sometimes referred to as lipodystrophy). In contrast to hypertrophy, fatty tissue under the skin is diminished and dents appear at the injection site. This was more common with the early porcine and bovine insulin preparations.

Absorption of insulin

There is considerable day-to-day variation in the rate of absorption of insulin from any given site; this seems to be most apparent with intermediate or long acting insulins. Anything that affects local blood flow to the injection site will affect the insulin absorption.

In addition, you should also remember that for most insulins, the insulin molecules need to dissociate from their clusters before they will be absorbed, so anything that affects this dissociation rate will also affect the rate of absorption. It is hoped that absorption of the new fast acting insulin analogues will prove to be less erratic because this variable has effectively been removed.

The following are just a few factors which are known to influence the absorption of insulin:

  • Site (abdomen>arm>thigh>buttock)
  • Massage - massage of the injection area increases the rate of absorption
  • Exercise - exercising muscles in the area of the injection site increases the rate of absorption
  • Temperature - higher temperatures increase the rate of absorption (beware of sunbathing, heated spa pools, and hot baths!)
  • Insulin type - there is more variation in the absorption of the more longer acting insulins
  • Smoking - smoking reduces the rate of insulin absorption

With care, you can use your knowledge to your advantage. Firstly though, you must adopt some sort of routine, a baseline from which to work. Stick to particular injection sites at particular times of the day. Then, suppose your blood glucose is slightly high; you may choose to inject into your abdomen, rather than your usual arm. As with all deviations from routine, it is advisable that you monitor the effects closely with blood glucose testing.

Injection devices

There are a number of different tools available to help with injecting insulin. These include pens, jet injectors and pressure injectors.

There are now a wide variety of pen needles available. Which particular one is most suitable to you will depend on your skin thickness and your body fat/muscle ratio. It is always best to check with your Diabetes Team to ensure that you are using the most appropriate needle length.

Insulin delivery devices available in NZ

Diabetes New Zealand have introduced a useful guide to what's available here in New Zealand:

>> click here.

contents

Insulin requirement

The total daily amount of insulin required by an individual depends on a number of factors:

  • Body weight
  • Body composition (i.e. amount of muscle)
  • Activity level
  • Food intake
  • Emotional status
  • General health
  • Other medications

Usually about half of the daily requirement is needed as 'background' insulin. This is the insulin which is required just to keep the body ticking over. The other half is needed specifically to cope with food intake.

If you have Type 2 diabetes, then the amount of insulin you need will additionally depend on how much insulin (if any) you are producing and your level of insulin resistance.

If you have just been diagnosed with Type 1 diabetes, then your insulin requirements may remain low, or decrease during the initial 'honeymoon period'. This is until the last few remaining beta cells have been destroyed by the autoimmune process.

In some people, insulin requirements have also been noted to change with the seasons and with the phase of the menstrual cycle.

In rare cases, some patients develop high levels of antibodies to injected insulin -  these people have trouble maintaining near normal blood glucose levels, in spite of ever increasing large doses of insulin. Bovine insulin is most 'antigenic', porcine less so. With the advent of 'human' insulin it was hoped that antibody production against injected insulin would be negligible; sadly this has not been the case. Perhaps it is not surprising, at least in patients with Type 1 diabetes, given the autoimmune mechanisms which lie at the root of the disease.

Dawn phenomenon

Many people need more insulin during the early hours of the morning; this is to counteract what's commonly referred to as the 'dawn phenomenon'. As the body is preparing to launch itself into action when the alarm goes off a number of stimulations cause the liver to increase its release of glucose into the bloodstream. This causes a rise in blood glucose levels at this time, which, in some people is problematic. Some people have less of a problem with the early hours, but do find that they need more insulin to cope with breakfast than they would if they ate that same breakfast later on in the day.

contents

Insulin regimens

The way in which your insulin injections are distributed over the day will be influenced by:

  • Your own insulin production
  • Your day-time/work schedule
  • Your knowledge of your diabetes
  • Your ability or willingness to carry out - and act upon the results of - self monitoring of blood glucose

One injection daily

One daily injection of long acting insulin is now a rather outdated approach to insulin therapy. It is very inflexible, but still appears to be successful in a small minority of people. In the early days of insulin, this was the norm, however few people with Type 1 diabetes now have one injection a day, since it is restrictive and less than ideal. The major disadvantage is that it allows for minimal intervention on the part of the patient, so accomodating changes in daily circumstances is difficult. This type of therapy may be most suitable in the elderly. It may also be useful in those with Type 2 diabetes who require extra help to lower fasting blood glucose levels; such people may also be taking oral medication (tablets).

Pre-mixed insulin twice daily

This regimen is also rather inflexible, but it is particularly convenient for young children. Because the insulin is mixed in predetermined ratios, adjusting the dose will affect the dose of both the short and the long acting component. Fine tuning may need to be carried out with dietary modifications, rather than insulin adjustment.

Short acting and intermediate acting, twice daily

Usually injections are taken before breakfast and before the evening meal. This does give more flexibility, with four points for adjusting the insulin dose, but mealtimes (especially lunch) are  pre-determined by the timing of the injections. High blood glucose levels on waking may be problematic if the evening meal is relatively early, especially if coupled with the dawn phenomenon.

Short acting three times daily, and intermediate/long acting at bedtime

Often referred to as 'multiple daily injections' (MDI), this regimen gives maximum flexibility with mealtimes, with short or fast acting insulin being given before each meal. The importance of the intermediate or long acting insulin should not be overlooked, however. Most of the intermediate acting insulins have effectively 'run out' by mid afternoon. If the evening meal is delayed (and the early evening short acting insulin with it) then there may be little or no insulin and the blood glucose may rise. This problem is more pronounced in those people using the new fast acting insulin analogues. Twice daily injections of intermediate acting insulin may provide a far more satisfactory background insulin level throughout the day. The advent of long acting insulin analogues - which provide an even background coverage over the 24-hour period - has significantly improved the effectiveness of MDI regimens.

Important points to consider about using insulin

  • If you do not have sufficient insulin, then your blood glucose level may climb, even if you do not eat - this is because the liver releases glucose into the bloodstream
  • Do not stop taking your insulin for any reason
  • Know when your insulin(s) act - time of onset, peak activity period, duration of action
  • With respect to timing of injections, also consider the potential for overlap of injections, or insulin running out
  • Adopt a routine, it is easier to be flexible (and successful at it) if you have a baseline to work from
  • Do not make major adjustments to your insulin therapy without first consulting your Diabetes Team

contents

Insulin Pump Therapy

Continuous subcutaneous insulin infusion (CSII) therapy should ideally be a consideration for all people with Type 1 diabetes. Here in the UK the use of insulin pumps is really quite limited. Unfortunately it is not currently funded by the NHS and is often recommended by physicians only as a last resort for 'difficult' patients. As a result, most of us are left in the dark when it comes to the potential value of CSII.

What does CSII involve?

Today’s insulin pumps are about the size of a pager and can be worn unobtrusively on a belt, or tucked away in a pocket. The pump includes a programmable computer and holds a vial of insulin.

Connected to the pump is the infusion set, which consists of a long thin tube with a small flexible piece of tube at the end of it (the 'cannula'). The tubing is inserted, usually into the abdomen, with a special needle which is then removed, leaving the cannula behind. The infusion set is normally replaced every two or three days.

The pump is programmed to deliver a small trickle of insulin throughout the day - the background, or basal insulin. Some pumps offer the option of different background rates for different times of the day which is particularly advantageous - a very effective way of combating the dawn phenomenon, for example.

At mealtimes, or if you fancy a snack, an extra bolus of insulin is given. The size of the dose is then based on the size of the meal (it's carbohydrate content).

Insulin pumps are used only in conjunction with short acting insulins, such as Actrapid, or the new fast acting insulin analogues, such as Humalog.

contents

The Pros and Cons of CSII

In Favour

Insulin pumps can mimic the body's natural production of insulin much more closely than can a series of separate insulin injections. Using CSII to its best advantage, people with Type 1 diabetes can maintain near normal blood glucose levels which will hold them in good stead against the threat of long term complications.

As only short acting insulins are used in CSII, the problems incurred by erratic absorption particularly of the intermediate and long acting insulins can be avoided.

Pump therapy can provide the ideal solution for people who lead active lives, shift workers and those with variable work schedules.

One injection every two or three days surely has to be preferable to three or four every single day!

Against?

A somewhat valid concern about CSII is the increased risk of diabetic ketoacidosis (DKA) if insulin delivery is interrupted for some reason. If the pump fails, insulin levels in the blood will drop rapidly (the half life on insulin in the bloodstream is only four minutes) and DKA becomes an almost immediate danger. DKA is much less of a risk for the patients on conventional insulin therapy using a mixture of short and intermediate/long acting insulins - the insulin supply from its subcutaneous depot (i.e. the injection site) is sufficient to stave off a diabetic emergency for several hours. However, I would point out that modern pumps contain a backup battery and have a series of alarms to alert the user of any problems.

In order to avoid any problems such as the scenario outlined above, there is a need for regular self monitoring of blood glucose - ideally at least four or five times a day, every day. Some people may have reservations about such an intense blood testing schedule. However, I advocate this amount of testing for any individual with Type 1 diabetes, regardless of their insulin regimen, so personally I cannot justify this as an argument against using the pump.

Insulin pumps and consumables (infusion sets, insulin vials, batteries and so on) generally need to be funded by personal finance in New Zealand, although the Ministry of Health does provide some insulin pumps free of cost along with meeting the ongoing cost of the disposable tubing, but there are certain criteria that need to be met in order to qualify for a subsidy to meet the cost of using an insulin pump.

In conclusion

The suitable candidate for insulin pump therapy then, would be someone

  • able to meet the initial cost of the pump (at least $6000) plus ongoing consumables (from $100 - $300 per month) (plus cash reserve for maintenance?)
  • willing to take responsibility for their diabetes
  • willing and able to perform regular self monitoring of blood glucose
  • with sufficient maturity and intelligence to be able to adjust insulin dose and troubleshoot the pump and accompanying equipment

Insulin Pumps and Pump Consumables available in NZ

Diabetes New Zealand have introduced a useful guide to what's available here in New Zealand:

>> click here.


contents