Physiology

Human insulin is a polypeptide of 51 amino acids and is formed by the removal of a connecting or ‘C’ peptide (34 amino acids) from pro-insulin (see Figure 25.1). It has A and B chains, which are joined by two disulfide bridges. A third disulfide bridge connects two regions of the A chain.

Figure 25.1 Conversion of pro-insulin to insulin and C peptide. (. … . = disulfide bridge).

Glucose forms the most potent stimulus for insulin release. It enters the β-cells of the islets of Langerhans in the pancreas, resulting in an increase in adenosine triphosphate (ATP), which closes K⁺ channels. This causes depolarisation and Ca²⁺ influx through voltage-sensitive Ca²⁺ channels, which triggers insulin release. By way of negative feedback, the K⁺ channels are re-opened.

In health there is a continuous basal insulin release, which is supplemented by bursts when plasma glucose levels rise. Following release, it is carried in the portal circulation to the liver (its main target organ) where about one-half is extracted and broken down, as glucose is converted to glycogen.

Insulin binds to the α subunit of the insulin receptor, which consists of two α and two β subunits that span the cell membrane. Once bound, the whole complex is internalised. The mechanism by which this complex produces its effects is unclear but the tyrosine kinase activity of the β subunit appears important.

Insulin affects carbohydrate, fat and protein metabolism in an anabolic fashion. It promotes hepatic (and extrahepatic) uptake of glucose from the circulation and subsequently facilitates the actions of enzymes required to convert glucose into glycogen. Glycogenolysis is inhibited. The net result is that blood glucose levels fall. Fat deposition is also increased by the promotion of hepatic fatty acid synthesis and subsequent storage as triglycerides. Lipolysis is inhibited. The storage of amino acids as proteins is promoted and protein breakdown is inhibited. Insulin therapy in diabetes mellitus is given to reduce blood glucose levels to within the normal range thus preventing a wide variety of tissue damage throughout the body.

Preparations

Early insulins were extracted from porcine or beef pancreas, but modern preparations are almost entirely produced by recombinant DNA technology.

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   1. Human insulin

   
   
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   2. Insulin analogues

   
   
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   3. Animal insulin

Human insulins (also known as soluble insulins) are identical to endogenous human insulin, although produced by recombinant techniques. Human insulins may be modified to produce insulin analogues that have altered molecular structures resulting in different characteristics, such as onset of action and duration of effect. Animal insulins are no longer given to new patients but may still be in use by existing patients who are unable to make the change to a recombinant insulin.

Insulin cannot be administered by the gastrointestinal (GI) route because it is inactivated by gastric enzymes. It should be injected subcutaneously (or rarely intravenously) into an area with good subcutaneous fat stores. Absorption from subcutaneous injection can be highly variable based on blood flow, central or peripheral location of the injection site or any areas of lipodystrophy due to repeated use. If given intravenously, human soluble insulin has an almost immediate effect that lasts only for several minutes.

Insulin preparations can be categorised into groups based on their speed of onset and duration of effect profiles: short-acting insulins (including soluble insulins and rapid-acting insulin analogues), intermediate-acting insulins and long-acting insulins. There is considerable inter-individual variability in the above characteristics.

Short-Acting Insulins

These can be either human soluble insulin (e.g. Actrapid, Humulin S) or a rapid-acting insulin analogue (e.g. insulin aspart (Novorapid), insulin glulisine (Apidra) and insulin lispro (Humalog)).

Rapid-acting insulin analogues are injected subcutaneously and have an onset of action within 15 minutes and a duration of up to 5 hours. They are commonly used as part of a treatment regime involving pre-meal injections to replicate endogenous pancreatic insulin surges with meals and can be combined with a long-acting insulin to provide a background basal level of insulin (‘basal bolus’ regime). In addition to management of diabetes mellitus in the community, their rapid onset of action has led to them being recommended in the management of peri-operative hyperglycaemia.

Human insulins are used in a similar manner to insulin analogues. Despite the perhaps confusing trade name of one of this group (Actrapid) their onset after subcutaneous injection is slower (30 minutes) than rapid-acting insulin analogues. They are most commonly used as part of variable rate intravenous insulin infusions (VRIII) where they have a rapid onset (minutes) and much shorter duration of action compared to administration via the subcutaneous route.

Intermediate-Acting Insulins

These are designed to mimic the effect of endogenous basal insulin. Onset when given subcutaneously is 1–2 hours, peaking at 3–12 hours with a duration of 11–24 hours. A number of different preparations exist. They are manufactured with the addition of substances such as zinc or protamine which reduce solubility and prolong the absorption. In addition, they can be combined with rapid acting insulins and taken immediately before meals.

Long-Acting Insulins

These are manufactured in a similar way and last up to 36 hours. Onset is slow requiring several days use to achieve constant insulin levels (aiming to mimic the basal insulin production by the pancreas). At steady state there are minimal, if any, peaks or troughs in insulin levels. Often combined in a basal bolus regime where the patient takes a long-acting insulin once or twice per day to cover basal requirements, and then administers a rapid-acting insulin analogue immediately prior to meals.

Safe Use of Insulin

Insulin is a lifesaving medication, but it also has the potential to be extremely dangerous. Insulin errors are a frequent cause of harm and death. The standard insulin concentration in the UK is 100 units per ml. When drawing up insulin it is vital that a dedicated insulin syringe is used, and one that is calibrated to 100 units per ml. Using the scale on the correct syringe, the correct number of units can be administered. Some patients with type 2 diabetes mellitus are extremely resistant to exogenous insulin and can be taking several hundred units per day. To facilitate this, manufacturers produce highly concentrated insulins of 200 or 300 units per ml and the potential for error here is obvious.

Care must be taken when prescribing to write the number followed by the word ‘units’. Abbreviations such as ‘U’ or ‘IU’ have led to serious administration errors.

The following recommendations have been used to promote the safe use of insulin.

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  Prescribe using the brand name written out in full

  
  
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  Avoid abbreviations

  
  
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  Where insulin is prescribed the treatment of hypoglycaemia must also be prescribed

  
  
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  The use of protocols and guidelines is recommended

  
  
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  When prescribed and used intravenously, a supply of substrate must be continuously and simultaneously infused to prevent hypoglycaemia (as in a variable rate intravenous insulin infusion).