Diabetes and its management

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Insulin in the Therapeutic Management of Diabetes

Abstract

Diabetes mellitus is a condition that affects individuals worldwide and can largely be categorised into two forms, type 1 and type 2 diabetes. Essentially, this illness arises due to an excess of glucose in the body, either due to an inability of the pancreas to produce sufficient insulin, or because insulin-producing cells are unable to respond sufficiently to the insulin that is produced.

Insulin, discovered in 1921, is a peptide hormone consisting of 51 amino acids and is produced by B-cells in the islets of Langerhans in the pancreas as a response to elevated levels of glucose. Initially extracted from animal subjects, further research led to the production of human insulin through genetic engineering techniques. Insulin works to control blood sugar levels by facilitating the absorption of glucose into muscle and adipose tissue. Shortage of insulin prevents these cells from absorbing sufficient amounts of glucose, which then accumulates in the blood stream, leading to hyperglycaemic episodes and associated complications.

The primary aim of insulin therapy is to control blood sugar levels in patients. This can be achieved through methods such as oral and intranasal insulin, but the most prevalent treatment in use is insulin injections. Mechanisms for delivery of insulin injections have developed considerably over the years, and insulin pens have now replaced preceding needle and syringe techniques. Ongoing research has led to the development of the insulin pump, which further simplifies the administration of insulin and it is likely that more novel and advanced methods will to replace this in the future in order to maximise the effectiveness of diabetic treatment through insulin therapy.

Introduction

Diabetes mellitus is a universal disease and has had a large impact on the global population. It is a risk factor for microvascular complications including retinopathy, nephropathy and neuropathy as well as for other macrovascular diseases such as coronary heart disease and stroke.1 Diabetes can occur at any age and has been divided into two main categories, these being Type 1 and Type 2 diabetes mellitus.2

Type 1 diabetes mellitus, previously called juvenile-onset diabetes, is diagnosed in children and young adults, typically before the age of 35. In type 1 diabetes, the destruction of B-cells in the pancreas due to the presence of autoantibodies3 as a result of an autoimmune disorder4 leads to a complete loss of insulin production. As a result, insulin therapy must be commenced immediately after diagnosis. If this fails to occur, patients retain glucose in their blood stream, which leads to symptoms of hyperglycaemia.

Type 2 diabetes on the other hand is sometimes called adult-onset diabetes, as this typically occurs after the age of 40. Here, the ability to produce insulin may diminish rather than cease completely, and the body instead exhibits resistance to insulin that is produced. Type 2 diabetes can generally be improved through use of oral hypoglycaemic agents (OHAs) such as biguanides and sulphonylureases, which act by increasing the body's release of or sensitivity to insulin.5 However, in around 10% of type 2 cases, the progressive advancement of the illness leads to a reduction in insulin secretion by B-cells, which necessitates the use of insulin therapy as a course of treatment as oral hypoglycaemic agents fail to prove sufficient control of blood sugar levels.6, 7 This initially begins with basal insulin administration, with prandial insulin being added if glycaemic control cannot be maintained.8, 9

Diagnosis

If diabetic symptoms such as polydipsia, polyuria and weight loss are observed, it is essential to run further tests in order to confirm a diagnosis of diabetes. These tests determine levels of glycosylated haemoglobin (Hb1Ac) and plasma glucose in the patient.10 Individuals with levels between 6.1-7.0mmol/L have impaired fasting glucose, while those with levels between 7.8-11.1mmol/L exhibit impaired glucose tolerance. 'Both impaired fasting glycaemia and impaired glucose tolerance represent a risk of 25-50% of developing diabetes over the next 10 years.'11 A fasting plasma glucose level >7.0mmol/L or a random glucose level >11.1mmol/L establishes a diagnosis of diabetes.

Aims of Treatment

Once diabetes has been diagnosed, a care plan should be constructed which suits the individual needs of the patient. Patients should receive sufficient information regarding the illness as well as guidance on how best to manage their treatment to control their diabetes. Those with type 1 diabetes should be taught how to administer insulin, as should type 2 diabetics, if previous glycaemic control using oral hypoglycaemic agents was seen to be unsuccessful. Additionally, patients should be informed on how best to compliment their drug therapy with weight control through maintaining a healthy diet and taking exercise, in order to minimise symptoms associated with diabetes and to reduce the risk of any complications.11

Insulin

Insulin is a polypeptide hormone, produced by B-cells in the islets of Langerhans of the pancreas. B-cells make up 65-80% of cells in the islets of Langerhans, which in turn make up 1-2% of cells in the pancreas.12, 13 Insulin has numerous metabolic effects within the body and is often referred to as an anabolic hormone.14 It facilitates the diffusion of glucose into the liver, where is inhibits gluconeogenesis, as well as muscle and adipose tissues, where it increases glycogen synthesis. This occurs through an increased recruitment of glucose (GLUT4) transporters in the cell membrane of these cells by up-regulation.15 Within adipose tissue, insulin affects lipid metabolism, resulting in an overall reduction in the release of fatty acids by simultaneously decreasing triacylglycerol degradation and by increasing triacylglycerol synthesis. Additionally, insulin influences protein synthesis, by potentiating the entry of amino acids into muscle cells and hence, protein synthesis.13

Insulin replacement therapy is used in instances where individuals produce insufficient endogenous insulin1 and is an essential progression towards achieving and maintaining normal blood glucose levels.16 While the long-term aims of insulin replacement therapy primarily involve maintaining blood sugar levels within a normal, healthy range, the short-term benefit of this method of treatment includes the alleviation of a range of symptoms associated with diabetes mellitus, from polyuria and polydipsia to sweating, nausea and confusion.17 Despite various currently available insulin treatments, there are constant efforts by the research fraternity to further improve the effectiveness and ease of insulin delivery to patients. In addition to insulin therapy, patients are educated regarding diabetes and encouraged to exercise and maintain a healthy diet. Insulin can be taken in order to mimic the body's normal levels of insulin between meals and during the night. This is referred to as basal insulin. Prandial insulin is taken around meal times and provides a further increase in insulin levels in situations when basal insulin is insufficient for lowering glucose levels.18

Structure and Anatomy of Insulin

The insulin molecule, with a molecular weight of 573419 and comprising 51 amino acids, is relatively small and consists of two polypeptide chains, linked by disulphide bonds.20 The amino acid sequence of its two chains, A and B, identified by Sanger et al through use of the technique of partial hydrolysis, is shown below.

Fraction A consists of 21 amino acids, while Fraction B consists of 30 amino acids. The two disulphide bonds linking the chains occur between the amino acid cysteine1 residues A7 to B7 and between A20 to B19. The insulin molecule also has a third disulphide bond. This however is an interchain bond, linking residues 6 and 11 in chain A, as shown.21

The insulin molecule forms crystalline structures of varying sizes based on certain conditions. At concentrations below 10-7mol, insulin exists as an active monomer, while at higher concentrations and in solution, insulin dimerises.22 Zinc has an essential role in the storage of insulin.23 In the presence of zinc, typically in blood, three insulin dimmers aggregate to form an inactive three dimensional hexamer structure,21 which is unable to bind to insulin receptors. As a result, the insulin molecules reach an equilibrium between the active monomers and inactive hexamers. This balance can be altered based on the body's requirements. The three dimensional structure of insulin is formed by folding of its chains, where typically, residues 1-8 and 22-30 on the B chain enfold the A chain, bringing residues A2 and A5 into contact with A19.21 C-peptide, a by-product of the cleavage of proinsulin, is crucial in ensuring accurate folding of the insulin molecule.13

Synthesis of Insulin within the Body

Synthesis of proteins typically occurs within ribosomes and their surrounding tissues, together known as the microsome. With regards to insulin, synthesis occurs in the microsome of B-cells in the islets of Langerhans in the pancreas.15

Insulin is derived from two protein precursors, preproinsulin and proinsulin, which are sequentially cleaved to produce insulin. Preproinsulin is a relatively inactive peptide product of transcription of the insulin gene, and is composed of 110 amino acids.24 The removal of the first 24 amino acids, the signal peptide, of the molecule produces proinsulin.

In the Golgi apparatus of B-cells, proinsulin is exposed to a trypsin-like protease, which cleaves the molecule, and also to the enzyme carboxypeptidase B, which removes the COOH terminal base residue, giving rise to biologically active insulin and C-peptide as a by-product.25 The signal peptide cleaved from preproinsulin and the C-peptide by-product are enveloped in secretory granules, which are then recycled in the cytosol.

Insulin Secretion

Insulin is stored in secretory granules in the cytosol along with zinc, which migrate to the cell surface15 and are released from the cell and secreted into the blood stream by exocytosis in the presence of an appropriate stimulus.13 The rate of secretion is influenced by nutrients and hormones, but is directly controlled by blood glucose levels.26 Insulin is secreted by the pancreas in response to a rise in blood glucose levels above 5mmol/l,15 detected by B-cells, occurring when carbohydrates and sugars are absorbed in the intestines post-prandially and enter the blood. An increase in glucose levels induces the membrane depolarisation of B-cells, which causes calcium to enter the cells and this increase in intracellular calcium stimulates insulin-containing secretory granules to be exocytosed from the cells. Although there is some direct secretion of proinsulin from B-cells, the majority of insulin secretion occurs via the calcium-dependent exocytosis pathway. Insulin is also released in response to the digestion of proteins, as a rise in amino acids and plasma arginine is a stimulus for insulin secretion. The gastrointestinal hormone secretin, released after the ingestion of food, also stimulates insulin secretion, by anticipating a rise in blood sugar levels.13 Insulin granules travel in the blood stream, and upon binding to appropriate insulin receptors, trigger a sequence of responses which ultimately lead to the absorption of glucose from the blood stream into the liver and then into muscle and adipose tissue. The uptake of insulin by the liver after a meal is relatively low, allowing for more insulin to reach peripheral cells in the body.15

Insulin Action

Insulin molecules bind to specific insulin receptors, which are a type of tyrosine kinase receptors found in liver, muscle and adipose cells. The insulin receptor has two a-subunits and two larger B-subunits, which are linked to one another by disulphide bonds, forming a (aB)2 complex. This complex has the ability to dissociate into 'two symmetrical (aB) halves', after which, an insulin molecule can bind to each component.11, 27 Binding of insulin to the a-subunit of the (aB) complex causes autophosphorylation of the tyrosine residue on the B-subunit.28 This triggers a cascade response which in turn initiates various biological responses within the body, the most immediate of which 'is an increase in glucose transport into adipocytes and skeletal muscle cells, which occurs within seconds of insulin binding to its membrane receptor.'13

The phosphorlyation of the insulin receptor substrate leads to the formation of protein kinase B, which when activated, enters the cytoplasm to inactivate glycogen synthase kinase 3 (GSK3). The enzyme glycogen synthase is then phosphorylated by GSK3, which inhibits glycogen synthesis. Consequently, this promotes cells and tissues to take up glucose and store it as glycogen.29, 30

History of Insulin

Insulin, discovered in 1921 by Frederick Banting in Toronto, Canada prompted a dramatic progression in the treatment of diabetes. Banting began his research in the summer of 1921. He ligated the pancreatic ducts of dogs and checked for the onset of diabetes through testing for the presence of glucose in blood and urine. Following this, pancreatectomies were conducted these dogs in order to completely remove the pancreas and then isolate and extract secretions made by the organ. Banting intended to treat dogs that had been previously made diabetic during the course of his research by injecting them with these internal secretions.31

Progress was very gradual and after several failed attempts, which resulted in the death of numerous dogs, Banting and fellow researcher Best identified a secretion from the pancreas that decreased the blood sugar of dogs having a hyperglycaemic episode and named it 'Isletin'. J.P. Collip, a new recruit to the research team, claimed 'we have obtained from the pancreas of animals a mysterious something which when injected into totally diabetic dogs completely removes all the cardinal symptoms of the disease...If the substance works on the human, it will be a great boon to Medicine.'31

Experimentation was fine tuned, this time being tested on other animals, including cats and rabbits until 11th January 1922, when it 'insulin was first used in the treatment of diabetes'32 on a human subject.

14 year old patient Leonard Thompson had suffered from diabetes for three years and the disease had severely debilitated him. 'The boy was reduced to skin and bones...he was pale, his hair falling out, abdomen distended, breath smelling of acetone.'31 Banting and Best filtered some of the pancreatic extract they had previously collected and then injected this into Thompson.

Over the course of a single day, the patient's blood sugar fell from 0.440 to 0.320. The presence of ketones in Thompson's urine was still high, but the levels of glucose in his urine dropped from 91.5g in 3,625cc of urine to 84g in 4,060cc, as seen below. While the patient showed some improvement following the injection, the results for human testing were still preliminary and so, lacked adequacy.31

As testing of the extract on additional human patients progressed, there was mounting pressure for insulin to be produced in larger volumes and at a higher potency for mass usage. Following publications of the amino acid sequence of insulin, news of the discovery circulated across North America and Europe. Clinicians began producing their own insulin by altering the initial extract and insulin was established as a mainstream therapy for diabetes.

Three main breakthroughs were made, one of which involved 'the modification of insulin to alter its time-action characteristics'17 such that the time lapse between administering the dosage and its visible effects were decreased. Furthermore, in 1926, Abel et al began the process of purification of insulin in 1926. The purity of insulin has improved substantially over the years, with highly purified samples of insulin in concentrations of 100 units per ml in currently in use today.33

Production of Human Insulin

Mirsky et al began the preparation of human insulin in 1963, when small quantities of insulin derived from the human pancreases of cadavers at autopsy was isolated and then crystallised 'by filtration through dextran gels' filtration columns.34 The high cost as well as the relatively low yield of viable insulin obtained through this process made it unsuitable for widespread clinical use. Since then, numerous methods have been employed in the synthesis of the hormone. These have involved the modification of porcine insulin into human insulin by means of enzymes35 and also, the production of insulin either through its precursor proinsulin, or through chemical combination of it's A and B chains, within bacteria, through use of recombinant DNA technology.36

The bacteria typically used for this is Escherichia coli and two techniques have been utilised in the production of insulin from E. coli. The first approach involves synthesising the DNA sequences of the A and B chains of insulin chemically. These two constructed genes are then placed into plasmids of E. coli and then cloned. The process of fermentation followed by oxidative sulphitolysis of its two insulin chains forms stable S-sulphonated salts, which are protected against proteolysis by enzymes within the body. These, when combined with additional unchanged A-chains, gives human insulin with a purity in excess of 97%.17

The second method in place for the production of insulin from Escherichia coli involves the production of a single gene, the tryptophan synthetase proinsulin gene, which has the ability to code for the entire human proinsulin molecule. Tryptophan synthetase proinsulin is fermented and then cleaved by cyanogen bromide, after which it undergoes oxidative sulphitolysis, to give proinsulin hexa S-sulphonate. In the presence of a reagent, the molecule folds, forming disulphide bonds, and producing a 45% yield of proinsulin. Proinsulin is then purified and through use of enzymes trypsin and carboxypeptidase B, is cleaved to give human insulin and the by-product C-peptide.25

Typically, insulin is injected through use of a syringe and needle, or more recently, through use of an insulin pen. Insulin pens are becoming increasingly popular due to their ease and accuracy. A dose can be administered by 'dialling' the number of units onto the insulin pen, inserting the needle into the skin and pushing a button to activate the mechanism for the release of insulin.

While the only course of treatment for Type 1 diabetics is insulin, patients are often reluctant to administer multiple daily injections, which can lead to poor compliance. In the case of Type 2 diabetics, the transition from oral hypoglycaemic agents to parenteral administration can come as a shock and pose some difficulties. Due to this, alternative methods of insulin delivery have been proposed and developed, as seen below.37

Oral Insulin

Since its discovery, numerous attempts have been made to identify the ideal route of administration of insulin as a treatment for diabetes, including nasal, sublingual and rectal administration. Oral administration is the least demanding method of insulin intake for patients. Unprotected insulin is however unable to enter the portal circulation orally, as the presence of enzymes in the digestive system interfere with the molecule and additionally, the gastrointestinal mucosa has a low permeability to insulin, resulting in a low rate of absorption from this surface. As a result, large quantities of insulin need to be administered for any significant observable decrease in blood sugar levels to be seen.

Lasch and Schonbrunner considered combining insulin with 'dyes in a lacquer covered tablet'38 in order to protect it from enzymatic degradation. The tablet was combined with saponin, an absorption-promoting agent. Acidic dyes 'congo red' and 'trypan red' protected insulin against pepsin, while basic dies 'malachite green' and 'rhodamine' protected it against the enzyme trypsin. The administration of these insulin tablets on an empty stomach had the maximum effect, and led to a decrease in both the blood and urinary glucose levels of patients.

These dyes never reached wider circulation in the administration of oral insulin for humans due to their side effects - studies on dogs revealed that the dyes stained skin, toenails and the sclera of the eyes red, and these effects lasted for at least a month.38

Bangham et al introduced the concept of liposomes, small phospholipid vesicles, which could be filled with insulin and used to deliver the hormone orally.39 Experimentation in rats later showed that these liposomes, filled with 5-12 units of insulin, had the potential of reducing blood glucose levels by 30 to 60% compared to the same amount of free insulin given orally, which had no significant effect on blood-glucose levels.40 Stability of the liposome was enhanced by increasing the positive charge of its membrane, thus increasing its affinity to insulin. Furthermore, liposomes had to be manufactured in order to withstand low pH as well as the activity of catabolic enzymes found within the gastrointestinal tract, in order to prevent the degradation of insulin carried within the liposomes. While Hashimoto and Kawada produced such liposomes in 1979, these vesicles were degraded in the presence of bile salts, indicating that they'd be unstable in the duodenum and jejunum of humans. Although this might indicate that liposomes were unsuitable for usage, they were still found to reduce blood glucose levels and although the mechanism of action is unclear, it is believed that liposomes are endocytosed by cells in the small intestine, while phospholipids in the cell membrane form complexes with insulin, thus preventing its degradation. Despite its benefits, oral insulin is rarely prescribed for clinical use, particularly due a lack of consistency in the correlation between dosage and response.

Intranasal Insulin

Drugs are increasingly available for administration via the nasal route. Studies on animals and then diabetic human subjects enabled the use of intranasal insulin in the 1980s. Early attempts to administer insulin alone, through the nasal passage, were unsuccessful due to the density of the nasal mucosa. It was concluded that surfactants were needed to augment the absorption of insulin in the nasal mucosa, as they demonstrated the ability to augment the absorption of insulin in the nasal mucosa by increasing its solubility, and by increasing membrane permeability to insulin.37 Bile salts in the digestive tract behave as natural surfactants, which facilitates the absorption of insulin across the gastrointestinal mucosa.

Studies have shown that the absorption of insulin via the nasal route is fairly rapid, and peaks between 10 and 15 minutes after administration of a nasal spray containing insulin. Aerosol sprays in the form of lyophilised insulin are better absorbed by the body than standard nasal spray and nasal drops. The freeze drying of insulin in lyophilisation is advantageous as it is more stable than insulin in solution and has the ability to concentrate insulin on the mucous membrane, reducing the potential loss of insulin to diffusion, as is possible in spray or liquid form.41 While the administration of intranasal insulin does induce a fall in blood glucose levels, the reduction in blood glucose is less than and lasts for a much shorter duration than, equivalent doses of insulin administered by subcutaneous injection. Consequently, intranasal insulin treatment needs to be used in conjunction with alternative sources of insulin, administered at the basal level.37

Suppository Insulin

While insulin can be taken as a suppository tablet, absorption through the rectum is poor and so, the dosage required is 10 times more than that needed by any alternative method of administering insulin to see a significant decrease in blood glucose.7

Inhaled Insulin

Insulin has been successfully administered as an aerosol spray, and due to its relatively fast absorption through the thin mucosa, is a fairly reliable method of administration. In children, insulin is inhaled with the aid of a nebuliser. The main disadvantage of this method of delivery is that it can take from 15 to 20 minutes simply to inhale one full dose of insulin, which negates the rapid response it produces once it has been absorbed through the mucosa.7

Insulin Analogues

One of the main drawbacks of insulin therapy is the delay between the point of injection and the time taken for insulin levels to peak within the body. This delay is due to the fact that insulin must dissociate from its hexamer form first into dimers, and then into active monomers, which are then able to interact with insulin receptors. The rate of dissociation is dependent on the concentration of insulin injected, as well as whether it's been combined with any agents that might promote hexamer formation in subcutaneous tissue.42

In 1987, Brange et al determined that by modifying the side chains of certain amino acids associated with dimer and hexamer formation within the insulin molecule through use of DNA technology, insulin analogues could be produced.43

It was thought that these analogues would have the ability to mimic a normal body's endogenous insulin secretions at both basal levels and after meals to a much closer degree than other synthetically produced human insulin available.17 The amino acid sequences of these synthetically produced insulins and their formation in the presence of zinc was found to influence the onset and duration of action of the insulin hormone.1 It was determined that monomeric insulin analogues were absorbed three times faster than human insulin when injected into subcutaneous tissue, which leads to a faster onset of action.

Treatment with Insulin Analogues

Insulin in basal or bolus form is referred to as a monophasic preparation. Basal doses of insulin are delivered through intermediate-acting natural insulin suspensions, Isophane (NHP) and Lente; the duration of action of Lente is shorter than that of Isophane. NPH insulin is typically marketed through brands Insulatard and Humulin NPH, among others, while the trade names of Lente are Humutard and Humulin Lente.7 Insulin analogues Glargine and Detemir are long-acting, the effects of which last for at least 24 hours. They are typically injected twice daily, to provide basal insulin between meals and through the night. Long-acting insulin is often used in conjunction with Humalog, a direct-acting insulin analogue.

Bolus insulins are taken before an expected rise in glucose levels, typically around meal times. Short-acting insulin, often sold under the brands Actrapid, Novolin R and Humulin S, have a slower onset but longer duration of action than direct or rapid-acting analogues, Humalog, Lispro and Aspart. Humalog dissolves and dissociates from the injected hexamer form into monomer form faster than other short-acting insulins and so, has a much faster time of action. Short-acting insulin is ideal for intravenous use during hyperglycaemic episodes due to its fast action and short half life.7 Short-acting insulins should be taken 30-45 minutes before meals so that maximum glucose absorption can occur at the time when insulin peaks. Rapid-acting insulin on the other hand can be injected 'immediately before, during or just after the meal', which allows more flexibility for the patient.1

Biphasic insulins are a combination of intermediate or long-acting basal and rapid or short-acting bolus insulin, available in a pre-mixed formulation. With this treatment, insulin injections are only required twice a day, before breakfast and dinner. The time course of long-acting insulin provides the patient with basal levels of insulin, which is sufficient to cover the mid-day meal, while the bolus insulin in the preparation covers breakfast and evening meals.1 Users of long-acting insulin analogues have typically reported lower rates of hypoglycaemia than users of pre-mixed analogues.44

Storage of Insulin

Insulin should ideally be stored in cold conditions and away from direct sunlight, in order to maintain its stability.45 Insulin is available in vials, cartridges for pens or inbuilt in disposable pre-filled pens. Insulin pens are the most commonly used delivery mechanism these days and the usage of vials is minimal. If refrigerated, insulin in unopened vials should be used by the expiry date and once opened, should be used within one to two months. At room temperature, insulin is only functional for a month, after which it begins to lose potency. Insulin cartridges in pens as well as disposable pre-filled pens should be used by the expiry date if refrigerated. In this same form, at room temperature, insulin is effective from between a week to a month, depending on the insulin preparation it contains.1

Insulin Pump Therapy

Recent advances in insulin administration have seen the increased usage of insulin pump therapy, or continuous subcutaneous insulin infusion (CSII) therapy, as opposed to insulin injections. CSII therapy involves placing a needle below the skin, to which an insulin pump is then attached. This pump is worn throughout the day and releases basal levels of rapid-acting46 insulin at a continuous rate. The basal rate of insulin delivery can be modified to suit each individual. Furthermore, patients may administer additional bolus doses of insulin via the pump if their blood glucose levels are high, typically after a meal.47 Insulin pump therapy is typically used by individuals who experience difficulties in stabilising their blood glucose through conventional insulin injections. Although CSII therapy is relatively expensive, the long-term reduction in diabetic complications by this method of treatment outweighs the costs.48

One of the benefits of insulin pump therapy is that it eliminates the need to inject insulin every day. Although the cannula needs to be replaced every two to three days, users have still found this more satisfactory than using insulin pens on a regular basis. Furthermore, as the pump is constantly secreting insulin at a basal rate, it allows for better glycaemic control. This has the added benefit of providing users with the luxury of 'sleeping in' on certain days, without having to worry about waking up to administer an insulin injection. These pumps have additional beneficial features such as 'reminders to check glucose levels' and alarms for when insulin levels in the reservoir are low.49

Although it may appear that delivering constant doses of insulin may lead to hypoglycaemic episodes, particularly at night, the versatility of the pump device allows the dosage of insulin to be altered and reduced when required, thus leading to an overall decrease in the number of patients that experience hypoglycaemia. Similarly, the pump allows users more flexibility in terms of their diet as they can adjust the insulin dosage based on the sugar content of the foods they intend to eat. As the pumps contain a combination of short-acting insulin and rapid-acting analogues, even instant changes to doses will be able to swiftly alter blood sugar levels.

Disadvantages of CSII therapy are that the pump has to be worn continuously. It may be removed for short periods of time, for activities such as exercise or taking a shower, but this has to be limited to 30 minutes. This may interfere with the daily routine of certain individuals, who may find it a hindrance, or as a negative alteration to their body image. While the pump has the ability to administer basal levels of insulin, it requires input by the user to release bolus insulin. Certain individuals may find constantly calculating and adjusting their insulin dosage tedious and so may prefer to continue with the more regimented injection therapy system.47 While it allows more flexibility than other methods of insulin administration, insulin pump therapy still requires patient input and the success of this treatment is thus dependent on patient motivation.50

Advantages and Disadvantages of Subcutaneous Insulin Treatment

Poor compliance is one of the main reasons for failures in insulin treatment. Compliance among patients may be low due to a fear of needles and the pain associated with them as well as the need to maintain a strict regimen with regards to frequency and timings of the insulin injection.

Although glass syringes are now not as commonly used by diabetic patients, in cases where they are, disadvantages associated with usage include the need to sterilise the syringe and needle prior to use as well as the risks associated with the breakage of the glass syringe.

The development of insulin pens has significantly reduced issues with compliance in diabetic patients. The pen allows the required dose of insulin to be dialled on the device and then ejected via a simple 'push-button' delivery mechanism, increasing the accuracy of volumes administered in comparison that of the use of syringes and insulin vials. They contain either a replaceable insulin cartridge or an integrated, disposable cartridge, which is already fixed within the pen device. Furthermore, the needles used with these pens are 8 to 12mm in length and are 'ultrafine', reducing the pain on injection. The disposable nature of these needles allows them to be replaced as necessary, also reducing the pain typically felt when using blunt needles.17 The discrete, portable nature of the device has also aided in increasing compliance.

Occasionally, individuals can enter a hypoglycaemic state, and this is more common among Type 1 diabetes than in Type 2 individuals. This typically happens at night, after a dose of insulin, as blood sugar levels fall while the patient is asleep. This can be avoided by eating a small snack before sleeping. Furthermore, individuals may see a weight gain of between 2-4kgs. This weight gain is accounted for by the biological effects of insulin and has been seen with various different insulin analogues,8 but it is thought that newer forms of premixed insulin are likely to cause more weight gain than long-acting insulin.51 More glucose is absorbed by the body and consequently, less glucose is lost in the urine. Furthermore, the anabolic effects of insulin may lead to an increase in appetite, which can again lead to a weight gain. In Type 2 patients, individuals may combine their insulin therapy with the oral hypoglycaemic agent Metformin, which is thought to minimise this gain in weight,1 as it puts patients at an increased risk for cardiovascular diseases.52

The 'aim of injecting insulin is to deposit the hormone in subcutaneous fat'53 and the site of insulin injection can affect the rate at which it's absorbed. While initially the thigh was recommended for the site of injection, research has since indicated that absorption of short-acting insulin is fastest from the abdomen and then the arm, while it is slowest from the gluteal region.54 Within the abdomen, it was determined that absorption was faster when insulin was injected into the upper abdomen as opposed to the lower abdomen. It has been suggested that patients should inject themselves with insulin in the same general site, while rotating the exact location of the needle within this area in order to minimise the risk of developing subcutaneous lumps due to lipohypertrophy, which slows the rate of insulin absorption. Massaging the site of injection can increase the rate of insulin absorption, as can injecting insulin deep into muscle. However, this can be painful for the patient and so should be avoided.

Another adverse effect of subcutaneous insulin treatment is the risk of lipoatrophy. Dents produced at the injection side can lead to a loss of fat tissue from the region. Occasionally, individuals may have an allergic response to insulin. While this could be a generalised response, or localised to the site of injection, incidences of these allergic reactions are very rare.1

Future Developments

Insulin pump therapy is still a relatively new concept and has fewer users than other methods of subcutaneous insulin delivery. It is likely that in the future, there will be a push towards producing smaller, more discrete pumps with the same essential features as the larger models, in order to increase the popularity of the insulin pump. Disposable devices may also be utilised. These may have a reservoir of insulin that can be replaced, and which attaches to a small battery device capable of controlling the flow of insulin.

Currently available in the USA is 'a wireless insulin pump that adheres to the skin as a patch, with an integral cannula, infusion set, insulin reservoir and battery'.47 It is accompanied by a wireless device that contains a blood glucose meter and has the ability to program the pump as well as release doses of insulin from the patch. Although this pump is currently unavailable in the UK, it is likely to become more accessible in the coming years. One of the main advantages of this device is that due to its wireless nature, it does not require clips and tubing and can be placed directly on the skin as opposed to being attached to clothing, which can hamper physical activity.

Another development may be the use of implantable insulin pumps. Theoretically, these seem favourable but could practically pose numerous difficulties. At present, implantable devices need to be inserted under the skin under general anaesthetic. These pumps have a reservoir of U400 strength insulin and last for a duration of between one and two months, after which another operation is required in order to refill the reservoir in the pump. Patients are provided with a remote control, which allow them to control their insulin dosage. While the main advantage of this method is that by delivering insulin directly into the abdomen, it reduces the risk of insulin resistance and also enables the use of lower doses, this process has disadvantages, including the expense of the devices as well as the need for repetitive surgery, which can carry the risk of infection.

Research is presently being conducted into the effectiveness of implantable closed loop systems. The aim of this treatment is to develop an insulin pump capable of automatically delivering insulin at variable rates in response to changes in blood glucose levels, without the need for any input by the patient. It is essential that this device is highly reliable and accurate in predicting the insulin requirements of the body, and should be longer-lasting than the currently available implantable pumps. While ongoing investigations have shown some promising results, a lot more research is needed before closed loop systems are available for general use.47

Concluding Remarks

Prior to the discovery of insulin, diabetics had to rely on a combination of strict diet control, exercise and herbal remedies to control their blood sugar levels. The limited success rates of these methods resulted in patients suffering from numerous complications associated with diabetes, as well as shortened life expectancy.55

The discovery of insulin in 1922 opened new doors into the treatment of diabetes and provided novel approaches to the management of this illness. The successes from the initial use of animal-derived insulin led to research and development into human insulin primarily through the genetic engineering of the insulin gene in Escherichia coli bacteria. Subsequent developments led to the production of insulin analogues, which demonstrated faster time-action properties, helping with better glycaemic control among diabetic patients.

The only method of treatment currently available for type 1 diabetics is insulin therapy. While syringes with needles were previously used to inject a dosage, the disadvantages of this technique initiated the development of insulin pens, which have significantly improved the efficacy and accuracy of insulin delivery and has led to an increase in patient compliance to their insulin treatment regime. Currently, continuous subcutaneous insulin infusion therapy would appear to be the most successful method of insulin administration for patients, particularly for type 1 diabetics, as it has shown significant decreases in blood glucose levels, particularly when used with rapid-acting insulin analogues.56

In type 2 diabetes, insulin treatment is commenced when an individual's diabetes cannot be controlled through a combination of strict diet, exercise and the use of hypoglycaemic agents. Although early insulin therapy would lead to a significant improvement in glycaemic control among patients, insulin therapy is more costly and time consuming than alternative approaches to treatments for type 2 diabetics, which accounts for its introduction only as secondary line of treatment.57

Successful glycaemic control in individuals with both type 1 and type 2 diabetes decreases the risk of diabetic complications, as well as other macrovascular diseases and requires strict compliance to diabetes care plans. While some individuals are unwilling to adhere to insulin therapy, increasingly, patients are becoming more receptive to their treatment due to the convenience and ease of new methods of insulin delivery. Current research into alternative treatments for diabetes looks promising, and seek to increase patient compliance and enhance glycaemic control further. Pancreatic islet transplantation is also being researched as a potential radical cure for this illness, particularly for type 1 diabetes, which could open doors to new and innovative treatment approaches in the future.

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