Insulin – its importance in the treatment of both Type 1 and Type 2 Diabetes Mellitus
Diabetes Mellitus is a Health condition in which the patient’s body cannot regulate their glucose levels on their own. There are two forms, Type 1 and 2. Type 1 is when the body is unable to produce insulin and often begins during childhood. This can be as a result of an autoimmune response in which the body attacks its own beta cells of the Islets of Langerhans(1). Type 2 is often due to glycoprotein receptors on body cells losing responsiveness to insulin, this usually develops in those over the age of 40 (2).There is an increasing number of people developing type 2 from poor diets in adolescents resulting in obesity. Roughly 90% of people with Diabetes have type 2(3). Insulin, being the main form of treatment for Diabetes Mellitus, was first discovered in 1921 by Canadian physician Frederick Banting and medical student Charles H Best, who were investigating pancreatic extracts of dogs. This discovery was as a result of much work from other scientists including a German medical student called Paul Langerhans. He discovered the Islets of Langerhans, a cluster of cells in the Pancreas where the beta cells are situated that produce insulin (4).
Beta Glucose:this is a hexose sugar, an example of a monosaccharide. There are two isomers, alpha and beta. The only difference being the hydroxyl and hydrogen attached to the first carbon swap positions, in bold. As a result of condensation reactions polysaccharides are formed. Glycogen being a great example as excess glucose is stored in muscles as this due to the action of insulin. This is called glycogenesis.
Figure 1- Beta Glucose
Insulin: the protein consists of 51 amino acids arranged into two chains. An Alpha (21 amino acids) and Beta (30 amino acids) that are bonded by two disulphide bridges. (See figure 2).
Figure 2- Insulin
The B26-B30 region of the insulin molecule is important for the insulin receptor to recognise insulin. It is in this region that amino acids are generally substituted. As a result giving rise to insulin analogues that are still recognized by the insulin receptor (6),see figure 3.
An understanding of chemical structure is crucial when considering how insulin converts glucose to glycogen via glycogenesis.
Figure 3- Insulin analogues (6)
Mechanism of Action
Increased levels of glucose trigger insulin secretion by releasing insulin from secretory granules from the B cells. When glucose enters the B cell via glycoprotein receptors Glucokinase senses it. This is an enzyme that phosphorylates glucose into glucose-6-phosphate producing ATP as a result. Potassium ATP dependant protein close resulting in membrane depolarization which activates calcium voltage gated channels to open(6). As a result of intracellular concentration of calcium ions increasing, pulsatile insulin is secreted.
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Insulin binds to insulin receptors to mediate its action, these receptors were discovered in 1971 and are made up of heterotetramers, proteins containing 4 non covalently bonded sub units, that are non-identical. The receptor has 2 alpha and 2 beta glycoprotein sub units linked by disulphide bridges. Insulin binds to the extracellular alpha subunit, resulting in a change that enables ATP to bind to the intracellular part of the β subunit(6). ATP binding triggers phosphorylation of the β subunit activating tyrosine kinase activity. This enables phosphorylation of insulin responsive substrates (IRS)(7). These substrates then bind other molecules that mediate cellular actions of insulin further. For example IRS 3 binds to src-homology-2 domain proteins (SH2) which releases enzymes such as phosphatidylinositol 3-kinase (PI 3-kinase). This enzyme plays a vital role in activation of glucose transporter proteins, mainly GLUT 4(7).
Adipose cells and muscle cells have GLUT 4 channel proteins. When insulin levels are low they are stored in vesicles in the cytoplasm of cells, but when insulin is present it binds to receptors on the cell surface membrane triggering the movement of GLUT 4 proteins to the membrane. Glucose is then transported into the cell via facilitated diffusion. They have a high affinity for glucose, thus a low Km value. This enables the adipose cells to store excess energy, as they respond to higher glucose levels such as that of the fed state. In muscle cells, the glucose is converted to glycogen (glycogenesis) for storage (7). As a result glucose levels have decreased and a negative feedback mechanism complete. An in depth understanding of how insulin works is required to discuss the different forms of treatment associated with Diabetes Mellitus.
Figure 4- GLUT4 Mechanism (7)
Insulin is the main form of treatment for those with type 1 diabetes mellitus and the route of administration being intravenous, intramuscular or subcutaneous. Without diabetes the Pancreas produces roughly 25-40 units of insulin. Insulin administration in most type 1 patients require much more, between 0.5 and 1.0 unit/Kg body weight daily, when administrated subcutaneously(9) . Common devices include syringes and 10ml vials as well as Insulin pens which are most commonly used in the UK(9). Administration varies depending on patient preference, there are multiple ways of doing so and monitoring as a result of technology.
Pump technology CSII
25% of people in the USA use this and up to 40% in Norway. This form of treatment has proved successful in children and adolescents, meta analysis suggests HbA1c levels (glucose levels in blood) are 0.3-0.6 % lower with the pump compared to regular insulin injections(9). The pump delivers multiple basal rates throughout the day and night. Advancement in pump technology include software integration to calculate and suggest doses, based on carbohydrate intake and current glucose levels. Sensor augmented pumps use continuous glucose monitors to relay glucose data to the pump display and administer the correct dosage. HbA1c levels fell by 0.5-0.6% from a baseline of 8.3% in a study involving 500 children of the age of 7(9). An excellent example conveying the importance of new technology and insulin to treat diabetes.
Continuous glucose monitoring CGM
This system measures interstitial glucose levels and has a delay of 15 minutes due to instrument processing and physiological delays. This proves an issue for real time monitoring and transmitting the data to insulin pumps (10). Long term use of CGM can lower HbA1c (glucose) levels by 0.5% in adults that are 25 or over. Furthermore a decrease in hypoglycaemic events(9). The major advantage of CGM is that you don’t need to prick your finger for calibration. Continuous monitoring allows the patient to adjust dietary intake and physical exercise, an excellent form of patient centred treatment.
Long acting insulin analogues are in clinical trials, for example insulin degludec, a soluble insulin analogue that can be administered three times per week (9). Others like glargine over 24 hours(11). This would prove easier for the patient as regular injections can have large impacts on day to day life, therefore improving their quality of life.
The main drawback of available formulations of insulin is they have to be injected and don’t mimic physiological postprandial insulin delivery into systemic circulation. Inhaled Insulin was approved by the Food and Drug Administration in 2014 as a route of administration for treating both type 1 and 2 Diabetes Mellitus(12). This has been developed by MannKind Corporation and is available as Afrezza. The pulmonary route of insulin delivery appears to be a valid option to reduce the gap between physiological and non-physiological insulin release as the lungs have a rich blood supply and a large surface area for quick absorption of insulin (11).
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Afrezza uses insulin particles that have an average diameter of 2.5 μm(12). This means they are suitable for inhalation as they will be delivered into the alveoli without hindrance. These particles are also very soluble at a PH of 6 and greater. This matches the physiological PH in the lungs therefore allowing easy dissolution and absorption into systematic circulation(12).
This route of administration results is a very rapid response with maximum plasma drug concentration (Cmax) reached between 10 and 15 minutes. This is crucial as it mimics ‘first phase’ insulin release after consuming food in non-diabetic individuals. However 60%of the inhaled insulin is deposited in the lungs(12) resulting in the below adverse effects.
Now looking at Clinical Efficacy, a trial was conducted on both type 1 and 2 patients in which Afrezza and injected insulin were used and the results compared. Both showed a 0.4% decline in HbA1c levels after 24 weeks(12). The Afrezza group had less incidence of hypoglycemic events, although overall glycaemic control was equal. Therefore similar and non-inferior results. Adverse effects include coughing, throat pain and irritation. There is also evidence for decline in FEV1 of the lungs. Major issues include bronchospasm in patients with asthma and Chronic Obstructive Pulmonary Disease(12). Therefore in terms of patient care this is not yet a completely viable option, but may be in the future. Main reasons being because of expense and low bioavailability (11), despite rapid Cmax.
Carcinogenic effects of insulin
Insulin has the potential to bind to the IGF-1 receptor (insulin growth receptor) mimicking insulin-like growth factor-binding proteins (IGFBPs). High concentrations may induce tumorogenesis as different analogues of insulin have different affinities for the receptor. Glargine supposedly has a 6-8 fold increase compared to regular human insulin. The reason for binding is because the IGF-1 receptor is a Tyrosine Kinase, which resembles the insulin receptor. This receptor regulates cell growth and apoptosis. Therefore unwanted activation may cause carcinogenic effects as mitosis is activated (13). This displays possible consequences of prolonged treatment.
Type 2 focused treatment
Most patients are overweight or obese when diagnosed with type 2. A BMI of 28-33 (higher for woman) is often the case(14). Therefore lifestyle interventions are effective to treat this form of diabetes. Weight loss, exercise and balance of macronutrient and micronutrient intake are viable interventions that aim to treat type 2 diabetes. Carbohydrates are recommended at 130g, proteins should make up 15-20% of total energy intake and cholesterol intake less than 200mg/day (9). This should result in weight loss if accompanied by exercise, 150 min/week (9) set by the diabetes prevention programme. Even though lifestyle changes are recommended for type 2 Diabetes, insulin too is a potential option.
Insulin Treatment for Type 2
Treatment for type 2 has a pharmacological focus as the UKPDS have indicated that insulin treatment is no more effective in glycaemic control than sulphonylureas or metformin. Insulin treatment has a higher risk of major hypoglycaemic events and does not confer micro or macrovascular advantages over pharmacological treatment. In a 6 month trial comparing twice daily biphasic insulin and metformin, both reduced HbA1c levels by 2.1%(9). The initial decline was quicker with insulin. Although,this is of no long term significance. Pharmacological treatment accompanied with lifestyle changes appear to be the most popular form of treatment, this is due to decreased hypoglycaemic events and weight gain associated with insulin (6). Also cardiovascular risk factors such as inflammatory markers do not improve with insulin, contrasting with pharmacological treatment such as metformin(9D).
Type 2 Pharmacological treatment of hyperglycaemia
First used in the 1950s as a first line treatment for overweight type 2 patients. It suppresses glycogenolysis and gluconeogenesis and stimulates insulin mediated muscle tissue glucose disposal. Effective at a dose of 500mg firstly, adjusted with response(15).
This drug stimulates pancreatic insulin secretion as it binds to the SUR1 receptor on the beta cell. This closes K-ATP channels resulting in an influx of calcium ions. As a result pre-formed insulin granules are released (9). This increases amount of natural insulin produced by pancreas (2B). A low does is required of around 40-80mg(16).
The role of insulin in treatment for diabetes mellitus is crucial as it is clear that it is an effective hypoglycaemic agent in both type 1 and 2. Knowledge of its mechanism of action and treatment methods are crucial to a pharmacist and integrated into both clinical and community care. A pharmacist role in treating Diabetes consists of identifying patients through screening as well as educating them on the health condition. It is possible to receive a certificate as a ‘diabetes educator’ which requires 1000 hours of experience in providing management for patients(17). Providing such services require excellent communication and effort resulting in professional satisfaction and increased awareness of diabetes. However treatment for Diabetes Mellitus is rather linear and no cure exists. Although advancements such as inhaled insulin have been analysed as a form of effective treatment but rendered inadequate compared to other forms and routes of admin(18). However, this reflects the drive for advancement in technology to treat this common condition through different dosage forms of insulin and routes of administration.
- Simon R Page & George M Hall, ‘Diabetes: Emergency and Hospital Management’ (1999), pg 1-18.
- Dr Charles Fox & Dr Anne Kilvert, ‘Type 2 DIABETES’ (2007), Vol 6 pg 24-51.
- David Levy ‘Practical Diabetes Care’ (2011), Third Edition, pg74-108
- Andrew J Krent & Clifford J Bailey ‘Type 2 Diabetes’ (2005),Second edition pg166-186.
- David Levy, ‘The Hands- On Guide to Diabetes Care in Hospital’ pg3-17.
- BNF pg678
- BNF pg692
- https://www.ncbi.nlm.nih.gov/pubmed/12489383 (Role of Pharmacist)