Diabetes mellitus is a metabolic disorder of the endocrine system, defined by chronic hyperglycaemia (Guyton and Hall, 2010). It is characterised by an acquired and/or idiopathic inability to produce insulin or increased insulin resistance, causing an imbalance between supply and demand of insulin. Insulin is a pancreatic hormone secreted by beta cells of the islets of Langerhans, essential for the metabolism of glucose. Insulin regulates blood glucose by facilitating the transport of glucose into the cell membrane. If these deficiencies are left unmanaged, or are managed incorrectly, this results in glucose homoeostatic imbalances known as hypoglycaemia or hyperglycaemia (Tortora and Derrickson, 2012).
Pathophysiology of diabetes
Body cells need energy to function; glucose (sugar obtained from digestion and metabolism of carbohydrates) is the body's main energy source. The glucose in digested food is absorbed in the small intestine via glucose co-transporters located on the intestinal epithelial cells, and subsequently into the bloodstream (Marieb, 2012). The hormone insulin facilitates the uptake of glucose into muscle, fat and liver cells, where it is stored as the rapidly accessible energy source glycogen. In the absence of insulin, these cells are unable to uptake glucose as the receptors that transport glucose (GLUT4) are inactive. Insulin bonds to GLUT4 receptor sites on the outside of cells, acting like a key unlocking the doorway allowing access to the cell. Glucose can then enter the cell through this channel. The inability of glucose to enter these cells in the absence of insulin means it remains circulating in the bloodstream, resulting in hyperglycaemia (Zhu et al, 2013).
Hyperglycaemia occurs when glucose is consumed and there is an inability to produce insulin, the amount of insulin produced is insufficient, or the cells become resistant to the effects of insulin (Kumar and Clark, 2012). The net result is that the level of glucose within the blood stream increases, as the capacity to move this into the intracellular spaces diminishes. The increasing concentration of glucose within the blood stream results in increased osmolarity, which is detected by osmoreceptors and triggers the thirst response. This increased thirst results in the symptom of polydipsia as the patient drinks excessively to combat the sensation of thirst. In order to compensate for increased osmotic pressure, the water contained within the cells moves, by osmosis, toward the intravascular space. This movement results in cellular dehydration and further triggers the thirst response (Munden, 2007). The increased water within the intravascular space results in a net increase in pressure within this system. The body attempts to counteract this by increasing the filtration of water and solutes at the kidneys; re-absorption in the distal convoluted tubule and collecting duct is reduced. This is due to the increased osmotic pressure within the tubule caused by the presence of glucose. This results in an increase in urine output and excretion of glucose in the urine. Glucose would normally be completely re-absorbed in the kidneys; therefore, the presence of glucose in the urine is a strong indicator of the diabetic state. The patient may complain of an increased frequency and volume of micturation (polyuria) (Longmore et al, 2010).
Regulation of blood glucose
The National Institute for Health and Care Excellence (NICE) (2008) highlight the significance of maintaining glucose balance to achieve homoeostasis. They regard a blood glucose level in excess of 11.1 mmol/L on two separate occasions, or in a single instance when associated with symptoms, as an indicator of diabetes (NICE, 2008). Glycaemic regulation is maintained primarily by two groups of hormone secreting cells (alpha cells and beta cells) located in structures named the Islets of Langerhans in the pancreas (Guyton and Hall, 2010).
Alpha cells are responsible for the secretion of glucagon, which increases blood glucose concentrations with the assistance of counter regulatory hormones, such as epinephrine, growth hormone, and the glucocorticoids. Glucagon and epinephrine work to promote glycogenolysis. Glycogenolysis is the process of breaking down stored glycogen in hepatic, adipose and muscle cells for release and use as an energy source (Guyton and Hall, 2010). Glucagon and the glucocorticoids act to increase gluconeogenesis. Gluconeogenesis is the production of glucose from a number of substrates, such as lactate, pyruvate and amino acids within the cells. The result of both processes is an increase in glucose production and release (O'Neill and Murphy, 2012).
Beta cells are responsible for the secretion of insulin, which decreases excess blood glucose concentrations by facilitating the movement of glucose into cells. This glucose is then synthesised into glycogen within the cells to form energy stores for periods of fasting. Insulin also opposes the effects of glucagon by decreasing hepatic production of glucose through glycogenolysis, restricting the release of glucose into the bloodstream. Amylin is also produced by pancreatic beta cells, and works in concurrence with insulin to regulate glucose concentrations; they are both found in low concentrations during fasting and increase during periods when glucose levels rise. The negative feedback systems of endocrine control maintains homeostatic balance of blood glucose by regulating glucagon and insulin secretions (O'Neill and Murphy, 2012).
Classifications of diabetes
The World Health Organization (2013) classifies diabetes as two distinguishable forms of a disease state.
Type 1 diabetes mellitus
Type 1 diabetes may be diagnosed at any age, but is usually diagnosed in childhood (Longmore et al, 2010). It is characterised by an insulin deficiency resulting from selective auto-immune destruction or idiopathic damage of pancreatic beta cells. Autoimmune destruction occurs from an inappropriate initiation of inflammatory and immune responses against endogenous cells; in the pancreas this is known as insulitis. The inflammatory response is an intrinsic part of both the innate and acquired immune system; it would normally respond only to exogenous antigens. In this instance the immune system attacks natural beta cells and triggers the release of inflammatory mediators. This results in increased immune activity and destruction of the affected cells (Yoon and Jun, 2005). As a result, lifelong supplementary insulin therapy is required to maintain homeostasis (Munden, 2007).
Type 2 diabetes mellitus
Type 2 diabetes is most commonly diagnosed in adulthood; however, there is an increasing prevalence of children with the condition. The American Diabetes Association (2005) recognises an increase of 30–50% in the number of type 2 diabetes diagnoses in children. This reflects lifestyle choices such as Fred's (see Case Study 1): reduced physical activity, excess calorific intake and increased alcohol intake, causing obesity, with the resultant insulin resistance leading to a diabetic state (Longmore et al, 2010).
Type 2 diabetes is characterised by cells with a resistance to the effects of insulin or a reduction in its production. Consequently, glucose cannot be transported into the cells and metabolised, resulting in hyperglycaemia (O'Neill and Murphy, 2012).
The symptoms of polyuria and polydipsia occur gradually and can often be missed or attributed to other lifestyle factors. As a result the patient may experience prolonged hyperglycaemia causing a number of complications such as retinopathy, nephropathy and vascular neuropathy (Rosenson et al, 2011). Pharmacological interventions (oral hypoglycaemic medications) are therefore required when diet alone is insufficient to maintain homeostasis. Fred is prescribed 500 mg metformin to be administered three times daily. Metformin is a member of the biguanide class of diabetic medications. It decreases gluconeogenesis in hepatic tissues and increases glucose uptake in muscle and adipose tissue, through a process of GLUT 4 translocation. Therefore, increased peripheral utilisation of glucose reduces blood concentrations. Biguanides are only effective if there is some endogenous insulin production from functioning pancreatic islet cells (Joint Formulary Committee, 2012).
Lifestyle risk factors
Fred's medical and social history consisted of multiple risk factors for cardiovascular disease (CVD). CVD accounts for 52% of deaths in type 2 diabetics, in comparison to 32% amongst the general population (Diabetes UK, 2010; British Heart Foundation Health Research Promotion Group, 2012). It is therefore imperative that drug therapy, together with lifestyle changes, aim to reduce risk factors for micro- and macro-vascular complications, including retinopathy, nephropathy and neuropathy. These conditions result from damage to the small vasculature micro-circulation in complicated organs such as the eyes and kidneys. They are caused by increased blood glucose damaging the tunica intima layer of vessel walls. Left untreated, retinopathy may result in blindness, nephropathy in kidney failure and failure of circulation in the peripheral nervous system in nerve dysfunction, or death. These risks can be managed by the addition of a sulphonylurea or a thiazolidinedione in addition to metformin. In Fred's case, he was prescribed a thiazolidinedione in the form of pioglitazone. This has the effect of reducing peripheral insulin resistance, further enhancing cellular glucose uptake and also promoting the effect of endogenous insulin. Further studies suggest that these drugs have benefits in the prevention and control of microvascular complications. This is achieved through their effect on the albumin creatinine ratio; however, the precise mechanism is as yet unclear (Viberti, 2005; Joint Formulary Committee, 2012).
Fred has multiple comorbidities that place him at increased risk of thrombotic and haemorrhagic events. As a type 2 diabetic, Fred experiences prolonged hyperglycaemia and insulin resistance. This results in circulating fats in the bloodstream binding to sugars, which contributes to the development of atherosclerosis. Colbert et al (2009) claim the formation of atherosclerosis is the result of fatty deposits (atheroma) accumulating in the walls of arteries. As atheromatous deposits accumulate, they form fatty cores between the tunica intima and tunica media of arterial vessel walls covered by fibrous caps, known as plaques. Plaque causes the arterial walls to stiffen and narrow. Narrowing of the lumen and stiffening of the affected artery results in reduced blood flow, causing inadequate perfusion. Hypo-perfusion means that oxygen and nutrients cannot reach the muscle, thus metabolic demands cannot be met in the affected area (British Heart Foundation, 2011). As a consequence of the risks posed by abnormal accumulation of fatty deposits, Fred is prescribed simvastatin. The statin family of drugs promote the uptake of low density lipoproteins (LDL) by the liver, where they are converted into high density lipoproteins (HDL). The ratio between the two is important in determining risk for CVD, given the danger posed by LDL and its inability to enter cells to be stored (Mihaylova et al, 2012).
The process of plaque formation and resultant vessel wall hardening increases the risk of it becoming unstable and rupturing. Exposure of an abnormal surface to the blood results in activation of the intrinsic clotting cascade, leading to development of thrombosis. The formation of a clot may cause an occlusion of the local artery, or if dislodged, may cause occlusion of a distant artery, causing a deep vein thrombosis (DVT) or a pulmonary embolism (PE) (Porter and Kaplan, 2011). Recent evidence suggests that the formation of atheromatous plaques and thrombi share a similar development profile (Libby, 2002). Only recently has the contribution of the inflammatory pathway been recognised as important in both cases. The recruitment of leukocytes and pro-inflammatory cytokines stimulate an inflammatory response between the tunica intima and media. This inflammation places the developing atheroma at great risk of rupture and the subsequent development of thrombi (Siegel et al, 2013). In the same way as the development of an atherosclerotic narrowing, blood supply to distal tissues is compromised by thrombosis. This thrombotic event may again lead to the problems with hypo-perfusion as previously described. In both scenarios, when metabolic demands cannot be met, ischaemia occurs. Prolonged ischaemia results in infarction, which if unresolved may lead to necrosis (death of tissue resultant from the compromise of circulation leading to hypoperfusion) of the affected tissues. The anatomy of the affected artery will dictate how it affects the tissue, e.g. occlusion of a coronary vessel resulting in myocardial infarction. Disease in the peripheral vasculature potentially results in claudication or gangrene, potentially leading to amputation. Necrosis causes a further inflammatory response in affected tissues (Snyder, 2007).
Fred also suffers from hypertension and examination revealed Fred's blood pressure to be 163/100 mmHg. NICE (2013) suggest hypertension affects 20–60% of diabetics, further increasing their risk of micro/macro vascular complications. They advocate a target blood pressure of less than 130/80 mmHg. Antihypertensive medication such as angiotensin converting enzyme (ACE) inhibitors (e.g. Ramipril) may be required to achieve successful control of blood pressure. The NICE (2013) guidelines suggest the use of a structured approach to blood pressure management, with ACE inhibitors being frontline treatment for patients under the age of 55 years. Ramipril is prescribed with the effect that it antagonises the effects of ACE, preventing the conversion of inactive angiotensin I to the active angiotensin II. Angiotensin II promotes vasoconstriction and increased sodium reabsorption at the kidneys. The result is that both peripheral resistance and circulating volume are increased, causing raised blood pressure. By antagonising the effects of ACE and preventing angiotensin II production, both peripheral resistance and circulating volume are reduced and blood pressure lowered (Guy, 2011).
Acute diabetic emergencies
Hypoglycaemia
Pathophysiology
At times of hypoglycaemic crisis, when blood glucose levels are less than 3.3 mmol/L (NICE, 2008), the brain's deprivation of glucose is demonstrated by neuroglycopenic symptoms. Fred presented with a number of neuroglycopenic symptoms such as drowsiness, confusion, difficulties concentrating, behavioural changes and weakness. The brain is the only organ in the body that is dependent exclusively upon glucose for energy. Specialised receptors (GLUT 1) located on the brain tissue cells have a very high affinity for glucose and are able to pick this up at very low blood concentrations (Guyton and Hall, 2010). These receptors are able to uptake glucose from the blood stream to concentrations as low as 1 mmol/L; however, these cannot maintain adequate supply when blood glucose falls below 3.3 mmol/L given their low capacity. This protects cerebral function and prevents damage to these important tissues. In extremis, the brain is able to use ketones as an energy source; however, this is inefficient and unsustainable. The result is that failure to correct low glucose concentrations leads to the neurological symptoms discussed, and in extreme instances, may result in brain death (Rosenthal et al, 2001).
Management of hypoglycaemic crisis
Prompt and appropriate management of hypoglycaemic events is imperative to prevent further deterioration and the development of long-term complications (Mukherjee et al, 2011). Within the scope of paramedic practice there are a few options that may be used to increase blood glucose concentration for the management of acute hypoglycaemic events. The manner in which this is achieved is determined by the severity of the patient's condition. Interventions may range from intensive intravenous therapies to advice regarding self-care and referral onto primary care providers. In this instance the treatment protocols followed reflect local ambulance service guidelines (NICE, 2008; Greaves and Porter, 2010).
Patients who are able to consume oral glucose are administered 40% dextrose gel. This oral intake mimics normal carbohydrate intake; however, it is a slow route of administration. Evidence suggests that peak blood glucose concentrations do not occur until 46 to 50 minutes after the ingestion of oral carbohydrates (Freckmann et al, 2007). This route may also be inappropriate in patients who are unable to cooperate or for whom oral administration may present an airway compromise (Greaves and Porter, 2010; Joint Royal Colleges Ambulance Liaison Committee (JRCALC), 2013).
For patients who are unable to consume oral glucose, treatment options include intra-muscular glucagon and/or intravenous 10% glucose fluid. The administration of exogenous glucagon increases the release of glucose from glycogen deposits as previously discussed. This method of treatment is effective and relatively quick; however, results may be limited if glycogen stores are already exhausted in patients when calorific intake has been insufficient for a protracted period. The route may also result in repeated hypoglycaemic events if the patient fails to replenish glycogen stores appropriately (Greaves and Porter, 2010; JRCALC, 2013). Alternatively, the administration of glucose 10% fluid is a rapid method of parenteral administration that quickly raises blood glucose levels. These patients will experience rapid correction of blood glucose levels. They will, however, once appropriately recovered, require administration of oral carbohydrates to prevent relapse (Greaves and Porter, 2010; JRCALC, 2013).
Hyperglycaemia
Pathophysiology
Type 2 diabetic patients are particularly at risk of hyperosmolar hyperglycaemic nonketotic syndrome due to the inability to balance fluid intake and loss (Kumar and Clark, 2012). This results in high plasma osmolarity and very high blood glucose concentrations; however, the condition occurs without the development of ketoacidosis. The condition may manifest in a manner that is asymptomatic, making detection difficult and potentially resulting in increased mortality. Patients may also develop the acute complication of ketoacidosis, which is a life-threatening emergency. This is the result of uncontrolled lipolysis augmented by excess glucagon unopposed by insulin, leading to the accumulation of acidic ketones in the blood. This problem is self-perpetuating and will be fatal without management (Lewis, 2000).
Management of hyperglycaemic crisis
Management options for hyperglycaemic crisis are limited within the scope of paramedic practice, due to paramedics' limited patient monitoring equipment and pharmacy. In many cases there are no drug therapies available and the management is confined to the administration of intravenous 0.9% sodium chloride to attempt to reduce blood osmolarity and lessen the damage caused. Ultimately these patients require immediate hospital treatment with a sliding scale insulin infusion that will reduce blood glucose levels (Greaves and Porter, 2010; JRCALC, 2013).
Conclusions
This case study has explored the multifaceted pathophysiology, complications and management strategies involved in dealing with a patient with type 2 diabetes and its associated co-morbidities. The patient in this instance had a range of treatment strategies in place aimed at reducing both the symptoms he was currently experiencing and the potential complications that may arise over the progression of his disease. This had necessitated an integrated pharmacological and lifestyle plan designed to gain maximal benefit based upon a strong understanding of the pathophysiology. The treatment regime followed both local and national guidelines detailing best evidence-based practice. Fred was able to lead a full and active life with regular monitoring to ensure that the disease did not worsen. The presentation of type 2 diabetes in later life often presents unique challenges in ensuring patient compliance given the need for lifestyle changes.
The aetiology of this acute hypoglycaemic episode was deemed to be a lack of carbohydrate intake during the previous 4 days owing to a viral infection. This, in combination with continued oral hypoglycaemic medications, led to a fall in blood glucose concentration. The management of diabetes in both the chronic and acute setting is aimed solely at symptomatic management, it does not treat the underlying pathology. In this instance, Fred was treated successfully for the hypoglycaemia and was referred back to his own doctor for a medications review. The case has demonstrated the need for a sound understanding of pathophysiology amongst practitioners in order to inform and guide their practice.