Type 1 Diabetes Mellitus
Miss GT was a 22-year-old woman with Type 1 diabetes mellitus (DM) since the age of 13. Initially she had been well controlled, but over the last year she had attended her local Accident and Emergency Department on several occasions with hypoglycaemic episodes. For the few days prior to this admission she had felt unwell – she developed an upper respiratory tract infection but despite monitoring her blood sugar more often and taking her insulin, she had started vomiting 8 hours prior to admission. By the time she arrived in the Accident and Emergency Department she was drowsy and had vomited on several further occasions. Her temperature was elevated, she demonstrated prolonged expiration in breathing (Kussmaul’s respiration), there was a smell of acetone on her breath and she appeared to be dehydrated and unwell. Her blood glucose was 24 mmol/L and she had both glycosuria and 3+ ketonuria on urinalysis. Blood gases were done immediately and showed a metabolic acidosis with pH 7.2, HCO3 14 mmol/L, PO2 12 kPa, PCO2 3.4 kPa. A diagnosis of diabetic ketoacidosis was made and routine therapy commenced, with IV fluids, potassium and insulin, according to local protocols.
Diabetic ketoacidosis (DKA) is a serious complication of Type 1 DM and presents as a medical emergency. It may be the way in which the disease presents or it may reflect poor compliance with diet and therapy or the effects of a superadded disease such as a chest infection. There is still a significant mortality rate of around 10% associated with DKA and it must be treated seriously, promptly and with meticulous attention to detail in monitoring the response to treatment.
Insulin lack creates a profoundly catabolic state (Fig. 40a). Without insulin, glucose is not taken up by the tissues, and hyperglycaemia results. The cells are deprived of an energy source and respond by glycogenolysis, gluconeogenesis and lipolysis to generate glucose for energy. This exacerbates the hyperglycaemia, and creates an acidosis through the increased production of ketone bodies, which can prove fatal. The break-down of body proteins and fats results in weight loss and the acidosis produces vasodilatation and hypothermia. The patient hyperventilates to blow off the acidosis in the form of carbon dioxide. The decreased anabolic state and hyperglycaemia cause fatigue.
Glucose is excreted in the urine, causing excessive diuresis, which in turn results in loss of body fluids and salts. The patient becomes dehydrated, is constantly thirsty and drinks copious volumes of water (polydipsia). Untreated, the patient will eventually fall into a coma, the aetiology of which is not fully understood, but it may result from the combined effects of hyperketonaemia, including dehydration, hyperosmolarity due to hyperglycaemia and problems within the cerebral microcirculation.
Type 1 diabetes mellitus (IDDM)
Type 1 diabetes is an autoimmune condition causing destruction of the pancreatic b cells resulting in absolute insulin deficiency. It presents in children and young adults and is more common in populations of north European origin than other ethnic groups. Infiltration of the pancreatic islets by activated macro- phages, cytotoxic and suppressor T lymphocytes and B lymphocytes produces a destructive ‘insulitis’ which is highly selective for the β cell population. Approximately 70–90% of β cells must be destroyed before the onset of clinical symptoms. Type 1 DM is a polygenic disorder with genetic factors accounting for about 30% of the susceptibility to the disease. There is an association with HLA haplotypes DR3 and DR4 in the major histocompatibility complex on chromosome 6, although these alleles may be markers for other loci responsible for the HLA class II antigens which are involved in initiating the immune response. Environmental factors may also be important in the aetiology of Type 1 diabetes and the role of viruses and diet has been investigated.
Treatment. Patients must take parenteral insulin and follow a carefully regulated diet. Human insulin is now prepared by recombinant DNA technology and is administered by a range of subcutaneous ‘pen’ devices which simplify insulin delivery. A wide range of insulin preparations are available, ranging from short-acting (soluble), to intermediate-acting to long-acting forms. The aim of treatment is to keep blood glucose levels as close as possible to normal levels, which vary from around 4–9 mmol/L. Patients monitor their own blood glucose regularly throughout the day using a glucometer device and adjust their insulin dosage accordingly. Modern therapy for patients with Type 1 diabetes involves a multidisciplinary approach with doctors, specialist nurses, dieticians, opticians and chiropodists all playing an important role. Patient education is vital to therapy – the more an individual with diabetes understands the condition and is able to regulate their insulin and food intake to their own lifestyle, the better the control and the less likely the onset of serious complications. The DAFNE programme of intensive education related to diet, lifestyle and insulin therapy has proved successful in improving individual’s diabetic control. Insulin pump therapy combining real-time glucose monitoring with on-demand insulin therapy offers improved diabetic control to selected patients.
Transplantation of human β-cells. A recent advance is the successful transplantation of human primary islets of Langerhans into patients with Type 1 diabetes. This technique offers hope of a cure, but at the moment the supply of tissue is sparse and the eventual manufacture of islets from stem cells is being investigated.
Poor diabetic control – microvascular complications
All patients with DM should be monitored carefully with the aim of preventing the onset of complications. Patients with Type 1 diabetes are at particular risk of microvascular compli- cations (Table 40.1). Improved glycaemic control reduces the likelihood of developing such complications, particularly diabetic retinopathy (Fig. 40c). Patents should have annual eye checks, preferably with retinal photography combined with direct ophthalmoscopy. The onset of nephropathy is heralded by proteinuria, initially in the form of ‘microalbuminuria’, that is 30–300 mg/24 h albuminuria. It is important to optimize glycaemic control and blood pressure and ACE inhibitors have been shown to delay progression of microalbuminuria to full blown nephropathy. Neuropathy should be managed by scrupulous foot care including regular chiropody to reduce the likelihood of neuropathic ulcer formation.
Traditionally, microvascular complications were thought to be found exclusively in patients with Type 1 DM. However, improved treatment of cardiovascular disease in patients with Type 2 diabetes means that these complications may be seen in patients with either form of the disease (see Chapter 41).
Islet cells have been generated from murine (mouse) stem cells, which offers hope that this may promise hope for human pancreatic regeneration.