Diabetes is the most common metabolic disorder of carbohydrate, fat and protein metabolism, and is primarily due to either a deficiency or complete lack of the secretion of insulin by the β-cells of the islets of Langerhans in the pancreas. It affects 1–2% of Western populations and 5–10% of the population over the age of 40. The disease is characterised by hyperglycaemia (elevated blood glucose level) leading to long-term complications. Diabetes can be classified into a number of types:
• Insulin-dependent diabetes (Type 1) (also called juvenile diabetes and brittle diabetes) is due to the autoimmune destruction of β-cells in the pancreas. Generally it has a rapid onset with a strong genetic link.
• Non-insulin-dependent diabetes (Type 2) (also called adult-onset diabetes and maturity-onset diabetes), is a complex progressive metabolic disorder characterised by β-cell failure and variable insulin resistance. A subtype is maturity-onset diabetes of the young (MODY) which usually occurs before the age of 25 years. It is the first form of diabetes for which a genetic cause and molecular consequence have been established. Mutations of the genes for hepatocyte nuclear factor 4α (MODY1), glucokinase (MODY2), HNF1α (MODY3), insulin promotor factor 1 (MODY4), HNF1β (MODY5) and neurogenic differentiation factor 1 (MODY6) have all been described.
• Impaired glucose tolerance where there is an inability to metabolise glucose in the ‘normal’ way, but not so impaired as to be defined as diabetes.
• Gestational diabetes that is any degree of glucose intolerance developed during pregnancy. It is characterised by a decrease in insulin sensitivity and an inability to compensate by increased insulin secretion. The condition is generally reversible after the termination of pregnancy, but up to 50% of women who develop it are prone to develop Type 2 diabetes later in life.
• Other types, which include certain genetic syndromes, pancreatic disease, endocrine disease and drug- or chemical-induced diabetes.
Insulin-Dependent Diabetes (Type 1)
Between 5% and 10% of all diabetics have the insulin-dependent form of diabetes requiring regular treatment with insulin. Type 1 develops in young people with a peak incidence of around 12 years of age. In this type of diabetes the degree of insulin deficiency is so severe that only insulin replacement can avoid the com plications of diabetes that are discussed later. Dietary control or oral drugs are not sufficient. The disease is caused by the autoimmune destruction of β-cells in the pancreas, thus reducing the ability of the body to produce insulin. Islet cell antibodies (ICA), IA-2 antibodies to the transmembrane protein tyrosine phosphatase-like molecule in islet cells, auto-antibodies to glutamic acid decarboxylase (GAD) found in β-cells and insulin auto-antibodies (IAA) are all used as diagnostic markers of the disease.
Non-Insulin-Dependent Diabetes (Type 2)
Type 2 diabetes accounts for 90% of all cases and develops later in life and can be exacerbated by obesity. MODY versions account for 1–5% of all cases and are not associated with obesity. From population screening studies it is thought that only half of those individuals with Type 2 have been diagnosed. Control of blood glucose levels in this group is normally by a combination of diet and oral drug therapy, but occasionally it may require insulin injection.
Diagnosis and Monitoring Control of Diabetes Diabetes
is frequently recognised by the symptoms it causes, but can be confirmed by clinical biochemical measurements based on World Health Organization (WHO) recommendations in which symptoms are accompanied by:
• a fasting (12 hours) plasma glucose level ≥ 7 mM;
• a random plasma glucose level ≥ 11.1 mM;
• application of an oral glucose tolerance test in which a 75 g dose of glucose is administered and the plasma glucose level measured after 2 hours. Diabetes is characterised by a value ≥ 11.1 mM.
The diagnostic cut-off values of 7.0 and 11.1 mM are based on the level at which retinopathy begins to appear in a population. The clinical aim in the treatment of Type 1 diabetes is to maintain plasma glucose levels in the healthy range of 4–6 mM. This is typically monitored by patients themselves by measuring their blood glucose at predetermined times that are inter-related to their mealtimes during the day. For example, the lowest blood glucose of the day is likely to be after the longest fast before breakfast and the highest blood glucose of the day is likely to be 1 hour after the main meal. By manipulating treatment around these highs and lows, good glycaemic control is generally maintained. The patients measure their blood glucose using hand-held, portable blood glucose meters based on glucose oxidase using dry stick technology to measure finger-prick blood samples.
Another measure of glycaemic control is by using haemoglobin A 1c ( HbA1c ) measurements. This testing strategy works on the basis that most proteins (in this case haemoglobin A) will bind glucose dependent on the length of time they are in contact with glucose, the temperature and the concentration of glucose. Hence haemoglobin, having a typical half-life of 120 days, will bind the appropriate amount of glucose depending on the concentration of glucose. HbA1c is typically measured in the clinic using HPLC to separate the different haemoglobins and was initially expressed as a percentage of total haemoglobin. Following introduction of standardisation that allowed traceability to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) standard and reference method, the units were changed from % to mmol per mol haemoglobin. This change was introduced in 2009 in the UK although some laboratories may still report results in both units for education purposes. The lower the result the better the control and a target of 48 mmol per mol haemoglobin has been proposed for good diabetic control. This test is extremely useful in measuring long-term control of diabetes, but is not without its pitfalls. For example, if the patient has very brittle diabetes with equal numbers of hypoglycaemic and hyperglycaemic periods (see below), then the hypo- will cancel out the hyper glycaemic periods and the HbA1c levels will falsely indicate good glycaemic control.
The test has also been adopted for the diagnosis of Type 2 diabetes as it does not require fasting or a glucose tolerance test (Table 1). There are a number of caveats to its use in this regard, including pregnancy, children and anyone with a genetic or haematological abnormality that can influence HbA1c or its measurement. In addition, a value less than 48 mmol per mol haemoglobin cannot exclude a diagnosis of diabetes made on blood glucose results.
Table1. Diagnostic criteria for diabetes using HbA1c
