Aetiology and pathogenesis

Diabetes mellitus (DM) is a systemic metabolic disorder characterized by a tendency to chronic hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism that arise from a defect in insulin secretion or action or both. It is a common condition, with a prevalence of approximately 4% in the western world. Diabetes can occur secondarily to other diseases (e.g. chronic pancreatitis), following pancreatic surgery and in conditions where there is increased secretion of hormones antagonistic to insulin (e.g. Cushing’s syndrome and acromegaly). Secondary diabetes is, however, uncommon. Most cases of diabetes are primary, that is, they are not associated with other conditions. There are two distinct types. In type 1 DM, there is destruction of pancreatic cells, leading to a decrease in, and eventually cessation of, insulin secretion. Approximately 10% of all patients with diabetes have type 1. They have an absolute requirement for insulin. In type 2 DM, insulin secretion is defective and delayed, and there is resistance to its actions. Most patients with type 2 DM can initially be successfully treated by diet, with or without oral hypoglycaemic drugs, but many eventually require treatment with insulin to achieve adequate glycaemic control. The prevalence of both types of diabetes (although particularly type 2) is increasing.

Type 1 DM usually presents acutely in younger people, with symptoms developing over a period of days or only a few weeks. However, there is evidence that the appearance of symptoms is preceded by a ‘prediabetic’ period of several months, during which growth failure (in children), a fall in insulin response to glucose and various immunological abnormalities can be detected. Type 2 DM tends to present more chronically in the middle-aged and elderly (although it is increasingly being diagnosed in obese young people), with symptoms developing over months or even longer. The prevalence of type 2 DM is over 10% in people over the age of 75 years.

The previously used terms, ‘insulin-dependent’ and ‘juvenile-onset’ diabetes (for type 1) and ‘non-insulin-dependent’ and ‘maturity-onset’ diabetes (for type 2) are obsolete. It has become apparent that some young patients with diabetes are not insulin dependent, while in approximately 10% of patients developing diabetes over the age of 25 years type 1 DM has a slower onset. These patients may be misclassified as having type 2 DM. However, in comparison with patients with true type 2 DM, they tend to present at a younger age, are less likely to be overweight, have plasma markers of autoimmunity and, although often initially treated successfully with diet alone or diet and oral agents, develop a requirement for insulin, often within a year of diagnosis. Some of the characteristics of type 1 and type 2 DM are shown in Figure 11.5.

Figure 11.5 Major characteristics of type 1 and type 2 diabetes mellitus.

‘Maturity onset diabetes of the young’ (MODY) is the term used to describe a small group of individuals who develop an inherited form of type 2 diabetes in youth (see below).

Pathophysiology and clinical features

There are two aspects to the clinical manifestations of DM: those related directly to the metabolic disturbance and those related to the long-term complications of the condition.

The hyperglycaemia of DM is mainly a result of increased production of glucose by the liver and, to a lesser extent, of decreased removal of glucose from the blood. In the kidneys, filtered glucose is normally completely reabsorbed in the proximal tubules, but at blood glucose concentrations much above 10 mmol/L (the renal threshold) reabsorption becomes saturated and glucose appears in the urine. There is some variation in the threshold between individuals. It is higher in the elderly and lower during pregnancy. Glycosuria results in an osmotic diuresis, increasing water excretion and raising the plasma osmolality, which in turn stimulates the thirst centre. Osmotic diuresis and thirst cause the classic symptoms of polyuria and polydipsia. Other causes of these symptoms include diabetes insipidus, hypercalcaemia, chronic hypokalaemia, chronic renal failure and excessive water intake.

Untreated, the metabolic disturbances may become profound, with the development of life-threatening ketoacidosis, non-ketotic hyperglycaemia or lactic acidosis.

The long-term complications of diabetes fall into two groups: microvascular complications (i.e. nephropathy, neuropathy and retinopathy) and macrovascular disease related to atherosclerosis. These occur in both type 1 and type 2 DM. The prevalence of all these complications increases with the duration of the disease. The risk of microvascular complications is clearly greater if glycaemic control is poor, but other factors are undoubtedly involved: some patients never develop these complications, even after many years of having diabetes; others develop them rapidly, even with seemingly good control. The development of microvascular disease appears to be directly related to hyperglycaemia, whereas that of macrovascular disease is more closely related to insulin resistance. The results of long-term prospective studies indicate that improved glycaemic control significantly reduces the risk of microvascular complications in both type 1 and type 2 DM. For macrovascular disease, there was a trend towards benefit, but this was not statistically significant. The risk of macrovascular disease is greater in type 2 diabetes than type 1.

The common pathological feature in microvascular disease is narrowing of the lumens of small blood vessels, and this appears to be directly related to prolonged exposure to high glucose concentrations. The processes involved are complex, and still not fully understood: two appear particularly important. One is increased formation of sorbitol (an alcohol derived from glucose) by the action of the enzyme aldose reductase, leading to accumulation of sorbitol in cells. This can cause osmotic damage, alter the redox state and reduce cellular myoinositol concentrations. The other relates to the formation of advanced glycation end-products. Glucose can react with amino groups in proteins to form glycated plasma and tissue proteins (glycated haemoglobin (see below) is one example). These can undergo cross-linking and accumulate in vessel walls and tissues, leading to structural and functional damage. Other mechanisms of tissue damage may include the generation of free radicals, and activation of tissue injury responses secondary to intracellular hyperglycaemia.

The increased predisposition to atherosclerosis in patients with diabetes is also multifactorial. The abnormalities of lipids that occur as a direct result of diabetes (see p. 197) and glycation of lipoproteins leading to altered function are particularly important. Other factors that are implicated include endothelial dysfunction and increased oxidative stress.

The long-term complications of diabetes are a significant source of morbidity and mortality. Their diagnosis, with the exception of nephropathy, is largely clinical, although measurement of plasma lipids is important in the investigation of macrovascular disease. In contrast, the management of the acute metabolic disturbances seen in diabetes requires close collaboration between the physician and laboratory staff.

Diagnosis

The diagnosis of DM depends on the demonstration of hyperglycaemia. In a patient with classic symptoms and signs, this may be inferred from the presence of glycosuria, but glycosuria is not diagnostic of diabetes, even in the presence of classic clinical features. In a patient with such features, a random venous plasma or capillary blood glucose concentration ≥11.1 mmol/L (venous blood glucose ≥10 mmol/L) is diagnostic of diabetes; so, too, is a fasting venous plasma glucose concentration ≥7.0 mmol/L (venous or capillary blood glucose ≥6.1 mmol/L). In the absence of symptoms, any of these limits must be exceeded on more than one occasion for the diagnosis to be made. Even in symptomatic patients, diabetes is unlikely if a random venous plasma glucose concentration is <5.5 mmol/L (venous or capillary blood glucose <4.4 mmol/L). Individuals who have fasting plasma glucose concentrations that are elevated (≥6.1 mmol/L) but not in the diabetic range have impaired fasting glycaemia. Their response to a glucose load should be tested to determine whether they have diabetes.

These values are those adopted by the World Health Organization (WHO) in 1996, based on the recommendations of an expert committee of the American Diabetic Association (ADA), but more recently (2003) the ADA has suggested that the upper limit of normal for fasting plasma glucose should be 5.6 mmol/L.

The other indications and the protocol for the oral glucose tolerance test (OGTT) are given in Figure 11.6, and the interpretation of results in Figure 11.7. In the majority of patients suspected of having diabetes, the measurements indicated above will establish the diagnosis, and formal glucose tolerance testing is superfluous: it is only indicated when the diagnosis is in doubt. Note that the diagnostic values are the glucose concentrations fasting and 2 h after glucose: taking samples at 30-min intervals, as used to be recommended, is not required.

Figure 11.6 The oral glucose tolerance test. The values given are those currently recommended by the World Health Organization but, in the USA, the American Diabetic Association now recommends a value of 5.6 mmol/L as the upper limit of normal for fasting plasma glucose. For the diagnosis of diabetes, only basal and 120 min samples are required. For the diagnosis of acromegaly and renal glycosuria, samples should be taken at 30-min intervals. For renal glycosuria, urine samples should also be collected to be tested for glucose.

Figure 11.7 Diagnostic blood glucose concentrations. If a patient is asymptomatic, two results in the diabetic range are required to establish a diagnosis of diabetes mellitus. ^aIf measured.

The OGTT also defines a category of hyperglycaemia termed impaired glucose tolerance (IGT), which does not equate to diabetes but represents a stage in the natural history of transition from normal glucose tolerance to frank diabetes. IGT is not a clinical entity in itself, but defines a risk category for progression to diabetes. Impaired fasting glycaemia is a further category of abnormal glucose tolerance: some individuals thus classified are found to be diabetic on formal testing; others have IGT. Patients with IGT should be given dietary and lifestyle advice and reviewed regularly. Some will become frankly diabetic; others revert to normal glucose tolerance. All appear to have a similar predisposition to myocardial infarction and stroke as patients with frank diabetes, but they are not at increased risk of microvascular complications.

It should be noted that measurements of blood glucose are no exception to the potential for analytical and biological variation to affect results (see Chapter 1). Although precise figures are used as cut-offs for diagnosis, the existence of such variation can result in patients being misclassified if their results are close to cut-off values: this is why a confirmatory measurement is required before diabetes is diagnosed in the absence of clinical features. The results of glucose tolerance tests are additionally affected by factors such as the rate of gastric emptying and, because of the implications of making a diagnosis of diabetes (or of missing it), it may be prudent to repeat an OGTT if the results are at the borderline for diagnosis.

Gestational diabetes is diabetes or IGT with onset or first recognized during pregnancy. Different authorities recommend different diagnostic criteria, but, in effect, pregnant patients with any degree of glucose intolerance should be managed as if they have diabetes. Pregnancy decreases glucose tolerance, and patients with gestational diabetes may revert to a normal glucose tolerance post-partum. This condition is discussed on p. 197.

Measurement of glycated haemoglobin (HbA_1c, see p. 190) has recently been recommended by the ADA as a diagnostic test for diabetes, with a cut-off of >48 mmol/mol (>6.5%) (the value at which the risk of retinopathy begins to increase), but this has only been conditionally endorsed by the WHO, and it should be emphasized that normal values do not exclude the diagnosis.

Management

There are many aspects to the management of DM. Education of patients is vital: they will have diabetes for the rest of their lives and must, to a considerable extent, be responsible for their own treatment, albeit with guidance from physicians, nurse specialists and other healthcare professionals. The successful management of diabetes requires effective team work, with the patient being an active member of the team. Regular follow-up is essential to monitor treatment and detect early signs of complications, particularly retinopathy, which can in many cases be treated successfully, and nephropathy, as treatment may slow its progression.

The aims of treatment are two-fold: to alleviate symptoms and prevent the acute metabolic complications of diabetes, and to prevent long-term complications. The first of these objectives is usually attainable with dietary control (essentially, substitution of complex for simple carbohydrates, an increase in dietary fibre and restriction of energy intake when necessary) with or without oral hypoglycaemic agents in patients with type 2 DM (at least initially: insulin is often required later in the course of the condition), and with diet and insulin in patients with type 1 DM.

The demonstration that intensive glycaemic control reduces the risk of microvascular complications in diabetes means that the goal of treatment should be to attempt to maintain the blood glucose concentration within the physiological range. In practice, this may be difficult to achieve, and intensification of treatment increases the risk of episodes of hypoglycaemia, particularly in patients treated with insulin. Indeed, some insulin-treated patients prefer to avoid the risk of hypoglycaemia by maintaining a level of glycaemic control that prevents the development of symptomatic acute hyperglycaemia but is less than optimal in terms of reducing the risk of complications long term. Treatment targets should be set and agreed individually with patients (see below).

It is beyond the scope of this book to discuss treatment strategies in detail. In type 1 DM, there is an increasing tendency to use ‘basal–bolus’ regimens of insulin injections, whereby a long-acting insulin is given at night (to mimic the basal insulin secretion that occurs even during fasting) with boluses of short-acting insulin at meal times. Such regimens can provide plasma insulin concentrations that more closely mimic those seen in non-diabetic individuals. They also allow greater flexibility with regard to meals (timing and content) than the traditional twice daily injections of short- and long-acting insulins. Continuous subcutaneous insulin infusion is also being used, but is demanding for the patient. Although alternative routes for insulin administration are being actively explored, the only licensed preparations currently available in the UK are for injection

In patients with type 2 DM, improved control over that achieved with oral hypoglycaemics alone can often be achieved by giving a single injection of a long-acting insulin at night, continuing with the oral agents during the day, but standard insulin regimens may be required for some patients.

Drugs used in the treatment of type 2 DM include metformin, a biguanide, the precise mechanism of action of which is unclear but which appears to increase sensitivity to insulin; sulphonylureas, which enhance insulin secretion; thiazolidinediones (glitazones), activators of the peroxisome proliferator-activated receptor γ (PPARγ), which enhance the actions of insulin; and meglitinides, rapidly (and short) acting insulin secretagogues. More recently, drugs based on the action of incretins have been developed. These are of two types: incretin enhancers and incretin mimetics. The first group (the gliptins) act by inhibiting dipeptidyl peptidase 4 (DPP-4), an enzyme responsible for the rapid degradation of GLP-1. The second group (e.g. exenatide and liraglutide) mimic the action of GLP-1 and are resistant to degradation by DPP-4.

It is sometimes considered that less strict glycaemic control may be acceptable in older patients developing type 2 DM on the basis that their life expectancy is such that they are not at significant risk of developing long-term complications. Such patients may not experience acute symptoms of hyperglycaemia, even with persisting blood glucose concentrations of the order of 15 mmol/L, and they are not at significant risk of developing ketoacidosis. However, although such a view may sometimes be appropriate, and the targets of treatment should always be assessed on an individual basis, the underlying metabolic abnormality will often have been present for several years before clinical presentation, and indeed patients with type 2 DM sometimes present clinically as a result of complications rather than symptoms of hyperglycaemia.

Whatever the treatment, the fluctuations in blood glucose concentration that occur in most diabetic patients are still greater than those that occur in normal subjects.

Monitoring treatment

The efficacy of treatment in diabetes is monitored clinically, by ensuring that the patient’s symptoms are controlled, and by measurement of blood glucose concentration and other objective indicators of glycaemic control.

Many patients (or their carers) monitor their own blood glucose concentrations at home using reagent strips and a glucose meter (see p. 184). This may be done more or less frequently as circumstances require: exercise, illness or a change of diet may alter insulin requirements, and more frequent testing will allow the patient to adjust the dosage accordingly. In type 1 diabetes, currently recommended targets for treatment in adults in the UK are preprandial blood glucose concentrations of 4.0–7.0 mmol/L and postprandial concentrations of <9.0 mmol/L. The corresponding figures in children are 4.0–8.0 mmol/L and <10 mmol/L. Urine testing for glucose is now little used; it should not be used to monitor type 1 diabetes. Such testing is only semi-quantitative and is of no value in the detection of hypoglycaemia: the urine is virtually free of glucose at normal blood glucose concentrations. Urine glucose excretion also depends on the renal threshold for glucose: if this is low (as, for example, in renal glycosuria, p. 198) glucose may be present in the urine at normal blood glucose concentrations. Urine testing for glucose should be used in type 2 diabetes only in patients unable or unwilling to do blood tests, and in older patients in whom control may not need to be so strict, particularly if they are treated with diet alone.