Type 1 diabetes	Type 2 diabetes
β-cell destruction	No β-cell destruction
Islet cell antibodies present	No islet cell antibodies present
Strong genetic link	Very strong genetic link
Age of onset usually below 30	Age of onset usually above 40
Faster onset of symptoms	Slower onset of symptoms
Insulin must be administered	Diet control and oral hypoglycaemic agents often sufficient control
Patients usually not overweight	Patients usually overweight
Extreme hyperglycaemia causes diabetic ketoacidosis	Extreme hyperglycaemia causes hyperosmolar hyperglycaemic state

Two other varieties of non-typical diabetes that may be seen are latent autoimmune diabetes in adults (LADA) and maturity-onset diabetes of the young (MODY). LADA occurs in younger, leaner individuals who appear to have type 2 diabetes as they do not become ketotic and may manage without insulin for a time. Antiglutamic acid decarboxylase (GAD) antibodies may be present and the individual usually progresses to insulin more rapidly than those with other varieties of type 2 diabetes. MODY was noted over 30 years ago and described a subset of type 2 diabetes of young onset, often with a positive family history. Genetic studies have now identified this to be a monogenic autosomal dominant form of diabetes. MODY related to the glucokinase gene typically causes a resetting of the glucose level with a ‘mild’ non-progressive hyperglycaemia in which diet treatment is usually sufficient. Other types of MODY are related to mutations in the hepatocyte nuclear factor genes and usually develop during adolescence or the early 20s. Pharmacological treatment is required, but sulphonylureas are extremely effective and insulin can usually be avoided.

Epidemiology

The incidence of type 1 diabetes is increasing worldwide, for unknown reasons. It is speculated that environmental changes may be causing modification to the diabetes-associated alleles. Also, since the introduction of insulin in the 1930s, an increasing number of people with type 1 diabetes have had children. There are major ethnic and geographical differences in the prevalence and incidence of type 1 diabetes. Figures are highest in Caucasians (especially Scandinavians), while the disorder is rare in Japan and the Pacific area. In northern Europe, the prevalence is approximately 0.3% in those under 30 years of age. Type 1 diabetes may present at any age, but there is a sharp increase around the time of puberty and a decline thereafter. Approximately 50–60% of patients with type 1 will present before 20 years of age.

Type 2 diabetes is much more common than type 1, accounting for 90% of people with diabetes. It usually occurs in those over the age of 40 years. Estimates in the UK suggest that type 2 diabetes currently affects approximately 2.3 million people, and up to another 500,000 are thought to be undiagnosed. The incidence of type 2 rises with age and with increasing obesity. As with type 1, there are major ethnic and geographical variations. In general, in non-obese populations, the prevalence is 1–3%. In the more obese societies, there is a sharp increase in prevalence with estimates of 6–8% in the USA, increasing to values as high as 50% in the Pima Indians of Arizona. Diabetes is six times more common among Asian immigrants in the UK than in the indigenous population. World studies of immigrants have suggested that the chances of developing type 2 are between two and 20 times higher in well-fed populations than in lean populations of the same race.

Aetiology

Both genetic and environmental factors are relevant in the development of type 1 diabetes, but the exact relationship between the two is still unknown. There is a strong immunological component to type 1 and a clear association with many organ-specific autoimmune diseases. Circulating islet cell antibodies (ICAs) are present in more than 70% of those with type 1 at the time of diagnosis. Family studies have shown that the appearance of ICAs often precedes the onset of clinical diabetes by as much as 3 years. Type 1 has been widely believed to be a disease of clinically rapid onset, but the development is related to a slow process of progressive immunological damage. However, it is not currently possible to use screening methods to reliably identify patients who will develop diabetes in the future. The final event that precipitates clinical diabetes may be caused by sudden stress such as an infection when the mass of β-cells in the pancreas falls below 5–10%.

Studies have been carried out in which patients with newly diagnosed type 1 were treated with immunosuppressive therapies such as ciclosporin, azathioprine, prednisolone and antithymocyte globulin. When started soon after diagnosis, these therapies showed transient improvements in clinical measures and increased the rate of remissions in which insulin was not required. However, their use is limited in an otherwise healthy and young population due to potential toxicity and the risks associated with immune suppression.

Studies have investigated the use of anti-CD3 monoclonal antibodies. When newly diagnosed type 1 patients are treated with short courses of anti-CD3 monoclonal antibodies, smaller insulin doses are required. This relates to better preservation of β-cell function.

Type 2 diabetes also has a strong genetic predisposition. Identical twins have a concordance rate approaching 100%, suggesting the relative importance of inheritance over environment. If a parent has type 2, the risk of a child eventually developing type 2 is 5–10% compared with 1–2% for type 1. Type 2 diabetes occurs because of the progressive development of insulin resistance and β-cell dysfunction, the latter leading to an inability of the pancreas to produce enough insulin to overcome the insulin resistance. About 85% of people with type 2 diabetes are obese. This highlights the clear association between type 2 and obesity, with obesity causing insulin resistance. In particular, central obesity, where adipose tissue is deposited intra-abdominally rather than subcutaneously, is associated with the highest risk. Body mass index (BMI) has been used as an indicator for predicting type 2 risk; however, it does not take fat distribution into account, so waist circumference measurements are now being increasingly used.

Pathophysiology

The islets of Langerhans form the endocrine component of the pancreas, constituting 1% of the total pancreatic mass. Insulin is synthesised in the pancreatic β-cells, initially as a polypeptide precursor, preproinsulin. The latter is rapidly converted in the pancreas to proinsulin. This forms equal amounts of insulin and C-peptide through removal of four amino acid residues. Insulin consists of 51 amino acids in two chains (the A chain contains 21 amino acids and B chain contains 30), connected by two disulphide bridges. In the islets, insulin and C-peptide (and some proinsulin) are packaged into granules. Insulin associates spontaneously into a hexamer containing two zinc ions and one calcium ion.

Glucose is the major stimulant to insulin release. The response is triggered both by the intake of nutrients and the release of gastro-intestinal peptide hormones. Following an intravenous injection of glucose, there is a biphasic insulin response. There is an initial rapid response in the first 2 min, followed after 5–10 min by a second response which is smaller but sustained over 1 h. The initial response represents the release of stored insulin and the second phase reflects discharge of newly synthesised insulin. Glucose is unique; other agents, including sulphonylureas, do not result in insulin biosynthesis, only release. Once released from the pancreas, insulin enters the portal circulation. The liver rapidly degrades it and only 50% reaches the peripheral circulation. In the basal state, insulin secretion is at a rate of approximately 1 unit/h. The intake of food results in a prompt five- to tenfold increase. Total daily secretion is approximately 40 units.

Insulin circulates free as a monomer, has a half-life of 3–5 min and is primarily metabolised by the liver and kidneys. In the kidneys, insulin is filtered by the glomeruli and reabsorbed by the tubules and degraded. In both renal and hepatic disease, there is a decrease in the rate of insulin clearance, which may necessitate dosage reduction for those using exogenous insulin. Peripheral tissues such as muscle and fat also degrade insulin, but this is of minor quantitative significance.

The interaction of insulin with the receptor on the cell surface sets off a chain of messengers within the cell. This opens up transport processes for glucose, amino acids and electrolytes.

In type 1 diabetes, there is an acute deficiency of insulin that leads to unrestrained hepatic glycogenolysis and gluconeogenesis with a consequent increase in hepatic glucose output. Also, glucose uptake is decreased in insulin-sensitive tissues such as adipose tissue and muscle; hence, hyperglycaemia ensues. Either as a result of the metabolic disturbance itself or secondary to infection or other acute illness, there is increased secretion of the counter-regulatory hormones glucagon, cortisol, catecholamine and growth hormone. All of these will further increase hepatic glucose production.

In type 2 diabetes, the process is usually less acute, since insulin production decreases over a sustained period of time. Hyperinsulinaemia is able to maintain glucose levels for a period of time, but eventually β-cell function deteriorates and hyperglycaemia ensues. If this cycle is not interrupted, type 2 diabetes develops. Impaired glucose tolerance (IGT), impaired fasting glucose or hyperinsulinaemia may be detected before overt diabetes develops, and if so, a strict diet and exercise regimen leading to weight loss and improved insulin sensitivity may delay or even prevent the onset of diabetes. At the time of diagnosis, those with type 2 diabetes may have already lost about 50% of their β-cell function. Irrespective of treatment, β-cell function continues to decline with time, often leading to the need for regular insulin therapy.

Type 2 diabetes is also associated with the metabolic syndrome (or syndrome X), although the real relevance of this ‘syndrome’ continues to be debated in the literature (Khan et al., 2005). The metabolic syndrome is a group of risk factors commonly found in those with type 2 diabetes, including insulin resistance, glucose intolerance (type 2 diabetes or IGT), hyperinsulinaemia, hypertension, dyslipidaemia, central obesity, atherosclerosis and increased levels of procoagulant factors, for example, plasminogen activator inhibitor-1 and fibrinogen.

Pathophysiology of insulin resistance

Abdominal fat, found in abundance in the majority of those with type 2 diabetes, is metabolically different from subcutaneous fat and can cause ‘lipotoxicity’. Abdominal fat is resistant to the antilipolytic effects of insulin, resulting in the release of excessive amounts of free fatty acids, which in turn lead to insulin resistance in the liver and muscle. The effect is an increase in gluconeogenesis in the liver and an inhibition of insulin-mediated glucose uptake in the muscle. Both these result in increased levels of circulating glucose. Further, excess fat itself may contribute to insulin resistance because when adipocytes become too large they are unable to store additional fat, resulting in fat storage in the muscles, liver and pancreas, causing insulin resistance in these organs.

Excess intra-cavity adipose tissue causes the oversecretion of some cytokines (adipokines or adipocytokines) associated with inflammation, endothelial dysfunction and thrombosis. Examples of such adipokines include plasminogen activator inhibitor-1 (which is prothrombotic), tumour necrosis factor-α and interleukin-6 (which are proinflammatory) and resistin (which causes insulin resistance). The atherosclerosis associated with insulin resistance is due to hypercoagulability, impaired fibrinolysis and the toxic combination of endothelial damage (caused by chronic, subclinical inflammation), oxidative stress and hyperglycaemia. Excess adipose tissue is also thought to cause undersecretion of a beneficial adipokine called adiponectin. Adiponectin suppresses the attachment of monocytes to endothelial cells, thereby protecting against vascular damage. People with type 2 diabetes have lower levels of adiponectin than those without diabetes and weight reduction increases adiponectin levels.

Clinical manifestations

The symptoms of both type 1 and type 2 diabetes are similar, but they usually vary in intensity. Those associated with type 1 diabetes are more severe and faster in onset. The symptoms are related to the osmotic effects of glucose and the abnormalities of energy partitioning. Common symptoms include polyuria (increased urine production, particularly noticeable at night) and polydipsia (increased thirst). These are a consequence of osmotic diuresis secondary to hyperglycaemia. These symptoms are frequently accompanied by fatigue due to an inability to utilise glucose and marked weight loss because of the breakdown of body protein and fat as an alternative energy source to glucose. Blurred vision caused by a change in lens refraction may also occur and patients should be advised that as glucose levels are normalised, vision normally improves and new spectacles should be avoided for the first 3 months of effective treatment of the hyperglycaemia. Patients may also experience a higher infection rate, especially Candida, and urinary tract infections due to increased urinary glucose levels.

Type 1 diabetes

The metabolic abnormality at presentation of an individual with type 1 diabetes is often profound. The symptoms mentioned earlier are usually extreme and of recent (days or weeks) onset. In a significant proportion, the presenting symptoms are those of diabetic ketoacidosis, nausea, vomiting, dehydration, shortness of breath secondary to an attempt by the respiratory system to neutralise the metabolic acidosis caused by the ketones and, in extreme cases, coma.

Type 2 diabetes

Many patients with type 2 diabetes have an insidious onset of hyperglycaemia, with few or no classic symptoms. This is particularly true in obese individuals, whose diabetes may be detected only after glycosuria or hyperglycaemia is found serendipitously. Some patients are unaware of the disease even with marked classic symptoms as they begin so gradually and over such a long period of time. Recurring infections, for example, urinary tract, chest, soft tissue, are common because sustained hyperglycaemia can result in severe impairment of phagocyte function, and raised glucose levels provide a growth medium for bacteria.

Generalised pruritus and symptoms of vaginitis, which may be due to candidal infection, are frequently the initial complaints of women with type 2 diabetes. Patients often present when the complications of sustained hyperglycaemia have already developed, for example, cardiovascular disease or renal disease. Retinopathy may be detected on routine ophthalmological examination. Alternatively, a combination of neuropathy, peripheral vascular disease (PVD) and infection may manifest as foot ulceration or gangrene. In some cases, patients present with hyperosmolar hyperglycaemic state (HHS) where glucose levels in excess of 35 mmol/L are found and excessive dehydration has occurred. Occasionally, patients with type 2 diabetes present with diabetic ketoacidosis, especially in severe infection or in those of African/Caribbean descent.

Diagnosis

In June 2000, the UK formally adopted the World Health Organization criteria for diagnosing diabetes mellitus that was initially published in 1999. It has since been updated and the diagnostic criteria have been reiterated (World Health Organization, 2006).

1. Diabetes symptoms (i.e. polyuria, polydipsia and unexplained weight loss) plus:

• a fasting serum glucose concentration ≥7.0 mmol/L

• or serum glucose concentration ≥11.1 mmol/L 2 h after 75 g anhydrous glucose in an oral glucose tolerance test (see later).

2. With no symptoms, diagnosis should not be based on a single glucose determination but requires confirmatory serum venous determination. At least one additional glucose test result, on another day with the value in the diabetic range, is essential, either fasting or from the 2-h post-glucose load. If the fasting value is not diagnostic, the 2-h value should be used.

Current recommendations are that the diagnosis is confirmed by a glucose measurement performed in an accredited laboratory on a venous serum sample. A diagnosis should never be made on the basis of glycosuria or a stick reading of a finger prick blood glucose alone, although such tests are being examined for screening purposes. Glycated haemoglobin (HbA_1c) is also not currently recommended for diagnostic purposes, although this is currently being considered.

Glucose tolerance test

The patient should not be taking any drugs which interfere with glucose handling. A normal diet with at least 150 g of carbohydrate per day should be consumed for the 3 days before the test, but the patient should be fasted from 8 pm (except for water) on the day before the test. The test should commence at around 9 am with a venous serum glucose test, followed by the administration of 75 g of glucose by mouth over a 5-min period. This is often given in the form of 394 mL of Lucozade® original. The second venous serum glucose sample is then taken 2 h after the drink. The patient should be seated and is not permitted to smoke, eat or drink anything other than water until the test is complete. As there is a risk of later-onset hypoglycaemia in some individuals, it is advisable to suggest that the patient has something to eat immediately upon completion of the test, especially if he/she is planning to drive.

Diabetic emergencies

Hypoglycaemia and extreme hyperglycaemia, causing diabetic ketoacidosis or hyperosmolar hyperglycaemic state, constitute the three acute emergencies associated with diabetes.

Hypoglycaemia

Hypoglycaemia can occur both with insulin treatment and in those taking some oral agents, especially the longer-acting sulphonylureas, for example, chlorpropamide and glibenclamide. Definitions of hypoglycaemia vary, and in particular, there is no WHO definition. However, symptoms caused by the release of counter-regulatory hormones predominantly adrenaline (epinephrine), noradrenaline (norepinephrine) and glucagon tend to occur when the venous serum glucose drops below 3.0 mmol/L in healthy individuals. These symptoms described in Box 44.2 are a normal physiological response to hypoglycaemia and should alert the person to consume carbohydrates. Individuals may not respond appropriately to hypoglycaemia of this degree for several reasons, termed hypoglycaemia unawareness. First, the relevance of the symptoms has not been explained to them. This is an educational failing. It is imperative, therefore, that people with diabetes who are prescribed medication which is known to cause hypoglycaemia should be educated about the autonomic symptoms so that they may take action to avoid further decline of serum glucose. Second, the symptoms simply may not occur because of autonomic neuropathy. One of the commonest complications of diabetes is neuropathy, and when this includes the autonomic nervous system, there are no reliable symptoms to warn the individual that they are hypoglycaemic. A similar situation may occur as a consequence of drugs which suppress autonomic symptoms, such as β-blockers. Third, the patient may have recurrent hypoglycaemia. In those individuals who suffer frequent hypoglycaemic episodes, the autonomic symptoms may cease to occur. There is some evidence that the symptoms can be regained if, for a period of a few weeks, the serum glucose level can be maintained out of the hypoglycaemic range. Finally, the individual may be hypoglycaemia unaware because of alcohol intoxication.

If the serum glucose is allowed to drop to around 2 mmol/L, there are acute changes in cerebral function which lead initially to confusion. This is followed by coma, seizures and death if the glucose drops below about 0.5 mmol/L. Any cerebral malfunction is termed neuroglycopaenia.

Causes of hypoglycaemia

The most common causes of hypoglycaemia are either a decrease in carbohydrate consumption, excess carbohydrate utilisation from unexpected exercise or increase in circulating insulin (Table 44.2).

Table 44.2 Causes of hypoglycaemia

Cause	Comment
Missed meals or delays in eating	Reduced carbohydrate intake, therefore reduction in glucose levels
Not eating the usual amount of carbohydrates	Reduced carbohydrate intake, therefore reduction in glucose levels
Increased doses of insulin	Increased uptake of glucose into cells and increased storage of glucose as glycogen
Increased doses of oral insulin secretagogues	Increased levels of insulin therefore increased uptake of glucose into cells and increased storage of glucose as glycogen
Introduction of other blood glucose-lowering agents to oral insulin secretagogues	Enhanced hypoglycaemic effects
Increase in exercise	Increased uptake of glucose into cells
Excessive alcohol consumption	Impaired gluconeogenesis
Liver disease	Impaired gluconeogenesis and glycogenolysis