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The World Health Organization’s classification of diabetes (WHO 1985) has been adopted internationally. The American Diabetes Association re-examined the diagnostic criteria and classification and recommended modifications in 1997, subsequently agreed by WHO (The Expert Committee 1997, Alberti et al 1998). The terms type 1 and type 2 diabetes (Table 1.1) replaced the old categories of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). The older classification was based upon treatment (many NIDDM patients are on insulin), but did not indicate the nature of the underlying cause (Wroe 1997).

TABLE 1.1 1997–1998 ADA and WHO classification of diabetes mellitus

Type 1
(beta-cell destruction, usually leading to absolute insulin deficiency)
Type 2
(may range from predominately insulin resistance with relative insulin deficiency to a predominately secretory defect with or without insulin resistance)
Other specific types
Genetic defects of beta-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Drug- or chemical-induced
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes mellitus (includes gestational impaired glucose tolerance)

Types 1 and 2 diabetes are compared in Table 1.2.

TABLE 1.2 Comparison of the characteristics of types 1 and 2 diabetes mellitus (Beers 1999)

Characteristic Type 1 diabetes Type 2 diabetes
Commonest age at onset Usually <30 years Most often >30 years, but note recent trends
Associated obesity No Yes
Propensity to develop ketoacidosis (requiring insulin to prevent/control) Yes No
Presence of classic symptoms of hyperglycaemia at diagnosis Yes, often severe May be absent
If present, often moderate
Endogenous insulin secretion Very low to undetectable Variable, but low relative to plasma glucose levels
Insulin resistance Not present Yes, but variable
Twin concurrence <50% >90%
Associated with specific HLA-D antigens Yes No
Islet cell antibodies at diagnosis Yes No
Islet pathology Insulitis, selective loss of most beta cells Smaller, normal-looking islets
Amyloid deposits common
Associated increased risks for micro-and macrovascular disease Yes Yes
Hyperglycaemia responds to oral agents No Yes, initially in most patients

© 2006 by Merck & Co., Inc., Whitehouse Station, NJ, USA



The distribution of plasma glucose concentrations is a continuum; so there needs to be a threshold that separates those who are at a substantially increased risk of developing adverse outcomes caused by diabetes from those who are not (The Expert Committee 2003b). The medical, social and economic costs of making a diagnosis in those not at increased risk must be balanced against the costs of failing to diagnose those at increased risk.

Historically, this threshold was determined by the relationship between blood glucose levels and microvascular complications in type 1 diabetics: however, it may be more important that this threshold is determined by the relationship between blood glucose levels and macrovascular risk in a wider population (i.e. those with either impaired glucose tolerance or type 2 diabetes).

The WHO and other bodies have adopted the ADA’s diagnostic criteria (The Expert Committee 1997), but there have been different recommended optimal methods of diagnosis. The WHO prefers the OGTT, supported by evidence that 2 hour post-load plasma glucose levels were more accurate than fasting plasma glucose levels in identifying those at increased risk of death associated with hyperglycaemia (DECODE 1999). The drawback of ADA’s preference for fasting plasma glucose levels is that “normal” results carry the risk of missing some diabetics, especially among the elderly and in some ethnic groups: the earliest defect in the natural history of beta cell dysfunction is the reduction of first-phase insulin release, associated with 2 hour post-load hyperglycaemia.

Although diabetes is “arbitrarily” and solely diagnosed on the basis of blood glucose levels, it should be regarded as a syndrome that includes other metabolic and haemodynamic features.



The chronic hyperglycaemia of type 2 diabetes results from diverse and progressive disease processes that cause:

In type 2 diabetes, both of these defects coexist and both can be caused by a plethora of genetic or environmental factors. Most commonly, type 2 diabetes appears to be inherited as a polygenic trait, with environmental factors also involved, often at a very young age.

Secretion of insulin, in response to rising blood glucose levels, occurs in two phases in healthy individuals:

Early in type 2 diabetes, β-cells begin to lose their initial response of increased insulin secretion (“first phase”). Sustained hyperglycaemia reduces β-cell function by “glucose toxicity”. With progression of the disease, the loss of first-phase secretion leads to early post-prandial hyperglycaemia, exaggerated late (“second-phase”) insulin secretion and late post-meal hypoglycaemia. Insulin secretory pulses become abnormal under basal conditions. The loss of first-phase insulin secretion, which leads to post-prandial glucose “spikes”, is associated with an increased risk of cardiovascular disease.

In insulin resistance, insulin is unable to produce its usual effects at concentrations that are effective in normal individuals. Its onset precedes the development of type 2 diabetes and may arise from a variety of genetic mutations. It is thought that the reduced action of insulin is linked closely with the cardiovascular risk factors, such as obesity, that are part of the insulin resistance syndrome (Reaven 1988).

Malnutrition in utero and during early infancy may be associated with an increased risk of developing type 2 diabetes later in life (the “thrifty phenotype” hypothesis) by affecting both β-cell function and insulin resistance. Regular physical exercise, when undertaken consistently from childhood, can protect against type 2 diabetes by improving insulin sensitivity.


Vascular tissues are freely permeable to glucose. Poor glycaemic control renders such tissues more vulnerable to insult, which starts insidiously and may eventually lead on to the failure of major systems. Abnormalities may occur in endothelial cells, vascular smooth muscle cells, glomeruli and mesangial cells, and cardiomyocytes. The clinical consequences of diabetic microvascular disease include visual impairment, chronic renal failure and neuropathic foot ulceration.

Four main mechanisms (not mutually exclusive) have been implicated in the pathogenesis of glucose-mediated vascular damage:

However, clinical complications are driven by raised blood pressure, dyslipidaemia and multiple other abnormalities, particularly those that contribute to insulin resistance. Some of these precede the onset of type 2 diabetes, by which time atheromatous changes have already been established. This is why prevention or early detection is important.

The precise pathogenesis of atheromatous change in patients with diabetes may vary not just between individuals, but also between sites and different calibre of arteries in the same individual. A better understanding of these mechanisms may help to identify potential therapeutic interventions, although lifestyle modification and vigorous correction of raised blood pressure and dyslipidaemia must remain central to reducing cardiovascular risk.


The term “pre-diabetes” has been used to categorise people with impaired glucose metabolism, but who are not diabetic. Many, but not all, progress to diabetes. The WHO term “intermediate hyperglycaemia” may be more accurate. Whichever term is used, identification followed by appropriate interventions (particularly aimed at optimising lifestyle) can achieve real benefit for this group.


These terms are not interchangeable and do not define identical groups of individuals. The rationale for establishing these intermediate categories of impaired glucose regulation is based on their value in predicting cardiovascular risk (IGT) and future diabetes mellitus (IFG).

Impaired glucose tolerance (IGT) refers to a glucose metabolic state that is intermediate between normal glucose homeostasis and diabetes mellitus. IGT only applies to a plasma glucose level in the range of 7.8 to 11.0 mmol/l at 2 hours after a 75 g glucose load. Patients can be labelled as having IGT only from an OGTT. Individuals with IGT are at increased risk of developing macrovascular disease. IGT progresses to type 2 diabetes in 37% at 5 years (Gillies 2007) and 50% at 10 years (Davies 2006). It is logical to regard IGT as a risk factor rather than as a disease entity, particularly as many individuals with IGT are asymptomatic and have normal plasma glucose levels in their daily lives. Some evidence suggests that the most cost-effective interventions to prevent or delay the onset of diabetes should target individuals with IGT, followed by high-risk groups.

Impaired fasting glucose (IFG) applies only to a fasting plasma glucose level in the range between a lower limit of 6.1 mmol/l (recommended by JBS2, WHO and the IDF) and an upper limit of 6.9 mmol/l. Some patients, particularly elderly or Indo-Asians, can have IFG, but fulfil the diagnostic criteria for diabetes because their 2 hour post 75 g load plasma glucose level is 11.1 mmol/l or greater. Thus, patients with IFG can have either diabetes or IGT or normal glucose homeostasis (based upon the 2 hour result). This has major implications for screening, because a fasting plasma glucose level below the diagnostic threshold for diabetes does not exclude current diabetes.

If IFG is defined as between 6.1 and 6.9 mmol/l, then it includes a much lower proportion of the population than is categorised as having IGT. One review found that of those who had IFG and/or IGT, 16% had both, 23% had IFG alone, and 60% had IGT alone, with significant age and gender differences between the glucose intolerance categories (Unwin et al 2002). IFG and IGT may be different metabolic states. Although the ADA has recommended a reduced lower limit for IFG to 5.6 mmol/l is, on balance, a better predictor for cardiovascular and metabolic outcomes (The Expert Committee 2003a), other guidance (WHO/IDF, JBS2, NICE/NSF still recommends that the lower limit should remain at 6.1 mmol/l (WHO/IDF 2006).

There has been considerable research into the factors that increase the likelihood of an individual with intermediate hyperglycaemia developing diabetes. It is also interesting to look earlier in the natural history at factors that may cause glucose intolerance. Smoking is thought to increase insulin resistance, but the evidence is inconclusive as to whether smoking is an independent risk factor for the development of diabetes. The CARDIA study found that, in young individuals with normal glucose tolerance, both active and passive smoking were associated (more so in whites) with the development of glucose intolerance (Houston et al 2006).