Oral glucose tolerance test

The ADA (1997) proposed measurement of fasting glucose as the principal means of diagnosing type diabetes. The WHO (1998) placed emphasis on the oral glucose tolerance test as the ’gold standard’, with both fasting and 120-min values being taken into consideration. Only when an OGTT cannot be performed should the diagnosis rely on fasting levels.

The OGTT is the most robust means of establishing the diagnosis of diabetes. Glucose tolerance tests should be carried out under controlled conditions after an overnight fast.

The patient is prepared as detailed in Table 1.1:

Table 1.1 Preparation for a fasting blood test

Interpretation of the results of a 75-g glucose tolerance test is presented in Table 1.2. Note that results apply to venous plasma: whole blood values are 15% lower than corresponding plasma values if the haematocrit is normal. For capillary whole blood, the diagnostic cut-offs for diabetes are ≥ 6.1 mmol/L (fasting) and 11.1 mmol/L (i.e. the same as for venous plasma). The range for impaired fasting glucose based on capillary whole blood is ≥ 5.6 and < 6.9 mmol/L. Note that marked carbohydrate deprivation can impair glucose tolerance; the subject should have received adequate nutrition in the days preceding the test.

Table 1.2 Interpretation of 75-g oral glucose tolerance test

Intercurrent illness

Patients under the physical stress associated with surgical trauma, acute myocardial infarction, acute pulmonary oedema or stroke may have transient increases of plasma glucose that often settle rapidly without specific antidiabetic therapy. However, such clinical situations are also liable to unmask asymptomatic pre-existing diabetes or to precipitate diabetes in predisposed individuals. Such increases, which may have short- and longer-term prognostic importance, should not be dismissed; as a minimum, appropriate follow-up and retesting is indicated following resolution of the acute illness. If there is doubt about the significance of hyperglycaemia, the blood glucose level should be rechecked 30–60 min later and the urine tested for ketones.

If hyperglycaemia is sustained, treatment with insulin may be indicated. More marked degrees of hyperglycaemia, particularly with ketonuria, demand vigorous treatment in an acutely ill patient.

Non-diabetic hyperglycaemia

As detailed above, impaired fasting glycaemia (IFG) is defined as a fasting glucose > 5.6 and < 7.0 mmol/L, whereas impaired glucose tolerance (IGT) is defined as fasting glucose < 7 mmol/L and 2-h glucose > 7.8 and < 11.1 mmol/L. IGT and IFG are both associated with an increased risk of future diabetes. However, IFG and IGT appear to have different underlying aetiologies. IFG reflects raised hepatic glucose output and a defect in early insulin secretion, whereas IGT predominantly reflects peripheral insulin resistance. IGT is also associated with an increased risk of cardiovascular disease (CVD) independently of other risk factors. The magnitude of this increased risk varies between studies, but for cardiovascular disease mortality the odds ratio was 1.34 (95% CI 1.14–1.57) in the DECODE (2003) meta-analysis. IFG appears to have only a slightly increased risk of CVD independently of other factors.

The term ‘pre-diabetes’, which is sometimes used to refer to IGT and/or IFG, is no longer the preferred term because not all patients go on to develop diabetes. A significant proportion of individuals who have impaired glucose tolerance diagnosed by an OGTT revert to normal glucose tolerance on retesting. Non-diabetic hyperglycaemia (NDH) is increasingly being used as a wider term that encompasses hyperglycaemia where the HbA1c level is raised but is below the diabetic range (Table 1.3).

Table 1.3 Diagnostic criteria for diabetes mellitus and non-diabetic hyperglycaemia

Glycated haemoglobin (HbA1c)

The ADA Joint Expert Committee has recommended HbA1c as a diagnostic tool with a cut-off ≥ 6.5% to diagnose diabetes. HbA1c is well established as a marker of glycaemic control in people with established diabetes as it reflects average plasma glucose over the previous 2–3 months. In addition, HbA1c has a number of advantages over fasting blood glucose or OGTT. HbA1c can be measured at any time of day and does not require special preparation such as fasting.

However, HbA1c testing is not widely available in many countries throughout the world and there are aspects of its measurement that are problematic. These include anaemia, abnormalities of haemoglobin, pregnancy and uraemia. Some of these problems may be a bigger problem in under-resourced countries owing to the high prevalence of anaemia and haemoglobinopathies.

Molecular genetic testing

Knowledge of the genotype in the unaffected child of a patient with this syndrome offers the possibility of a firm diagnosis or, importantly, exclusion of the possibility of diabetes in later life. If the genetic testing is negative, no screening will be necessary and individuals and their families can be reassured. If an unaffected offspring is found to have a MODY2 mutation, then annual testing of fasting plasma glucose and, for females, awareness of the importance of excellent glycaemic control before conception and during pregnancy are required. Identification of a MODY1 or MODY3 genotype necessitates more rigorous, regular screening through childhood, adolescence and early adult life to detect the development of diabetes, as pharmacological treatment, including insulin, is likely to prove necessary. Such testing raises ethical issues and it has been suggested that it should be offered only after appropriate genetic counselling. Whether such knowledge will ultimately allow intervention to prevent or retard the appearance of diabetes is currently uncertain.

Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness. The most common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like) syndrome; however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion.

Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern. The resultant glucose intolerance is mild. Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families. It is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism.