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ORAL GLUCOSE TOLERANCE TEST
CHAPTER ONE
INTRODUCTION
In the late 1970s, both World Health Organization (WHO) and the National Diabetes Data Group produced new diagnostic criteria and a new classification system for diabetes mellitus (World Health Organization, 1985). This brought order to a chaotic situation in which nomenclature varied and diagnostic criteria showed enormous variations using different oral glucose loads. In 1985 WHO slightly modified their criteria to coincide more closely with the NDDG values. There are now many data available, and also much more aetiological information has appeared. It seemed timely to re-examine the issues and to update and refine both the classification and the criteria, and to include a definition of the "Metabolic Syndrome" (World Health Organization, 1985).
An American Diabetes Association (ADA) expert group was convened to discuss these issues. It published its recommendations in 1997. WHO convened a Consultation on the same subject in London, United Kingdom, in December 1996 (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). In general, the ADA and WHO groups reached similar conclusions.
1.1 LITERATURE REVIEW
One hundred years ago, the answer seemed easy enough. Diabetes was a condition with characteristic symptoms and glucose in the urine. Furthermore, those affected were obviously unwell and would deteriorate or die in the absence of effective therapy. Physicians such as Elliot Joslin (1870-1962) were well aware that some individuals had a higher than normal blood-glucose without symptoms, and even used the term “prediabetes” to describe them, but did not consider the diagnosis useful to make .
The 1930s showed increasing awareness of the problem of late complications of diabetes. Physicians became aware that insulin was not a panacea and that the life expectancy of insulin was reduced by conditions such as diabetic nephropathy and heart disease (Finch , Zimmet , Albert, 1997). Fifty years were to pass before it was demonstrated that treatment directed towards careful control of blood-glucose levels could prevent or delay the small vessel complications of diabetes.
Before the 1950s, there were only two treatments of diabetes: diet and insulin. Diet was the mainstay of those deemed not to need insulin, and little effort was made to screen for diabetes. Urine tests were used for routine screening and undoubtedly failed to detect many people with a raised blood-glucose that did not exceed the renal threshold for glucose (De Vegt et al., 1997).
The basis for treating hyperglycemia was provided by large population studies, the most famous of which was the Framingham study in the USA. By following the health of several thousand individuals prospectively, the investigators identified simple clinical measures which predicted future health problems. Prominent among these were “risk factors” (a term coined in the course of the study) such as hypertension, hypercholesterilaemia and hyperglycaemia. A disease was no longer something that made you ill, but something that – although asymptomatic – could easily turn into something that made you ill.
This was the prelude to the first large controlled intervention trials, made possible by the availability of the thiazides to treat hyoertension, and of introduction of tolbutamide, the first sulfonylurea agent in 1957. The first trials of antihypertensive therapy were dramatically successful but the first major trial of antidiabetic therapy program (UGOP) appeared to show that treatment with sulfonylureas or phenformin actually increased the cardiovascular mortality associated with diabetes (Harris, Eastman, Cowie, Flegal, Eberhardt, 1997).
Clinicians, meanwhile still argued as to the glucose level that defined diabetes. It was generally agreed that the oral glucose tolerance test (OGTT) was the best means of diagnosis but there was wide discrepancy as to his interpretation.
The situation was resolved by prospective population studies which examined the risks associated with hyperglycaemia, including studies of Pima Indians in the US and the Whitehall study in the UK. These indicated that diabetic retinopathy was much more commonly seen in those with 2 hours glucose values > 200mg/dl (11.1mmol/L) following an OGTT and this went on to become the agreed cut off for the definition of diabetes, prospective study also revealed the existence of an intermediate group with 2-hour values of 140-200mg/dl (7.2-11.1mmol/L). These people had an increased cardiovascular mortality (as seen in those with Frank diabetes) but a low risk of small vessel complications. This was termed impaired glucose tolerance (IGT) and was considered not to require specific glucose lowering therapy (Ramachandran, Snehalatha, Latha, Vijay, 1998 ).
The Diabetes Control and Complications Trial (DCIT) and the UK Prospective Diabetes Study (UKPDS) proved beyond doubt that intensified glucose control was effective in preventing the microvascular complications of diabetes, but the benefits for arterial disease appeared more marginal. This has been confirmed by a series of large clinical trials which examined cardiovascular risk in relation to glucose control. These results were generally disappointing and mainly served to emphasise the importance for other risk factors (smoking, blood pressure, lipids) in the management of diabetes (Kuzuya, Matsuda, 1997).
1.2 DEFINITION OF DIABETES MELLITUS
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both (Kuzuya T, Matsuda A, 1997). The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease (Hoet, Tripathy, Rao, Yajnik, 1996).
Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.
1.2.1 DIAGNOSIS
If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully established since the consequences for the individual are considerable and lifelong. The requirements for diagnostic confirmation for a person presenting with severe symptoms and gross hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to be just above the diagnostic cut-off value. Severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value. For the asymptomatic person, at least one additional plasma/blood glucose test result with a value in the diabetic range is essential, either fasting, from a random (casual) sample, or from the oral glucose tolerance test (OGTT). If such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance with periodic re-testing until the diagnostic situation becomes clear. In these circumstances, the clinician should take into consideration such additional factors as ethnicity, family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action. An alternative to blood glucose estimation or the OGTT has long been sought to simplify the diagnosis of diabetes (Hoet, Tripathy, Rao, Yajnik, 1996). Glycated haemoglobin, reflecting average glycaemia over a period of weeks, was thought to provide such a test. Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement (6), it is not available in many parts of the world and is not well enough standardized for its use to be recommended at this time.
Diagnostic Criteria
The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma; high levels of glycosuria are usually present (Hoet, Tripathy, Rao, Yajnik, 1996). For clinical purposes, an OGTT to establish diagnostic status need only be considered if casual blood glucose values lie in the uncertain range (i.e. between the levels that establish or exclude diabetes) and fasting blood glucose levels are below those which establish the diagnosis of diabetes. If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 hours after a 75 g oral glucose load.
Glucose concentration, mmol l-1 (mg dl-1)
Whole blood Whole blood Plasma*
Venous Capillary Venous
Diabetes Mellitus:
Fasting >=6.1 (>=110) >=6.1 (>=110) >=7.0 (>=126)
or
2-h post glucose load >=10.0 (>=180) >=11.1 (>=200) >=11.1 (>=200)
or both Impaired Glucose Tolerance (IGT):
Fasting (if measured) <6.1 (<110) <6.1 (<110) <7.0 (<126)
and 2-h post glucose load >=6.7 (>=120) and >=7.8 (>=140) and >=7.8 (>=140) and
<10.0 (<180) <11.1 (<200) <11.1 (<200)
Impaired Fasting Glycaemia (IFG):
Fasting >=5.6 (>=100) and >=5.6 (>=100) and >=6.1 (>=110) and
<6.1 (<110) <6.1 (<110) <7.0 (<126)
and (if measured) 2-h post glucose load <6.7 (<120) <7.8 (<140) <7.8 (<140)
* Corresponding values for capillary plasma are: for Diabetes Mellitus, fasting >=7.0 (>=126), 2-h >=12.2 (>=220); for Impaired Glucose Tolerance, fasting <7.0 (<126) and 2-h >=8.9 (>=160) and <12.2 (<220); and for Impaired Fasting Glycaemia >=6.1 (>=110) and <7.0 (<126) and if measured, 2-h <8.9 (<160).
For epidemiological or population screening purposes, the fasting or 2-h value after 75 g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms (Tripathy, Samal, 1997).
Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable under-estimation of the true concentrations. It should be stressed that glucose preservatives do not totally prevent glycolysis. If whole blood is used, the sample should be kept at 0-4 °C or centrifuged immediately, or assayed immediately.
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