See also separate Diabetes in Pregnancy, Metabolic Syndrome, Managing Impaired Glucose Tolerance In Primary Care and Gestational Diabetes articles.
The oral glucose tolerance test (OGTT) evaluates the efficiency of the body to metabolise glucose. For many years the OGTT was used as the 'gold standard' for diagnosis of diabetes. An increase in postprandial glucose concentration usually occurs before fasting glucose increases. Therefore, postprandial glucose is a sensitive indicator of the risk for developing diabetes and an early marker of impaired glucose tolerance. Evidence has suggested that, when compared with fasting blood glucose, an increased two-hour plasma glucose during an OGTT is a better predictor of both all-cause mortality and cardiovascular mortality or morbidity. However extensive patient preparation is necessary to perform an OGTT. Important conditions include, among others, ingestion of at least 150 g of dietary carbohydrate per day for three days prior to the test, a 10- to 16-hour fast, and commencement of the test between 7:00 am and 9:00 am. In addition, numerous conditions other than diabetes can influence the OGTT. Evidence also indicates a high degree of individual patient variability in the OGTT, with greater variability than fasting blood glucose. The lack of reproducibility, the inconvenience and the cost of the OGTT led to the recommendation that fasting blood glucose should be the preferred glucose-based diagnostic test.
Definitions of diabetes and impaired glucose metabolism
The information in this article is mainly concerned with the diagnosis of type 2 diabetes, where a lack of symptoms, and insidious onset to the illness, mean that diagnostic tests may be needed to confirm a clinical suspicion of the disease, or investigate significant risk factors for the illness. Those with type 1 diabetes are much more likely to present with symptoms and a fairly rapid onset of illness, glycosuria and significant random hyperglycaemia.
There are a variety of definitions and diagnostic criteria for concepts such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), the metabolic syndrome and 'pre-diabetes'. The most important concern for primary care practitioners is that they can identify those patients with frank type 1 or type 2 diabetes and be able to advise and monitor patients with indicators of impaired glucose metabolism who are at risk of developing type 2 diabetes.
Some definitions associated with altered glycaemic control, according to World Health Organization/International Diabetes Federation guidelines
- Diabetes symptoms (polyuria, polydipsia and unexplained weight loss) plus:
- A random venous plasma glucose concentration ≥11.1 mmol/L; or
- A fasting plasma glucose concentration ≥7.0 mmol/L (whole blood ≥6.1 mmol/L); or
- Two-hour plasma glucose concentration ≥11.1 mmol/L two hours after 75 g anhydrous glucose in an OGTT.
- With no symptoms, diagnosis should not be based on a single glucose determination. At least one additional glucose test result on another day, with a value in the diabetic range, is essential - either fasting, from a random sample or from the two-hour post-glucose load. If the fasting or random values are not diagnostic, the two-hour value should be used.
Impaired glucose tolerance (IGT)
- Fasting plasma venous glucose <7 mmol/L; AND
- Two-hour OGTT plasma venous glucose ≥7.8 mmol/L and <11.1 mmol/L.
Impaired fasting glucose (IFG)
- Fasting plasma venous glucose measurement 6.1-6.9 mmol/L; AND (if measured)
- Two-hour OGTT plasma venous glucose <7.8 mmol/L, after a 75 g glucose load (otherwise it would be IGT).
NB: If the two-hour glucose is raised then a fasting glucose of 6.1-6.9 is defined as IGT and not IFG. If fasting glucose is 6.1-6.9 but two-hour glucose is normal then it is IFG. However, such clarification of the diagnosis is not essential in practice. The essential issue is that the patient should be considered as being at increased risk of diabetes and cardiovascular disease.
- Diabetes may be diagnosed on the basis of one abnormal plasma glucose (random ≥11.1 mmol/L or fasting ≥7 mmol/L) in the presence of diabetic symptoms such as thirst, increased urination, recurrent infections, weight loss, drowsiness and coma.
- In asymptomatic people with an abnormal random plasma glucose, two fasting venous plasma glucose samples in the abnormal range (≥7 mmol/L) are recommended for diagnosis.
- The World Health Organization (WHO) now recommends that glycated haemoglobin (HbA1c) can be used as a diagnostic test for diabetes (see below).
- OGTT is not recommended as a screening test for diabetes mellitus.
HbA1c testing is used for both monitoring blood sugar control in patients with diabetes and as a diagnostic test for diabetes. An HbA1c of 6.5% is recommended as the cut-off point for diagnosing diabetes. A value less than 6.5% does not exclude diabetes diagnosed using glucose tests.
Situations where HbA1c is not appropriate for diagnosis of diabetes include:
- Children and young people.
- Patients suspected of having type 1 diabetes.
- Patients with symptoms of diabetes for less than two months.
- Patients at high diabetes risk who are acutely ill.
- Patients taking medication that may cause rapid glucose rise - eg, steroids, antipsychotics.
- Patients with acute pancreatic damage, including pancreatic surgery.
- Presence of other factors that influence HbA1c and its measurement:
- Increased HbA1c: iron, vitamin B12 deficiency, decreased erythropoiesis.
- Decreased HbA1c: administration of erythropoietin, iron, vitamin B12, reticulocytosis, chronic liver disease.
- Altered haemoglobin:
- Genetic or chemical alterations in haemoglobin: haemoglobinopathies, HbF and methaemoglobin may increase or decrease HbA1c.
- Increased HbA1c: alcoholism, chronic kidney disease.
- Decreased HbA1c: aspirin, vitamin C and E, certain haemoglobinopathies.
- Erythrocyte destruction:
- Increased HbA1c: increased erythrocyte lifespan - eg, splenectomy.
- Decreased HbA1c: decreased erythrocyte lifespan - eg, haemoglobinopathies, splenomegaly, rheumatoid arthritis or drugs such as antiretrovirals, ribavirin and dapsone.
- Other factors:
- Increased HbA1c: hyperbilirubinaemia, alcoholism, large doses of aspirin, chronic opiate use.
- Variable HbA1c: haemoglobinopathies.
- Decreased HbA1c: hypertriglyceridaemia.
Screening for diabetes
Screening for diabetes is now included in the NHS Health Check for adults in England between the ages of 40 and 74 years.
- It is estimated that more than 500,000 people have undiagnosed type 2 diabetes in the UK. Up to 50% of people may already have complications when they are diagnosed with type 2 diabetes.
- Screening of an older, predominantly white, socially representative cohort of patients enrolled in population-based heart disease studies has revealed a prevalence of frank undiagnosed type 2 diabetes in this group, of around 7%. IGT had a prevalence of about 20%. There is good evidence that an appropriately designed and targeted screening strategy is effective at detecting undiagnosed type 2 diabetics in a UK-based primary care setting:
- The number of patients needing to be screened to detect one case of type 2 diabetes, or IFG, is relatively low at 7-13[7, 8]. Random population screening has been found to diagnose type 2 diabetes in 4.3%.
- Screening for diabetes appears to be cost-effective for the 40- to 70-year age group - increasingly more cost-effective for the older age bands. Screening is more cost-effective for people in the hypertensive and obese subgroups and the costs of screening are offset in many groups by lower future treatment costs.
- There are no agreed hard-and-fast criteria for selection of the screening population. Screening on the basis of age alone has been shown to have a low yield. Most studies have used some or all of the following criteria:
- Age >45 years[11, 12].
- Body mass index (BMI) >27-30.
- High-risk ethnic groups for type 2 diabetes - eg, UK-based African-Caribbean or Asian-origin populations.
- Family history of type 2 diabetes.
- High waist circumference.
- Sedentary lifestyle.
- Other criteria, which might include: patients with cardiovascular disease, history of gestational diabetes, women with polycystic ovary syndrome and previous evidence of IGT.
- Some studies have used scoring systems based on easy-to-measure criteria such as age, BMI, waist circumference, family history of diabetes, and sedentary physical activity, to assign scores and risk-stratify the population before testing. The Cambridge risk scoring system has been found to be a useful tool in this regard.
Indications for the oral glucose tolerance test
- There is no clear-cut consensus on the role of the OGTT in both clinical practice and research, and for epidemiological purposes[2, 17].
- It is thought by the American Diabetic Association that the OGTT is a valid method of diagnosing diabetes but that fasting plasma venous glucose measurements should be preferred as a routine clinical test because the OGTT is deemed to be more inconvenient, to cost more and to be less reproducible.
- There is also the problem that various studies have shown that fasting plasma venous glucose measurements and OGTT do not identify the same patients as having diabetes.
- One study showed the following distribution of patients in terms of their fit for the criteria used to diagnose diabetes for both tests:
- 40% meet criteria for diagnosis of diabetes based on fasting plasma venous glucose measurement.
- 31% meet criteria for diagnosis of diabetes based on two-hour plasma venous glucose measurement, after OGTT.
- 28% meet both sets of criteria for diagnosis of diabetes.
Studies of outcome based upon the mode of diagnosis of diabetes show worse outcomes in terms of cardiovascular morbidity and mortality in those diagnosed on the basis of the two-hour plasma glucose result, as part of the OGTT. For this reason, and the fact that OGTT is the only useful method for diagnosing patients with IGT, the WHO still recommends the retention of the OGTT as a diagnostic test for diabetes mellitus and/or IGT.
- Fasting plasma glucose of ≥7 mmol/L, if reproduced and outside of context of acute illness, is diagnostic of diabetes mellitus.
- However, fasting plasma glucose alone will fail to diagnose around 30% of cases of diabetes.
- OGTT is the only means of identifying people with IGT.
- An OGTT is frequently needed to confirm or exclude an abnormality of glucose tolerance in asymptomatic people.
- An OGTT should be used in individuals who are suspected of having diabetes and who have a fasting venous plasma glucose of 6.1-6.9 mmol/L, to determine glucose tolerance status.
The oral glucose tolerance test and pregnancy
The most appropriate strategies for screening and diagnosing gestational diabetes mellitus remain controversial. There is a continuous relationship between maternal glucose level at 24-28 weeks and pregnancy outcomes (macrosomia, fetal insulin, clinical neonatal hypoglycaemia and caesarean section). Women should be screened for glycosuria at each antenatal visit. The National Institute for Health and Care Excellence (NICE) recommends:
- Assess risk of gestational diabetes using the following risk factors for gestational diabetes:
- BMI above 30 kg/m2.
- Previous macrosomic baby weighing 4.5 kg or above.
- Previous gestational diabetes.
- Family history of diabetes (first-degree relative with diabetes).
- Minority ethnic family origin with a high prevalence of diabetes.
- Offer women with any one of these risk factors testing for gestational diabetes. Do not use fasting plasma glucose, random blood glucose, HbA1c, glucose challenge test or urinalysis for glucose to assess risk of developing gestational diabetes.
- Use the two-hour 75 g OGTT to test for gestational diabetes in women with any of the above risk factors.
- Offer women who have had gestational diabetes in a previous pregnancy:
- Early self-monitoring of blood glucose; or
- A 75 g two-hour OGTT as soon as possible after booking (whether in the first or second trimester) and a further 75 g two-hour OGTT at 24-28 weeks if the results of the first OGTT are normal.
- Offer women with any of the other risk factors for gestational diabetes a 75 g two-hour OGTT at 24-28 weeks.
- Diagnose gestational diabetes if the woman has either:
- Fasting plasma glucose level of 5.6 mmol/L or above; or
- Two-hour plasma glucose level of 7.8 mmol/L or above.
Conducting the oral glucose tolerance test
- The test should be preceded by ≥3 days of normal, unrestricted diet (>150 g carbohydrate daily) with normal physical activity. There should be a carbohydrate-rich meal (30-50 g) on the night before the test. There should then be an overnight fast of 8-14 hours; drink only water.
- Record any factors that may affect interpretation of the test, such as medication, inactivity, infection, gestation of pregnancy, acute psychological stress, etc. The patient should not smoke during the test.
- Collect fasting (and all other) samples in a tube that permits measurement of plasma glucose (eg, a sodium fluoride tube). Timing of test (0 hours) starts at the beginning of the glucose drink.
- Adults ingest 75 g glucose in 250-300 ml water over five minutes. Children ingest 1.75 g/kg body weight in a similar volume of water by ratio (max 75 g as for adults).
- Take a blood sample at two hours; some schema suggest taking a one-hour sample but this is not strictly necessary in terms of diagnosing diabetes. Ideally, take the sample from a warmed vein on the back of the patient's hand (antecubital fossa samples may be artificially lower).
- An indwelling 'butterfly' or conventional cannula can be left in situ throughout the test (affix in place and dress); flush with saline after taking a fasting sample, then draw at least 10 ml and discard before drawing a sample for the assay tube.
- Glucose should be measured immediately after collection by near-patient testing or, if a blood sample for a laboratory is collected, plasma should be immediately separated, or the sample should be collected into a container with glycolytic inhibitors and placed in ice-water until separated prior to analysis.
- An extended glucose tolerance test may be conducted to detect cases of reactive hypoglycaemia or other abnormalities of glucose metabolism with samples taken at 0, 30, 60, 90, 120, 150 and 180 minutes. The extended test may also be used to diagnose acromegaly when samples are also taken for growth hormone levels.
If the test is conducted correctly and blood sampling performed appropriately, there are no causes of false-positive results other than factors that can provoke hyperglycaemia that should be checked for before performing the test:
- Undisclosed medication changes (eg, steroids).
- Other acute illness.
- Acute psychological stress.
- Failure to comply with the pre-test feeding/fasting regimen.
Further reading and references
Sacks DB; A1C versus glucose testing: a comparison. Diabetes Care. 2011 Feb34(2):518-23. doi: 10.2337/dc10-1546.
Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia; World Health Organization/International Diabetes Federation, 2006
Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus; World Health Organization, 2011
Thomas MC, Walker MK, Emberson JR, et al; Prevalence of undiagnosed Type 2 diabetes and impaired fasting glucose in older British men and women. Diabet Med. 2005 Jun22(6):789-93.
Finding type 2 diabetics in primary care; Bandolier, 2004
Greaves CJ, Stead JW, Hattersley AT, et al; A simple pragmatic system for detecting new cases of type 2 diabetes and impaired fasting glycaemia in primary care. Fam Pract. 2004 Feb21(1):57-62.
Waugh N, Scotland G, McNamee P, et al; Screening for type 2 diabetes: literature review and economic modelling. Health Technol Assess. 2007 May11(17):iii-iv, ix-xi, 1-125.
Klein Woolthuis EP, de Grauw WJ, van Weel C; Opportunistic screening for type 2 diabetes in primary care. Lancet. 2010 Aug 28376(9742):683-4.
Klein Woolthuis EP, de Grauw WJ, van Gerwen WH, et al; Yield of opportunistic targeted screening for type 2 diabetes in primary care: the diabscreen study. Ann Fam Med. 2009 Sep-Oct7(5):422-30.
Gillies CL, Lambert PC, Abrams KR, et al; Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis. BMJ. 2008 May 24336(7654):1180-5. Epub 2008 Apr 21.
Rutten G; Screening for type 2 diabetes - where are we now? Lancet. 2010 Apr 17375(9723):1324-6. Epub 2010 Mar 29.
Ramachandran A, Snehalatha C, Vijay V, et al; Derivation and validation of diabetes risk score for urban Asian Indians. Diabetes Res Clin Pract. 2005 Oct70(1):63-70. Epub 2005 Apr 15.
Type 2 diabetes: prevention in people at high risk; NICE Public Health Guidance (July 2012)
Rahman M, Simmons RK, Harding AH, et al; A simple risk score identifies individuals at high risk of developing Type 2 diabetes: a prospective cohort study. Fam Pract. 2008 May 30.
Barr RG, Nathan DM, Meigs JB, et al; Tests of glycemia for the diagnosis of type 2 diabetes mellitus. Ann Intern Med. 2002 Aug 20137(4):263-72.
Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period; NICE Clinical Guideline (February 2015)