See also separate articles Screening for Diabetes, Diabetes Mellitus in Pregnancy, Metabolic Syndrome and Managing Impaired Glucose Tolerance In Primary Care.

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. Type 1 diabetics are much more likely to present with symptoms and a fairly rapid onset of illness, glycosuria and significant random hyperglycaemia, making diagnosis easier.

Research into diabetes and impaired glucose metabolism has created a bewildering array of terminology and definitions relating to this area of study and clinical practice. There are a variety of differing definitions and diagnostic criteria for concepts such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), the metabolic syndrome and 'prediabetes'.

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. This article will therefore use the current (2006) recommendations of the World Health Organisation (WHO)/International Diabetes Federation, which are based upon being able 'to distinguish a group of patients with significantly increased premature mortality and increased risk of microvascular and cardiovascular complications',¹ rather than becoming tied up in differing definitions based on epidemiological data and variable clinical practice.

Diagnosing diabetes

• 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, at least one and preferably two fasting venous plasma glucose in the abnormal range (≥7 mmol/L) are required for diagnosis.
• An OGTT is indicated where repeat testing is inconclusive, where fasting plasma venous glucose measurements are in the range 6.1-6.9 mmol/L, or if fasting blood glucose is normal but the patient:
  • Is older.
  • Is not significantly obese.
  • Has had gestational diabetes, in a postpartum testing situation.
  • Is of African-Caribbean/Asian origin, where fasting plasma venous glucose measurement is thought to be less useful, and there are possible symptoms of diabetes/suspicion of IGT.
• The OGTT is not recommended as a screening test for diabetes mellitus, fasting plasma venous glucose being preferred (see separate Screening for Diabetes article).

Glycated haemoglobin (HbA1c)²

Although HbA1c testing is mainly used for monitoring blood sugar control in patients with diabetes, the WHO now recommends that HbA1c can be used as a diagnostic test for diabetes, provided that stringent quality assurance tests are in place and assays are standardised to criteria aligned to the international reference values. 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 2 months
• Patients at high diabetes risk who are acutely ill
• Patients taking medication that may cause rapid glucose rise e.g. steroids, antipsychotics
• Patients with acute pancreatic damage, including pancreatic surgery
• Pregnancy
• Presence of other factors that influence HbA1c and its measurement:
  • Erythropoiesis:
    • 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
  • Glycation:
    • Increased HbA1c: alcoholism, chronic kidney disease
    • Decreased HbA1c: aspirin, vitamin C and E, certain haemoglobinopathies
  • Erythrocyte destruction:
    • Increased HbA1c: increased erythrocyte life span, e.g. splenectomy
    • Decreased HbA1c: decreased erythrocyte life span, e.g. 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

Indications for oral glucose tolerance test

• There is no clear-cut consensus on the role of the oral glucose tolerance test (OGTT) in both clinical practice and research, and for epidemiological purposes.^1,3
• 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.¹
• 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.¹
  • 40% meet criteria for diagnosis of diabetes based on fasting plasma venous glucose measurement.
  • 31% meet criteria for diagnosis of diabetes based on 2-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 2-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:

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. Scottish Intercollegiate Guidelines Network (SIGN) guidance recommends:⁴

• Screening at the first antenatal visit:
  • At time of booking, all women should be assessed for the presence of risk factors for gestational diabetes. All women with risk factors should have HbA1c or fasting glucose measured.
  • Women with intermediate levels of glucose (HbA1c 6.0 to 6.4%, fasting glucose 5.1-6.9 mmol/L or 2-hour glucose 8.6-11.0 mmol/L) should be assessed to determine the need for immediate home glucose monitoring and, if the diagnosis remains unclear, assessed for gestational diabetes by 75 g OGTT at 24-28 weeks.
• Screening later in pregnancy:
  • All women with risk factors should have a 75 g OGTT at 24-28 weeks. A fasting plasma glucose at 24-28 weeks is recommended in low-risk women. The National Institute for Health and Clinical Excellence (NICE) also recommends the 2 hour 75 g OGTT as the diagnostic test for gestational diabetes administered at 24-28 weeks of gestation.⁵

Risk factors for gestational diabetes are defined as:⁴

• BMI more than 30 kg/m².
• Previous macrosomic baby weighing 4.5 kg or more.
• Previous gestational diabetes.
• Family history of diabetes (first-degree relative with diabetes).
• Family origin with a high prevalence of diabetes, including South Asian, Black Caribbean and Middle Eastern.

Conducting the oral glucose tolerance test⁶

• Test preceded by ≥3 days of normal, unrestricted diet (>150 g carbohydrate daily) with normal physical activity.
• Carbohydrate-rich meal (30-50 g) on night before test.
• 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.
• Collect fasting (and all other) samples in a tube that permits measurement of plasma glucose (e.g. 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 5 minutes.
• Children ingest 1.75 g/kg body weight in a similar volume of water by ratio (max 75 g as for adults).
• No smoking during the test.
• Take a blood sample at 2 hours; some schema suggest taking a 1-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.¹
• 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.

Interpreting the results of the test

• It is important not to over-interpret the results of the OGTT, and to realise that it has variable reproducibility in and between individual patients.
• Use the WHO criteria above to interpret whether or not the test indicates a diagnosis of IFG, IGT or diabetes.
• It is rarely necessary to take and analyse anything other than 0 and 2-hour samples, especially in a primary care setting.
• If there is any uncertainty about the diagnosis of diabetes in potentially symptomatic individuals with equivocal test results, seek advice from your local diabetes service.
• Unusually low blood glucose results during OGTT should prompt consideration of referral for endocrinological assessment.
• If the test is conducted correctly and blood sampling performed appropriately, there are no causes of false-positive results, as such, other than factors that can provoke hyperglycaemia that should be checked for before performing the test:
  • Undisclosed medication changes (e.g. steroids).
  • Inactivity.
  • Infection.
  • Other acute illness.
  • Pregnancy.
  • Acute psychological stress.
  • Failure to comply with the pre-test feeding/fasting regimen.

Document references

1. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia, World Health Organization/International Diabetes Federation, 2006
2. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus, World Health Organization (2011)
3. Barr RG, Nathan DM, Meigs JB, et al; Tests of glycemia for the diagnosis of type 2 diabetes mellitus. Ann Intern Med. 2002 Aug 20;137(4):263-72. [abstract]
4. Management of diabetes, Scottish Intercollegiate Guidelines Network - SIGN (March 2010)
5. Diabetes in pregnancy, NICE Clinical Guideline (March 2008); Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period
6. Diagnosis and Classification of Diabetes Mellitus and its Complications: Part 1, World Health Organization, 1999; gives detail of standardised method for administering the test

Internet and further reading

• Diabetes policy and guidance including National Service Framework, Dept of Health; links to useful resources