Diabetes

OPINION | Laboratory tests in diabetes mellitus - past, present and future

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Unmanaged diabetes can be fatal.
Unmanaged diabetes can be fatal.
Towfiqu Barbhuiya, Unsplash

Until fairly recently, Type 2 diabetes mellitus was considered a major health issue only in developed countries, but there’s been an increase in prevalence in developing countries. This has beenattributedto rapid urbanisation, increased fast food consumption and general lack of exercise.

According to the International Diabetes Federation, African countries can expect an increase of up to 143% in the number of people with diabetesby 2045. Their latest report shows that South Africa has the highest prevalence of diabetes on the continent, and the highest number of diabetes-related deaths.

The country’s diabetes-related expenditure – 23% of the total health budget spent on the management of the disease in 2019 – is also the highest. With the number of cases set to increase in the coming decades, diagnosing diabetes early could prove vital in saving people’s lives. To mark this year’s World Diabetes Day (14 November), we would like to focus on the importance of diagnostic tests in the fight against the disease.

The early days

The diagnosis of diabetes goes back millennia. As far back as 1552 BC, the Egyptian physician Hesy-Ra documented frequent urination and emaciation in diabetics. The Indian physician Sushrata noted that ants were attracted to the urine of diabetics and used this for diagnosis.

In the 1st Century A.D., the Greek physician Arateus described diabetes as "the melting down of flesh and limbs" into urine, naming the affliction "diabetes," the Greek word for “siphon”.

The traditional triad of polyuria, polydipsia and polyphagia was described in 200 AD in China. Centuries later, “water tasters” noticed a sweet taste in the urine of diabetics and hence the name “mellitus” which means honey.

In the early 20th century, Stanley Benedict described the estimation of urinary glucose in a test that is still used in laboratories to this day. In 1921, Canadian scientist Frederick Banting discovered insulin and the structure was described by English biochemist Frederick Sanger in 1958.

The first radio-immunoassay (using radioactive materials to look for tiny amounts of substances in the body) for insulin was developed by Rosalyn Yalow and Solomon Berson a year later. The oral glucose tolerance test (OGTT) was first described by American endocrinologist Jerome Conn in 1923. His findings were based on the work of A.T.B Jacobsen who, in 1913, demonstrated that carbohydrate ingestion leads to glucose fluctuations.

The diagnosis of diabetes for several years rested on the use of the OGTT and over the years the test was standardised. A standard dose of 75g of glucose dissolved in approximately 300 ml of water is ingested and blood glucose levels are checked two hours later.

A blood sample is also taken just prior to drinking the solution. The aim is to measure how well, or poorly, their body is able to return their glucose levels back to normalcy.

Present

To get a better idea of where we are today regarding diagnostic tests, we have to go back to the 1950’s and 60’s. In 1958, Titus Huisman and his co-authors first described glycated haemoglobin A1c (HbA1c) which refers to the molecule formed when glucose is added to a haemoglobin molecule.

It took more than 10 years before the diabetes connection was confirmed in 1969 by Samuel Rahbar, an Iranian scientist. Glycation refers to the non-enzymatic bonding of carbohydrate to a protein or lipid. This leads to protein modification and is caused by hyperglycaemia and aging.

As the average lifespan of a red blood cell is 120 days, HbA1c gives an indication of the individual’s glucose levels for the last three months. The importance of HbA1c became evident after the publication of two landmark diabetes trails, namely the Diabetes Control and Complications Trail and the United Kingdom Prospective Diabetes Study which was performed in type 1 and type 2 diabetics respectively.

Both trials documented the benefit of tight glucose control as measured by HbA1c levels and clinical outcome. A linear correlation was observed between average HbA1c levels and the risk of long-term diabetes complications affecting the small blood vessels – a minor decrease in HbA1c resulted in significant changes in the relative risk of microvascular complications.

This led to improvements in the HbA1c laboratory test and standardisation so that results were comparable to those landmark trials and also between laboratories. Although HbA1c was used for follow up of glycaemic control, the diagnosis of diabetes mellitus was still determined using the OGTT.

This test was inconvenient and cumbersome – the patient had to fast and side effects such as nausea were often experienced after the glucose intake. Additionally, a glucose test is prone to interferences and affected by numerous patient influences.

In 2010, after improvement of the HbA1c laboratory test, a correlation between HbA1c and early onset retinopathy, a complication of diabetes, was noticed. This led to the American Diabetes Association recommending a cut-off of 6.5% for the diagnosis of diabetes mellitus in 2009. This had numerous advantages over the OGTT.

The HbA1c assay was standardised, had less pre-analytical variability, levels gave a better indication of overall glycaemic control and less biological variability than glucose and importantly for patients, there was no need for fasting and uncomfortable tests.

There are, however, concerns about the overall accuracy of HbA1c as subsequent studies have found that numerous non-glycaemic factors may increase or decrease a person’s HbA1c level irrespective of glucose levels. Ethnic differences and anaemia have also been shown to affect HbA1c which led to scientists questioning whether this cut-off of 6.5% is appropriate for all populations.

Future

So, what does the future hold for laboratory tests in diabetes mellitus?

As the problems with HbA1c became more apparent, the search for newer diagnostic markers began. One of them that may be particularly be suited to the African environment where haemoglobin abnormalities are common is glycated albumin – formed by glycation of albumin, the most abundant protein in human serum.

As the half-life of albumin is only 21 days, this gives an indication of glycaemic control over the last three weeks and is useful when interventions are initiated or when a shorter follow-up is indicated.

However, albumin has numerous functions and is a negative acute phase reactant. Therefore, levels of glycated albumin may be affected when albumin levels change such as in inflammation, or in obesity and protein losing conditions.

Another possible new diagnostic marker may be microRNA (miRNA). The study of genetic mechanisms such as miRNAs is known as epigenetics. This is an umbrella of various mechanisms revolving around genetic changes that may occur due to our habits and surrounding environment.

These adverse genetic changes may subsequently result in increased risk of disease. MiRNAs are small molecules that control which type of proteins develop, and which don’t.

Abnormal miRNA expression may result in under- or overproduction of proteins involved in essential bodily processes and possible adverse effects. The underproduction of a miRNA involved in insulin production leads to reduced insulin levels and uncontrolled blood glucose levels.

Emerging evidence suggests that altered miRNA expressions may either precede or play a role in the development of type 2 diabetes.

In a recent local study, Cecil Weale and his co-researchers identified miRNAs which are associated with abnormal glucose levels. Three separate groups were studied: a control group with normal glucose levels; a prediabetic group with intermediate glucose levels; and a group of newly diagnosed type 2 diabetics.

Higher levels of the miRNAs were found in the prediabetic and diabetic groups, with higher levels in prediabetes.

This study showed that measuring the expression of these miRNAs could be used to identify people with prediabetes and future studies are needed to assess whether their measurement may be superior to that of HbA1c.

As technology improves, newer and better laboratory tests are continuously being developed for the diagnosis and follow up of diabetes. These tests will also help to predict people’s risk for diabetes so that they can make the necessary lifestyle changes as early as possible. With the number of diabetics set to increase globally, more studies are urgently needed.

*Profs Annie Zemlin and Rajiv Erasmus are affiliated with the Division of Chemical Pathology in the Faculty of Medicine and Health Sciences at Stellenbosch University and the National Health Laboratory Service. Prof Tandi Matsha-Erasmus is from the MRC Unit on Cardio-Metabolic Diseases at the Cape Peninsula University of Technology.

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