Diabetes: The Role of Fructosamine
Diabetes Week is an annual week to raise awareness of diabetes. This year, the aim is to increase the public’s understanding of diabetes 1. Diabetes mellitus (DM) is a global epidemic, increasing at an alarming rate and burdening healthcare systems 2. DM is a life-long condition characterised by the body’s inability to produce / respond to insulin resulting in the abnormal metabolism of carbohydrates and elevated blood glucose levels.
Whilst it is important to increase the public’s understanding of DM, it is imperative that clinicians and physicians are aware of the different in vitro diagnostic tests to diagnose and monitor DM. Not only is this vital, but is also important that clinicians and physicians also understand the different methodologies available when choosing the diagnostic test.
It has been highlighted in numerous clinical studies that diabetic complications may be reduced through the long-term monitoring and tight control of blood glucose levels. Both fasting plasma glucose (FPG) and glycated haemoglobin A1c (HbA1c) tests are universally accepted as reliable measurements of diabetic control. However, studies have emerged highlighting the role of fructosamine in diabetes monitoring. Whilst HbA1c provides an index of glycaemia over 2 to 3 months, fructosamine provides this index over the course of 2 to 3 weeks, enabling closer monitoring of diabetic control 1.
Drawbacks of Traditional Diabetes Tests
The FPG test measures the level of blood sugars which is used to diagnose and monitor diabetes based on insulin function. The main drawback of this test is that a hormone called glucagon, produced in the pancreas, is triggered during prolonged fasting, signalling the liver to release glucose into the bloodstream. In diabetic conditions, either the body is unable to generate enough insulin or cannot appropriately respond to insulin. Consequently, FPG levels remain high 4.
In the 1980’s, HbA1c was incorporated into clinical practice as HbA1c levels correlated well with glycaemic control over a 2 to 3-month period. The main drawback of this test is that any condition that reduces the survival rate of erythrocytes such as haemolytic anaemia will falsely lower the HbA1c test results, regardless of the assay method utilised 5.
In a diabetic patient where blood glucose levels are abnormally elevated, the concentration levels of fructosamine also increase as fructosamine is formed by a non-enzymatic Maillard reaction between glucose and amino acid residues of proteins. During this glycation process, an intermediate labile Schiff base is produced which is converted to a more stable ketoamine (fructosamine) via an Amadori rearrangement 2.
Fructosamine has been identified as an early indicator of diabetic control compared to other markers such as HbA1c. Red blood cells live for approximately 120 days, HbA1c represents the average blood glucose levels for the previous 2 to 3 months. Conversely fructosamine has a shorter lifespan, about 14 to 21 days, reflecting average blood glucose levels from the previous 2 to 3 weeks. Due to the shorter time span of fructosamine, it is also used to evaluate the effectiveness of medication changes and to monitor the treatment of gestational diabetes. The test is also particularly useful in situations where HbA1c cannot be reliably measured e.g. haemolytic anaemia, thalassemia or with genetic haemoglobin variants 5.
Fructosamine Assay Methodology
The most commonly utilised method for fructosamine testing is the colorimetric method. Whilst widely available, automated and inexpensive, the main drawback is the lack of standardisation across the different fructosamine assays 4.
Randox, on the other hand, utilise an enzymatic method, offering improved specificity and reliability compared to conventional NBT-based methods. The Randox enzymatic method does not suffer from non-specific interferences unlike existing methods which can also be time consuming and difficult to automate.
The Randox fructosamine assay is also standardised to the highest level as the Randox fructosamine calibrator and control is assigned relative to human serum glycated with 14C-glucose, which directly reflects the nature of the patient sample.
With an excellent stability of 28 days on-board the analyser, the Randox fructosamine assay is developed in a liquid ready-to-use format for convenience and ease-of-use.
Randox offer fully automated applications detailing instrument-specific settings for the convenient use of the Randox fructosamine assay on a wide range of clinical chemistry analysers.
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Reagents Resource Hub
 Diabetes UK. Diabetes Week. [Online] 2019. [Cited: May 31, 2019.] https://www.diabetes.org.uk/get_involved/diabetes-week.
 Gounden, Verena and Jialal, Ishwarlal. Fructosamine. [Online] January 23, 2019. [Cited: April 11, 2019.] https://www.ncbi.nlm.nih.gov/books/NBK470185/.
 World Health Organization (WHO). Diabetes. [Online] October 30, 2018. [Cited: May 2, 2019.] https://www.who.int/news-room/fact-sheets/detail/diabetes.
 Manzella, Debra. The Fasting Plasma Glucose Test. very well health. [Online] November 16, 2018. [Cited: April 11, 2019.] https://www.verywellhealth.com/understanding-the-fasting-plasma-glucose-test-1087680.
 BMJ. Using haemoglobin A1c to diagnose type 2 diabetes or to identify people at high risk of diabetes. [Online] 2014. [Cited: April 11, 2019.] https://www.bmj.com/content/348/bmj.g2867/rr/695927.
Lactic acid is an organic compound which produces the conjugate base lactate through a dissociation reaction. Due to it being a chiral compound, two optical isomers of lactate exist; D-Lactate and L-Lactate. The lactate dehydrogenase (LDH) enzyme can produce and metabolise both isomer forms to pyruvate, however due to the isomer-specific nature of LDH different forms of the enzyme are required. D-Lactate requires a D-LDH form whereas L-Lactate requires L-LDH. As a result of this requirement, combined with the fact that mammalian cells only contain L-LDH, the lactate produced in humans is almost exclusively L-Lactate.
One of the roles of L-Lactate is its involvement in the Cori Cycle, a metabolic pathway involved in the production of glucose. The cycle involves the rotatory transportation of lactate and glucose from the liver and the muscle. Lactate is produced in the muscle through glycolysis which is then transported to the liver through the blood stream. In the liver, the lactate is oxidised to pyruvate and then converted to glucose by gluconeogenesis, which is then transported back to the muscle for the process to start again. 1500 mmol of lactate is produced daily by the body and is cleared at a constant rate via the liver.
Problems can arise if the liver fails to regulate the lactate produced. Hyperlactamia is the name given to elevated levels of lactate in the body, as a result of the rate of production exceeding the rate of disposal. This is due to a lack of oxygen that reduces blood flow to the tissues. If levels continue to rise a patient is at risk of lactic acidosis.
The liver is an important tissue in the regulation of lactate, it is therefore no surprise that liver damage can prevent this process resulting in a further diagnosis of lactic acidosis. A healthy liver is a vital part of lactate regulation as it acts as the main consumer of lactate and contributes to 30-40% of lactate metabolism. Potential victims are patients who suffer with cirrhosis, a complication of liver disease, which is commonly caused by alcohol abuse and viral Hepatitis B and C.
Patients with liver cirrhosis have a higher risk of increased lactate levels. Increased levels of the lactate ions disturbs the acid-base equilibrium, causing a tilt towards lactic acidosis. The mortality rate of patients who develop lactic acidosis is high, prompt recognition and treatment of the underlying cause remain the only realistic hope for improving survival.
The Randox L-Lactate reagent allows for a prompt and accurate diagnosis of lactic acidosis.
Randox L-Lactate Reagent
The Randox L-Lactate key benefits include:
- Excellent working reagent stability of two weeks when stored at + 15 – +25°C
- Exceptional correlation of r = 0.99 when compared against other commercially available methods
- A wide measuring range of 0.100 – 19.7 mmol/l and so is capable of detecting abnormal levels in a sample
- Colorimetric method
- Lyophilised reagents for enhanced stability
A peer-reviewed study, published in The Lancet Medical Journal suggests there are five types of diabetes. Could diabetes be more complex than we once thought? Could diabetes be segmented into five separate diseases?
What is diabetes?
Diabetes is an incurable disease which prohibits the body’s ability to produce and respond to insulin. Currently, diabetes is classified into two main forms, type 1 and type 2.
Type 1 diabetes is an autoimmune disease which manifests in childhood. In type 1 diabetes, the body’s white blood cells attack the insulin-producing cells in the pancreas. As a result, individuals with Type 1 diabetes rely on the injection of insulin for the remainder of their lives.
Type 1 diabetes affects 10 percent of individuals with diabetes. 96 percent of children diagnosed with diabetes have type 1. Type 1 diabetes in children is commonly diagnosed between the ages of 10 and 14. The prevalence of type 1 diabetes in children and young people (under the age of 19) is 1 in every 430-530 and the incidence of type 1 in children under 14 years of age is 24.5/100,000 (Diabetes UK, 2014).
Type 2 diabetes is the result of insulin resistance, meaning that the pancreas does not produce enough insulin or the body’s cells do not respond to the insulin produced. As type 2 diabetes is a mixed condition, with varying degrees of severity, there are a few methods to manage the disease, including dietary control, medication and insulin injections.
Type 2 diabetes is the most common form of diabetes, affecting 90 percent of individuals with diabetes, and has now become a global burden. The global prevalence of diabetes has almost doubled from 4.7 percent in 1980 to 8.5 percent in 2014, with a total of 422 million adults living with diabetes in 2014. It is expected to rise to 592 million by 2035. In 2012, diabetes accounted for 1.5 million deaths globally with hypertension causing a further 2.2 million deaths. 43 percent of these deaths occurred before 70 years of age. Previously type 2 diabetes was commonly seen in young adults but is now commonly seen in children as well. In 2017, 14% more children and teenagers in the UK were treated for diabetes compared to the year before (World Health Organization, 2016).
In both forms of diabetes, hyperglycemia can occur which can lead to number of associated complications including renal disease, cardiovascular disease, nerve damage and retinopathy.
The novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables – peer-review study
This new research studied 13,270 individuals from different demographic cohorts with newly diagnosed diabetes, taking into consideration body weight, blood sugar control and the presence of antibodies, in Sweden and Finland.
This peer-reviewed study identified 5 disease clusters of diabetes, which have significantly different patient characteristics and risk of diabetic complications. The researchers also noted that the genetic associations in the clusters differed from those seen in traditional type 2 diabetes.
Cluster One – Severe autoimmune diabetes (SAID)
SAID is similar to type 1 diabetes. SAID manifests in childhood, in patients with a low BMI, have poor blood sugar and metabolic control due to insulin deficiency and GADA. 6% of individuals studied in the ANDIS study were identified with having SAID.
Cluster Two – Severe insulin-deficient diabetes (SIDD)
SIDD is similar to SAID, however, GADA is negative. This means that the characteristics of SIDD are the same as SAID, young, of a healthy weight and struggled to make insulin, however, SIDD is not the result of an autoimmune disorder as no autoantibodies are present. Patients have a higher risk of diabetic retinopathy. 18% of subjects in the ANDIS study were identified with having SIDD.
Cluster Three – Severe insulin-resistant diabetes (SIRD)
SIRD is similar to that of type 2 diabetes and is characterised by insulin-resistance and a high BMI. Patients with SIRD are the most insulin resistant and have a significantly higher risk of kidney disease, and microalbuminuria, and non-alcoholic fatty liver disease. 15% of subjects in the ANDIS study were identified as having SIRD.
Cluster Four – Mild obesity-related diabetes (MOD)
MOD is a mild form of diabetes which generally affects a younger age group. This is not characterised by insulin resistance but by obesity as their metabolic rates are close to normal. 22% of subjects in the ANDIS study were identified as having MOD.
Cluster Five – Mild age-related diabetes (MARD)
MARD is the most common form of diabetes manifesting later in life compared to the previous four clusters. Patients with MARD have mild problems with glucose regulation, similar to MOD. 39% of subjects in the ANDIS study were identified with having MARD.
This new sub-classification of diabetes could potentially enable doctors to effectively diagnose diabetes earlier, through the characterisation of each cluster, including: BMI measurements, age, presence of autoantibodies, measuring HbA1c levels, ketoacidosis, and measuring fasting blood glucose levels. This will enable a reduction in the incidence of diabetes complications and the early identification of associated complications, and so patient care can be tailored, thus improving healthcare (NHS, 2018) (The Week, 2018) (Ahlqvist, et al., 2018) (Collier, 2018) (Gallagher, 2018).
The Randox diabetes reagents cover the full spectrum of laboratory testing requirements from risk assessment, using our Adiponectin assay, to disease diagnosis and monitoring, using our HbA1c, glucose and fructosamine assays, to the monitoring of associated complications, using our albumin, beta-2 microglobulin, creatinine, cystatin c, d-3-hydroxybutyrate, microalbumin and NEFA assays.
Whilst this study is valuable, alone it is not sufficient for changes in the diabetes treatment guidelines to be implemented, as the study only represents a small proportion of those with diabetes. For this study to lead the way, the clusters and associated complications will need to be verified in ethnicities and geographical locations to determine whether this new sub-stratification is scientifically relevant.
Ahlqvist, E. et al., 2018. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. [Online]
Available at: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30051-2/fulltext?elsca1=tlpr
[Accessed 16 April 2018].
Collier, J., 2018. Diabetes: Study proposes five types, not two. [Online]
Available at: https://www.medicalnewstoday.com/articles/321097.php
[Accessed 16 April 2018].
Diabetes UK, 2014. Diabetes: Facts and Stats. [Online]
Available at: https://www.diabetes.org.uk/resources-s3/2017-11/diabetes-key-stats-guidelines-april2014.pdf
[Accessed 16 April 2018].
Gallagher, J., 2018. Diabetes is actually five seperate diseases, research suggests. [Online]
Available at: http://www.bbc.co.uk/news/health-43246261
[Accessed 16 April 2018].
NHS, 2018. Are there actually 5 types of diabetes?. [Online]
Available at: https://www.nhs.uk/news/diabetes/are-there-actually-5-types-diabetes/
[Accessed 16 April 2018].
The Week, 2018. What are the five types of diabetes?. [Online]
Available at: http://www.theweek.co.uk/health/92048/what-are-the-five-types-of-diabetes
[Accessed 16 April 2018].
World Health Organization, 2016. Global Report on Diabetes, Geneva: World Health Organization.