Diabetes mellitus (DM), a global epidemic, is increasing at an alarming rate and is associated with both increased morbidity and mortality. It appears that only plasma glucose and glycated hemoglobin (HbA1c) are universally accepted as reliable measures of diabetes control. Data has been evolving with other measures that bridge the span of short-term glycemic control from an isolated glucose level to HBA1c which provided an index of glycemia over 2 to 3 months. Fructosamine is a measure of non-enzymatic glycation resulting in a ketamine linkage to circulating proteins including albumin, globulins and lipoproteins and glycated albumin (GA), is a measure of the percent albumin that is glycated; both provide a measure of glycemia of 2 to 3 weeks duration. Fructosamine and GA have a potential role in the diagnoses and management of diabetes.
Fructosamine (1-amino-1-deoxy fructose), is a stable ketoamine, formed by the non-enzymatic reaction product of sugar (usually glucose) and the amino group of protein (usually albumin but includes globulins and lipoprotein). The attachment of the aldehyde group of the carbohydrate with the N terminal amino acid of the protein forms the reversible Schiff base and intermediate. The Schiff base may be converted back to glucose and protein or undergo the Amadori rearrangement to form stable fructosamine. This process is known as non-enzymatic glycation and is also referred to as the Maillard reaction. The Maillard reaction causes the browning phenomenon that occurs in milk and other food products when heated.
Glycated albumin refers to the formation of ketoamine specifically involving the major circulating protein albumin (3.5 g/dl to 5 g/dl). Glycated albumin is an example of a fructosamine (FA). Because albumin is the most abundant of the serum proteins, fructosamine is predominantly a measure of glycated albumin. The formation of fructosamine and glycated albumin are post-translational modifications that occur to proteins. This is different from a glycoprotein which is a protein molecule that contains a carbohydrate moiety(group). The formation of a glycoprotein is an enzymatic dependent reaction. The rate of non-enzymatic glycation of albumin is much higher than that of hemoglobin.
Sample type: Serum or plasma are the sample types used for the measurement of fructosamine and glycated albumin. Fasting specimens are not required.
The most common assays available for fructosamine involve a colorimetric methodology. The reaction occurs in an alkaline buffer where fructosamine as a reducing agent and involves a color change of the substrate which is measured spectrophotometrically.
These assays are widely available, can be automated and fairly inexpensive. However, unlike HbA1c there is a serious lack of standardization across the different fructosamine assays.
There are several different assay methodologies available for the analysis of glycated albumin. These include:
Fructosamine assays are affected by changes in temperature and by the increased presence of reducing substances in serum, for example, vitamin C and bilirubin. Fructosamine and GA are both not standardized assays. Additionally, both fructosamine and glycated albumin are affected by the presence of any conditions that influence serum albumin concentrations. However, this is minimized for GA since GA is expressed as a percentage of total albumin. Fructosamine will be unreliable when serum albumin is less than 3.0 g/dl. This will include conditions where there is decreased albumin synthesis, for example, liver cirrhosis or albumin/protein loss such as nephrotic syndrome and protein-losing enteropathies. Fructosamine levels may also be affected by conditions with raised total protein levels such as in multiple myeloma (due to increased immunoglobulins) and polyclonal gammopathies.
A reference range for fructosamine in non-diabetic individuals is generally 200 to 285 umol/L.
While GA assays also suffer from standardization, a newer assay appears to be much improved such as the automated immunoassay developed by Asahi Kasei. According to this assay, normal persons have values around 14% and those with diabetes greater than 17%. Values in diabetes are generally two to five times upper limit of normal.
The clinical utility of fructosamine and GA includes monitoring of diabetes, diagnosis of pre-diabetes and prediction of both the microvascular and macrovascular complications. They have the advantage of not requiring a fasting sample.
Monitoring of glucose control in diabetes
Fructosamine and glycated albumin can be utilized as short-term markers of glucose control. Both correlate significantly with HBAIc levels. While HbA1c reflects glucose control over a period of the preceding 8 to 12 weeks, fructosamine reflects the average glycemia over the preceding 2 to 3 weeks. This is as a result of the inherent shorter half-life of albumin in comparison to hemoglobin in the erythrocyte.
Fructosamine has largely been used as an alternative to the use of HbA1c monitoring in the presence of certain conditions that preclude the use of HbA1c such as hemoglobin variants and alterations in erythrocyte lifespan. Fructosamine and glycated albumin are not affected by hemoglobin or red blood cell characteristics to which HbA1c is susceptible. This includes conditions such as hemoglobinopathies, sickle cell anemia and anemia related to iron or vitamin B12 deficiency.
Additionally, fructosamine has clinical utility in conditions where information regarding short-term glucose control is important in the management of the patient such as in pregnancy. FA and GA also useful in monitoring people with diabetes with fluctuating or poorly controlled diabetes.
Diagnosis of Diabetes
Recent studies have evaluated the use of the alternate glycaemic markers of fructosamine and glycated albumin for the diagnosis of diabetes. It has been reported that in the diagnosis of diabetes, serum GA measurements can be used to ascertain the need for an oral glucose tolerance test (OGTT). There appears to be a negative correlation between GA and body mass index (BMI), and hence it could potentially underestimate glycemia in the obese. Currently, no guidelines support the use of GA or FA for the diagnosis of diabetes or pre-diabetes.
Previously there was little evidence of the relationship of fructosamine and glycated albumin with diabetes complications and long-term outcomes. Recent studies, for example, the Atherosclerosis Risk in Communities Study (ARIC), have demonstrated that fructosamine and glycated albumin were strongly associated with retinopathy as well as being significantly associated with risk of incident chronic kidney disease and incident diabetes. In addition, both Fructosamine and GA, even following adjustment for HBAIc, significant prognosticators of cardiovascular outcomes and mortality.
Fructosamine and GA have utility as alternate markers in those patients where the HbA1c assay is unreliable. Also, they can identify poor glucose control more rapidly than HbA1c, i.e., short-term hyperglycemia. A major promise will be their ability to predict those pre-diabetic patients who go on to clinical diabetes since this could lead to major lifestyle and pharmacological interventions to prevent the onset of diabetes and its complications. Finally, they may also have a role in pregnancy for the management of diabetes given that they can provide a measure of glycemia over 2 to 3 weeks rather than 8 to 12 weeks.
Glycated albumin has been reported to be a better marker than HbA1c for the assessment of glucose control in people with diabetes with chronic kidney disease and those on hemodialysis and peritoneal dialysis.
Commerical assays for fructosamine and glycated albumin have internal quality control materials available for use. Additionally, laboratories measuring these assays would subscribe to a recognized proficiency testing scheme to monitor test performance.