Diabetes mellitus (DM), a global epidemic, is increasing at an alarming rate and is associated with both increased morbidity and mortality. In 2018 the estimated prevalence of diabetes in the USA was 34.2 million people. Globally, the prevalence was 425 million people and this is expected to rise to 629 million by 2045. Currently, only plasma glucose and glycated hemoglobin (HbA1c) are universally accepted as reliable measures of diabetes control. In certain conditions, the HbA1c measurement is not reliable. An example is in patients with red blood cell (RBC) disorders and renal disease. Fructosamine, which is a measure of non-enzymatic glycation of circulating proteins including albumin, globulins, and lipoproteins, has evolved to be a reasonable alternative to HbA1c measurement in situations where HbA1c is not reliable. Because albumin is the most abundant of the serum proteins, fructosamine is predominantly a measure of glycated albumin (GA), which represents the percent of albumin that is glycated. Fructosamine and GA have a potential role in the diagnosis, monitoring, and management of diabetes. 
HbA1c is a product of non-enzymatic glycation of hemoglobin. Red blood cells have a lifespan of approximately 90 to 120 days, hence HbA1c indicates the mean blood glucose concentration over the lifespan of the RBC. HbA1c is influenced by conditions affecting RBC survival. Conditions causing low RBC turnover like untreated iron, vitamin B12, or folic acid deficiency anemias, will result in falsely high HbA1c values. On the other hand, conditions causing high RBC turnover like hemolytic anemia, in patients treated for iron, vitamin B12, or folate deficiencies, as well as in patients treated with erythropoietin (like in chronic kidney disease), there will be falsely low HbA1c values.
Fructosamine (1-amino-1-deoxy fructose), is a stable ketoamine, formed by the reaction between glucose and the amino group of protein (predominantly albumin, but also including 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 product, the aldimine intermediate. The Schiff base product 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.
Non-immunoglobulin serum proteins have a much lower half-life, approximately 14-21 days. The measurement of fructosamine or GA provides information on glucose control within the previous 2-3 weeks. Another important difference with HbA1c is the rate of nonenzymatic glycation of albumin, which is approximately 9- to 10-fold higher than that of HbA1c.
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 assay available for fructosamine measurement in serum is the colorimetric-based assay. This assay utilizes the reduction of the dye nitroblue tetrazolium (NBT) to formazan. The rate of formazan formation is directly proportional to the fructosamine concentration and is measured with the spectrophotometric technique. These assays are widely available, can be automated, and fairly inexpensive. The reference range for fructosamine in non-diabetic individuals is generally 200 to 285 umol/L. 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:
The enzymatic assay (Lucica GA-L kit, Asahi Kasei Pharma, Tokyo, Japan) is easier to use, highly accurate, and automated. First, there is the elimination of endogenous glycated amino acids and peroxide by a ketoamine oxidase, followed by a peroxidase reaction. An albumin-specific proteinase hydrolyzes the GA. The products of this reaction are oxidized by ketoamine oxidase to hydrogen peroxide, which is then measured quantitatively by a colorimetric method. The albumin concentration is also measured concurrently. The final result is expressed as the ratio of glycated to total albumin.
The normal value is around 14% and it becomes greater than 17% in diabetes patients. Values in diabetes can go as high as two to five times the upper limit of normal.
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 both do not have 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 this 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, like in liver cirrhosis, or when there is albumin/protein loss such as in nephrotic syndrome and protein-losing enteropathies. Fructosamine levels may also be affected by conditions with raised total protein levels, like in multiple myeloma (due to increased immunoglobulins) and in 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, the newer assay developed by Asahi Kasei appears to be much improved. According to this assay, normal persons have values around 14% and those with diabetes greater than 17%. Values in diabetes can go as high as two to five times the 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 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 level, or red blood cell characteristics to which HbA1c is susceptible. This includes conditions such as hemoglobinopathies, sickle cell anemia, and anemia related to iron, vitamin B12, or folate 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, or recent medication adjustment. FA and GA can also be 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, like for example, the Atherosclerosis Risk in Communities Study (ARIC), have demonstrated that fructosamine and glycated albumin were strongly associated with retinopathy as well as significantly associated with the risk of incident chronic kidney disease and incident diabetes. Besides, both Fructosamine and GA, even following adjustment for HBAIc, are significant prognosticators of cardiovascular outcomes and mortality.
Commercial 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.
Healthcare workers including the nurse practitioner should be familiar with the diagnosis of diabetes. Fructosamine and GA can be utilized 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 of the tests is their ability to predict those pre-diabetic patients who progress 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 the management of diabetes during pregnancy since pregnant patients need frequent glucose monitoring. They can provide a measure of glycemia over 2 to 3 weeks rather than 8 to 12 weeks as is with HbA1c.
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.
|||Neelofar K,Ahmad J, A comparative analysis of fructosamine with other risk factors for kidney dysfunction in diabetic patients with or without chronic kidney disease. Diabetes [PubMed PMID: 30641705]|
|||Garrahy A,Mijares Zamuner MB,Byrne MM, An evolving spectrum of diabetes in a woman with GCK-MODY. Endocrinology, diabetes [PubMed PMID: 30608898]|
|||Pedrosa W,Sander Diniz MFH,Barreto SM,Vidigal PG, Establishing a blood fructosamine reference range for the Brazilian population based on data from ELSA - Brasil. Practical laboratory medicine. 2019 Jan; [PubMed PMID: 30581949]|
|||Roohk HV,Zaidi AR, A review of glycated albumin as an intermediate glycation index for controlling diabetes. Journal of diabetes science and technology. 2008 Nov [PubMed PMID: 19885300]|
|||Muñoz-Prieto A,Escribano D,Cerón JJ,Martínez-Subiela S,Tvarijonaviciute A, Glucose, fructosamine, and insulin measurements in saliva of dogs: variations after an experimental glucose administration. Domestic animal endocrinology. 2019 Jan; [PubMed PMID: 30472034]|
|||Gingras V,Rifas-Shiman SL,Switkowski KM,Oken E,Hivert MF, Mid-Pregnancy Fructosamine Measurement-Predictive Value for Gestational Diabetes and Association with Postpartum Glycemic Indices. Nutrients. 2018 Dec 18; [PubMed PMID: 30567328]|
|||Rivera-Velez SM,Hwang J,Navas J,Villarino NF, Identification of differences in the formation of plasma glycated proteins between dogs and humans under diabetes-like glucose concentration conditions. International journal of biological macromolecules. 2019 Feb 15; [PubMed PMID: 30465839]|
|||Kouzuma T,Usami T,Yamakoshi M,Takahashi M,Imamura S, An enzymatic method for the measurement of glycated albumin in biological samples. Clinica chimica acta; international journal of clinical chemistry. 2002 Oct [PubMed PMID: 12204426]|
|||Kouzuma T,Uemastu Y,Usami T,Imamura S, Study of glycated amino acid elimination reaction for an improved enzymatic glycated albumin measurement method. Clinica chimica acta; international journal of clinical chemistry. 2004 Aug 16 [PubMed PMID: 15256314]|
|||Kohzuma T,Koga M, Lucica GA-L glycated albumin assay kit: a new diagnostic test for diabetes mellitus. Molecular diagnosis & therapy. 2010 Feb 1 [PubMed PMID: 20121290]|
|||Selvin E,Rawlings AM,Grams M,Klein R,Sharrett AR,Steffes M,Coresh J, Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. The lancet. Diabetes & endocrinology. 2014 Apr [PubMed PMID: 24703046]|
|||Roberts AB,Baker JR, Serum fructosamine: a screening test for diabetes in pregnancy. American journal of obstetrics and gynecology. 1986 May [PubMed PMID: 3706426]|
|||Zheng CM,Ma WY,Wu CC,Lu KC, Glycated albumin in diabetic patients with chronic kidney disease. Clinica chimica acta; international journal of clinical chemistry. 2012 Oct 9 [PubMed PMID: 22579765]|
|||Freedman BI,Shenoy RN,Planer JA,Clay KD,Shihabi ZK,Burkart JM,Cardona CY,Andries L,Peacock TP,Sabio H,Byers JR,Russell GB,Bleyer AJ, Comparison of glycated albumin and hemoglobin A1c concentrations in diabetic subjects on peritoneal and hemodialysis. Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 2010 Jan-Feb [PubMed PMID: 20056983]|