Diabetes and its complications impose severe economic burden on individuals, families and the U.S. healthcare delivery system. The total costs of diagnosed diabetes due to both direct medical costs and lost productivity in the United States in 2017 was $327 billion dollars. After adjusting for population age and sex differences, the average medical expenditures among people with diagnosed diabetes were 2.3 times higher than non-diabetics.1
Currently, blood glucose and hemoglobin A1c are the standard measures for the diagnosis and monitoring of diabetes. There has recently been increasing interest in nontraditional diabetes biomarkers, including fructosamine, glycated serum protein (GSP), glycated albumin (GA), and 1,5 anhydorglucitol (1,5 AG). Recent studies suggest that expanded use of these tests has the potential to improve diabetes care, as these assays overcome the limitations of HbA1c in some patients, while providing additional insight into shorter-term glycemic control and improving risk stratification for diabetes and its complications.2
Glycation of hemoglobin and serum proteins
Blood glucose nonenzymatically and irreversibly attaches to intracellular and blood proteins via a slow Maillard reaction between glucose and amino acid residues of proteins to form glycated proteins (Figure 1). HbA1c is produced in this manner by the reaction between glucose and hemoglobin and is considered the standard for monitoring long-term glycemic control in patients with diabetes. Because red blood cells are replaced every 90 days, HbA1c provides a glycemic picture of blood glucose over the previous two to three months. HbA1c has been shown to predict complications of diabetes such as cardiovascular disease, neuropathy, and nephropathy clinically through randomized clinical trials, including the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).3,4
There are, however, some well-understood shortcomings of HbA1c testing for certain groups of patients, which result in lower diagnostic and prognostic performance. These patients include pregnant women and the elderly. There also exists the risk of decreased reliability of HbA1c in patients with decreased red cell lifespan, including patients on hemodialysis, as well as those with hemolytic anemia, end-stage renal disease, and heavy alcohol consumption. Additionally, there are potential analytical difficulties, depending on the HbA1c method used, with variant hemoglobins, persistent fetal hemoglobin, and chemically modified derivatives such as carbamylated and acetylated hemoglobins,5 which may reduce the reliability of the assay.
Glycated serum protein (glycated albumin)
Blood glucose also reacts with serum proteins via a slow, non-revisable Maillard reaction to form glycated serum protein (GSP). Serum albumin composes 60 percent to 70 percent of serum protein and represents > 90 percent of total serum glycated proteins.6 GSP is used for monitoring average blood glucose levels over the past two to three weeks, making it more useful for showing problems with control in the short term than HbA1c. By combining GSP measurements with HbA1c, it is possible to see a more complete picture of a patient’s long term and intermediate glycemic control (Figure 2). Although HbA1c continues to be considered the standard, a number of clinical studies have found that GSP is at least as predictive of future complications as HbA1c.7 Armed with a better understanding of the patient’s glycemic profile, the physician may be able to recommend a more informed treatment plan.
In the literature, glycated serum protein (GSP) is also known as fructosamine. Fructosamine is traditionally measured by a non-specific chemical method using nitroblue tetrazolium (NBT) that is interfered with by various reducing substances in patient samples (Figure 3). Although rapid, inexpensive, and available for automation, the method remains poorly standardized. Moreover, due to the technical nature of the assay, all molecules with reducing activity, such as bilirubin and vitamins, may interfere in the measurement, thus biasing the test results, especially when present in large concentrations. Recently, a more specific fructosamine assay has been developed, a new enzymatic GSP assay for clinical laboratory determination of GSP or GA that is formulated with ready-to-use liquid stable reagents. Another GA assay has been developed in Japan, which measures the percentage of glycated albumin to total albumin; this assay is not yet widely available in the U.S.
The Diabetes Control and Complications Trial (DCCT) effectively showed that HbA1c concentrations are associated with microvascular complications, but it also showed that HbA1c alone fails to explain all the observed risk.8 This has led to the hypothesis9 that microvascular complications may result from both chronic hyperglycemia and from glycemic excursion, also known as glycemic variability. 1,5 anhydroglucitol (AG) correlates with post-meal hyperglycemia and reflects trends over a period of one to two weeks. Unlike the glycated hemoglobin and glycated serum proteins, 1,5 AG does not reflect an average blood glucose but rather reflects hyperglycemia and glycemic variability.
1,5 AG is a monosaccharide that is freely filtered in the renal glomerulus and competes with glucose for active transport back to the bloodstream by the renal tubular cells. As the level of glucose increases, renal tubular cells preferentially reabsorb glucose, and 1,5 AG passes into the urine and is cleared from the blood. As blood glucose rises, 1,5 AG concentrations decrease. Recent studies have shown that 1,5 AG is strongly and independently associated with long-term risk of complications including microvascular outcomes,10 retinopathy, albuminuria, and cardiovascular disease.11 Most important, when adjusted for HbA1c and fasting glucose, 1,5 AG was associated with a fivefold increase of retinopathy and twofold increased risk of chronic kidney disease.
The future of non-traditional markers
Nontraditional glycemic biomarkers are not replacements for the HbA1c assay, but rather are complementary assays to HbA1c that can improve quality in diagnosing diabetes and monitoring glycemic control, especially for those patients whose HbA1c levels do not truly reflect the mean blood glucose levels or those with glycemic variability. GSP (GA) provides a picture of past two-week average blood glucose levels, and is a short- to medium-term index for glycemic control. GSP is especially useful in the management of various diabetic conditions such as diabetic pregnancy, dialysis of diabetic patients, and diet or medication adjustment. GSP bridges the gap between blood glucose testing (a transient index) and HbA1c testing (a long-term index), and provides a complementary and unique system to the existing methods for glycemic control. A small improvement in glycemic control may lead to a significant improvement in the quality of life and a huge reduction in the economic burdens currently imposed on the families of people with diabetes and the healthcare systems on which they rely.12
- Centers for Disease Control and Prevention. National diabetes statistics report. 2017.
- Parrinello CM, Slevin E. Beyond HbA1c and glucose: the role of nontraditional glycemic markers in diabetes diagnosis, prognosis, and management. Curr Diab Rep. 2014;14(11):548. doi: 10.1007/s11892-014-0548-3.
- Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus. NEJM. 1993;329(14):977–986.
- UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UK PDS 33). Lancet. 1998;352(9131):837-853.
- Weykamp CW, Penders TJ, Siebelder CW, Muskiet FA, van der Slik W. Interference of carbamylated and acetylated hemoglobins in assays of glycohemoglobin by HPLC, electrophoresis, affinity chromatography, and enzyme immunoassay. Clin Chem. 1993;39(1):138-142.
- Rodriguez-Capote K, Tovell K, Holmes D, Dayton J, Higgins TN. Analytical evaluation of the Diazyme glycated serum protein assay on the siemens ADVIA 1800: comparison of results against HbA1c for diagnosis and management of diabetes. J Diabetes Sci Technol. 2015;9(2):192-199.
- Selvin E, Rawlings AM, Grams M, et al. Prognostic utility of fructosamine and glycated albumin for incident diabetes and microvascular complications. Lancet Diabetes Endocrinol. 2014;2(4):279-288.
- Lawler PR, Mora S. Moving beyond mean glycemia: 1,5-anhydroglucitol and microvascular complications of diabetes, Clin Chem. 2014; 60(11):1409-1418.
- Stand E, Schell O, Ceriello A. Postprandial hyperglycemia and glycemic variability should we care? Diabetes Care. 2011;34(Supplement 2): S120-S127.
- Selvin E, Rawlings AM, Grams M, Klein R, Steffes M, Coresh J. Association of 1,5-
anhydroglucitol with diabetes and microvascular conditions. Clin Chem. 2014;60(11):1409-1418.
- Selvin E, Rawlings A, Lutsey P, et al. Association of 1,5-anhydroglucitol with cardiovascular disease and mortality Diabetes. 2016;65(1): 201-208.
- Sumner AE, Duoung MT, Bingham BA, et al. Glycated albumin identifies prediabetes not detected by hemoglobin A1c: The Africans in America study. Clin Chem. 2016;62(11):1524-1532.
- Schleicher ED, Mayer R, Wagner EM, Gerbitz KD. Is serum fructosamine assay-specific for determination of glycared serum protein? Clin Chem. 1988;34(2):320-323.
- Abidin D, Liu L, Dou C, Datta A, Youan C. An improved enzymatic assay for glycated serum protein. Analytical Methods. 2013;5(10):2461.