Comparing multiple measures of glycemia: how to transition from biomarker to diagnostic test?

The underlying pathophysiology of diabetes varies, but all patients share a common a metabolic derangement of carbohydrate metabolism, which causes hyperglycemia. Many patients with diabetes develop debilitating complications, ranging from retinopathy and nephropathy, to myocardial infarction and stroke. The accumulated evidence reveals that reducing an increased glucose concentration, as documented by a lower hemoglobin A1c (Hb A1c) 4 concentration, decreases complications (1, 2 ). Hb A1c is extensively used to monitor glycemic control and to adjust therapy, and it has recently been accepted as a criterion for the diagnosis of diabetes (3 ). Hb A1c reflects long-term glycemia, because glucose attaches irreversibly (the process is termed glycation) to hemoglobin in erythrocytes. Hb A1c can be modified independently of glycemia, however, by conditions (e.g., anemia or renal failure) that alter the mean age of erythrocytes by changing either their production or their rate of disappearance. Recent observations have revealed that the life span of erythrocytes in healthy individuals who have normal blood counts and indices can vary sufficiently from the commonly taught 120 days to cause clinically relevant differences in Hb A1c concentrations (4 ). These limitations have led to investigations of an expanding group of alternative markers of glycemia. The best studied of these analytes is fructosamine, which is the generic name for plasma protein ketoamines. Because albumin is the most abundant protein in serum, fructosamine is predominantly a measure of glycated albumin. The covalent attachment of glucose to albumin forms glycated albumin, which can also be assayed directly (5 ). The half-life of albumin in the blood is 14 –20 days, so both fructosamine and glycated albumin indicate the mean blood glucose concentration over the preceding 2 weeks. The fructosamine assay was developed in 1983 (6 ), but it was modified— and improved—in 1990 by the addition of uricase, a nonionic detergent, and polylysine calibrators (7 ). Automated assays of glycated albumin have been available for approximately 10 years. Fructosamine and glycated albumin are extracellular and have several useful attributes, including independence from both erythrocyte life span and glucose transport across membranes. The assays are rapid, technically easy, and inexpensive; however, changes in protein concentration and half-life affect fructosamine, and whether the results need to be corrected for albumin concentration remains controversial. Glycated albumin is also altered by conditions other than glycemia, including the nephrotic syndrome, thyroid dysfunction, hepatic cirrhosis, smoking, hyperuricemia, and hypertriglyceridemia (5 ). Another indicator of glycemia is 1,5-anhydroglucitol (1,5-AG), a 6-carbon monosaccharide that is not metabolized (8 ). Because glucose in the urine competes for reabsorption of 1,5-AG by the kidneys, blood glucose concentrations that exceed the renal threshold [usually approximately 180 mg/dL (10 mmol/L)] reduce the circulating 1,5-AG. The clinical value of 1,5-AG as a marker of short-term glycemia, especially the postprandial glucose concentration, is limited by other factors that modify 1,5-AG, including diet, sex, and renal impairment (8 ). Although several assays for these alternative markers are commercially available, these analytes all suffer from a major deficiency: clinical studies have been limited, and there is a paucity of rigorous analysis in the literature. For example, the number of PubMed hits in humans for fructosamine, glycated albumin, and 1,5-AG is 3.75%, 2.3%, and 0.35%, respectively, of that for Hb A1c. In this issue of Clinical Chemistry, Juraschek et al. describe their study of the relationships of fructosamine, glycated albumin, and 1,5-AG to Hb A1c and the fasting glucose concentration in a communitybased cohort (9 ). The authors report that nonlinear equations best fit the relationship of fructosamine and glycated albumin with both Hb A1c and fasting glucose, albeit with considerable scatter. A careful inspection of Table 2 in their report, however, reveals 2 important caveats. The first is that a major proportion of the correlation in the population as a whole depends on the 1 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; 2 Cincinnati VA Medical Center, Cincinnati, OH; 3 Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD. * Address correspondence to this author at: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati Medical Center, P.O. Box 670547, Cincinnati, OH 45267-0547. Fax 513-558-8581; e-mail [email protected]. Received October 5, 2012; accepted October 11, 2012. Previously published online at DOI: 10.1373/clinchem.2012.196139 4 Nonstandard abbreviations: Hb A1c, hemoglobin A1c; 1,5-AG, 1,5-anhydroglucitol; ARIC, Atherosclerosis Risk in Communities (study). Clinical Chemistry 58:12 1615–1617 (2012) Editorials