Moving beyond mean glycemia: 1,5-anhydroglucitol and microvascular complications of diabetes.

Defining the risk of microvascular complications associated with diabetes mellitus is clinically important for identifying at-risk individuals and evaluating treatment efficacy. The standard measure of mean glycemia, glycohemoglobin A1c (Hb A1c), 3 is associated with incident microvascular complications among diabetic patients, but this biomarker fails to explain all of the observed risk (1 ). This has led to the hypothesis that microvascular complications may result not only from chronic sustained hyperglycemia but also from glycemic excursions (1 ). Therefore, identifying biomarkers that are associated with glycemic excursions has direct clinical significance. For example, in the landmark Diabetes Control and Complications Trial (DCCT) of conventional diabetes therapy vs intensive insulin therapy targeting low Hb A1c, matching attained Hb A1c across the 2 treatment arms did not produce similar reductions in incident microvascular complications (2 ). The higher rate of microvascular complications observed in the conventional therapy arm of DCCT may have been due to larger glycemic excursions, as this group had fewer insulin injections per day (3 ). Indeed, in DCCT, greater variability in an individual’s Hb A1c measurements was associated with a higher risk of microvascular complications and added risk information beyond standard glycemic measures (4 ). Mechanistically, both hyperglycemia and glycemic excursions result in oxidative stress, likely through overproducing superoxide by the mitochondrial electron-transfer chain (5, 6 ), which generates advanced glycation end products, activates protein kinase C and nuclear factorB, enhances polyol activity, and increases hexosamine pathway flux (1, 7 ). 1,5-Anhydroglucitol (1,5-AG) is a candidate biomarker for glycemic excursions (8 ). 1,5-AG is a dietary monosaccharide, similar to glucose, that is freely filtered in the renal glomerulus and subsequently competes with glucose for reabsorption in the renal tubules. In the presence of high blood glucose concentrations, 1,5-AG resorption is reduced and serum concentrations of 1,5-AG decrease. Hence, lower concentrations of 1,5-AG correlate with more frequent hyperglycemic episodes (most commonly postprandial hyperglycemia) and reflect trends over a 1to 2-week timeline. 1,5-AG is currently marketed for clinical use under the trade name GlycoMark® in the US, despite the limited information regarding its potential role in clinical practice. Several previous studies have suggested an association between 1,5-AG and diabetic microvascular complications (9, 10 ) and atherosclerosis (11 ). However, these studies have been limited in their sample size and the scope of end points that were assessed. In this issue of Clinical Chemistry, Selvin et al. conducted an elegant study that used data from 10 000 participants in the Atherosclerosis Risk in Communities (ARIC) population to examine the association of 1,5-AG with prevalent retinopathy, incident chronic kidney disease (CKD), and incident diabetes (12 ). The study benefited from the prospective follow-up (approximately 20 years) for incident CKD and diabetes. Although 1,5-AG was measured years after sample procurement, the interassay agreement between randomly selected duplicate samples was excellent (reliability 0.99). For the analysis of the association between 1,5-AG and incident CKD, the investigators excluded all patients with a baseline estimated glomerular filtration rate (eGFR) 60 mL min 1 (1.73 m) , leaving 12 083 participants. For the analysis of incident diabetes, 10 948 participants were included who were free of diabetes at baseline. Mydriatic retinography was used to diagnose prevalent retinopathy in 9447 participants. Because retinography was available at only one time point, the investigators examined the association of 1,5-AG with prevalent retinopathy. Exposure categories of 1,5-AG were defined according to the assay 1 Cardiovascular Division and 2 Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. * Address correspondence to this author at: Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston, MA 02215. Fax 617-264-9194; e-mail [email protected]. Received August 26, 2014; accepted August 28, 2014. Previously published online at DOI: 10.1373/clinchem.2014.231720 © 2014 American Association for Clinical Chemistry 3 Nonstandard abbreviations: Hb A1c, glycated hemoglobin A1c; DCCT, Diabetes Control and Complication Trial; 1,5-AG, 1,5-anhydroglucitol; ARIC, therosclerosis Risk in Communities; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IDI, integrated discrimination-improvement; NRI, net reclassification index. Clinical Chemistry 60:11 1359–1361 (2014) Editorials