Gaps in the Glycation Gap Hypothesis

Patients with diabetes mellitus are at risk for developing severe debilitating complications, including retinopathy, nephropathy, neuropathy, myocardial infarction, and stroke. Randomized trials have documented that lowering hemoglobin A1c (Hb A1c)4 concentrations significantly reduces the onset and rate of progression of microvascular complications (1, 2). Moreover, Hb A1c, which is formed by the nonenzymatic attachment of glucose (termed glycation) to hemoglobin and reflects the mean glucose concentration over the preceding 8 to 12 weeks (3, 4), correlates with the risk for developing microvascular and cardiovascular complications in diabetes (5, 6). Hb A1c measurement is widely used to monitor glycemic control and to adjust therapy. More recently, its use has been advocated for diagnosing diabetes (7). Although intraindividual variation in Hb A1c values is minimal in nondiabetic persons (8), considerable interindividual variation has been reported (9, 10).Evidence that has accumulated over the last few years suggests that race influences Hb A1c. Mexican Americans and blacks have higher mean Hb A1c values than whites (9, 10). Similarly, Hb A1c values increase with age (11). In addition to these factors, some investigators have proposed that interindividual variation is due to differences in the glycation rate (9, 12), a premise that is not accepted by all (13). A large retrospective observational analysis that appears in this issue (14) provides additional information to consider.Cohen et al. suggested that a “glycosylation gap,” defined as the difference between the Hb A1c concentration and that predicted by the fructosamine concentration, could explain the excess interindividual variation in Hb A1c (15). They also suggested that the glycosylation gap predicted the progression of nephropathy, although Hb A1c in their small cohort was not itself associated with such …