Translating the A1C Assay

In the clinical management of diabetes, the A1C assay has become indispensable. Used worldwide to monitor chronic glycemia, the assay is an essential tool to determine whether a patient has achieved the core goal of therapy for diabetes: a marked and sustained reduction in plasma glucose to achieve as close to a normal level as can be safely attained. With the publication of the A1c-Derived Average Glucose (ADAG) study in this issue of Diabetes Care (1), the evolution of the A1C assay continues and an important milestone has been reached. To better appreciate this recent report, a brief and admittedly incomplete historical perspective may be useful. It was 60 years ago that Allen et al. (2) showed that hemoglobin A (which makes up about 97% of total hemoglobin) contains three minor components, designated HbA1a, HbA1b, and HbA1c (A1C). In the decades that followed, we learned that a hexose molecule is attached to these components (3) and that hemoglobin A actually has two more minor glycated derivatives. The five altogether comprise ∼5–7% of the HbA molecule (4). In the early course of the biochemical dissection of hemoglobin, Huisman and Dozy (5) noted, virtually in passing, that the level of glycated hemoglobin components was increased in a few individuals they studied who happened to have diabetes. It took 4 more years, however, for Rahbar and colleagues (6,7) to document that diabetes is clearly associated with an elevation in glycated hemoglobin. The Rahbar reports stimulated other investigators to confirm these initial findings and to seek an explanation for how glucose binds to hemoglobin. It was not for another few years, in 1972, that Bunn et al. (8) elegantly showed that the cause of the increased glycated hemoglobin in diabetes, which was predominantly the A1C component, …