Hemoglobin A1c in Diabetes: Panacea or Pointless?

Glycation is the nonenzymatic attachment ofa monosaccharide to amino groups of proteins.The reaction has been recognized for manyyears in the food industry, where it is known as browning (also termed the Maillard reaction) and is re-sponsible for the formation of commonly ingested items, such as toast. In patients with diabetes, glucose accumu-lation results in enhanced glycation of many proteins, both in tissues (e.g., the lens) and in the blood. Of these, glycated hemoglobin (GHb) is by far the most frequently measured in patient care. Hemoglobin (Hb) in healthy adults consists predominantly of HbA, which has 2a- and 2b-chains. Glucose can attach to several amino acid resi-dues in these chains. HbA1c is formed when glucose attaches specifically to the NH2-terminal valine of the b-chain. Formation of HbA1c is essentially irreversible, and its concentration in the blood depends on both the life span of the red blood cell (RBC), which averages w120 days, and the blood glucose concentration. Because the rate of formation of HbA1c is directly proportional to the concentration of glucose in the blood, HbA1c represents integrated values for glucose over the preceding 8 to 12 weeks (Table 1). CLINICAL VALUE OF HbA1c Initially described 57 years ago (1), GHb was first reported to be increased in patients with diabetes in the late 1960s (2). The clinical value of GHb was soon realized and the American Diabetes Association (ADA) began encouraging the routine measurement of GHb in all patients with di-abetes (3). The fundamental role of GHb in diabetes was accentu-ated by the publication in 1993 of the Diabetes Control and Complications Trial (DCCT) (4). The study, which compared intensive to conventional insulin therapy in patients with type 1 diabetes, documented a direct relation-ship between blood glucose concentrations (assessed by HbA1c) and the risk of microvascular complications. The absolute risks of retinopathy and nephropathy were di-rectly proportional to the mean HbA1c concentration. (To prevent assay variability [see “Development of Accurate HbA1c Measurements ” below], all GHb assays in the DCCT were performed in a single laboratory that measured