Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions

Abstract

Blood oligosaccharides are attached to many proteins after translation, forming glycoproteins. Glycosylation refers to an enzyme-mediated modification that alters protein function, for example, their life span or their interactions with other proteins (1). By contrast, glycation refers to a monosaccharide (usually glucose) attaching nonenzymatically to the amino group of a protein. Glycated hemoglobin is formed by the condensation of glucose with select amino acid residues, commonly lysine, in hemoglobin to form an unstable Schiff base (aldimine, pre-HbA1c) (Fig. 1). The Schiff base may dissociate or may undergo an Amadori rearrangement to form a stable ketoamine. Figure 1 Formation of glycated protein. A reversible interaction between a primary amino group (depicted as NH2) of a protein and the carbonyl group of d-glucose yields a labile intermediate, called a Schiff base. This can undergo a slow and spontaneous Amadori rearrangement to form a stable ketoamine. HbA1c is formed if glucose attaches to the N-terminal valine of the β-chain of hemoglobin. If the glucose attaches to proteins in the plasma, fructosamine or glycated albumin results. RBC, red blood cell. Glycated hemoglobin, particularly HbA1c, has for decades been widely incorporated into the management (and, more recently, the diagnosis) of patients with diabetes. An important attribute is that glycation occurs continuously over the lifetime of the protein, so the concentration of the glycated protein reflects the average blood glucose value over a period of time. This contrasts with the measurement of blood glucose, which reveals the glucose concentration at the instant blood is sampled and which is acutely altered by multiple factors such as hormones, illness, food ingestion, and exercise (2). While HbA1c is by far the most extensively used—and studied—glycated protein (2–4), other glycated proteins that have been evaluated in clinical studies include fructosamine, glycated albumin, and …