Analysis of human red cell hemolysates by cation-exchange chromatography reveals several negatively charged minor hemoglobins that are designated AIa, AIb, and AIc, corresponding to their order of elution. These hemoglobins are formed by the nonenzymic interaction of glucose with the alpha-amino groups of valine residues at the N terminus of the beta chains of hemoglobin. (See Figure 6.19)

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The best characterized of the acquired variants is hemoglobin A1c, which constitutes about 3.5% of the hemoglobin in normal subjects and may be increased two- to threefold in individuals with diabetes mellitus. Its level is directly proportional to the time-integrated mean blood glucose concentration over the life of the red cell, typically the preceding 2 to 3 months. In the nonenzymic glycation of hemoglobin A, a molecule of glucose forms a Schiff base with the N terminal of the beta chain, the undergoes an Amadori rearrangement to a stable ketamine, 1-amino, 1-deoxy fructose.

Because the glycated (or, as often called, glycosylated) hemoglobins are synthesized throughout the lifespan of the red cell, older cells contain a higher proportion of these modified hemoglobins than younger ones. Preferential destruction of older cells explains the observation that the proportion of hemoglobin in A1c is reduced in hemolytic anemia.

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