Role of nonenzymatic glycosylation in the development of the sequelae of diabetes mellitus.

The increased level of the glycosylated hemoglobin (hemoglobin A1c) in the diabetic patient has proved to be an interesting clue to understanding the biochemical basis of the sequelae of diabetes. This minor hemoglobin, which arises as nonenzymatic postsynthetic addition of glucose to hemoglobin A, acts as an indicator molecule for the glucose environment over a 3-5-wk period prior to measurement. Reasoning that a similar glycosylation reaction could be occurring with other body proteins, we have studied the ocular lens. The lens, like the erythrocyte, is not dependent on insulin for glucose concentration in the extracellular milieu that would be elevated in the diabetic state. These studies have revealed that a high glucose in vivo or an increased glucose or glucose-6-phosphate concentration in vitro leads to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. This glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence of the crystallin solutions.