Adult diabetic mice (C57Bl/KsJ--db/db) have increased amounts of a minor hemoglobin in their peripheral blood compared to wild-type (+/+) mice. This increase is analogous to the 2-fold increase of a glycohemoglobin with similar chromatographic mobility (Hb AIc) seen in the blood of patients with diabetes mellitus. Although the exact chemical nature of human or mouse Hb AIc is unknown, both contain a sodium-borohydride-reducible linkage on the beta chain which is a presumed Schiff base between a sugar moiety and the protein. The db/db animals, which have normal amounts of mouse Hb AIc at weaning, show the increase approximately 4 weeks after the onset of the signs of diabetes. This rise is brought about by an increase in a circulating factor that determines directly or indirectly the synthesis of mouse Hb AIc as a post-synthetic modification of Hb A. Evidence for this was obtained by showing that the rate of synthesis of the modified Hb is linear for at least the first 50 days of the life of the red cell and that the rate of synthesis is dependent on the environment in which the cells circulate. Thus the rate of mouse Hb AIc synthesis in +/+ cells is greater when those cells circulate in a db/db host than when they circulate in a +/+ host. The nature of the humoral factor is unknown. If glycosylations of basement membrane proteins and hemoglobin proceed via a common mechanism, then the monitoring of Hb AIc could provide a useful model for studying the early events of basement membrane thickening.