Clearance of apoptotic beta-cells is reduced in neonatal autoimmune diabetes-prone rats.

The kinetics of beta-cell death in neonatal diabetes-prone (BBdp) and diabetes-resistant (BBdr) BioBreeding rats was investigated using both direct (histochemical) and indirect (mathematical modelling) techniques. In both BBdp and BBdr rats, the incidence of TUNEL positive beta-cells increased until 10 days of age before declining. The number of apoptotic beta-cells was significantly higher in BBdp as compared to BBdr neonates from birth until 20 days of age (P<0.05). Using a mathematical model applied to the time course of beta-cell mass and replication rate, a wave of net beta-cell loss was detected between 10 and 20 days of age in both strains. In contrast to the observed difference in the incidence of TUNEL positive beta-cells, with the model-based approach we found no difference in the rate of beta-cell apoptosis between BBdp and BBdr rats prior to weaning. As the number of apoptotic cells present in a tissue depends on the rate at which cells die and the rate at which the apoptotic cell debris is cleared, we compared in vitro phagocytosis of apoptotic thymocytes by peritoneal macrophages from 2-week-old BBdp and BBdr rats. Macrophages from BBdp neonates engulfed significantly less apoptotic cells as compared to BBdr neonates (P<0.0005). Taken together, these findings suggest that there is impaired clearance of apoptotic beta-cells in diabetes-prone BB rats during the neonatal period.