Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse

To determine whether loss of beta-cell mass and function in the NOD mouse o ccurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, beta-cell mass and rates of beta-cell p roliferation and insulin secretory responses from the perfused pancreas wer e measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age . Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol /l) at 13 and 18 weeks of age, respectively. beta-cell mass in 8-week-old N OD mice was 69% of control mice (P > 0.05), but the rate of 5-bromo-2-deoxy uridine uptake was greater, suggesting a compensatory proliferative respons e to ongoing autoimmune beta-cell destruction, Despite an increase in the r ate of beta-cell proliferation, beta-cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than beta-cell mass, suggesting the presence of beta-cell dysfunction in addition to reduced mass. These re sults suggest that in the NOD mouse, beta-cell destruction begins soon afte r the onset of insulitis. Despite a compensatory beta-cell proliferative re sponse, beta-cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be prese nt when residual beta-cell mass represents 30% of control levels.