We now describe experiments that allow one to determine the consequences of B cell reduction alone vs. those that result from superimposed mild hyperglycemia. Male CD rats underwent a 60% pancreatectomy (Px); controls were sham operated. 1 wk later, either 10% sucrose (SUC) was substituted as fluid supply or tap water was continued (WAT). Plasma glucose and insulin values in Px-WAT remained equal to the sham groups; in Px-SUC the values were euglycemic for 25 d, but then nonfasting plasma glucose rose 15 mg/dl. After 6 wk, B cell mass in Px-WAT was reduced by 45% and non-B cell mass by 57%. In contrast, in Px-SUC both masses were comparable to the sham groups. The insulin response to 27.7 mM glucose was measured using the in vitro perfused pancreas. The responses were reduced in Px-WAT but in proportion to their reduced B cell mass; in contrast, it was 75% less than expected in Px-SUC. Also, the response to arginine given at 16.7 mM glucose was reduced only in Px-SUC. These results show that a lowering of B cell mass that does not result in hyperglycemia has no adverse effect on the remaining B cells. On the other hand, if even mild hyperglycemia develops, B cell function becomes impaired and results in inappropriately reduced insulin stores and insulin responses to marked stimuli.