The effect of feeding a diet that produces a high or low incidence of diabetes on immune abnormalities proposed to contribute to the pathogenesis of autoimmune-mediated diabetes was investigated. Diabetes-prone (BBdp) and nondiabetes-prone (BBn) BB rats (21 d) were fed for 21 d a nonpurified (high incidence) or purified (low diabetes incidence) diet. Compared with BBn, immune cells from spleen and mesenteric lymph nodes of BBdp rats demonstrated higher rates of metabolite production from glucose and glutamine, higher splenic cytotoxicity (lysis of 51Cr-labeled YAC-1 cells) and lower mitogen responses (3H thymidine uptake). Bypassing the membrane, using the mitogen phorbol myristate acetate + lonomycin, improved the BBdp mitogen response, suggesting a membrane defect. Immune cells from BBdp rats fed the purified, compared with the nonpurified, diet had lower rates of glutamine (spleen) and glucose (lymph nodes) metabolism and lower splenic cytotoxic activity. Although diet altered the proportion of T and B cells in lymph nodes of BBdp rats, it did not correct the abnormal lymphocyte distribution or effect mitogen responses. Feeding the purified, compared with nonpurified, diet to BBn rats altered energy metabolism by lymph node cells and resulted in lower splenic cytotoxic activity. Reduced splenic natural killer cell activity and decreased immune cell metabolism are unlikely the mechanism for the preventative effect of feeding a purified diet to BBdp rats but are indicative of reduced immune activity.