Increased apoptosis of pancreatic -cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic -cell apoptosis and its potential mechanism in OLETF rats, an established animal model of human type 2 diabetes, at prediabetic and diabetic stage. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets and proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg · kg^-1 · day^-1, administered intraperitoneally) inhibited -cells apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet -cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r=0.913, P < 0.0001). Further study demonstrated that diazoxide upregulated Bcl-2 expression, and p38 MAPK, which expressed at very low levels due to the high glucose, but not JNK and ERK. Hence diazoxide may play a critical role in protection from apoptosis. In this study we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting -cell apoptosis via increasing p38 MAPK, elevating Bcl-2/Bax ratio, and by ameliorating insulin secretory capacity and action.