The study was carried out using a new rat model of naturally occurring obese, nonketotic diabetes, Otsuka Long-Evans Tokushima Fatty rat (Kawano et al., Diabetes 41: 1422-1428, 1992), which closely resembles obese noninsulin-dependent diabetes in human. At the age of 3.5 wk, body weight, glucose tolerance and plasma insulin level after glucose load were normal in Otsuka Long-Evans Tokushima Fatty rats, indicating the animals are at nonobese, prediabetic phase. At this age, however, glucose-stimulated insulin release by pancreatic islets in vitro was abnormally exaggerated whereas the islet insulin content and glucose metabolism by the islet cells were normal. Administration of diazoxide (0.2% in diet), an inhibitor of insulin secretion, to Otsuka Long-Evans Tokushima Fatty rats from the age of 4 to 12 wk completely prevented the development of obesity and insulin resistance, which was accompanied by marked improvement of glucose tolerance and disappearance of exaggerated B cell response to glucose in vitro. This is the first report of successful pharmacological prevention of genetically determined obese diabetes.