Pancreatic islet beta cells secrete insulin in response to blood glucose to maintain body's metabolic fuel homeostasis. On the other hand. beta cells are susceptible to a range of toxic signals such as high glucose, free fatty acids, oxidative stress, and inflammation, which are major contributing factors to the development of diabetes. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular defense against oxidative and inflammatory insults. We have previously found that mice with targeted knockout (KO) of Nrf2 were sensitive to streptozotocin (STZ) induced diabetic lesions. In the present study, islet beta cells from NrfZ wild-type (WT) and KO mice were analyzed in vivo and in vitro. Treatment with STZ induced diabetic conditions that were significantly more severe in Nrf2 KO than WT mice (blood glucose of 55B+/-38 mg/dl for KO and 380+/-17 for WT). ln addition to reducing pancreatic islet size, STZ induced islet oxidative stress and inflammation that were significantly more apparent in KO than WT. Characterization of Nrf2 KO mice revealed that loss of Nrf2 induced a sub-diabetic condition with significantly reduced glucose tolerance and reduced levels of serum insulin. To examine if Nrf2 directly affects islet functions, pancreatic islets were isolated. Islet cells from KO mice showed increased oxidative stress and apoptosis, and reduced survival in the presence of high glucose. Furthermore. Nrf2 KO islets exhibited significantly decreased insulin secretion upon stimulation with glucose in comparison with WT. Taken together the findings revealed that Nrf2 directly regulates islet beta cell functions by modulating glucose stimulated insulin secretion and by boosting protection against oxidative stress and STZ toxicity.