Streptozotocin (STZ), a pancreatic beta cell toxin, is used to induce diabetic conditions by targeting the Glut-2 transporter. We have recently identified decreased Glut-2 expression in beta cells of mice lacking the transcription factor Mist1 (MiSt1(KO)). Given the loss in Glut-2 expression, we examined whether Mist1(KO) beta cells have an increased resistance to STZ. Mist1(KO) and wild-type (WT) female mice received a single 100 or 200 mg/kg injection of STZ, and resting glucose levels and islet morphology were assayed 3-7 days after injection. Ten-month-old Mist1(KO) mice have less beta cell damage when exposed to high levels of STZ while 2-month-old Mist1(KO) mice exhibit a dose-dependent resistance. Surprisingly, Mist1(KO) mice still have elevated fasting glucose levels when compared to WT mice. These results suggest that while Mist1(KO) islets have increased resistance to STZ, additional effects outside of beta cell loss alter blood glucose homeostasis. (c) 2006 Elsevier Inc. All rights reserved.