In wild type mice, a single injection of streptozotocin (STZ, 200 mg/kg body weight) caused within 4 days severe hyperglycemia, hypoinsulemia, significant glucose intolerance, loss of body weight and the disappearance of pancreatic -cells. However, in KATP channel deficient mice (Kir6.2^-/- mice), STZ had none of these effects. Exposing isolated pancreatic islets to STZ caused severe damage in wild type but not in Kir6.2^-/- islets. Following a single injection, plasma STZ levels were slightly less in Kir6.2^-/- mice than wild type mice. Despite the difference in plasma STZ, wild type and Kir6.2^-/- liver accumulated the same amount of STZ whereas Kir6.2^-/- pancreas accumulated 4.1-fold less STZ than wild type pancreas. Kir6.2^-/- isolated pancreatic islets also transported less glucose than wild type ones. Quantification of GLUT2 protein content by Western blot using an antibody with an epitope in the extracellular loop showed no significant difference in GLUT2 content between wild type and Kir6.2^-/- pancreatic islets. However, visualization by immunofluorescence with the same antibody gave rise to 32% less fluorescence in Kir6.2^-/- pancreatic islets. The fluorescence intensity using another antibody, with an epitope in the C-terminus, was 5.6 times less in Kir6.2^-/- than in wild type pancreatic islets. It is concluded 1) that Kir6.2^-/- mice are STZ resistant because of a decrease in STZ transport by GLUT2 in pancreatic -cells and 2) that the decreased transport is due to a downregulation of GLUT2 activity involving an effect at the C-terminus.