KATP channel-deficient pancreatic -cells are streptozotocin resistant because of lower GLUT2 activity

Xu J, Zhang L, Chou A, Allaby T, Bélanger G, Radziuk J, Jasmin BJ, Miki T, Seino S, Renaud J-M. KATP channel-deficient pancreatic -cells are streptozotocin resistant because of lower GLUT2 activity. Am J Physiol Endocrinol Metab 294: E326–E335, 2008. First published November 27, 2007; doi:10.1152/ajpendo.00296.2007.—In wild-type mice, a single injection of streptozotocin (STZ, 200 mg/kg body wt) caused within 4 days severe hyperglycemia, hypoinsulinemia, significant glucose intolerance, loss of body weight, and the disappearance of pancreatic -cells. However, in ATP-sensitive K channel (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 in 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 glucose transporter 2 (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 COOH terminus, was 5.6 times less in Kir6.2 / than in wild-type pancreatic islets. We conclude that 1) Kir6.2 / mice are STZ resistant because of a decrease in STZ transport by GLUT2 in pancreatic -cells and 2) the decreased transport is due to a downregulation of GLUT2 activity involving an effect at the COOH terminus.