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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/E326    most recent 00296.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xu, J. Articles by Renaud, J.-M. Search for Related Content PubMed PubMed Citation Articles by Xu, J. Articles by Renaud, J.-M.

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

¹Department of Cellular and Molecular Medicine and ²Ottawa Hospital and Ottawa Health Research Institute, University of Ottawa, Ottawa, Canada; and ³Division of Cellular and Molecular Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan

Submitted 15 May 2007 ; accepted in final form 9 November 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 β-cells. However, in ATP-sensitive K⁺ channel (K_ATP 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 β-cells and 2) the decreased transport is due to a downregulation of GLUT2 activity involving an effect at the COOH terminus.

knockout; insulin; liver; glucose transporter; glucose tolerance; diabetic model