KATP channel-deficient pancreatic beta-cells are streptozotocin resistant because of lower GLUT2 activity.
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 beta-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 beta-cells and 2) the decreased transport is due to a downregulation of GLUT2 activity involving an effect at the COOH terminus.
Xu
Jin
J
Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada.
Zhang
Li
L
Chou
Andrew
A
Allaby
Tim
T
Bélanger
Guy
G
Radziuk
Jerry
J
Jasmin
Bernard J
BJ
Miki
Takashi
T
Seino
Susumo
S
Renaud
Jean-Marc
JM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004351:Drug Resistance; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology; D013311:Streptozocin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D000099161:Kcnj11 Channel
D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D013311:Streptozocin; D000099161:Kcnj11 Channel; C495682:Slc2a2 protein, mouse