TY - JOUR
T1 - Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic β-cells
AU - Imasawa, Toshiyuki
AU - Koike, Kentaro
AU - Ishii, Isao
AU - Chun, Jerold
AU - Yatomi, Yutaka
N1 - Funding Information:
We thank Ms. Mori Tachibana and Ms. Akiko Miyashita for technical support. This work was supported by research grants from the Policy-based Medical Service Network for the National Hospitals of Japan (to T.I.), the Takeda Science Foundation (to I.I.), and the National Institutes of Health ( DA019674 and NS048478 to J.C.).
PY - 2010/2/5
Y1 - 2010/2/5
N2 - Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P1-S1P5) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic β-cells in which genes for S1P1-S1P4 are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P2 in streptozotocin (STZ)-induced apoptosis of pancreatic β-cells and progression of diabetes. S1P2-deficient (S1P2-/-) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic β-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P2-/- mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P2-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P2 signaling attenuates STZ-induced apoptosis of pancreatic β-cells and decreases the incidence of diabetes.
AB - Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P1-S1P5) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic β-cells in which genes for S1P1-S1P4 are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P2 in streptozotocin (STZ)-induced apoptosis of pancreatic β-cells and progression of diabetes. S1P2-deficient (S1P2-/-) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic β-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P2-/- mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P2-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P2 signaling attenuates STZ-induced apoptosis of pancreatic β-cells and decreases the incidence of diabetes.
KW - Blood glucose
KW - Diabetes
KW - Insulin
KW - S1P-deficient mice
KW - S1P-specific antagonist
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U2 - 10.1016/j.bbrc.2010.01.016
DO - 10.1016/j.bbrc.2010.01.016
M3 - Article
C2 - 20060809
AN - SCOPUS:75749105853
SN - 0006-291X
VL - 392
SP - 207
EP - 211
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
