PMID- 23839933
OWN - NLM
STAT- MEDLINE
DCOM- 20131216
LR  - 20131001
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 27
IP  - 10
DP  - 2013 Oct
TI  - Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting 
      pancreatic beta-cell death in diet-induced obese mice.
PG  - 4294-304
LID - 10.1096/fj.13-230052 [doi]
AB  - Lipotoxic stress-induced beta-cell death (lipotoxicity) is recognized as a key 
      contributor to the development of type 2 diabetes mellitus (T2DM). The current 
      study reports a critical role of sphingosine kinase 1 (SphK1) in beta-cell survival 
      under lipotoxic conditions. In an attempt to investigate the role of SphK1 in 
      lipotoxicity in vivo, we fed Sphk1(-/-) and wild-type (WT) mice with a high-fat 
      diet (HFD) or normal chow diet. Remarkably, while HFD-fed WT mice developed 
      glucose intolerance and compensatory hyperinsulinemia, all HFD-fed Sphk1(-/-) 
      mice manifested evident diabetes, accompanied by a nearly 3-fold reduction in 
      insulin levels compared with the WT mice. Pancreatic beta-cell mass was increased by 
      140% in HFD-fed WT mice but decreased to 50% in HFD-fed Sphk1(-/-) mice, in 
      comparison with the chow diet control groups, respectively. Accordingly, by 
      blocking the enzyme activity, expression of a dominant negative form of SphK1 
      markedly promoted palmitate-induced cell death in MIN6 and INS-1 beta-cell lines. 
      Moreover, primary islets isolated from Sphk1(-/-) mice exhibited higher 
      susceptibility to lipotoxicity than WT controls. Of note, sphingosine 1-phosphate 
      (S1P) profoundly abrogated lipotoxicity in beta cells or the cells lacking SphK1 
      activity and Sphk1(-/-) islets, highlighting a pivotal role of S1P in beta-cell 
      survival under lipotoxic conditions. These findings could suggest a new 
      therapeutic strategy for preventing beta-cell death and thus the onset of T2DM.
FAU - Qi, Yanfei
AU  - Qi Y
AD  - 1Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, 
      China. xiapu_fudan@163.com.
FAU - Chen, Jinbiao
AU  - Chen J
FAU - Lay, Angelina
AU  - Lay A
FAU - Don, Anthony
AU  - Don A
FAU - Vadas, Mathew
AU  - Vadas M
FAU - Xia, Pu
AU  - Xia P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130709
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Dietary Fats)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
SB  - IM
MH  - Animals
MH  - Cell Death
MH  - Diabetes Mellitus/genetics/*pathology
MH  - Dietary Fats
MH  - *Genetic Predisposition to Disease
MH  - Insulin-Secreting Cells/cytology/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/physiology
MH  - Obesity/*complications/genetics/pathology
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
OTO - NOTNLM
OT  - apoptosis
OT  - lipotoxicity
OT  - sphingolipids
OT  - type 2 diabetes
EDAT- 2013/07/11 06:00
MHDA- 2013/12/18 06:00
CRDT- 2013/07/11 06:00
PHST- 2013/07/11 06:00 [entrez]
PHST- 2013/07/11 06:00 [pubmed]
PHST- 2013/12/18 06:00 [medline]
AID - fj.13-230052 [pii]
AID - 10.1096/fj.13-230052 [doi]
PST - ppublish
SO  - FASEB J. 2013 Oct;27(10):4294-304. doi: 10.1096/fj.13-230052. Epub 2013 Jul 9.