| First Author | Qi Y | Year | 2013 |
| Journal | FASEB J | Volume | 27 |
| Issue | 10 | Pages | 4294-304 |
| PubMed ID | 23839933 | Mgi Jnum | J:201168 |
| Mgi Id | MGI:5511106 | Doi | 10.1096/fj.13-230052 |
| Citation | Qi Y, et al. (2013) Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic beta-cell death in diet-induced obese mice. FASEB J 27(10):4294-4304 |
| abstractText | 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.-Qi, Y., Chen, J., Lay, A., Don, A., Vadas, M., Xia, P. Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic beta-cell death in diet-induced obese mice. |
