Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β‐cell death in diet‐induced obese mice

Lipotoxic stress‐induced β‐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 β‐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 β‐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 β‐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 β cells or the cells lacking SphK1 activity and Sphk1 –/– islets, highlighting a pivotal role of S1P in β‐cell survival under lipotoxic conditions. These findings could suggest a new therapeutic strategy for preventing β‐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 β‐cell death in diet‐induced obese mice. FASEB J. 27, 4294–4304 (2013). www.fasebj.org