title: Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β-cell death in diet-induced obese mice.
abstract: 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.
authors.affiliation: 1Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China. xiapu_fudan@163.com.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Chen
authors.forename: Angelina
authors.initials: A
authors.lastname: Lay
authors.forename: Anthony
authors.initials: A
authors.lastname: Don
authors.forename: Mathew
authors.initials: M
authors.lastname: Vadas
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
mesh_terms: D000818:Animals; D016923:Cell Death; D003920:Diabetes Mellitus / Q000235:genetics / Q000473:pathology*; D004041:Dietary Fats; D020022:Genetic Predisposition to Disease; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D004041:Dietary Fats; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
keywords: apoptosis; lipotoxicity; sphingolipids; type 2 diabetes