TY - JOUR A1 - Japtok, Lukasz A1 - Schmitz, Elisabeth I. A1 - Fayyaz, Susann A1 - Krämer, Stephanie A1 - Hsu, Leigh J. A1 - Kleuser, Burkhard T1 - Sphingosine 1-phosphate counteracts insulin signaling in pancreatic beta-cells via the sphingosine 1-phosphate receptor subtype 2 JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology N2 - Glucolipotoxic stress has been identified as a key player in the progression of pancreatic beta-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic beta-cells but also regulate beta-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in beta-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P(2)) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P(2) axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by beta-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P(2), the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued beta-cell damage clearly indicating an important role of the S1P(2) in beta-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish beta-cell dysfunction and the development of T2D. KW - type 2 diabetes mellitus KW - sphingolipids KW - survival KW - proliferation KW - Akt signaling Y1 - 2015 U6 - https://doi.org/10.1096/fj.14-263194 SN - 0892-6638 SN - 1530-6860 VL - 29 IS - 8 SP - 3357 EP - 3369 PB - Federation of American Societies for Experimental Biology CY - Bethesda ER - TY - THES A1 - Fayyaz, Susann T1 - Bedeutung bioaktiver Lipidderivate bei der Entstehung hepatischer Insulinresistenz Y1 - 2015 ER -