Sphingosine 1‐phosphate counteracts insulin signaling in pancreatic β‐cells via the sphingosine 1‐phosphate receptor subtype 2

Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β‐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 β‐cells but also regulate β‐cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β‐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 β‐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 β‐cell damage clearly indicating an important role of the S1P 2 in β‐cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β‐cell dysfunction and the development of T2D.—Japtok, L., Schmitz, E. I., Fayyaz, S., Krämer, S., Hsu, L. J., Kleuser, B., Sphingosine 1‐phosphate counteracts insulin signaling in pancreatic β‐cells via the sphingosine 1‐phosphate receptor subtype 2. FASEB J. 29, 3357‐3369 (2015). www.fasebj.org