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

Abstract

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 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 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 S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D.

Integrated Remodeling of Gut–Liver Metabolism Induced by Moderate Protein Restriction Contributes to Improvement of Insulin Sensitivity

“…Several of different metabolites were identified in portal venous plasma upon moderate PR, including numbers of protein/AA metabolites, fatty acid metabolites, and sphingolipid metabolites, as well as pantothenic acid. Among them, elevated plasma S1P has been established as a feature of both human and rodent obesity and correlates with insulin resistance, and it seems to interrupt insulin signaling via promoting beta cell dysfunction . In the present study, S1P was decreased at 0.5 h preprandial upon moderate PR.…”

Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease

“…Nevertheless, ceramides can be further metabolized to S1P, which is a bioactive lipid mediator that is involved in numerous signaling pathways and regulates a wide variety of cellular functions [21]. Several studies indicate an increase of S1P in response to palmitate in different cell types such as myotubes and pancreatic β-cells either via activation of sphingosine kinase or de novo synthesis [22,23]. S1P exhibits pro-as well as anti-fibrotic activities depending on the site of action.…”

NMR metabolomics highlights sphingosine kinase‐1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells

“…Sph and S1P were extracted as recently described (Japtok et al ., ; Pewzner‐Jung et al ., ) using D7‐S1P and D7‐Sph as internal standards. Sphingolipids were separated by reverse‐phase high‐performance liquid chromatography (HPLC) (Agilent 1290 series; Agilent Technologies, Waldbronn, Germany) using a ZORBAX Eclipse Plus C8 column (2.1 × 150 mm, ID: 3.5 μm) (Agilent Technologies).…”