title: Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by Lipotoxicity.
abstract: Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic β cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic β cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic β cells. The review highlights the role of a sphingolipid biostat on the dysregulation of β cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.
authors.affiliation: University Paris Diderot, Sorbonne Paris City, Unit of Functional and Adaptative Biology UMR 8251 CNRS, 75205 Paris Cedex 13, France. julienveret@free.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Véret
authors.affiliation: University Paris Diderot, Sorbonne Paris City, Unit of Functional and Adaptative Biology UMR 8251 CNRS, 75205 Paris Cedex 13, France. lbellini88@gmail.com.
authors.forename: Lara
authors.initials: L
authors.lastname: Bellini
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA Segrate, Via Fratelli Cervi 93, 20090 Segrate (MI), Italy. paola.giussani@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
authors.affiliation: School of Biology and Environmental Science and UCD Earth Institute, University College Dublin, Belfield, Dublin 4, Ireland. carl.ng@ucd.ie.
authors.forename: Carl
authors.initials: C
authors.lastname: Ng
authors.affiliation: University Paris Diderot, Sorbonne Paris City, Unit of Functional and Adaptative Biology UMR 8251 CNRS, 75205 Paris Cedex 13, France. christophe.magnan@univ-paris-diderot.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: University Paris Diderot, Sorbonne Paris City, Unit of Functional and Adaptative Biology UMR 8251 CNRS, 75205 Paris Cedex 13, France. herve.le-stunff@univ-paris-diderot.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
keywords: apoptosis; ceramide; gluco-lipotoxicity; insulin; islet of Langherans; obesity; pancreas; sphingolipids; sphingosine-1-phosphate; type 2 diabetes