Roles Of Sphingolipid Metabolism In Pancreatic Beta Cell Dysfunction Induced By Lipotoxicity

Pancreatic beta 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 beta cells and pancreatic beta 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 beta cell apoptosis. Importantly, the chronic adverse effects of FFAs on beta 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 beta 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 beta 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 beta cells. The review highlights the role of a sphingolipid biostat on the dysregulation of beta cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.