Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction

Recent technical advances have re-invigorated the study of sphingolipid metabolism in general, and helped to highlight the varied and important roles that sphingolipids play in pancreatic beta-cells. Sphingolipid metabolites such as ceramide, glycosphingolipids, sphingosine-1-phosphate and gangliosides modulate many beta-cell signaling pathways and processes implicated in beta-cell diabetic disease such as apoptosis, beta-cell cytokine secretion, ER-to-golgi vesicular trafficking, islet autoimmunity and insulin gene expression. They are particularly relevant to lipotoxicity. Moreover, the de novo synthesis of sphingolipids occurs on many subcellular membranes, in parallel to secretory vesicle formation, traffic and granule maturation events. Indeed, the composition of the plasma membrane, determined by the activity of neutral sphingomyelinases, affects beta-cell excitability and potentially insulin exocytosis while another glycosphingolipid, sulfatide, determines the stability of insulin crystals in granules. Most importantly, sphingolipid metabolism on internal membranes is also strongly implicated in regulating beta-cell apoptosis.