On ceramides, other sphingolipids and impaired glucose homeostasis☆

In most people with type 2 diabetes, progression from obesity to diabetes is accompanied by elevated tissue exposures to a variety of lipids. Among these lipid species, ceramides and more complex sphingolipids have gained recent attention as being pathophysiologically relevant for the development of insulin resistance and impaired glycemic control. Upon excess intake of saturated fat, ceramides accumulate in insulin sensitive tissues either as a consequence of de novo synthesis or through mobilization from complex sphingolipids. Clinical studies have confirmed positive correlation between plasma and tissue levels of several ceramide species and insulin resistance. At the cellular level, it has been demonstrated that ceramides impair insulin signaling and intracellular handling of glucose and lipids with resulting deleterious effects on cellular metabolism. Hence, we are reviewing whether therapeutic interventions aiming at reducing tissue exposure to ceramides or other sphingolipids represent viable therapeutic approaches to improve glucose metabolism in people with diabetes.