Defect of insulin signal in peripheral tissues: Important role of ceramide

Abstract

In healthy people, balance between glucose production and its utilization is precisely controlled. When circulating glucose reaches a critical threshold level, pancreatic β cells secrete insulin that has two major actions: to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver. Interestingly, dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues. Normally, the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods. Thus, adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides. When the buffering action of adipose tissue to store fatty acids is impaired, fatty acids that build up in other tissues are metabolized as sphingolipid derivatives such as ceramides. Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.

Keywords: Diabetes; Insulin resistance; Lipids; Insulin signaling; Triglycerides; Palmitate; Sphingolipid; Akt; Ceramide synthase; Protein phosphatase 2A; Protein kinase C ζ/λ

Core tip: Muscle and liver represent major sites for insulin-mediated glucose metabolism. The ability of insulin to promote its peripheral action is reduced significantly by excess of saturated fat that stimulates intracellular production of second-messenger lipids such as ceramide. Studies suggest that ceramide could be important contributors to lipotoxicity, as the inhibition of early steps its biosynthesis pathway has large beneficial effects in rodent models of obesity and diabetes. In this review, we describe mechanisms by which ceramide acts on insulin-sensitive tissues and we propose that targeting this lipid family could be an interesting approach to fight diabetes.