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

Figure 1

Insulin signaling pathway. Insulin binds with insulin receptor (IR) that activates the IR substrates (IRSs), the phosphoinositide-3-kinase (PI3K), and protein kinase B/Akt (PKBAkt). Activated PKB/Akt mediates insulin metabolic effects and regulates nutrients homeostasis. PIP₂: Phosphorylate phosphatidylinositol, 4, 5-bisphosphate; PDK1: 3-phosphoinositide-dependent protein kinase 1; mTORC2: Mammalian target of rapamycin complex 2.

Figure 2

Sphingolipid metabolism. Ceramide can either be newly synthesized in de novo ceramide synthesis pathway (1), or it can be the product of complex sphingolipids degradation, including sphingomyelin hydrolysis (2). The degradation of glycosylsphingolipids constitutes the salvage pathway (3). GCase: Glucosyl ceramidase; GCS: Glucosylceramide synthase; SMases: Sphingomyelinases; SMSases: Sphingomyelin synthases.

Figure 3

Ceramide inhibits insulin-induced activation of protein kinase B via two distinct mechanisms. Ceramide inhibits insulin-activation of protein kinase B (PKB/Akt) either by activating atypical PKC (PKCζ) or by stimulating the phosphatase PP2A. Activation of either mechanism depends on plasma membrane enrichment with caveolae: (1) Ceramide-activated PKCζ phosphorylates the PH domain of PKB/Akt on Thr/Ser34, changing the recognition site of PKB/Akt, and disabling its activation by PIP3; (2) PP2A dephosphorylates PKB/Akt, inhibiting its kinase activity. IR: Insulin receptor; IRS: IR substrates; PI3K: Phosphoinositide-3-kinase; PP2A: Protein phosphatase 2A.