Circulating Sphingolipids and Glucose Homeostasis: An Update.

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles.

Ceramide analog C2-cer induces a loss in insulin sensitivity in muscle cells through the salvage/recycling pathway.

Ceramides have been shown to play a major role in the onset of skeletal muscle insulin resistance and therefore in the prevalence of type 2 diabetes. However, many of the studies involved in the discovery of deleterious ceramide actions used a nonphysiological, cell-permeable, short-chain ceramide analog, the C2-ceramide (C2-cer). In the present study, we determined how C2-cer promotes insulin resistance in muscle cells.

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology.

Sphingolipids represent one of the major classes of eukaryotic lipids. They play an essential structural role, especially in cell membranes where they also possess signaling properties and are capable of modulating multiple cell functions, such as apoptosis, cell proliferation, differentiation, and inflammation. Many sphingolipid derivatives, such as ceramide, sphingosine-1-phosphate, and ganglioside, have been shown to play many crucial roles in muscle under physiological and pathological conditions.

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes.

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity.

[Ceramides, crucial actors in the development of insulin resistance and type 2 diabetes].

In healthy subjects, the balance between glucose production and its usage is precisely controlled. When circulating glucose reaches a critical threshold, pancreatic β-cells secrete insulin, which has two major actions: lowering circulating glucose concentrations by facilitating its uptake mainly in skeletal muscles and the liver, and inhibiting glucose production. Triglycerides are the main source of fatty acids to meet the energy needs of oxidative tissues and any excess is stored in adipocytes.

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells.

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance.