Role of Sphingosine Kinase in Type 2 Diabetes Mellitus

Abstract

Sphingolipids are a class of essential lipids, functioning as both cell membrane constituents and signaling messengers. In the sphingolipid metabolic network, ceramides serve as the central hub that is hydrolyzed to sphingosine, followed by phosphorylation to sphingosine 1-phosphate (S1P) by sphingosine kinase (SphK). SphK is regarded as a "switch" of the sphingolipid rheostat, as it catalyzes the conversion of ceramide/sphingosine to S1P, which often exhibit opposing biological roles in the cell. Besides, SphK is an important signaling enzyme that has been implicated in the regulation of a wide variety of biological functions. In recent years, an increasing body of evidence has suggested a critical role of SphK in type 2 diabetes mellitus (T2D), although a certain level of controversy remains. Herein, we review recent findings related to SphK in the field of T2D research with a focus on peripheral insulin resistance and pancreatic β-cell failure. It is expected that a comprehensive understanding of the role of SphK and the associated sphingolipids in T2D will help to identify druggable targets for future anti-diabetes therapy.

Keywords: ceramide; insulin resistance; sphingolipid; sphingosine 1-phosphate; β-cell.

Figure 1

Sphingolipid metabolic network. SPT, serine palmitoyltransferase; KDSR, 3-keto-dihydrosphingosine reductase; CerS, ceramide synthase; DEGS, dihydroceramide desaturase; CDase, ceramidase; SphK, sphingosine kinase; SPGL1, sphingosine 1-phosphate lyase.

Figure 2

Roles of SphK1 and SphK2 in T2D. Most of the literature supports an anti-diabetic role (denoted by green arrows) of SphK1 in skeletal muscle, adipose tissue and pancreas as well as SphK2 in the liver. In contrast, SphK2 is primarily a pro-diabetic factor (denoted by the red arrow) for its proapoptotic effects in pancreatic β-cells. The roles of SphK1 in the liver and SphK2 in skeletal muscle and adipose tissue are controversial (denoted by grey lines). Created in BioRender.com.