es-285 and Diabetes-Mellitus--Type-2

The 1-deoxysphingolipids (1-deoxySLs) are formed by an alternate substrate usage of the enzyme, serine-palmitoyltransferase, and are devoid of the C1-OH-group present in canonical sphingolipids. Pathologically elevated 1-deoxySL levels are associated with the rare inherited neuropathy, HSAN1, and diabetes type 2 and might contribute to β cell failure and the diabetic sensory neuropathy. In analogy to canonical sphingolipids, it was assumed that 1-deoxySLs also bear a (4E) double bond, which is normally introduced by sphingolipid delta(4)-desaturase 1. This, however, was never confirmed. We therefore supplemented HEK293 cells with isotope-labeled D3-1-deoxysphinganine and compared the downstream formed D3-1-deoxysphingosine (1-deoxySO) to a commercial synthetic SPH m18:1(4E)(3OH) standard. Both compounds showed the same m/z, but differed in their RPLC retention time and atmospheric pressure chemical ionization in-source fragmentation, suggesting that the two compounds are structural isomers. Using dimethyl disulfide derivatization followed by MS(2) as well as differential-mobility spectrometry combined with ozone-induced dissociation MS, we identified the carbon-carbon double bond in native 1-deoxySO to be located at the (Δ14) position. Comparing the chromatographic behavior of native 1-deoxySO to chemically synthesized SPH m18:1(14Z) and (14E) stereoisomers assigned the native compound to be SPH m18:1(14Z). This indicates that 1-deoxySLs are metabolized differently than canonical sphingolipids.

Topics: Carbon; Diabetes Mellitus, Type 2; Diabetic Neuropathies; HEK293 Cells; Hereditary Sensory and Autonomic Neuropathies; Humans; Lipids; Oxidoreductases; Serine C-Palmitoyltransferase; Sphingosine

Sphingolipids are increasingly recognized to play a role in insulin resistance and diabetes. Recently we reported significant elevations of 1-deoxysphingolipids (1-deoxySL) - an atypical class of sphingolipids in patients with metabolic syndrome (MetS) and diabetes type 2 (T2DM). It is unknown whether 1-deoxySL in patients with diabetes type 1 (T1DM) are similarly elevated.. We analyzed the long chain base profile by LC-MS after hydrolyzing the N-acyl and O-linked headgroups in plasma from individuals with T1DM (N = 27), T2DM (N = 30) and healthy controls (N = 23). 1-deoxySLs were significantly higher in the groups with T2DM but not different between T1DM and controls. In contrast to patients with T2DM, 1-deoxSL levels are not elevated in T1DM.. Our study indicates that the 1-deoxySL formation is not per-se caused by hyperglycemia but rather specifically associated with metabolic changes in T2DM, such as elevated triglyceride levels.

Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Lipids; Male; Middle Aged; Sphingolipids; Sphingosine