Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence

Abstract

BACKGROUND. Sphingolipids (SPs) are ubiquitous, structurally diverse molecules that include ceramides, sphingomyelins (SMs), and sphingosines. They are involved in various pathologies, including obesity and type 2 diabetes mellitus (T2DM). Therefore, it is likely that perturbations in plasma concentrations of SPs are associated with disease. Identifying these associations may reveal useful biomarkers or provide insight into disease processes. METHODS. We performed a lipidomics evaluation of molecularly distinct SPs in the plasma of 2302 ethnically Chinese Singaporeans using electrospray ionization mass spectrometry coupled with liquid chromatography. SP profiles were compared to clinical and biochemical characteristics, and subjects were evaluated with follow-up visits for 11 years. RESULTS. We found that ceramides correlated positively but hexosylceramides correlated negatively with BMI and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, SPs with a d16:1 sphingoid backbone correlated more positively with BMI and HOMA-IR, while d18:2 SPs correlated less positively, relative to canonical d18:1 SPs. We also found that higher concentrations of 2 distinct SMs were associated with a higher risk of T2DM (HR 1.45 with 95% CI 1.18-1.78 for SM d16:1/18:0 and HR 1.40 with 95% CI 1.17-1.68 for SM d18:1/18:0). CONCLUSIONS. We identified significant associations between SPs and obesity/T2DM characteristics, specifically, those of hexosylceramides, d16:1 SPs, and d18:2 SPs. This suggests that the balance of SP metabolism, rather than ceramide accumulation, is associated with the pathology of obesity. We further identified 2 specific SPs that may represent prognostic biomarkers for T2DM.

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

“…1A) and significantly higher in females than in males. This confirms data from two recent epidemiologic studies, which also report gender-specific difference in d18:2-based SLs (16,17).…”

“…Little is known about the function of d18:2-based SLs. Previously, plasma levels of d18:2 SLs were inversely associated with the incidence of cardiovascular events (8), the body mass index, and the HOMA (homeostatic model assessment) index (16). It serves as a backbone for complex sphingolipids (Fig.…”

“…Lipidomics analysis was performed as described previously (13,28) using the internal standards (100 pmol/ml, Avanti Polar Lipids): (d5) 1-desoxymethylsphinganine (m17:0), dihydroceramide (d18:0:12:0), ceramide (d18:1/12:0), 1-deoxydihydroceramide (m18:0/12:0), 1-deoxyceramide (m18:1/12:0), glucosylceramide (d18:1/8:0), and sphingomyelin (d18:1/12:0).…”

Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer’s disease and vascular cognitive impairment

“…Dots and lines in red represent significant association biomarkers for various conditions including cancer, neurodegenerative, metabolic, autoimmune. and vascular diseases [25,[44][45][46][47][48][49][50]. In the current study, we observed alterations of plasma sphingosine-1-phosphate (S1P) species in a cohort of aged cognitively normal subjects as well as people with vascular cognitive impairment (VCI) and Alzheimer's disease (AD).…”

Structure-function relationships of HDL in diabetes and coronary heart disease

“…We previously found plasma levels of sphingadienine inversely associated with the risk of major cardiovascular events during a follow-up of 8 years in patients who underwent coronary angiography (44). Most recently, plasma levels of sphingadienine-based lipids were found inversely associated with BMI and the HOMA insulin resistance index (47). Sphingadienine is likely generated by the desaturation of sphingosine through an as yet unknown enzyme.…”