Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence
Wee Siong Chew, … , E. Shyong Tai, Deron R. Herr
Wee Siong Chew, … , E. Shyong Tai, Deron R. Herr
Published June 4, 2019
Citation Information: JCI Insight. 2019;4(13):e126925. https://doi.org/10.1172/jci.insight.126925.
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Clinical Research and Public Health Endocrinology

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.FUNDING National University Health System (NUHSRO/2014/085/AF-Partner/01) and the National Research Foundation Investigatorship grant (NRF-NRFI2015-05).

Authors

Wee Siong Chew, Federico Torta, Shanshan Ji, Hyungwon Choi, Husna Begum, Xueling Sim, Chin Meng Khoo, Eric Yin Hao Khoo, Wei-Yi Ong, Rob M. Van Dam, Markus R. Wenk, E. Shyong Tai, Deron R. Herr

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Figure 7

SP metabolism.

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SP metabolism. This schematic shows a simplified representation of the S...
This schematic shows a simplified representation of the SP metabolic pathway. (A) De novo synthesis results in the formation of the essential sphingoid backbone with the condensation of serine and a fatty acyl CoA by SPT. (B) The sphingomyelinase pathway generates ceramides from the catabolism of membrane stores of SM. (C) Ceramides are glycosylated into complex ceramides (including HexCer and Hex2Cer) and can be recycled back to ceramides through the scavenge/salvage pathway. (D) The degradation pathway terminates with the irreversible catabolism of S1P by SPL. The resulting products may enter the Kennedy pathway for the de novo synthesis of membrane phospholipids.