PMID- 31162145 OWN - NLM STAT- MEDLINE DCOM- 20200916 LR - 20200916 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 5 IP - 13 DP - 2019 Jun 4 TI - Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence. LID - 126925 [pii] LID - 10.1172/jci.insight.126925 [doi] LID - e126925 AB - BACKGROUND: Sphingolipids (SPs) are ubiquitous, structurally diverse molecules that include ceramides, sphingomyelins, 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 2,302 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 by follow-up visits for 11 years. RESULTS: We found that ceramides correlate positively but hexosylceramides correlate negatively with body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, SPs with a d16:1 sphingoid backbone correlate more positively with BMI and HOMA-IR, while d18:2 SPs correlate less positively, relative to canonical d18:1 SPs. We also found that higher concentrations of two distinct sphingomyelins were associated with a higher risk of T2DM (HR 1.45, 95% CI 1.18-1.78 for SM d16:1/C18:0; and HR 1.40, 95% CI 1.17-1.68 for SM d18:1/C18:0). CONCLUSION: We identified significant associations between SPs and obesity/T2DM characteristics, specifically, that 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 two specific SPs that may represent prognostic biomarkers for T2DM. FUNDING: Funding sources are listed in the Acknowledgements section. FAU - Chew, Wee Siong AU - Chew WS AD - Department of Pharmacology and. FAU - Torta, Federico AU - Torta F AD - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. AD - Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore. FAU - Ji, Shanshan AU - Ji S AD - Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore. FAU - Choi, Hyungwon AU - Choi H AD - Saw Swee Hock School of Public Health, National University of Singapore, Singapore. AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National Health System, Singapore. AD - Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore. FAU - Begum, Husna AU - Begum H AD - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. AD - Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore. FAU - Sim, Xueling AU - Sim X AD - Saw Swee Hock School of Public Health, National University of Singapore, Singapore. FAU - Khoo, Chin Meng AU - Khoo CM AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National Health System, Singapore. FAU - Khoo, Eric Yin Hao AU - Khoo EYH AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National Health System, Singapore. FAU - Ong, Wei-Yi AU - Ong WY AD - Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Van Dam, Rob M AU - Van Dam RM AD - Saw Swee Hock School of Public Health, National University of Singapore, Singapore. AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National Health System, Singapore. FAU - Wenk, Markus R AU - Wenk MR AD - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. AD - Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore. FAU - Tai, E Shyong AU - Tai ES AD - Saw Swee Hock School of Public Health, National University of Singapore, Singapore. AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National Health System, Singapore. AD - Duke-NUS Graduate Medical School, Singapore. FAU - Herr, Deron R AU - Herr DR AD - Department of Pharmacology and. AD - Department of Biology, San Diego State University, San Diego, California, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190604 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (Ceramides) RN - 0 (Sphingolipids) RN - 0 (Sphingomyelins) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Adult MH - Body Mass Index MH - Ceramides/blood MH - China/ethnology MH - Chromatography, Liquid MH - Diabetes Mellitus, Type 2/blood/*epidemiology MH - Female MH - Humans MH - Incidence MH - Insulin Resistance MH - *Lipidomics MH - Male MH - Middle Aged MH - Multivariate Analysis MH - Proportional Hazards Models MH - Singapore/epidemiology MH - Spectrometry, Mass, Electrospray Ionization MH - Sphingolipids/*blood MH - Sphingomyelins/blood MH - Sphingosine/blood PMC - PMC6629294 OTO - NOTNLM OT - Diabetes OT - Endocrinology OT - Epidemiology OT - Obesity COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2019/06/05 06:00 MHDA- 2020/09/17 06:00 PMCR- 2019/07/11 CRDT- 2019/06/05 06:00 PHST- 2019/06/05 06:00 [entrez] PHST- 2019/06/05 06:00 [pubmed] PHST- 2020/09/17 06:00 [medline] PHST- 2019/07/11 00:00 [pmc-release] AID - 126925 [pii] AID - 10.1172/jci.insight.126925 [doi] PST - epublish SO - JCI Insight. 2019 Jun 4;5(13):e126925. doi: 10.1172/jci.insight.126925.