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Associations among circulating sphingolipids, β-cell function, and risk of developing type 2 diabetes: A population-based cohort study in China.

Abstract：

BACKGROUND:Animal studies suggest vital roles of sphingolipids, especially ceramides, in the pathogenesis of type 2 diabetes (T2D) via pathways involved in insulin resistance, β-cell dysfunction, and inflammation, but human studies are limited. We aimed to evaluate the associations of circulating sphingolipids with incident T2D and to explore underlying mechanisms. METHODS AND FINDINGS:The current study included 826 men and 1,148 women who were aged 50-70 years, from Beijing and Shanghai, and without T2D in 2005 and who were resurveyed in 2011. Cardiometabolic traits were measured at baseline and follow-up surveys. A total of 76 sphingolipids were quantified using high-coverage targeted lipidomics. Summary data for 2-sample Mendelian randomization were obtained from genome-wide association studies of circulating sphingolipids and the China Health and Nutrition Survey (n = 5,731). During the 6-year period, 529 participants developed T2D. Eleven novel and 3 reported sphingolipids, namely ceramides (d18:1/18:1, d18:1/20:0, d18:1/20:1, d18:1/22:1), saturated sphingomyelins (C34:0, C36:0, C38:0, C40:0), unsaturated sphingomyelins (C34:1, C36:1, C42:3), hydroxyl-sphingomyelins (C34:1, C38:3), and a hexosylceramide (d18:1/20:1), were positively associated with incident T2D (relative risks [RRs]: 1.14-1.21; all P < 0.001), after multivariate adjustment including lifestyle characteristics and BMI. Network analysis further identified 5 modules, and 2 modules containing saturated sphingomyelins showed the strongest associations with increased T2D risk (RRQ4 versus Q1 = 1.59 and 1.43; both Ptrend < 0.001). Mediation analysis suggested that the detrimental associations of 13 sphingolipids with T2D were largely mediated through β-cell dysfunction, as indicated by HOMA-B (mediation proportion: 11.19%-42.42%; all P < 0.001). Moreover, Mendelian randomization evidenced a positive association between a genetically instrumented ceramide (d18:1/20:1) and T2D (odds ratio: 1.15 [95% CI 1.05-1.26]; P = 0.002). Main limitations in the current study included potential undiagnosed cases and lack of an independent population for replication. CONCLUSIONS:In this study, we observed that a panel of novel sphingolipids with unique structures were positively associated with incident T2D, largely mediated through β-cell dysfunction, in Chinese individuals.

journal_name

PLoS Med

journal_title

PLoS medicine

authors

Yun H,Sun L,Wu Q,Zong G,Qi Q,Li H,Zheng H,Zeng R,Liang L,Lin X

doi

10.1371/journal.pmed.1003451

subject

Has Abstract

pub_date

2020-12-09 00:00:00

pages

e1003451

issue

eissn

1549-1277

issn

1549-1676

pii

PMEDICINE-D-20-01516

journal_volume

pub_type

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Associations among circulating sphingolipids, β-cell function, and risk of developing type 2 diabetes: A population-based cohort study in China.