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

Author summary Why was this study done? Ceramides are members of the sphingolipid family that have been reported to be pathophysiologically relevant for the development of impaired glucose homeostasis and type 2 diabetes (T2D) through inducing insulin resistance, impairing beta-cell function, and promoting inflammation. Sphingolipids represent a class of structurally and functionally diverse lipids that may exert different impacts on T2D outcome. However, the majority of available studies covered only 4 to 15 species and may have missed certain T2D-associated sphingolipid species or subclasses. To our knowledge, no epidemiological study has examined the relationships between genetically predicted sphingolipids and T2D risk so far. Most previous studies of sphingolipid-T2D associations were conducted in Western populations. It remains largely unknown whether the associations differ between Western and Asian populations, and to what extent they are mediated by beta-cell dysfunction or insulin resistance. What did the researchers do and find? By applying high-coverage targeted lipidomics to measure 76 sphingolipids in 1,974 Chinese men and women, 11 novel (3 monounsaturated ceramides, 7 sphingomyelins, and 1 hexosylceramide) and 3 previously reported sphingolipids were identified to be positively associated with incident T2D, independent of conventional risk factors including lifestyle characteristics and BMI. We conducted a network analysis to determine the collective effects of the sphingolipids on the onset of T2D. Of 5 identified groupings (modules) of sphingolipids, 2 modules containing saturated sphingomyelins showed the strongest associations with incident T2D. Mediation analysis showed that the detrimental associations of 13 out of the 14 sphingolipids with risk of T2D were largely mediated through beta-cell dysfunction. We performed genome-wide association studies for the sphingolipids and also conducted 2-sample Mendelian randomization analysis. A positive association between a genetically instrumented ceramide (d18:1/20:1) and T2D was evidenced. What do these findings mean? Our study is the first to our knowledge that simultaneously discovered the largest number of T2D-associated sphingolipid species-which covered 3 subclasses, including ceramides, sphingomyelins, and a hexosylceramide-and also identified predominantly monounsaturated ceramides associated with T2D in the Chinese population, rather than saturated ceramides as reported in Western populations. High-coverage targeted lipidomics in our study revealed comprehensive details about how and to what extent altered absolute concentrations of sphingolipids with specific structures were associated with T2D development, raising attention to structurally diverse sphingolipids and the fact that they might have different associations with T2D. Our results highlight a stronger mediation effect of beta-cell dysfunction than of insulin resistance in the sphingolipid-T2D associations in Chinese individuals. We found a positive association between a genetically instrumented ceramide (d18:1/20:1) and T2D. Together, our findings underscore potential applications of sphingolipids as early biomarkers or intervention targets for prevention and control of T2D. Background Animal studies suggest vital roles of sphingolipids, especially ceramides, in the pathogenesis of type 2 diabetes (T2D) via pathways involved in insulin resistance, beta-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 P-trend < 0.001). Mediation analysis suggested that the detrimental associations of 13 sphingolipids with T2D were largely mediated through beta-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 beta-cell dysfunction, in Chinese individuals.