CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
PLoS Med. 2020 Dec 9;17(12):e1003451. doi: 10.1371/journal.pmed.1003451. eCollection 2020 Dec.
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.
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.
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.
动物研究表明，鞘脂类，尤其是神经酰胺，在 2 型糖尿病（T2D）的发病机制中起着重要作用，其涉及胰岛素抵抗、β细胞功能障碍和炎症等途径，但人体研究有限。我们旨在评估循环鞘脂与 T2D 发病的相关性，并探讨潜在机制。
本研究包括 826 名男性和 1148 名女性，年龄在 50-70 岁之间，来自北京和上海，在 2005 年没有 T2D，并在 2011 年进行了重新调查。在基线和随访调查中测量了心脏代谢特征。使用高覆盖率靶向脂质组学定量了 76 种鞘脂。2 样本孟德尔随机化汇总数据来自循环鞘脂的全基因组关联研究和中国健康与营养调查（n=5731）。在 6 年期间，有 529 名参与者患上了 T2D。11 种新型和 3 种已报道的鞘脂，即神经酰胺（d18:1/18:1、d18:1/20:0、d18:1/20:1、d18:1/22:1）、饱和神经酰胺（C34:0、C36:0、C38:0、C40:0）、不饱和神经酰胺（C34:1、C36:1、C42:3）、羟基神经酰胺（C34:1、C38:3）和半乳糖基神经酰胺（d18:1/20:1），与 T2D 发病呈正相关（相对风险[RR]：1.14-1.21；所有 P<0.001），在包括生活方式特征和 BMI 的多变量调整后。网络分析进一步确定了 5 个模块，并且包含饱和神经酰胺的 2 个模块与增加的 T2D 风险具有最强的关联（RRQ4 与 Q1=1.59 和 1.43；所有 Ptrend<0.001）。中介分析表明，13 种鞘脂与 T2D 的不良关联主要通过β细胞功能障碍介导，由 HOMA-B 表示（中介比例：11.19%-42.42%；所有 P<0.001）。此外，孟德尔随机化证明了一种遗传上检测到的神经酰胺（d18:1/20:1）与 T2D 之间存在正相关（优势比：1.15[95%CI 1.05-1.26]；P=0.002）。本研究的主要局限性包括潜在的未确诊病例和缺乏独立的复制人群。
在这项研究中，我们观察到一组具有独特结构的新型鞘脂与中国人群中 T2D 的发病呈正相关，主要通过β细胞功能障碍介导。
