Journal Article

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

Wu, Qingqing, Zheng, He, Zong, Geng, Liang, Liming, Qi, Qibin, Sun, Liang, Li, Huaixing, Lin, Xu, Yun, Huan, Zeng, Rong

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aged / Animal models / Beta cells / Biology and Life Sciences / Biomarkers - blood / Blood Glucose - metabolism / Body mass index / China - epidemiology / Cholesterol / Cohort analysis / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - diagnosis / Diabetes Mellitus, Type 2 - epidemiology / Diabetes Mellitus, Type 2 - genetics / Drinking behavior / Fatty acids / Female / Genetic analysis / Genome-Wide Association Study / Glucose / Homeostasis / Humans / Incidence / Inflammation / Insulin / Insulin - blood / Insulin resistance / Insulin-Secreting Cells - metabolism / Kinases / Lipidomics / Lipids / Male / Mass spectrometry / Mediation / Medicine and Health Sciences / Mendelian Randomization Analysis / Metabolism / Metabolites / Middle Aged / Mitochondria / Nutrition Surveys / Physical activity / Physical Sciences / Population / Population studies / Population-based studies / Prospective Studies / Protein kinase / Quality control / Reactive oxygen species / Risk Assessment / Risk Factors / Scientific imaging / Single-nucleotide polymorphism / Sphingolipids / Sphingolipids - blood / Threonine / Toxicity