Integrative metabolomics and genomics reveal molecular signatures for type 2 diabetes and its cardiovascular complications

作者：Chunxiao Cheng, Yuanjiao Liu, Lingyun Sun, Jiayao Fan, Xiaohui Sun, Ju‐Sheng Zheng, Zheng Lin, Yimin Zhu, Dan Zhou · 发表于：Cardiovascular Diabetology · 年份：2025 · DOI：10.1186/s12933-025-02718-4 · 被引用次数：19 · 研究领域：Metabolomics and Mass Spectrometry Studies、Genetic Associations and Epidemiology、Metabolism and Genetic Disorders

BACKGROUND: Metabolites are pivotal in the biological process underlying type 2 diabetes (T2D) and its cardiovascular complications. Nevertheless, their contributions to these diseases have not been comprehensively evaluated, particularly in East Asian ancestry. This study aims to elucidate the metabolic underpinnings of T2D and its cardiovascular complications and leverage multi-omics integration to uncover the molecular pathways involved. METHOD: This study included 1180 Chinese participants from the Zhejiang Metabolic Syndrome Cohort (ZMSC). A total of 1912 metabolites were profiled using high-coverage widely targeted and non-targeted metabolic techniques. Multivariable logistic regression models and orthogonal partial least squares discriminant analysis were used to identify T2D-related metabolites. A metabolome-wide genome-wide association study (GWAS) in ZMSC, followed by two-sample Mendelian randomization (MR) analyses, was conducted to explore potential causal metabolite-T2D associations. To enhance cross-ancestry generalizability, MR analyses were conducted in European ancestry to explore the potential causal effects of serum metabolites on T2D and its cardiovascular complications. Furthermore, multi-omics evidence was integrated to explore the underlying molecular mechanisms. RESULTS: We identified six metabolites associated with T2D in Chinese, supported by metabolome analysis and genetic-informed causal inference. These included two potential protective factors (P...