基于两个前瞻性队列研究血浆脂质组分水平与2型糖尿病发生风险及其主要危险因素的关联性

The epidemic of type 2 diabetes (T2D) is rapidly increasing and has become a worldwide major public health concern, especially in China. Current preventive initiatives are not sufficiently effective, and uncertainties remain concerning the etiology of T2D. Dysregulated lipid metabolism, characterized mainly by triglyceridemia and low serum high-density lipidprotein cholesterol, lies fundamentally in the pathogenesis of T2D; however, it is unclear how individual lipid species is associated with T2D risk and whether lipid species could predict T2D beyond established risk factors. In the present study, we plan to perform Liquid Chromatography-Mass Spectrometry-based plasma lipid profiling among two large nested case-control studies within the Dongfeng-Tongji (DFTJ) cohort and Jiangsu Noncommunicable Disease (JSNCD) cohort, which targeted at 166 lipid species from 9 different classes. After excluding participants with baseline cardiovascular disease, stroke and cancer, 1039 and 520 eligible participants developed incident T2D in these two cohorts, respectively, and controls were 1:1 matched with cases by age (± 5 years) and sex, separately within each cohort. We aim to identify lipid species consistently associated with the risk of developing T2D in both cohorts, evaluate the dose-response associations and predictive utility of these lipid species, and further explore their associations with established T2D risk factors such as waist circumference and fasting glucose levels, as well as risk of developing T2D complications. If achieved, our findings may identify novel T2D risk markers which may help to facilitate targeted preventive care.

2型糖尿病的流行趋势是世界各国、尤其是我国亟待解决的重大公共卫生问题之一，但病因仍不清楚，预防效果亦不显著。传统以高甘油三酯、低高密度脂蛋白胆固醇血症为主要特征的脂代谢异常是2型糖尿病发生的重要病理生理过程，但具体脂质组分、水平与2型糖尿病发生风险的关系尚不清楚。本项目基于两个前瞻性队列，采用巢式病例对照设计，排除基线心血管疾病、中风、肿瘤患者后，以东风-同济队列的1039例和江苏慢性病队列的520例新发2型糖尿病病例分别为病例组，在两队列未发病人群中分别按年龄（±5岁）、性别1:1随机匹配对照，利用液相色谱-质谱联用技术检测基线血浆中9类166种脂质组分水平，发现脂质组分与2型糖尿病发生风险的剂量效应关系及其预测效能，并探索这些脂质组分与传统危险因素（腰围、空腹血糖等）、以及后续糖尿病并发症发生风险的关联性。本研究预期结果将发现新的2型糖尿病危险因素，为制定更有效的预防对策提供科学依据。

脂质组分、各组分间的相互作用在2型糖尿病发病过程中的作用仍不清楚，其在2型糖尿病从危险因素进展到发病过程中的作用也尚未有研究报道。在本项目通过对东风同济队列和江苏慢性病队列各1039对和520对新发2型糖尿病病例-对照基线血浆的脂质组分检测，研究发现：所检测到的166种脂质中，27种脂质在两个队列中与2型糖尿病发病风险关联一致，其中10种脂质为首次报道，且27种脂质在包括空腹血糖在内的传统危险因素模型基础上可进一步显著改善2型糖尿病的风险预测；与2型糖尿病发病风险相关联的27种脂质中16种为TAG，与发病风险正相关的TAG多含有16:0脂肪酸链，与发病风险负相关的TAG多含有18:2脂肪酸链；通过对与2型糖尿病发病风险相关联的27种脂质的网络分析，发现含有18:1脂肪酸链的TAG 50:3与多种脂质在两个队列中有一致的共调节作用，且TAG 50:3均处于调节网络核心；通过中介效应分析，发现27种脂质中共有13种脂质在肥胖与2型糖尿病风险的关联性中起显著中介效应、且中介效应在两个队列间一致。本研究的相关发现为2型糖尿病的发病机制、尤其是脂质共调节在其中的作用提示了新的科学线索；考虑到肥胖已成为2型糖尿病全球流行的主要驱动力，本研究发现也为制定高效合理的2型糖尿病预防对策提供了科学依据。