Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
Am J Clin Nutr. 2024 Aug;120(2):336-346. doi: 10.1016/j.ajcnut.2024.05.003. Epub 2024 May 8.
Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking.
Our study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults.
This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes.
The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18-26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset.
These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.
长链游离脂肪酸（FFAs）与糖尿病发病风险相关。然而，在血糖正常的人群中，对其关联的综合评估仍存在不足。
本研究旨在全面探讨血糖正常的中国成年人中 FFA 谱与糖尿病风险的前瞻性关联和模式。
这是一项来自中国心血管代谢疾病与癌症队列研究（4C 研究）的前瞻性巢式病例对照研究。我们使用靶向代谢组学方法定量测量了 1707 例新诊断糖尿病患者和 1707 例倾向评分匹配的血糖正常对照者的 53 种血清 FFA。采用条件逻辑回归模型估计关联的比值比（ORs）。实施最小绝对收缩和选择算子（LASSO）惩罚回归和分位数 g 计算（qg-comp）分析以估计多 FFA 暴露与新发糖尿病之间的关联。
大多数奇数链 FFAs 与新发糖尿病呈负相关，其中所有 7 种饱和脂肪酸（SFAs）、单不饱和脂肪酸 15:1 和多不饱和脂肪酸 25:2 的每标准差增加的 OR 范围为 0.79 至 0.88（95%置信区间范围在 0.71 至 0.97 之间）。偶数链 FFAs 占总 FFAs 的 99.3%，与新发糖尿病呈异质性。18-26 个碳原子的 SFAs 与新发糖尿病呈负相关，OR 范围为 0.81 至 0.86（95%置信区间范围在 0.73 至 0.94 之间）。MUFA 26:1（OR：0.85；95%CI：0.76，0.94）、PUFA 20:4（OR：0.84；95%CI：0.75，0.94）和 24:2（OR：0.87；95%CI：0.78，0.97）显示出显著关联。在多 FFA 暴露模型中，24 种 FFA 与新发糖尿病显著相关，其中大多数与单变量结果一致。混合 OR 为 0.78（95%CI：0.61，0.99；P=0.04159）。差异相关网络分析显示，在糖尿病发病前，FFA 类内和类间的核心调控已经存在预先存在的扰动。
这些发现强调了不同链长和不饱和程度的 FFA 与糖尿病风险的变化，突出了在糖尿病发病机制中识别 FFA 亚型的重要性。
