Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

BackgroundWhether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.Methods and FindingsPlasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.ConclusionsThese large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.研究背景：n-3和n-6多不饱和脂肪酸（polyunsaturated fatty acids, PUFAs）是否以及如何与2型糖尿病（type 2 diabetes, T2D）相关，目前仍存在争议。客观检测血浆中的多不饱和脂肪酸，有助于阐明二者之间的关联。 研究方法与结果：本研究依托欧洲癌症与营养前瞻性调查（European Prospective Investigation into Cancer and Nutrition, EPIC）-InterAct研究，覆盖欧洲8个国家，共纳入12132例新发2型糖尿病患者与15919名亚队列参与者，采用气相色谱法检测其血浆磷脂多不饱和脂肪酸水平。采用Prentice加权Cox回归模型估算国家特异性风险比（hazard ratio, HR），并通过随机效应荟萃分析进行合并。此外，本研究还系统检索了已发表的关于循环多不饱和脂肪酸与2型糖尿病风险的前瞻性研究，汇总其定量研究结果，以与EPIC-InterAct研究的结果进行对比。 在EPIC-InterAct研究中，长链n-3多不饱和脂肪酸中，α-亚麻酸（α-linolenic acid, ALA）与2型糖尿病风险呈负相关（每标准差[standard deviation, SD]对应的风险比为0.93；95%置信区间[confidence interval, CI]为0.88~0.98），但二十碳五烯酸（eicosapentaenoic acid, EPA）与二十二碳六烯酸（docosahexaenoic acid, DHA）与2型糖尿病无显著关联。在n-6多不饱和脂肪酸中，亚油酸（linoleic acid, LA）（0.80；95%CI 0.77~0.83）与二十碳二烯酸（eicosadienoic acid, EDA）（0.89；95%CI 0.85~0.94）与2型糖尿病风险呈负相关，而花生四烯酸（arachidonic acid, AA）与2型糖尿病无显著关联；但γ-亚麻酸（γ-linolenic acid, GLA）、二高-γ-亚麻酸、二十二碳四烯酸（docosatetraenoic acid, DTA）以及二十二碳五烯酸（n6型，docosapentaenoic acid, n6-DPA）与2型糖尿病风险呈显著正相关，每标准差对应的风险比介于1.13至1.46之间。EPIC-InterAct研究的上述结果，与纳入71~2499例2型糖尿病患者的最多9项研究的汇总估计结果基本一致。 研究局限性：本研究可能存在残余混杂因素，且无法区分膳食与代谢因素对血浆磷脂多不饱和脂肪酸的影响。 结论：本项大规模研究结果显示，循环中植物源性n-3多不饱和脂肪酸（ALA）与2型糖尿病风险呈显著负相关，但海洋源性n-3多不饱和脂肪酸（EPA与DHA）与2型糖尿病无明确关联。此外，研究结果表明，含量最丰富的n-6多不饱和脂肪酸（LA）与2型糖尿病风险呈负相关。本次研究发现了此前较少被探究的多不饱和脂肪酸与2型糖尿病的关联，提示我们应关注单一脂肪酸的作用，而非仅聚焦于脂肪酸类别。