$Background:$ Whether 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.

$Methods and Findings:$ Plasma phospholipid PUFAs were measured by gas-chromatography among 12,132 incident T2D cases and 15,919 sub-cohort participants in EPIC-InterAct study across 8 European countries. Country-specific hazard ratios (HR) 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 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; 0.77,0.83) and eicosadienoic acid (EDA) (0.89; 0.85,0.94) were inversely related, 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 9 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.

$Conclusions:$ These large-scale findings suggest important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA, 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 a focus on fatty acid class.