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

Abstract

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.

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

“…The opposing associations of erythrocyte phospholipids and plasma phospholipids with arachidonic acid identified by semiparametric analyses require further investigation; these results could be due to chance because arachidonic acid concentrations in these two compartments are highly correlated and are known to readily interexchange. 29 Consistent with this suggestion, in the EPIC cohort, 28 levels of plasma phospholipid arachidonic acid were not associated with type 2 diabetes. Our new findings of a protective association between arachidonic acid in total plasma and incident type 2 diabetes, based on findings in six cohorts, should be explored further.…”

“…A 2016 nested case-cohort analysis from the European Prospective Investigation into Cancer (EPIC) cohort, 28 published during the preparation of our manuscript, found an inverse association between plasma phospholipid linoleic acid and type 2 diabetes (HR per SD increase 0·80, 95% CI 0·77–0·83), and no significant association between arachidonic acid and type 2 diabetes (HR 1·02, 0·98–1·06). Our findings are consistent with this report, and include a worldwide perspective, using data from multiple lipid compartments and detailed assessment of potential effect modification, including by variation in the genes encoding FADS.…”

High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case–control study

“…A recent large cohort study including over 27 000 participants in the EPIC-InterAct study across European countries observed that LA is inversely associated with type 2 diabetes (T2D). The results also suggested an inverse association of ALA but no convincing association of marine-derived n-3 PUFA with T2D 27. Also a recent large pooled analysis of individual-level data for nearly 40 000 adults from 20 prospective studies has shown that higher levels of LA biomarkers were independently associated with a lower risk of T2D 53…”

Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies

“…Thus, participant characteristics may have an impact on FA metabolism and should be further explored. It is possible that delta 6-desaturase activity, the enzyme converting LA into gamma-linoleic acid, is altered in participants with insulin resistance, although at present there are no studies supporting this finding [30, 31]. Another explanation may be that in the presence of non-alcoholic fatty liver disease, hypertriglyceridemia, and insulin resistance, de novo lipogenesis is upregulated or FA oxidation is downregulated, promoting a higher proportion of SFA and MUFA in blood, and consequently a lower proportion of circulating LA [4, 32].…”