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
Open accessAbstract
Background The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.Methods We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.Findings Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m 2, who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I 2=53·9%, p heterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I 2=63·0%, p heterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all p heterogeneity≥0·13).Interpretation Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.Funding Funders are shown in the appendix.
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Large epidemiologic studies have found that consumption of polyunsaturated fat or biomarkers of polyunsaturated fatty acids are associated with lower risk of type 2 diabetes.
“Large epidemiologic studies have found that consumption of polyunsaturated fat or biomarkers of polyunsaturated fatty acids are associated with lower risk of type 2 diabetes (67).”
From Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report (2019) · cites this paper as [67]
The Findings report that higher linoleic acid biomarker levels were associated with lower type 2 diabetes risk in 20 prospective cohorts. The paper did not directly establish the claimed association for polyunsaturated fat consumption, and it found no significant association for another omega-6 biomarker, arachidonic acid (Findings; Discussion). (LLM, conf=0.86)
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References 31 · Cited by 298
- Authors
- Wu, J. H. Y., Marklund, M., Imamura, F., Tintle, N., Ardisson Korat, A. V., de Goede, J., Zhou, X., Yang, W.-S., de Oliveira Otto, M. C., Kröger, J., Qureshi, W., Virtanen, J. K., Bassett, J. K., Frazier-Wood, A. C., Lankinen, M., Murphy, R. A., Rajaobelina, K., Del Gobbo, L. C., Forouhi, N. G., Luben, R., Khaw, K.-T., Wareham, N., Kalsbeek, A., Veenstra, J., Luo, J., Hu, F. B., Lin, H.-J., Siscovick, D. S., Boeing, H., Chen, T.-A., Steffen, B., Steffen, L. M., Hodge, A., Eriksdottir, G., Smith, A. V., Gudnason, V., Harris, T. B., Brouwer, I. A., Berr, C., Helmer, C., Samieri, C., Laakso, M., Tsai, M. Y., Giles, G. G., Nurmi, T., Wagenknecht, L., Schulze, M. B., Lemaitre, R. N., Chien, K.-L., Soedamah-Muthu, S. S., Geleijnse, J. M., Sun, Q., Harris, W. S., Lind, L., Ärnlöv, J., Riserus, U., Micha, R., & Mozaffarian, D.
- Affiliations
- UNSW Sydney (AU)
- Uppsala University (SE)
- University of Cambridge (GB)
- Dordt University (US)
- University of Minnesota (US)
- National Taiwan University (TW)
- German Institute of Human Nutrition (DE)
- Wake Forest University (US)
- University of Eastern Finland (FI)
- Cancer Council Victoria (AU)
- Agricultural Research Service (US)
- University of British Columbia (CA)
- Université de Bordeaux (FR)
- Indiana University Bloomington (US)
- Harvard University (US)
- National Taiwan University Hospital (TW)
- New York Academy of Medicine (US)
- Icelandic Heart Association (IS)
- National Institutes of Health (US)
- Vrije Universiteit Amsterdam (NL)
- Inserm (FR)
- University of Washington (US)
- Wageningen University & Research (NL)
- University of South Dakota (US)
- Dalarna University (SE)
- Tufts University (US)
- Corresponding author
- Wu, Jason H Y
- ORCID
- Marklund, Matti
- Imamura, Fumiaki
- Tintle, Nathan
- Virtanen, Jyrki K
- Lankinen, Maria
- Forouhi, Nita G
- Luben, Robert
- Khaw, Kay-Tee
- Kalsbeek, Anya
- Luo, Juhua
- Hu, Frank B
- Siscovick, David S
- Steffen, Brian
- Steffen, Lyn M
- Hodge, Allison
- Smith, Albert V
- Harris, Tamara B
- Brouwer, Ingeborg A
- Berr, Claudine
- Helmer, Catherine
- Laakso, Markku
- Giles, Graham G
- Chien, Kuo-Liong
- Geleijnse, Johanna M
- Ärnlöv, Johan
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 5
- Issue
- 12
- Pages
- 965-974
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC6029721
- OpenAlex
- W2761192596
- Cited by
- 298
- References
- 31
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 29 · 2023: 34 · 2022: 40 · 2021: 42 · 2020: 34 · 2019: 34 · 2018: 34 · 2017: 5
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- Research portal (Tilburg University) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Dordt Digital Collections (Dordt College) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- IUScholarWorks Open (Indiana University) (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Apollo
- Funders
- AstraZeneca
- University of Washington
- University of South Dakota
- Cancer Research UK (14136)
- National Institute for Health and Care Research (NF-SI-0512-10114)
- European Commission (37197)
- Institut National de la Santé et de la Recherche Médicale
- University of New South Wales
- Cambridge University Hospitals (146281)
- Karolinska Institutet
- Högskolan Dalarna
- National Institutes of Health
- Medical Research Council (MC_UU_12015/1, MC_UU_12015/5, MR/N003284/1)
- National Institute on Aging (ZIAAG007380)
- National Heart, Lung, and Blood Institute (R01HL085710)
- National Human Genome Research Institute (R15HG006915)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- omega-6 fatty acids, linoleic acid, arachidonic acid, type 2 diabetes, incident diabetes risk, fatty acid biomarkers, phospholipids, cholesterol esters, adipose tissue, plasma lipids, primary prevention, prospective cohort, heterogeneous effects
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Humans, Prospective Studies, Risk Factors, Statistics as Topic, Cohort Studies, Biomarkers, Incidence, Arachidonic Acid, Linoleic Acid, Fatty Acids, Omega-6
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