Jason H Y Wu1, Matti Marklund2, Fumiaki Imamura3, Nathan Tintle4, Andres V Ardisson Korat5, Janette de Goede6, Xia Zhou7, Wei-Sin Yang8, Marcia C de Oliveira Otto9, Janine Kröger10, Waqas Qureshi11, Jyrki K Virtanen12, Julie K Bassett13, Alexis C Frazier-Wood14, Maria Lankinen12, Rachel A Murphy15, Kalina Rajaobelina16, Liana C Del Gobbo17, Nita G Forouhi3, Robert Luben18, Kay-Tee Khaw19, Nick Wareham3, Anya Kalsbeek20, Jenna Veenstra20, Juhua Luo21, Frank B Hu5, Hung-Ju Lin22, David S Siscovick23, Heiner Boeing10, Tzu-An Chen14, Brian Steffen24, Lyn M Steffen7, Allison Hodge13, Gudny Eriksdottir25, Albert V Smith25, Vilmunder Gudnason25, Tamara B Harris26, Ingeborg A Brouwer27, Claudine Berr28, Catherine Helmer16, Cecilia Samieri16, Markku Laakso29, Michael Y Tsai24, Graham G Giles13, Tarja Nurmi12, Lynne Wagenknecht11, Matthias B Schulze10, Rozenn N Lemaitre30, Kuo-Liong Chien31, Sabita S Soedamah-Muthu6, Johanna M Geleijnse6, Qi Sun5, William S Harris32, Lars Lind33, Johan Ärnlöv34, Ulf Riserus2, Renata Micha35, Dariush Mozaffarian35. 1. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: jwu1@georgeinstitute.org.au. 2. Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden. 3. Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK. 4. Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA. 5. Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 6. Division of Human Nutrition, Wageningen University, Wageningen, Netherlands. 7. School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. 8. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. 9. Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center, School of Public Health, Houston, TX, USA. 10. German Institute of Human Nutrition, Potsdam, Germany. 11. Wake Forest University, Winston-Salem, NC, USA. 12. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 13. Cancer Council Victoria, Melbourne, VIC, Australia. 14. US Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Houston, TX, USA. 15. University of British Columbia, Vancouver, BC, Canada. 16. University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, UMR 1219, Bordeaux, France. 17. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. 18. Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK. 19. Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA. 20. Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA; Department of Biology, Dordt College, Sioux Center, IA, USA. 21. Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IN, USA. 22. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 23. The New York Academy of Medicine, New York, NY, USA. 24. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 25. Icelandic Heart Institute, Kópavogur, Iceland. 26. National Institute on Aging, Bethesda, MD, USA. 27. Health Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands. 28. INSERM U1061, Neuropsychiatry: Epidemiological and Clinical Research, and Montpellier University Hospital, Montpellier University, Montpellier, France. 29. Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. 30. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. 31. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 32. Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA; OmegaQuant Analytics, Sioux Falls, SD, USA. 33. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 34. Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Karolinska Institute, Stockholm, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden. 35. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Abstract
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/m2, 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; I2=53·9%, pheterogeneity=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; I2=63·0%, pheterogeneity<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 pheterogeneity≥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.
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/m2, 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; I2=53·9%, pheterogeneity=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; I2=63·0%, pheterogeneity<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 pheterogeneity≥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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