Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies

InterAct Consortium

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Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Original languageEnglish
Article numbere1003102
JournalPLoS Medicine
Issue number6
Publication statusPublished - Jun 2020

Bibliographical note

No specific funding was received for this study. This manuscript does not reflect opinions or conclusions of any funding agency. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FI, NGF, and NJW were funded by the United Kingdom Medical Research Council Epidemiology Unit core grant (MC_UU_12015/5 and MC_UU_12015/1); NJW, NGF and AK acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre Cambridge (IS-BRC-1215-20014); NJW is an NIHR Senior Investigator; IAB, by the European Union (FP7 and Horizon2020) and the Dutch Scientific Organization (ZonMW); CS, by the Foundation Plan Alzheimer; and AAK, by the NIH training grant (3T32DK007703 and T32CA009001). Alpha Omega Cohort was funded by the Netherlands Heart Foundation (grant 2000T401), the NIH (NIH/ National Heart, Lung, and Blood Institute [NHLBI], and ODS, grant R01HL- 076200), and Unilever R&D, Vlaardingen (margarine production and distribution). The authors acknowledge Kamalita Pertiwi, Wageningen University, the Netherlands, for analyses of data from the Alpha Omega Cohort. Age, Gene/Environment Susceptibility Study Reykjavik was funded by Office of Dietary Supplements, the United States National Institute of Health (NIH) contract N01-AG012100, the National Institute of Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Additional support was provided by the Michael Smith Foundation for Medical Research (#17644) and the Canadian Cancer Society (grant #704735). Chin-Shan Community Cardiovascular Study was funded by Ministry of Science and Technology and National Taiwan University, Taiwan (MOST 103-2314-B-002 -135 –MY3, NSC 100-2314-B-002 -113 –MY3, NTUH 105-S3120, NTUH 106-S3453). The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants R01-HL-085710, U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from NIA. The Framingham Heart Study was supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). The Health Professionals Follow-up Study was funded by UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712, and P30 DK46200 from the NIH. The Insulin Resistance Atherosclerosis Study was funded by grants U01-HL-47892, U01-HL-47902, DK-29867, R01-58329, and DK-079888 from NHLBI and grant M01-RR-43 from the NIH. The InterAct project was funded by the EU FP6 programme (grant no. LSHM_CT_2006_037197). The Kuopio Ischaemic Heart Disease Risk Factor Study was supported mainly by the funding from the Academy of Finland to Jukka T. Salonen. The Melbourne Collaborative Cohort Study was funded by VicHealth and Cancer Council Victoria; and by grants 209057 and 126403 from Australia’s National Health and Medical Research Council and by infrastructure provided by Cancer Council Victoria. Multi-ethnic Study of Atherosclerosis was funded by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the NHLBI and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The Metabolic Syndrome in Men Study was funded by the grants from the European Union, the Academy of Finland, and the Juselius Foundation. The Nurses’ Health Study was funded by the NIH (CA186107, CA87969, CA49449, HL34594, HL35464, CA167552, HL60712, and HL088521). Prospective Investigation of the Vasculature in Uppsala Seniors was supported by Uppsala University Hospital and the Swedish Research Council for Health, Working Life and Welfare. The Tree City Study was conducted under a partnership agreement between the Institut National de la Sante et de la Recherche Medicale, the University Bordeaux 2 Victor Segalen, and Sanofi; and funded by the Fondation pour la Recherche Medicale, the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Conseils Regionaux d’Aquitaine et Bourgogne, Fondation de France, Ministry of Research–Institut National de la Sante and de la Recherche Medicale Programme Cohortes, grant COGINUT ANR-06-PNRA-005 from the Agence Nationale de la Recherche, grant FCS 2009-2012 from the Fondation Plan Alzheimer, and the Caisse Nationale pour la Solidarite et l’Autonomie. The Uppsala Longitudinal Studies of Adult Men 50 and 70 were funded by the Swedish Research Council for Health, Working Life and Welfare, Uppsala City Council, Swedish Research Council, and Swedish Diabetes Foundation (UR). The Women’s Health Initiative was funded by the NHLBI, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. A full listing of each of CHS, MESA, and WHI investigators can be found at http://www.CHS-NHLBI.org, http://www.mesa-nhlbi.org, and http://www.whi.org/researchers/, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2020 Imamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Other keywords

  • Diabetes Mellitus, Type 2 / metabolism
  • Fatty Acids / metabolism
  • Incidence
  • Lipogenesis


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