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

Authors: IMAMURA, FUMIAKI - University Of Cambridge; FRETTS, AMANDA - University Of Washington; MARKLUND, MATTI - Uppsala University; ARDISSON KORAT, ANDRES - Harvard School Of Public Health; YANG, WEI - National Taiwan University; LANKINEN, MARIA - University Of Eastern Finland; QURESHI, WAQAS - Wake Forest School Of Medicine; HELMER, CATHERINE - University Of Bordeaux; CHEN, TZU - Children'S Nutrition Research Center (CNRC); VIRTANEN, JYRKI - University Of Eastern Finland; WONG, KERRY - Cancer Council Victoria; BASSETT, JULIE - Cancer Council Victoria; MURPHY, RACHEL - University Of British Columbia; TINTLE, NATHAN - Dordt College; YU, CHAOYU - University Of Washington; BROUWER, INGEBORG - Vrije University; CHIEN, KUO - National Taiwan University; CHEN, YUN - National Taiwan University; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); DEL GOBBO, LIANA - Stanford University School Of Medicine; DJOUSSE, LUC - Brigham & Women'S Hospital; GELEIJNSE, JOHANNA - Wageningen University; GILES, GRAHAM - Cancer Council Victoria; DE GOEDE, JANETTE - Wageningen University; GUDNASON, VILMUNDUR - Icelandic Heart Association; HARRIS, WILLIAM - University Of South Dakota; HODGE, ALLISON - Cancer Council Victoria; HU, FRANK - Harvard School Of Public Health; KOULMAN, ALBERT - University Of Cambridge; LAAKSO, MARKKU - University Of Eastern Finland; LIND, LARS - Uppsala University; LIN, HUNG - National Taiwan University; MCKNIGHT, BARBARA - University Of Washington; RAJAOBELINA, KALINA - University Of Bordeaux; RISERUS, ULF - Uppsala University; ROBINSON, JENNIFER - University Of Iowa; SAMIERI, CECILIA - University Of Bordeaux; SENN, MACKENZIE - Children'S Nutrition Research Center (CNRC); SISCOVICK, DAVID - New York Academy Of Medicine; SOEDAMAH-MUTHU, SABITA - Wageningen University; SOTOODEHNIA, NONA - University Of Washington; SUN, QI - Harvard School Of Public Health; TSAI, MICHAEL - University Of Minnesota; TUOMAINEN, TOMI - University Of Eastern Finland; UUSITUPA, MATTI - University Of Eastern Finland; WAGENKNECHT, LYNNE - Wake Forest School Of Medicine; WAREHAM, NICK - University Of Cambridge; WU, JASON - University Of New South Wales; MICHA, RENATA - Friedman School At Tufts; LEMAITRE, ROZENN - University Of Washington; MOZAFFARIAN, DARIUSH - Friedman School At Tufts; FOROUHI, NITA - University Of Cambridge

Submitted to: PLoS Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/28/2020
Publication Date: 6/12/2020
Citation: Imamura, F., Fretts, A.M., Marklund, M., Ardisson Korat, A.V., Yang, W.S., Lankinen, M., Qureshi, W., Helmer, C., Chen, T.A., Virtanen, J.K., Wong, K., Bassett, J.K., Murphy, R., Tintle, N., Yu, C.I., Brouwer, I.A., Chien, K.L., Chen, Y.Y., Wood, A.C., Del Gobbo, L.C., Djousse, L., Geleijnse, J.M., Giles, G.G., De Goede, J., Gudnason, V., Harris, W.S., Hodge, A., Hu, F., Koulman, A., Laakso, M., Lind, L., Lin, H.J., McKnight, B., Rajaobelina, K., Riserus, U., Robinson, J.G., Samieri, C., Senn, M., Siscovick, D.S., Soedamah-Muthu, S.S., Sotoodehnia, N., Sun, Q., Tsai, M.Y., Tuomainen, T.P., Uusitupa, M., Wagenknecht, L.E., Wareham, N.J., Wu, J.H., Micha, R., Lemaitre, R.N., Mozaffarian, D., Forouhi, N.G. 2020. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. PLoS Medicine. 17(6):e1003102. https://doi.org/10.1371/journal.pmed.1003102.
DOI: https://doi.org/10.1371/journal.pmed.1003102

Interpretive Summary: De novo lipogenesis (DNL) is the process by which fatty acids are made in the body from the food we eat. Some studies have supported the idea that some of the fatty acids made via DNL contribute to the development of type 2 diabetes (T2D), but others have shown different results. To better resolve the differences in research findings, the current analyses used combined data from 17 cohorts to examine the association between fatty acids made via DNL and the development of T2D. Our study found each of the four fatty acids were positively associated with the development of T2D, even when we considered the role of other T2D risk factors such as a higher body mass index (BMI). In the largest analysis of its kind to date, our study suggested that higher levels of fatty acids made via DNL increase T2D risk, and therefore will help us better understand why some people develop T2D while others do not.

Technical Abstract: 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). 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. 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.