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Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in U.S. Adults: A Cohort Study

Dariush Mozaffarian, MD, DrPH; Haiming Cao, PhD; Irena B. King, PhD; Rozenn N. Lemaitre, PhD, MPH; Xiaoling Song, PhD; David S. Siscovick, MD, MPH; and Gökhan S. Hotamisligil, MD, PhD
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From Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts; National Institutes of Health, Bethesda, Maryland; University of New Mexico, Albuquerque, New Mexico; and Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington.

Acknowledgment: The authors thank the CHS participants. A full list of participating CHS investigators and institutions is available at www.chs-nhlbi.org.

Grant Support: By the National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grants R01-HL085710, DK064360, and DK71507-04 and grants N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through -85086, N01-HC-15103, N01-HC-55222, and U01-HL080295 for the CHS), with additional contributions from the National Institutes of Health Office of Dietary Supplements and National Institute of Neurological Disorders and Stroke. A subset of additional fatty acid measurements was supported by a Searle Scholar Award.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1274.

Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Mozaffarian (e-mail, dmozaffa@hsph.harvard.edu). Data set: Available through established Cardiovascular Health Study procedures for obtaining and analyzing data; see www.chs-nhlbi.org/CHS_DistribPolicy.htm.

Requests for Single Reprints: Dariush Mozaffarian, MD, DrPH, Harvard School of Public Health; 665 Huntington Avenue, Building 2-319, Boston, MA 02115; e-mail, dmozaffa@hsph.harvard.edu.

Current Author Addresses: Dr. Mozaffarian: Harvard School of Public Health, 665 Huntington Avenue, Building 2-319, Boston, MA 02115.

Dr. Cao: National Institutes of Health, 10 Center Drive, Building 10, 8N105A, Bethesda, MD 20892.

Dr. King: University of New Mexico, 2703 Frontier Avenue Northeast, Suite 190, Albuquerque, NM 87131.

Drs. Lemaitre and Siscovick: Cardiovascular Health Research Unit, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101.

Dr. Song: Fred Hutchinson Cancer Research Center, M5 A864, 1100 Fairview Avenue North, Seattle, WA 98109.

Dr. Hotamisligil: Harvard School of Public Health, 665 Huntington Avenue, Building 1-605, Boston, MA 02115.

Author Contributions: Conception and design: D. Mozaffarian, H. Cao, I.B. King, G.S. Hotamisligil.

Analysis and interpretation of the data: D. Mozaffarian, H. Cao, I.B. King, R.N. Lemaitre, X. Song, D.S. Siscovick, G.S. Hotamisligil.

Drafting of the article: D. Mozaffarian.

Critical revision of the article for important intellectual content: D. Mozaffarian, I.B. King, R.N. Lemaitre, X. Song, D.S. Siscovick, G.S. Hotamisligil.

Final approval of the article: D. Mozaffarian, H. Cao, I.B. King, R.N. Lemaitre, X. Song, D.S. Siscovick, G.S. Hotamisligil.

Statistical expertise: D. Mozaffarian.

Obtaining of funding: D. Mozaffarian.

Administrative, technical, or logistic support: H. Cao, X. Song.

Collection and assembly of data: D. Mozaffarian, I.B. King, X. Song, D.S. Siscovick.

Ann Intern Med. 2010;153(12):790-799. doi:10.7326/0003-4819-153-12-201012210-00005
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Background: Palmitoleic acid (cis-16:1n-7), which is produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative.

Objective: To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes.

Design: Prospective cohort study from 1992 to 2006.

Setting: Four U.S. communities.

Patients: 3736 adults in the Cardiovascular Health Study.

Measurements: Anthropometric characteristics and levels of plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose–insulin measured at baseline in 1992 and dietary habits measured 3 years earlier. Multivariate-adjusted models were used to investigate how demographic, clinical, and lifestyle factors independently related to plasma phospholipid trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). Findings were validated for metabolic risk factors in an independent cohort of 327 women.

Results: In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels (1.9% across quintiles; P = 0.040), lower triglyceride levels (−19.0%; P < 0.001), a lower total cholesterol–HDL cholesterol ratio (−4.7%; P < 0.001), lower C-reactive protein levels (−13.8%; P = 0.05), and lower insulin resistance (−16.7%, P < 0.001). Trans-palmitoleate was also associated with a substantially lower incidence of diabetes, with multivariate hazard ratios of 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5 versus quintile 1 (P for trend < 0.001). Findings were independent of estimated dairy consumption or other fatty acid dairy biomarkers. Protective associations with metabolic risk factors were confirmed in the validation cohort.

Limitation: Results could be affected by measurement error or residual confounding.

Conclusion: Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation.

Primary Funding Source: National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.





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Summary for Patients

Dietary Trans-Palmitoleic Acid and Diabetes

The full report is titled “Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in U.S. Adults. A Cohort Study.” It is in the 21 December 2010 issue of Annals of Internal Medicine (volume 153, pages 790-799). The authors are D. Mozaffarian, H. Cao, I.B. King, R.N. Lemaitre, X. Song, D.S. Siscovick, and G.S. Hotamisligil.


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