Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in US Adults

Background—Palmitoleic acid (cis-16:1n-7), 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. Address for reprints: D. Mozaffarian, 665 Huntington Ave, Bldg 2-319, Boston, MA 02115; 617-432-2887; fax=617-432-2435; [email protected]. Author addresses: Dariush Mozaffarian: Harvard School of Public Health, 665 Huntington Ave, Bldg 2-319, Boston, MA 02115 Haiming Cao: National Institutes of Health, 10 Center Dr, Building 10, 8N105A, Bethesda, MD 20892 Irena B. King: University of New Mexico, 2703 Frontier Ave NE, Suite #190, Albuquerque, NM 87131 Rozenn Lemaitre: Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101 Xiaoling Song: Fred Hutchinson Cancer Research Center, M5-A864, 1100 Fairview Avenue North, Seattle, WA 98109 David Siscovick: Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101 Gökhan Hotamisligil: Harvard School of Public Health, 665 Huntington Avenue Bldg 1-605, Boston, MA 02115 Conflict of Interest Disclosures: Harvard University has filed a provisional patent application, that will be assigned to Harvard University, that lists Drs. Mozaffarian, Cao, and Hotamisligil as inventors to the US Patent and Trademark Office for use of trans-16:1n-7 to prevent and treat insulin resistance, type 2 diabetes, and related conditions. Author Contributions: Dr. Mozaffarian: Conception and design, obtained funding, data collection, statistical analysis, data interpretation, manuscript drafting, manuscript critical revision, and approval of final submitted manuscript. Drs. Cao and Hotamisligil: Conception and design, data interpretation, critical revision of the manuscript, and approval of final submitted manuscript. Dr. King: Obtained funding, data collection, data interpretation, critical revision of the manuscript, and approval of final submitted manuscript. Dr. Song: Data collection, data interpretation, critical revision of the manuscript, and approval of final submitted manuscript. Drs. Lemaitre and Siscovick: Obtained funding, data collection, data interpretation, critical revision of the manuscript, and approval of final submitted manuscript. Availability to Readers: Study Protocol: Available to interested readers by contacting Dr. Mozaffarian at [email protected] Statistical Code: Available to interested readers by contacting Dr. Mozaffarian at [email protected] Data: Available to interested readers through established Cardiovascular Health Study procedures for obtaining and analyzing data; see www.chs-nhlbi.org/CHS_DistribPolicy.htm NIH Public Access Author Manuscript Ann Intern Med. Author manuscript; available in PMC 2011 December 21. Published in final edited form as: Ann Intern Med. 2010 December 21; 153(12): 790–799. doi: 10.1059/0003-4819-153-12-201012210-00005. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Objective—We investigated whether circulating trans-palmitoleate was independently related to lower metabolic risk and incident type2 diabetes. Design—Prospective cohort study (1992–2006). Setting—Four US communities. Patients—3,736 adults in the Cardiovascular Health Study. Measurements—Plasma phospholipid fatty acids, anthropometry, blood lipids, inflammatory markers, and glucose-insulin levels were measured at baseline in 1992; and diet, 3 years earlier. In multivariable-adjusted models, we investigated how demographic, clinical, and lifestyle factors independently related to trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). We validated findings for metabolic risk factors in an independent cohort of 327 women. Results—In multivariable-analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate. Higher trans-palmitoleate was associated with slightly lower adiposity and, independently, higher high-density-lipoprotein(HDL)-cholesterol (across quintiles: +1.9%, P=0.04), lower triglycerides (−19.0%, P<0.001), lower total:HDL-cholesterol (−4.7%, P<0.001), lower C-reactive protein (−13.8%, P=0.05), and lower insulin resistance (−16.7%, P<0.001). Trans-palmitoleate was associated with substantially lower incidence of diabetes, with multivariable-hazard-ratios=0.41 (95%CI=0.27–0.64) and 0.38 (95%CI=0.24–0.62) in quintile-4 and quintile-5, versus quintile-1 (P-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. Limitations—Measurement error; residual confounding. Conclusions—Circulating trans-palmitoleate is associated with lower insulin resistance, atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support need for detailed further experimental and clinical investigation. Primary Funding Source—National Institutes of Health.