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Original Research Annals of Internal Medicine 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 Go¨ khan S. Hotamisligil, MD, PhD Background: Palmitoleic acid (cis-16:1n-7), which is produced by Higher trans-palmitoleate levels were associated with slightly lower endogenous fat synthesis, has been linked to both beneficial and adiposity and, independently, with higher high-density lipoprotein deleterious metabolic effects, potentially confounded by diverse cholesterol levels (1.9% across quintiles; P 0.040), lower triglyc- determinants and tissue sources of endogenous production. Trans- eride levels (19.0%; P 0.001), a lower total cholesterol–HDL palmitoleate (trans-16:1n-7) represents a distinctly exogenous cholesterol ratio (4.7%; P 0.001), lower C-reactive protein lev- source of 16:1n-7, unconfounded by endogenous synthesis or its els (13.8%; P 0.05), and lower insulin resistance (16.7%, determinants, that may be uniquely informative. P 0.001). Trans-palmitoleate was also associated with a substan- tially lower incidence of diabetes, with multivariate hazard ratios of Objective: To investigate whether circulating trans-palmitoleate is 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles independently r