Abstract 12: Prospective Associations of Fatty Acids in the De Novo Lipogenesis Pathway and Stearoyl CoA-desaturase-1 Activity with Risk of Type 2 Diabetes: the Cardiovascular Health Study
Authors: Ma Wenjie , Wu Jason H , Wang Qianyi , Lemaitre Rozenn N , Mukamal Kenneth J , Djousse Luc , King Irena B , Song Xiaoling , Biggs Mary L , Delaney Joseph A , Ix Joachim H , Kizer Jorge R , Siscovick David S , Mozaffarian Dariush 
Published: July 2021

Background:
Experimental evidence suggests de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated (SFA) and monounsaturated fatty acids (MUFA), and also through altered activity of the key regulatory enzyme, Stearoyl-CoA desaturase-1 (SCD-1). Only limited studies have utilized biomarkers of SFA, MUFA and estimated SCD-1 activity to assess their prospective association with risk of type 2 diabetes (T2D).

Objective:
To investigate the association of 3 major circulating SFA (palmitic acid,16:0, stearic acid,18:0) and MUFA (oleic acid,18:1n-9) in the DNL pathway with metabolic risk factors and incident T2D in a community based cohort of US adults (aged≥65y). In secondary analyses, we assessed relations of other fatty acid biomarkers in the DNL pathway (14:0, 16:1n-7, 16:1n-9, 18:1n-7, and SCD-1 activity estimated by 16:1n-7/16:0 and 18:1n-9/18:0), as well as dietary intake of individual SFA and MUFA with incident T2D.

Methods:
Among 3060 participants free of T2D and with plasma phospholipid fatty acid measures in 1992 (study baseline), incident T2D cases were identified by medication use assessed annually and repeated blood glucose measures. Usual dietary habits were assessed by repeated FFQs. Associations of fatty acids with metabolic risk factors and incident diabetes were evaluated by multivariate linear regression and Cox proportional models, respectively.

Results:
During 30,763 person-years of follow-up, 353 incident cases were identified. Higher circulating 16:0 and 18:0 were associated with adverse metabolic profiles including greater BMI, inflammation biomarkers and HOMA-IR (P-trend<0.01 for each), whereas higher 18:1n-9 showed generally beneficial associations (P-trend<0.001 for each). After adjustment for demographic and lifestyle factors, a higher risk of T2D was seen for 16:0 (quintile 5 vs. 1 HR 2.39, 95% CI 1.65-3.46, P-trend<0.001) and 18:0 (HR 1.48, 95% CI 1.04-2.11, P-trend=0.009), but not for 18:1n-9 (HR 0.87, 95% CI 0.59-1.27, P-trend=0.77). In secondary analyses, 16:1n-7 (HR 1.50, 95% CI 1.03-2.20, P-trend=0.03) was positively associated while 18:1n-7 (HR 0.50, 95% CI 0.35-0.72, P-trend<0.001) was inversely associated with risk of T2D. Other fatty acid biomarkers, estimated SCD-1 activity and dietary intake of individual fatty acids, as isocaloric replacement for carbohydrate, were not significantly associated with incident T2D.

Conclusion:
Circulating levels of 16:0, 18:0 and 16:1n-7 were associated with an increased risk of incident T2D in older adults, whereas 18:1n-7 was associated with lower risk. These results highlight the need for further investigation of biological mechanisms that link specific fatty acids in the DNL pathway to pathogenesis of T2D.