Abstract
AIMS: To examine whether zinc (Zn) and copper (Cu) status influence the association of estimated delta-5 desaturase (D5D), delta-6 desaturase (D6D), and stearoyl-CoA desaturase-1 (SCD1) activities with type 2 diabetes (T2D) risk. METHODS: We used a nested case-cohort design within the EPIC-Potsdam Study (n = 1979; 447 incident T2D cases). Desaturase activities were estimated using erythrocyte fatty acids (FA): D5D (20:4n-6/20:3n-6), D6D (18:3n-6/18:2n-6), and SCD1 (16:1/16:0 [SCD1-16], 18:1/18:0 [SCD1-18]). We evaluated associations between desaturases and serum Zn or Cu, assessed interactions between serum Zn or Cu and desaturase activities in Cox regression models for T2D risk, and examined modification by Zn transporter SLC30A8 genetic variant and metal-related polygenic risk scores. RESULTS: Higher serum Zn was significantly associated with lower SCD1-18 activity (β per 1 SD = -0.09). Zn status showed a non-linear modifying effect on the D5D-T2D relationship (p-interaction = 0.03), though an inverse D5D association was observable consistently across Zn levels. Serum Cu was positively associated with SCD1-16 (β = 0.13) and SCD1-18 (β = 0.08) and negatively associated with D5D activity (β = -0.13). Stronger inverse associations of higher D5D activity with T2D risk were observed at low Cu levels (HR 0.69, 95% CI 0.58-0.81) versus higher levels (HR 0.95, 95% CI 0.80-1.13) (p-interaction = 0.009). The SLC30A8 variant rs13266634 significantly modified the D5D-T2D association. Furthermore, the inverse association of D5D with T2D was stronger among participants with a higher Cu genetic score. CONCLUSIONS: Zn and Cu status modified the relationship between FA desaturases and T2D risk. This was supported by serum Zn and Cu levels and by genetic variation related to their transport and homeostasis.