Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.