Metabolic profiling of smoking, associations with type 2 diabetes and interaction with genetic susceptibility

Background Smokers are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms are unclear. We investigated if the smoking-T2D association is mediated by alterations in the metabolome and assessed potential interaction with genetic susceptibility to diabetes or insulin resistance.Methods In UK Biobank (n = 93,722), cross-sectional analyses identified 208 metabolites associated with smoking, of which 131 were confirmed in Mendelian Randomization analyses, including glycoprotein acetyls, fatty acids, and lipids. Elastic net regression was applied to create a smoking-related metabolic signature. We estimated hazard ratios (HR) of incident T2D in relation to baseline smoking/metabolic signature and calculated the proportion of the smoking-T2D association mediated by the signature. Additive interaction between the signature and genetic risk scores for T2D (GRS-T2D) and insulin resistance (GRS-IR) on incidence of T2D was assessed as relative excess risk due to interaction (RERI).Findings The HR of T2D was 1 center dot 73 (95% confidence interval (CI) 1 center dot 54 - 1 center dot 94) for current versus never smoking, and 38 center dot 3% of the excess risk was mediated by the metabolic signature. The metabolic signature and its mediation role were replicated in TwinGene. The metabolic signature was associated with T2D (HR: 1 center dot 61, CI 1 center dot 46 - 1 center dot 77 for values above vs. below median), with evidence of interaction with GRS-T2D (RERI: 0 center dot 81, CI: 0 center dot 23 - 1 center dot 38) and GRS-IR (RERI 0 center dot 47, CI: 0 center dot 02 - 0 center dot 92).Interpretation The increased risk of T2D in smokers may be mediated through effects on the metabolome, and the influence of such metabolic alterations on diabetes risk may be amplified in individuals with genetic susceptibility to T2D or insulin resistance.