Associations between artificial sweetener intake from cereals, coffee, and tea and the risk of type 2 diabetes mellitus: A genetic correlation, mediation, and mendelian randomization analysis.

Background: Previous studies have emphasized the association between the intake of artificial sweeteners (AS) and type 2 diabetes mellitus (T2DM), but the causative relationship remains ambiguous.

Methods: This study employed univariate Mendelian randomization (MR) analysis to assess the causal link between AS intake from various sources and T2DM. Linkage disequilibrium score (LDSC) regression was used to evaluate the correlation between phenotypes. Multivariate and mediation MR were applied to investigate confounding factors and mediating effects. Data on AS intake from different sources (N = 64,949) were sourced from the UK Biobank, while T2DM data were derived from the DIAbetes Genetics Replication And Meta-analysis.The primary method adopted was inverse variance weighted (IVW), complemented by three validation techniques. Additionally, a series of sensitivity analyses were performed to evaluate pleiotropy and heterogeneity.

Results: LDSC analysis unveiled a significant genetic correlation between AS intake from different sources and T2DM (rg range: -0.006 to 0.15, all P < 0.05). After correction by the false discovery rate (FDR), the primary IVW method indicated that AS intake in coffee was a risk factor for T2DM (OR = 1.265, 95% CI: 1.035-1.545, P = 0.021, PFDR = 0.042). Further multivariable and mediation MR analyses pinpointed high density lipoprotein-cholesterol (HDL-C) as mediating a portion of this causal relationship. In reverse MR analysis, significant evidence suggested a positive correlation between T2DM and AS intake in coffee (β = 0.013, 95% CI: 0.004-0.022, P = 0.004, PFDR = 0.012), cereal (β = 0.007, 95% CI: 0.002-0.012, P = 0.004, PFDR = 0.012), and tea (β = 0.009, 95% CI: 0.001-0.017, P = 0.036, PFDR = 0.049). No other causal associations were identified (P > 0.05, PFDR > 0.05).

Conclusion: The MR analysis has established a causal relationship between AS intake in coffee and T2DM. The mediation by HDL-C emphasizes potential metabolic pathways underpinning these relationships.