Multidimensional plasma lipid composition and its causal association with type 2 diabetes mellitus: A Mendelian randomization study

Recent research extends our knowledge of plasma lipid species, building on established links between serum lipid levels and Type 2 Diabetes Mellitus (T2DM) risk. Identifying the causal roles of these lipid species is key to improving T2DM risk assessment. This study employs Mendelian randomization (MR) to investigate the causal relationship between 179 lipid species across 13 lipid categories and T2DM. Summary-level data were sourced from genome-wide association studies. The primary analytical methods included the inverse variance weighted (IVW) approach and the Wald ratio, complemented by a series of sensitivity analyses to ensure the robustness of results. The IVW analysis reveals a significant causal association between elevated levels of ceramide (d40:2) (OR = 1.071, 95% CI 1.034–1.109, P = 1.36 × 10−4), sphingomyelin (d38:1) (OR = 1.052, 95% CI 1.028–1.077, P = 1.80 × 10−5), and triacylglycerol (56:8) (OR = 1.174, 95% CI 1.108–1.243, P = 4.65 × 10−8), and an increased risk of T2DM. Conversely, Wald ratio analysis indicates that higher levels of phosphatidylcholine (O-16:1_16:0) (OR = 0.928, 95% CI 0.892–0.966, P = 2.37 × 10−4), phosphatidylcholine (O-16:1_20:4) (OR = 0.932, 95% CI 0.897–0.967, P = 2.37 × 10−4), and phosphatidylcholine (O-18:2_20:4) (OR = 0.872, 95% CI 0.812–0.935, P = 1.24 × 10−4) are significantly associated with a reduced risk of T2DM. Furthermore, suggestive causal evidence for 22 additional lipid species was identified. This MR study establishes a causal relationship between specific lipid classes in modulating the risk of T2DM. It offers new insights for risk assessment and potential therapeutic targets in T2DM. •Mendelian Randomization study on 179 lipid species identifies key lipid types influencing T2DM risk.•Elevated levels of ceramide and sphingomyelin significantly increase T2DM risk; specific phosphatidylcholines lower it.•Results provide new insights for T2DM risk assessment, highlighting potential therapeutic targets.•Study uses genetic variants as instrumental variables to establish causal relationships between lipid types and T2DM.•Findings suggest that precise lipid profiling can refine T2DM risk stratification and guide interventions.