Associations of Insomnia With Insulin Resistance Traits: A Cross-sectional and Mendelian Randomization Study

Abstract Context Insomnia is associated with insulin resistance (IR) in observational studies; however, whether insomnia is causally associated with IR remains unestablished. Objective This study aims to estimate the causal associations of insomnia with IR and its related traits. Methods In primary analyses, multivariable regression (MVR) and 1-sample Mendelian randomization (1SMR) analyses were performed to estimate the associations of insomnia with IR (triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol [TG/HDL-C] ratio) and its related traits (glucose level, TG, and HDL-C) in the UK Biobank. Thereafter, 2-sample MR (2SMR) analyses were used to validate the findings from primary analyses. Finally, the potential mediating effects of IR on the pathway of insomnia giving rise to type 2 diabetes (T2D) were examined using a 2-step MR design. Results Across the MVR, 1SMR, and their sensitivity analyses, we found consistent evidence suggesting that more frequent insomnia symptoms were significantly associated with higher values of triglyceride-glucose index (MVR, β = 0.024, P < 2.00E-16; 1SMR, β = 0.343, P < 2.00E-16), TG/HDL-C ratio (MVR, β = 0.016, P = 1.75E-13; 1SMR, β = 0.445, P < 2.00E-16), and TG level (MVR, β = 0.019 log mg/dL, P < 2.00E-16, 1SMR: β = 0.289 log mg/dL, P < 2.00E-16) after Bonferroni adjustment. Similar evidence was obtained by using 2SMR, and mediation analysis suggested that about one-quarter (25.21%) of the association between insomnia symptoms and T2D was mediated by IR. Conclusions This study provides robust evidence supporting that more frequent insomnia symptoms are associated with IR and its related traits across different angles. These findings indicate that insomnia symptoms can be served as a promising target to improve IR and prevent subsequent T2D.