Physical Activity, Sedentary Behavior, and Type 2 Diabetes: Mendelian Randomization Analysis

Context The causality and pathways of the associations between physical activity and inactivity and the risk of type 2 diabetes remain inconclusive. Objective We conducted an updated mendelian randomization (MR) study to explore the associations of moderate-to-vigorous physical activity (MVPA) and leisure screen time (LST) with type 2 diabetes mellitus (T2DM). Methods Genetic variants strongly associated with MVPA or LST with low linkage disequilibrium were selected as instrumental variables from a genome-wide meta-analysis including more than 600 000 individuals. Summary-level data on T2DM were obtained from the DIAbetes Genetics Replication And Meta-analysis consortium including 898 130 individuals. Data on possible intermediates (adiposity indicators, lean mass, glycemic traits, and inflammatory biomarkers) were extracted from large-scale genome-wide association studies (n = 21 758-681 275). Univariable and multivariable MR analyses were performed to estimate the total and direct effects of MVPA and LST on T2DM. Methylation MR analysis was performed for MVPA in relation to diabetes. Results The odds ratio of T2DM was 0.70 (95% CI, 0.55-0.88; P = .002) per unit increase in the log-odds ratio of having MVPA and 1.45 (95% CI, 1.30-1.62; P = 7.62 x 10(-11)) per SD increase in genetically predicted LST. These associations attenuated in multivariable MR analyses adjusted for genetically predicted waist-to-hip ratio, body mass index, lean mass, and circulating C-reactive protein. The association between genetically predicted MVPA and T2DM attenuated after adjusting for genetically predicted fasting insulin levels. Two physical activity-related methylation biomarkers (cg17332422 in ADAMTS2 and cg09531019) were associated with the risk of T2DM (P < .05). Conclusion The study suggests causal associations of MVPA and LST with T2DM that appear to be mediated by obesity, lean mass, and chronic low-grade inflammation.