Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

<b>Objective:</b> Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. <p> </p> <p><b>Research design and methods:</b> We used genetic variants associated (p < 5×10⁻⁸) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n=32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. </p> <p> </p> <p><b>Results:</b> Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio (OR) per one standard deviation (SD) higher exposure 2.16 [2.02 - 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume on risk of type 2 diabetes (1.27 [1.08,1.49] or 27% increased risk and 0.76 [0.62,0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes.</p> <p> </p> <p><b>Conclusions:</b> Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.</p> <p> </p>