Insulin response to oral glucose and cardiometabolic disease: A Mendelian randomization study to assess potential causality

Abstract

<p> </p> <p>Mendelian randomization (MR) suggests post-prandial hyperinsulinemia (unadjusted for plasma glucose) increases body mass index (BMI) but its impact on cardiometabolic disease (CMD), a leading cause for mortality and morbidity in people with obesity is not established. Fat distribution i.e. increased centripetal and/or reduced femoro-gluteal adiposity is causally associated with and better predicts CMD than BMI. We therefore undertook bi-directional MR to assess the effect of corrected insulin response (CIR, insulin 30 minutes after a glucose challenge adjusted for plasma glucose) on BMI, waist-to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), high-density lipoprotein (HDL), liver fat, hypertension and CAD in people of European descent.</p> <p>Inverse variance weighted MR suggests a potential causal association between increased CIR and increased BMI (b= 0.048±0.02, p=0.03), increased leg fat (b=0.029±0.012, p=0.01), reduced T2D (b=-0.73±0.15, p=6x10-7, OR 0.48 (0.36-0.64), reduced TG (b=-0.07±0.02, p=0.003) and increased HDL (b=0.04±0.01, p=0.006) with some evidence of horizontal pleiotropy. CIR had neutral effects on WHR (b=0.009±0.02, p=0.69), liver fat (b=-0.08±0.04, p=0.06), hypertension (b=-0.001±0.004, p=0.7, odds ratio (OR) (95% confidence interval (CI)) OR 1.00 (0.99-1.01) and coronary artery disease (b=-0.002±0.002, p=0.48, OR 0.99 (0.81-1.21). T2D decreased CIR (b-0.22±0.04, p=1.3x10-7), with no evidence that BMI, TG, HDL, liver fat, hypertension and CAD modulate CIR. </p> <p>In conclusion, we did not find evidence that increased CIR increases CMD. It might increase BMI with favorable fat distribution, reduce T2D and improve lipids.</p>