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

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.

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. 

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.