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=6×10-7, 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=1.3×10-7), 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.

中文翻译：

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胰岛素对口服葡萄糖和心脏代谢疾病的反应：评估潜在因果关系的孟德尔随机研究

孟德尔随机化 (MR) 表明餐后高胰岛素血症（未经血糖调整）会增加体重指数 (BMI)，但其对心脏代谢疾病 (CMD) 的影响尚未确定，心脏代谢疾病是肥胖人群死亡和发病的主要原因。脂肪分布，即增加的向心性和/或减少的股臀脂肪与 CMD 有因果关系，并且比 BMI 更能预测 CMD。因此，我们进行了双向 MR 来评估校正后的胰岛素反应（CIR，葡萄糖激发后 30 分钟胰岛素）对 BMI、腰臀比 (WHR)、腿部脂肪、2 型糖尿病的影响。 T2D)、甘油三酯 (TG)、高密度脂蛋白 (HDL)、肝脂肪、高血压和欧洲血统人群的 CAD。