Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study.

Hua Xu,Chuandi Jin,Qingbo Guan

doi:10.3389/fgene.2020.00603

Abstract

Overall and abdominal obesity were significantly associated with insulin resistance and type 2 diabetes mellitus (T2DM) risk in observational studies, though these associations cannot avoid the bias induced by confounding effects and reverse causation. This study aimed to test whether these associations are causal, and it compared the causal effects of overall and abdominal obesity on T2DM risk and glycemic traits by using a two-sample Mendelian randomization (MR) design. Based on summary-level statistics from genome-wide association studies, the instrumental variables for body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) were extracted, and the horizontal pleiotropy was analyzed using MR–Egger regression and the MR–pleiotropy residual sum and outlier (PRESSO) method. Thereafter, by using the conventional MR method, the inverse-variance weighted method was applied to assess the causal effect of BMI, WHR, and WHRadjBMI on T2DM risk, Homeostatic model assessment of insulin resistance (HOMA-IR), fasting insulin, fasting glucose, and Hemoglobin A1c (HbA1c). A series of sensitivity analyses, including the multivariable MR (diastolic blood pressure, systolic blood pressure, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol as covariates), MR–Egger regression, weighted median, MR–PRESSO, and leave-one-out method, were conducted to test the robustness of the results from the conventional MR. Despite the existence of horizontal pleiotropy, consistent results were found in the conventional MR results and sensitivity analyses, except for the association between BMI and fasting glucose, and WHRadjBMI and fasting glucose. Each one standard deviation higher BMI was associated with an increased T2DM risk [odds ratio (OR): 2.741; 95% confidence interval (CI): 2.421–3.104], higher HbA1c [1.054; 1.04–1.068], fasting insulin [1.202; 1.173–1.231], and HOMA-IR [1.221; 1.187–1.255], similar to findings for causal effect of WHRadjBMI on T2DM risk [1.993; 1.704–2.33], HbA1c [1.061; 1.042–1.08], fasting insulin [1.102; 1.068–1.136], and HOMA-IR [1.127; 1.088–1.167]. Both BMI (P = 0.546) and WHRadjBMI (P = 0.443) were unassociated with fasting glucose in the multivariable MR analysis. In conclusion, overall and abdominal obesity have causal effects on T2DM risk and insulin resistance but no causal effect on fasting glucose. Individuals can substantially reduce their insulin resistance and T2DM risk through reduction of body fat mass and modification of body fat distribution.

Highlights

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia secondary to insulin resistance and pancreatic β-cell failure (Alejandro et al, 2015)
This study aimed to explore the causal effect of waist-to-hip ratio (WHR), body mass index (BMI), and WHRadjBMI on the risk of T2DM and glycemic traits (HOMA-IR, fasting insulin, fasting glucose, and Hemoglobin A1c (HbA1c)) in an European population, and used diastolic blood pressure (DBP), systolic blood pressure (SBP), HDL-C, and low-density lipoprotein cholesterol (LDL-C) as the covariates
The genomewide association study summary statistics datasets used in this study were obtained from Zenodo1 for WHR (Censin et al, 2019), BMI (Censin et al, 2019), and WHRadjBMI (Censin et al, 2019); the Program in Complex Trait Genomics2 for T2DM (Xue et al, 2018); MAGIC Consortium3 for HOMA-IR (Dupuis et al, 2010), fasting glucose (Manning et al, 2012), fasting insulin (Manning et al, 2012), and HbA1c (Wheeler et al, 2017); the

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia secondary to insulin resistance and pancreatic β-cell failure (Alejandro et al, 2015). Many observational epidemiologic studies, including case–control and cohort studies, have demonstrated that higher WHR and BMI are two important risk factors for developing T2DM (Vazquez et al, 2007; Lv et al, 2017). Cohort and cross-sectional studies (Wang et al, 2018; Benites-Zapata et al, 2019) demonstrated that BMI and WHR were associated with glycemic traits, including fasting insulin, Hemoglobin A1c (HbA1c), and insulin resistance [measured by Homeostatic model assessment of insulin resistance (HOMAIR)]. Longitudinal and cross-sectional studies have found an association between increased risk of T2DM and higher genetic predisposition to both BMI and WHRadjBMI in European and East Asian populations (Robiou-du-Pont et al, 2013; Zhu et al, 2014; Huang et al, 2015)

Objectives

Methods

Results

Conclusion