Cargando…

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

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 associat...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Hua, Jin, Chuandi, Guan, Qingbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343715/
https://www.ncbi.nlm.nih.gov/pubmed/32714368
http://dx.doi.org/10.3389/fgene.2020.00603
_version_ 1783555805127114752
author Xu, Hua
Jin, Chuandi
Guan, Qingbo
author_facet Xu, Hua
Jin, Chuandi
Guan, Qingbo
author_sort Xu, Hua
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7343715
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-73437152020-07-25 Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study Xu, Hua Jin, Chuandi Guan, Qingbo Front Genet Genetics 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. Frontiers Media S.A. 2020-07-02 /pmc/articles/PMC7343715/ /pubmed/32714368 http://dx.doi.org/10.3389/fgene.2020.00603 Text en Copyright © 2020 Xu, Jin and Guan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Xu, Hua
Jin, Chuandi
Guan, Qingbo
Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title_full Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title_fullStr Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title_full_unstemmed Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title_short Causal Effects of Overall and Abdominal Obesity on Insulin Resistance and the Risk of Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study
title_sort causal effects of overall and abdominal obesity on insulin resistance and the risk of type 2 diabetes mellitus: a two-sample mendelian randomization study
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343715/
https://www.ncbi.nlm.nih.gov/pubmed/32714368
http://dx.doi.org/10.3389/fgene.2020.00603
work_keys_str_mv AT xuhua causaleffectsofoverallandabdominalobesityoninsulinresistanceandtheriskoftype2diabetesmellitusatwosamplemendelianrandomizationstudy
AT jinchuandi causaleffectsofoverallandabdominalobesityoninsulinresistanceandtheriskoftype2diabetesmellitusatwosamplemendelianrandomizationstudy
AT guanqingbo causaleffectsofoverallandabdominalobesityoninsulinresistanceandtheriskoftype2diabetesmellitusatwosamplemendelianrandomizationstudy