Wang T, Ma X, Tang T, Jin L, Peng D, Zhang R, Chen M, Yan J, Wang S, Yan D, He Z, Jiang F, Cheng X, Bao Y, Liu Z, Hu C, Jia W
Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Int J Obes (Lond). 2016 Nov;40(11):1736-1741. doi: 10.1038/ijo.2016.155. Epub 2016 Aug 29.
BACKGROUND/OBJECTIVES: Clinical heterogeneity exists in overall obesity and obesity in terms of susceptibility to type 2 diabetes, but the relationship is vulnerable to be confounded by traditional risk factors in epidemiological studies. We aimed to characterize the impact of obesity in insulin secretion and sensitivity by using Mendelian randomization (MR) approach with genetic variants.
SUBJECTS/METHODS: We first constructed two genetic risk scores based on 38 established loci for body mass index (BMI; a surrogate of overall obesity) and 13 waist-to-hip ratio (WHR; a surrogate of central obesity) to assess the causal effects of BMI and WHR on several glycaemic-related traits in 2884 community-based Han Chinese individuals.
Both of BMI and WHR were observationally correlated with insulin secretion and sensitivity indices. The MR analysis demonstrated that a genetically determined 1 s.d. (3.35 kg m) higher BMI caused a unit of 178.18 pmol l higher Stumvoll first-phase and 35.52 pmol l higher Stumvoll second-phase insulin secretion (P=0.001 and 0.002, respectively), which were even independent of central obesity (P=0.019 and 0.039, respectively). In contrast, a genetically determined 1 s.d. higher WHR (a change of 0.002 in WHR) caused a unit of 1.21 higher homeostasis model assessment of insulin resistance and 18.40 lower Gutt index (representing the insulin sensitivity) (P=0.048 and 0.028, respectively). No substantial heterogeneity existed between the observed associations and the genetic estimated associations (P for difference >0.05).
We provide new causal evidence that the impact of obesity on insulin secretion and sensitivity could vary between overall obesity and central obesity in Han Chinese populations and also identify the extent to which overall obesity affects compensatory insulin secretion and central obesity inversely links to insulin sensitivity.
背景/目的：总体肥胖和肥胖在2型糖尿病易感性方面存在临床异质性，但在流行病学研究中，这种关系容易受到传统危险因素的混淆。我们旨在通过使用带有基因变异的孟德尔随机化（MR）方法来描述肥胖对胰岛素分泌和敏感性的影响。
受试者/方法：我们首先基于38个已确定的体重指数（BMI；总体肥胖的替代指标）位点和13个腰臀比（WHR；中心性肥胖的替代指标）构建了两个遗传风险评分，以评估BMI和WHR对2884名社区汉族个体中几种血糖相关性状的因果效应。
BMI和WHR在观察上均与胰岛素分泌和敏感性指标相关。MR分析表明，遗传决定的BMI每增加1个标准差（3.35kg/m²），导致Stumvoll第一相胰岛素分泌增加178.18pmol/L，Stumvoll第二相胰岛素分泌增加35.52pmol/L（P分别为0.001和0.002），且这些结果独立于中心性肥胖（P分别为0.019和0.039）。相比之下，遗传决定的WHR每增加1个标准差（WHR变化0.002），导致胰岛素抵抗稳态模型评估增加1.21，Gutt指数（代表胰岛素敏感性）降低18.40（P分别为0.048和0.028）。观察到的关联与遗传估计的关联之间不存在实质性异质性（差异P>0.05）。
我们提供了新的因果证据，表明在汉族人群中，肥胖对胰岛素分泌和敏感性的影响在总体肥胖和中心性肥胖之间可能有所不同，同时还确定了总体肥胖影响代偿性胰岛素分泌的程度以及中心性肥胖与胰岛素敏感性呈负相关的程度。
