Overall and abdominal obesity with insulin sensitivity and secretion in a Han Chinese population: a Mendelian randomisation study

Abstract

BackgroundClinical heterogeneity exists in overall obesity and central obesity in terms of susceptibility to type 2 diabetes, but the relationship is susceptible to be confounded by traditional risk factors (eg, population admixture and lipid concentration patterns) in epidemiology studies. We aimed to characterise the causal role of obesity in insulin sensitivity and secretion by using a Mendelian randomisation approach with genetic variants for measuring overall and abdominal obesity. MethodsWe constructed two genetic risk scores on the basis of 38 established loci for BMI (a surrogate of overall obesity) and 13 established loci for waist-to-hip ratio (a surrogate of abdominal obesity) in east Asian populations to assess the effects of BMI and waist-to-hip ratio on several glycaemic-related traits in community-based Han Chinese individuals. Patients with cancer, severe disability, or severe psychiatric disturbances were excluded. Ethical approval was granted by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Informed patient consent was given by all participants. The causal relationships between two types of obesity and the indices of insulin secretion and sensitivity (eg, homeostasis model assessments of β-cell function and insulin resistance, Stumvoll first and second phase insulin secretion indices, and Gutt's insulin sensitivity index) were estimated with the framework of Mendelian randomisation analysis. FindingsBetween November, 2009 and February, 2012, we enrolled 2884 Han Chinese individuals aged between 34 years and 70 years. The mean BMI of the study participants was 24·42 (SD 3·35 kg/m2), and 46% of patients were men. Both BMI and waist-to-hip ratio were observationally correlated with insulin sensitivity and secretion indices. The Mendelian randomisation analysis showed that a genetically determined 1 SD (3·35 kg/m2) higher BMI caused a unit of 178·18 pmol/L higher Stumvoll first phase (95% CI 105·70–191·26, p=0·0012) and 35·52 pmol/L higher Stumvoll second phase insulin secretion (95% CI 20·00–91·74, p=0·0022), which were independent of abdominal obesity (p=0·019 in the Stumvoll first phase and p=0·039 in the Stumvoll second phase). By contrast, a genetically determined 1 SD higher waist-to-hip ratio (0·002 in waist-to-hip ratio) caused a unit of 1·21 higher homeostasis model assessments of insulin resistance (95% CI 0·01–2·41, p=0·048) and 18·40 lower Gutt insulin sensitivity index; 95% CI 1·91–35·02, p=0·028). No substantial heterogeneity existed between the observed association of BMI or waist-to-hip ratio with glycaemic-related traits and the association estimated by Mendelian randomisation analysis (pdifference>0·05). InterpretationOverall obesity might affect compensatory insulin secretion but abdominal obesity is inversely associated with insulin sensitivity in the Han Chinese population. Funding973 Program of China, programme from National Natural Science Foundation of China grants, The Shanghai Jiaotong Medical/Engineering Foundation, National Program for Support of Top-notch Young Professionals and grants from the State Key Laboratory of Medical Genomics, and Youth research project of Shanghai Municipal Health Bureau.