Overall and central obesity with insulin sensitivity and secretion in a Han Chinese population: A mendelian randomization analysis.

BACKGROUND/OBJECTIVES: Clinical heterogeneity exists in overall obesity and central obesity in terms of susceptibility to type 2 diabetes (T2D), but the relationship is vulnerable to be confounded by traditional risk factors in epidemiology 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 firstly constructed two genetic risk scores (GRSs) 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.

RESULTS: Both of BMI and WHR were observationally correlated with insulin secretion and sensitivity indices. The MR analysis demonstrated that a genetically determined one standard deviation (s.d., 3.35 kg/m(2)) higher BMI caused a unit of 178.18 pmol/l higher Stumvoll 1st phase and 35.52 pmol/l higher Stumvoll 2nd 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 (the change of 0.002 in WHR) caused a unit of 1.21 higher homeostasis model assessments of insulin resistance (HOMA-IR) 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).

CONCLUSIONS: 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.International Journal of Obesity accepted article preview online, 29 August 2016. doi:10.1038/ijo.2016.155.