Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood

Abstract

Aims/hypothesis Determining how high BMI at different time points influences the risk of developing type 2 diabetes and

affects insulin secretion and insulin sensitivity is critical.

Methods By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had

larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were

then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk

of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation. We performed two-sample MR using

external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity.

Results We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for

the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin

sensitivity and secretion, including increased insulin sensitivity index (β=0.15; 95% CI 0.067, 0.225; p=2.79Å~10−4) and

reduced fasting glucose levels (β=−0.053; 95% CI −0.089, −0.017; p=4.31Å~10−3). However, there was little to no evidence

of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to

adulthood BMI.

Conclusions/interpretation Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion

and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead

to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects

and the limitations of this type of study