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

Determining how high body-mass index (BMI) at different time points influences the risk of developing type two diabetes (T2D), and affects insulin secretion and insulin sensitivity, is critical. 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 high adulthood BMI on the risk of T2D and insulin related phenotypes using Mendelian randomisation and studies of T2D, and oral and intravenous measures of insulin secretion and sensitivity. We found that a 1.s.d. (= 1.97kg/m2) higher childhood BMI, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including an increased insulin sensitivity index ({beta} = 0.15 [0.067, 0.225], p = 2.79x10-4), and reduced fasting glucose ({beta} = -0.053 [-0.089, -0.017], p = 4.31x10-3). There was however little to no evidence of a direct protective effect on T2D (OR = 0.94 [0.85 - 1.04], p = 0.228), independently of genetic liability to adulthood BMI. Our results thus cumulatively 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 in biological pathway of these effects, and the limitations of this type of study. Research in ContextO_LIHigh BMI in adulthood is associated with higher risk of type two diabetes, coupled with lower insulin sensitivity and secretion. C_LIO_LIRichardson et al [2020] used genetics to show that high BMI in childhood does not appear to increase the risk of type diabetes independently from its effect on adult BMI. C_LIO_LIWe asked: does high childhood BMI affect insulin related traits such as fasting glucose and insulin sensitivity, independently of adulthood BMI? C_LIO_LIWe used genetics to show that high childhood BMI has a protective effect on seven insulin sensitivity and secretion traits, including fasting glucose and measures of insulin sensitivity and secretion, independently of adulthood BMI. C_LIO_LIOur work has the potential to turn conventional understanding on its head - high BMI in childhood improves insulin sensitivity (when adjusting for knock on effects to high adult BMI) and opens up important questions about plasticity in childhood and compensatory mechanisms. C_LI