189-LB: Using Genetics to Separate Childhood from Adult BMI Shows That Higher Childhood BMI Has No Direct Effect on Reduced Insulin Secretion or Sensitivity in Later Life

Abstract

Higher BMI during childhood is associated with an increased likelihood of remaining overweight later in life, leading to higher risk of developing type 2 diabetes (T2D). Using a Mendelian randomisation approach, a recent study found no evidence that childhood BMI has a direct causal effect on T2D. However, the extent to which high BMI in childhood directly alters insulin secretion and sensitivity in later life requires further investigation. We aimed to use genetic variants associated with differential effects on childhood and adult BMI to test their separate effects on insulin secretion and insulin sensitivity. We first generated a measure of childhood BMI aged 10 using self-reported categories in the UK Biobank, which we approximated to a normal distribution. We then performed separate genome wide association studies (GWAS) of childhood and adult BMI. This approach increased the number of genetic instruments by a factor of two as compared to previous methods. We used a multivariable Mendelian Randomisation approach, with childhood and adult BMI as exposure variables, and 5 measures of insulin secretion and insulin sensitivity in nondiabetic adults from previous GWAS studies as outcome variables. We found no evidence (at p<0.05) that higher BMI in childhood has a direct adverse effect on type 2 diabetes (OR 0.94, 95%CI 0.82-1.08), fasting insulin (OR 1.00, 0.95 - 1.05), insulin sensitivity (OR 1.11, 0.97-1.27) or sensitivity-index adjusted acute insulin response (OR 1.11, 0.88-1.42) in adults. There was some evidence of a protective effect, with higher childhood BMI associated with lower fasting glucose (OR 0.96, 0.93 - 1.00) and insulin secretion (OR 1.30, 1.04 - 1.63). Crucially, our results are consistent with no adverse direct effect of higher childhood BMI on adult type 2 diabetes, insulin secretion or sensitivity. Disclosure G. Hawkes: None. T. G. Richardson: None. G. M. Power: None. G. Davey smith: None. T. M. Frayling: None. Funding Innovative Medicines Initiative 2 Joint Undertaking (875534)