Fetal/Maternal-Determined Birth Weight and Adulthood Type 2 Diabetes and Its Subtypes: A Mendelian Randomization Study

Background Lower birth weight (BW) might increase the risk of adulthood type 2 diabetes, but its associations with the highly heterogeneous type 2 diabetes subtypes remain to be studied. In addition, whether the associations between lower BW and adulthood type 2 diabetes risks depend on fetal or maternal effect is largely unknown.Methods In this study, we performed a two-sample Mendelian randomization analysis to study the associations between overall, fetal-determined, and maternal-determined BW and the risks of type 2 diabetes and its subtypes, namely mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), and severe insulin-resistant diabetes (SIRD).Results Lower BW was genetically associated with increased risks of type 2 diabetes (odds ratio [OR]: 1.86; 95% CI: 1.53, 2.26), MARD (OR: 2.15; 95% CI: 1.43, 3.23), MOD (OR: 1.75; 95% CI: 1.10, 2.77), SIDD (OR: 1.86; 95% CI: 1.11, 3.10), and SIRD (OR: 1.66; 95% CI: 1.06, 2.60). When examining the fetal-determined genetic effects independently, lower BW remained associated with type 2 diabetes and its subtypes, except for MOD. Using maternal-determined BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it raised offspring risks of type 2 diabetes.Conclusion Fetal-determined but not maternal-determined lower BW were associated with increased risks of adulthood type 2 diabetes and its subtypes. Our results underscored the importance of early targeted management among people with a low BW in the prevention of type 2 diabetes.