Fetal insulin affects birth weight, but the extent of this relationship has not been established in humans, nor whether it has any implications for postnatal growth. We sought to investigate this by studying birth size and postnatal growth in individuals with monogenic diseases which result in absent insulin secretion in utero. We studied birth size in individuals with a homozygous insulin gene (INS) mutation or pancreatic agenesis (n=64 for weight, n=17 for length) born after 31 weeks gestation and compared with international growth standards for gestational age and sex (SDS). Postnatal growth was studied in individuals with INS mutations. We analyzed serial measures of weight and length until the age of four years (n=10 and 9, respectively) and most recent available weight and height (n=16 and 15, respectively). In all individuals birth weight and length were low (median (IQR) SDS -3.11 (-3.53,-2.61) and -2.86 (-3.62,-1.90), respectively). Birth weight adjusted to 40 weeks gestation was 1711 g (95% CI 1601,1821 g) vs expected of 3320 g (Fig. 1), showing non-insulin-mediated growth represents 52% of normal birth weight at term. Catch-up growth was rapid with median (IQR) weight and length SDS -0.27 (-0.37,-0.17) and -0.30 (-1.33,0.002), respectively, at 12 months, and 0.02 (-0.35,0.78) and 0.00 (-0.34,0.21), respectively, at 24 months (Fig. 2). Most recent available weight and height SDS were 0.19 (-0.67,1.33) and -0.78 (-1.78,-0.19), respectively. Monogenic diseases resulting in absent fetal insulin have enabled us to answer fundamental questions about early growth in humans. Ultimately, fetal insulin accounts for half of birth weight at term and could be an important cause of fetal growth restriction that is characterised by rapid catch-up growth. Future studies investigating outcomes arising from low and high birth weight should determine differences in insulin and non-insulin-mediated fetal growth, and consider whether they might have different implications for pregnancy outcomes and long-term risk of disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)