Fetal insulin has long been considered an important contributor to birth weight in humans. Its effects on fetal growth are commonly observed in pregnancies affected by diabetes. Mothers with diabetes in pregnancy tend to have heavier babies because higher levels of maternal glucose reach the fetal pancreas and stimulate fetal insulin secretion. Fetal insulin-mediated growth mainly leads to fetal fat accretion, but it also promotes skeletal growth. Genetic studies have provided valuable insights into fetal insulin-mediated growth. Very low birth weights are observed in individuals who have rare variants in single genes that cause neonatal diabetes, suggesting that their reduced insulin secretion is present before birth. Common genetic variants that predispose to a higher risk of type 2 diabetes in adulthood tend to be associated with lower birth weight when inherited by the fetus. The same genetic variants in the mother raise offspring birth weight, consistent with their effect on raising glucose levels. It is assumed that these genetic variants affect fetal insulin levels. A scenario where genetically determined fetal insulin levels are clinically relevant to pregnancy relates to a genetic cause of diabetes called Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY). Inactivating heterozygous variants in the gene encoding glucokinase (GCK), the enzyme responsible for the rate-limiting step in glycolysis, raise fasting glucose and lower insulin secretion. GCK-MODY variants cause lower birth weight when inherited by the fetus from the father. If the mother and baby both have GCK-MODY, birth weight is normal. Higher birth weight is observed where the mother has GCK-MODY and their fetus has not inherited their GCK variant, akin to the situation observed in most diabetes pregnancies. Knowledge of fetal genotype in pregnancies where the mother has GCK-MODY would be useful, since insulin treatment of maternal hyperglycaemia is not recommended where the fetus has inherited a maternal GCK variant. This thesis aims to further extend the knowledge of fetal insulin-mediated growth. It will achieve this aim using clinically relevant studies that incorporate genetics into their methodology. Following an outline in Chapters 1 and 2 of the current knowledge of fetal insulin-mediated growth, our understanding of its genetic components, and the shared genotype of lower birth weight and higher risk of type 2 diabetes, I present five studies that address the aim of the thesis. In Chapter 3, I quantify the contribution of fetal insulin to birth weight in 64 individuals without fetal insulin due to a loss-of-function mutation in the insulin gene (INS), or a single-gene mutation causing pancreatic agenesis. I show that fetal insulin accounts for half of birth weight by term gestation. I study the postnatal growth of up to 10 individuals with an INS mutation to show that there is rapid catch-up growth once insulin is replaced. In Chapter 4, I compare the accuracy of two approaches to predict fetal genotype in pregnancies where the mother has GCK-MODY: non-invasive prenatal testing and a measurement of fetal abdominal circumference on ultrasound at 28 weeks’ gestation. I show that non-invasive prenatal testing is more accurate and could help with a more tailored approach to pregnancy management. In Chapter 5, I study the clinical features of three cases of GCK-MODY presenting with neonatal hyperglycaemia. I demonstrate that GCK-MODY is a rare, but benign cause of neonatal hyperglycaemia, and that normal or lower birth weight is not a consistent feature amongst the cases examined. In Chapter 6, I compare the effects of maternal fasting plasma glucose (FPG) with a genetic score containing common genetic variants that raise birth weight on newborn adiposity, measured by umbilical cord leptin levels. I observe that the genetic score has a greater impact on overall birth weight, but less of an impact on umbilical cord leptin compared with maternal FPG. Unlike maternal FPG, the genetic score is not strongly associated with umbilical cord insulin levels, which may explain its lesser relationship with adiposity at birth. In Chapter 7, I perform a multi-ancestry genome-wide association study (GWAS) of umbilical cord insulin and C-peptide measurements. I do not find any genome-wide significant variants associated with umbilical cord insulin and C-peptide, nor do I see enrichment of association in genetic variants known to be associated with glycaemic traits. However, there are consistent directional relationships pooled across the genetic variant groups of interest; genetic variants associated with lower insulin levels in the mother raise her offspring’s umbilical cord insulin levels, whereas the same genetic variants in the fetus lower their own umbilical cord insulin levels. The thesis is concluded in Chapter 8, including a commentary on the studies’ findings and implications, a summary of subsequent work, and a discussion of avenues for future research. The studies making up this thesis have made an important contribution to our understanding of the effects of fetal insulin on birth weight and early growth. The work emphasises the utility of studies incorporating genetics in helping to understand fundamental aspects of human fetal physiology and improving clinical care in pregnant patients and their families with monogenic diabetes.