Low birth weight has been reported to be associated with impaired insulin secretion and
insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between
birth weight and genetically determined defects in insulin secretion, we measured the
birth weights of neonates derived from crosses of male pancreatic beta-cell type
glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring,
birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller
birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [
n = 30] vs. 1.63+/-0.03 [
n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair
insulin response to
glucose and alter intrauterine growth as well as
glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced
birth weights and has provided direct evidence for a link between
insulin and fetal growth. Moreover,
birth weights were reduced in
insulin receptor substrate-1 knockout mice despite normal
insulin levels. Taken together, these results suggest that a genetically programmed
insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between
birth weight and susceptibility to
type 2 diabetes.