Postnatal growth responses to insulin-like growth factor I in insulin receptor substrate-1-deficient mice

Organ weight was compared in adult mice with deletion of one (IRS-1(-/+)) or both (IRS-1(-/-)) copies of the insulin receptor substrate-1 (IRS-1) gene and IRS-1(+/+) Littermates. IRS-1(-/+) mice showed modest reductions in weight of most organs in proportion to a decrease in body weight. IRS-1(-/-) mice showed major reductions in weight of heart, liver, and spleen that were directly proportional to a decrease in body weight. In IRS-1(-/-) mice, kidney and particularly small intestine and brain exhibited proportionately smaller weight reductions, and gastrocnemius muscle showed a proportionately greater weight reduction than the decrease in body weight. Growth deficits in IRS-1(-/-) mice could reflect impaired actions of multiple hormones or cytokines that activate IRS-1. To assess the requirement for IRS-1 in insulin-like growth factor I(EGF-I)-dependent postnatal growth, IRS-1(-/+) mice were cross-bred with mice that widely overexpress a human IGF-I transgene (IGF+) to generate IGF+ and wild-type mice on an IRS-1(+/+), IRS-1(-/+), and IRS-1(-/-) background. IGF-I overexpression increased body weight and weight of brain, small intestine, kidney, spleen, heart, and gastrocnemius muscle in IRS-1(+/+) mice. EGF-I overexpression could not completely reverse the body growth retardation in IRS-1(-/-) mice. Absolute or partial IRS-1 deficiency impaired IGF-1-induced body overgrowth more in females than in males. In males and females, IGF-I stimulated similar overgrowth of brain regardless of IRS-1 status, and intestine and spleen showed dose dependence on IRS-1 for IGF-1-induced growth. IGF-1-induced growth of gastrocnemius muscle had an absolute requirement for IRS-1. IGF-1-induced growth of kidney and heart was impaired by IRS-1 deficiency only in females. In vivo, therefore, most organs do not require IRS-1 for IGF-1-induced growth and can use alternate signaling molecules to mediate IGF-1 action. Other organs, such as gastrocnemius muscle, require IRS-1 for IGF-1-induced growth in vivo.