Role of insulin receptors and IGF receptors in growth and development.

Observations in targeted mouse mutants and patients with genetic abnormalities grant insight into the various and distinct roles of insulin-like growth factor receptors (IGF-Rs) and insulin receptors (IRs) during early development. While IGF-1Rs (mediating both IGF-1 and IGF-2 actions) are important for embryonic and fetal growth, IRs (mediating IGF-2 rather than insulin action) play a minor role. However, it is an oversimplification to conclude that IGF-1Rs mediate growth and IRs mediate metabolic responses. Mice lacking both IRs and IGF-1Rs are more severely growth retarded than mice lacking either receptor alone. The phenotype of combined deficiency of IRs and IGF-1Rs is similar to the phenotype caused by the absence of IGF-1 and IGF-2. This provides genetic proof that these two receptors account for the entirety of the growth promoting effects of IGF-1 and IGF-2. There is little evidence that hybrid insulin/IGF-1 receptors promote embryonic growth to a significant degree. The clinical presentation regarding severity of growth retardation and metabolic disturbances observed in animal models versus in humans may differ greatly and the reasons will be reviewed in detail.