Insulin Resistance and Growth Retardation in Mice Lacking Insulin Receptor Substrate‐1 and Identification of Insulin Receptor Substrate‐2

To clarify the physiological roles of insulin receptor substrate‐1 (IRS‐1) in vivo, we made mice with a targeted disruption of the IRS‐1 gene locus. Mice homozygous for targeted disruption of the IRS‐1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose‐lowering effects of insulin, insulin‐like growth factor‐1 (IGF‐1) and factor‐2 (IGF‐2). These data suggest the existence of both IRS‐1‐dependent and IRS·1·independent pathways for signal transduction of insulin and IGFs. Moreover, we identified tyrosine phosphorylation of a 190‐kDa protein (pp190) as a novel substrate (IRS‐2) for insulin receptor kinase in livers of IRS‐1 deficient mice which can bind both P13‐kinase and Ash/Grb2.