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 (IR S-1) in vivo, we made mice with a targeted disruption of the IRS-1 gen e locus. Mice homozygous for targeted disruption of the IRS-1 gene wer e born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, insul in-like growth factor-1 (IGF-1) and factor-2 (IGF-2). These data sugge st the existence of both IRS-1-dependent and IRS-1-independent pathway s for signal transduction of insulin and IGFs. Moreover, we identified tyrosine phosphorylation of a 190-kDa protein (pp190) as a novel subs trate (IRS-2) for insulin receptor kinase in livers of IRS-1 deficient mice which can bind both P13-kinase and Ash/Grb2.