INSULIN-RESISTANCE AND GROWTH-RETARDATION IN MICE LACKING INSULIN-RECEPTOR SUBSTRATE-1

INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent rela tive molecular mass of 160-190,000 (M(r), 160-190K) on SDS polyacrylam ide gel(1-3). Tyrosine-phosphorylated IRS-1 binds the 85K subunit of p hosphatidylinositol 3-kinase(4,5) which may be involved in the translo cation of glucose transporters(6,7) and the abundant src homology prot ein (ASH)/Grb2(8,9) which may be involved in activation of p21(ras) an d MAP kinase cascade(10). IRS-1 also has binding sites for Syp(11) and Nck(12) and other src homology 2 (SH2) signalling molecules. To clari fy the physiological roles of IRS-1 in vivo, we made mice with a targe ted disruption of the IRS-1 gene locus. Mice homozygous for targeted d isruption of the IRS-1 gene were born alive but were retarded in embry onal and postnatal growth. They also had resistance to the glucose-low ering effects of insulin, IGF-1 and IGF-2. These data suggest the exis tence of both IRS-1-dependent and IRS-1-independent pathways for signa l transduction of insulin and IGFs.