Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1

Abstract

INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent relative molecular mass of 160–190,000 (M_r, 160–190K) on SDS polyacrylamide gel^1–3. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase^4,5 which may be involved in the translocation of glucose transporters^6,7 and the abundant src homology protein (ASH)/Grb2^8,9 which may be involved in activation of p2l^ras and MAP kinase cascade¹⁰. IRS-1 also has binding sites for Syp¹¹ and Nck¹² and other src homology 2 (SH2) signalling molecules¹⁰. To clarify the physiological roles of 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, IGF-1 and IGF-2. These data suggest the exis-tence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.