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

Nature. 1994 Nov 10;372(6502):182-6. doi: 10.1038/372182a0.


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. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase which may be involved in the translocation of glucose transporters and the abundant src homology protein (ASH)/Grb2 which may be involved in activation of p21ras and MAP kinase cascade. IRS-1 also has binding sites for Syp and Nck and other src homology 2 (SH2) signalling molecules. 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 existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.

MeSH terms

  • Animals
  • Base Sequence
  • Blood Glucose / metabolism
  • Female
  • Fetal Growth Retardation / physiopathology
  • Growth / physiology*
  • Growth Disorders / physiopathology
  • Heterozygote
  • Homozygote
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Insulin-Like Growth Factor I / physiology
  • Insulin-Like Growth Factor II / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Molecular Sequence Data
  • Phosphoproteins / deficiency
  • Phosphoproteins / physiology*
  • Receptor, Insulin / physiology
  • Signal Transduction / physiology*


  • Blood Glucose
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Receptor, Insulin