Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality

EMBO J. 1996 Apr 1;15(7):1542-7.


Targeted disruption of the insulin receptor gene (Insr) in the mouse was achieved using the homologous recombination approach. Insr+/- mice were normal as shown by glucose tolerance tests. Normal Insr-/- pups were born at expected rates, indicating that Insr can be dispensable for intrauterine development, growth and metabolism. However, they rapidly developed diabetic ketoacidosis accompanied by a marked post-natal growth retardation (up to 30-40% of littermate size), skeletal muscle hypotrophy and fatty infiltration of the liver and they died within 7 days after birth. Total absence of the insulin receptor (IR), demonstrated in the homozygous mutant mice, also resulted in other metabolic disorders: plasma triglyceride level could increase 6-fold and hepatic glycogen content could be five times less as compared with normal littermates. The very pronounced hyperglycemia in Insr-/- mice could result in an increased plasma insulin level of up to approximately 300 microU/ml, as compared with approximately 25 microU/ml for normal littermates. However, this plasma level was still unexpectedly low when compared with human infants with leprechaunism, who lack IR but who could have extremely high insulinemia (up to > 4000 microU/ml). The pathogenesis resulting from a null mutation in Insr is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Base Sequence
  • DNA Primers / genetics
  • Diabetic Ketoacidosis / etiology
  • Female
  • Gene Targeting*
  • Genes, Lethal
  • Glucose / metabolism
  • Heterozygote
  • Homozygote
  • Humans
  • Infant, Newborn
  • Mice
  • Molecular Sequence Data
  • Pregnancy
  • Receptor, Insulin / genetics*
  • Recombination, Genetic
  • Signal Transduction


  • DNA Primers
  • Receptor, Insulin
  • Glucose