title: Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality.
abstract: 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.
authors.affiliation: Institut Cochin de Génétique Moléculaire, INSERM U257, Paris, France.
authors.forename: R L
authors.initials: RL
authors.lastname: Joshi
authors.forename: B
authors.initials: B
authors.lastname: Lamothe
authors.forename: N
authors.initials: N
authors.lastname: Cordonnier
authors.forename: K
authors.initials: K
authors.lastname: Mesbah
authors.forename: E
authors.initials: E
authors.lastname: Monthioux
authors.forename: J
authors.initials: J
authors.lastname: Jami
authors.forename: D
authors.initials: D
authors.lastname: Bucchini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D016883:Diabetic Ketoacidosis / Q000209:etiology; D005260:Female; D018390:Gene Targeting; D005804:Genes, Lethal; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008969:Molecular Sequence Data; D011247:Pregnancy; D011972:Receptor, Insulin / Q000235:genetics*; D011995:Recombination, Genetic; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D011972:Receptor, Insulin; D005947:Glucose