Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality.
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.
Joshi
R L
RL
Institut Cochin de Génétique Moléculaire, INSERM U257, Paris, France.
Lamothe
B
B
Cordonnier
N
N
Mesbah
K
K
Monthioux
E
E
Jami
J
J
Bucchini
D
D
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
D017931:DNA Primers; D011972:Receptor, Insulin; D005947:Glucose