TARGETED DISRUPTION OF THE INSULIN-RECEPTOR GENE IN THE MOUSE RESULTSIN NEONATAL LETHALITY

Targeted disruption of the insulin receptor gene (Insr) in the mouse w as achieved using the homologous recombination approach, Insr(+/-) mic e were normal as shown by glucose tolerance tests, Normal Insr(-/-) pu ps were born at expected rates, indicating that Insr can be dispensabl e for intrauterine development, growth and metabolism, However, they r apidly developed diabetic ketoacidosis accompanied by a marked post-na tal growth retardation (up to 30-40% of littermate size), skeletal mus cle hypotrophy and fatty infiltration of the liver and they died withi n 7 days after birth. Total absence of the insulin receptor (IR), demo nstrated in the homozygous mutant mice, also resulted in other metabol ic disorders: plasma triglyceride level could increase 6-fold and hepa tic 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 similar to 300 m u U/ml, as compared with similar to 25 mu U/ml for normal littermates. However, this plasma insulin level was still unexpectedly low when co mpared with human infants with leprechaunism, who lack IR but who coul d have extremely high insulinemia (up to >4000 mu U/ml), The pathogene sis resulting from a null mutation in Insr is discussed.