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.

Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis

“…Somewhat unexpectedly, Joshi et al [7] have reported that skin and pericapsular kidney fat are normally represented in a strain of IR ±/± mice. A major impediment to these experiments is the scarcity of fat tissue in newborn mice, in which it represents approximately 2 % of total body mass, unlike in humans, in whom it represents approximately 16 % [13].…”

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

“…The crucial role of IR in insulin action was confirmed by targeted disruption of the IR gene [2,3]. IRdeficient mice developed severe metabolic disorders soon after suckling, leading to diabetes mellitus, diabetic ketoacidosis (DKA) and liver steatosis, and died within 1 week after birth.…”

“…Production of mice with targeted disruption of the IR gene has been described [3]. The IR +/-mice were crossed with the L-GK transgenic line to generate IR +/-mice carrying the GK transgene.…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…Insulin knockout mice show no obvious developmental phenotypes but develop diabetes and die within 2 to 3 days of birth [31], while insulin receptor knockout mice are also postnatal lethal [31,32] making it difficult to understand insulin's role in bone metabolism. However, insulin has been suggested to be a bone anabolic agent [33] and does improve the low bone mass phenotype and fracture repair in both T1DM humans and rodents [34].…”