Early neonatal death in mice homozygous for a null allele of the insulin receptor gene

Accili, Domenico; Drago, John; Lee, Eric J.; Johnson, Mark D.; Cool, Martha H.; Salvatore, Paola; Asico, Laureano D.; José, Pedro A.; Taylor, Simeon I.; Westphal, Heiner

doi:10.1038/ng0196-106

Cited by 542 publications

(372 citation statements)

References 26 publications

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“…Mice bearing a null allele of the IR have been described previously [5]. A rabbit polyclonal antiserum against the IR b-subunit was used for immunohistochemistry [5].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 1998

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Insulin receptors (IRs) mediate insulin action upon target cells [1]. Disorders of IR function are a well established, albeit rare, cause of insulin resistance and diabetes mellitus [2±4]. In mice, targeted ablation of IR expression results in lethal diabetic ketoacidosis [5±7]. Unlike children with homozygous nonsense mutations of the IR gene, IR ±/± mice do not develop substantial growth retardation, fasting hypoglycaemia, or signs of hyperandrogenism.The lack of gross growth retardation in IR ±/± mice is an unexpected finding. To understand better the causes of this apparent discrepancy between the human paradigm and the mouse model, we have recently performed genetic crosses of IR ±/± mice with mice lacking insulin-like growth factor-1 (IGF-1) receptors (IGF-1Rs) and . The results of these experiments indicate that IRs do indeed affect embryonic growth. The growth-promoting actions of IRs occur in response to IGF-2, rather than insulin, binding. The interaction between IRs and IGF-2 plays an important role during the last phase of mouse gestation. Based on these data, we have suggested that the lack of a growth-retarded phenotype in IR ±/± mice may be due to the shorter duration of mouse gestation Diabetologia (1998) 41: 171±177

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“…Mice bearing a null allele of the IR have been described previously [5]. A rabbit polyclonal antiserum against the IR b-subunit was used for immunohistochemistry [5].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 1998

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“…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.…”

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confidence: 99%

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

et al. 2002

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Aims/hypothesis. Insulin receptor null mutant mice develop severe diabetes, ketoacidosis and liver steatosis and die within 1 week after birth. Since the liver plays an essential role in the control of glucose homeostasis, we examined in this work whether the metabolic disorders of insulin receptor-deficient mice could be improved upon restoration of hepatic glucose metabolism by transgenic constitutive overexpression of glucokinase selectively in the liver. Methods. We first generated transgenic mice overexpressing rat glucokinase cDNA under control of the liver-specific phenylalanine hydroxylase gene promoter. These transgenic mice were crossed with heterozygous insulin-receptor-null mutants to produce homozygous insulin-receptor-null mice overexpressing glucokinase in the liver. Results. The transgenic mice overexpressing glucokinase in the liver showed improved glucose tolerance and were mildly hypoglycaemic and hyperlipidaemic under starved conditions. The introduction of the glucokinase transgene in insulin receptor null mice did not prevent the development of glycosuria. However, ketoacidosis was delayed by more than 1 week and survival was prolonged to 10 to 16 days in 16% of the pups. In these longer surviving pups, serum glucose and triglyceride concentrations were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with the pups which had developed strong ketoacidosis and died earlier.Conclusions/interpretation. These results show that overexpression of hepatic glucokinase can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice. This shows the importance of improving hepatic function in diabetes and must revive interest in enhancement of glucokinase activity as a therapeutic strategy for the treatment of diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1292[Diabetologia ( -1297

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“…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].…”

Section: Insulin Treatment In Type 1 Diabetes Mellitus and Bone Fracturementioning

confidence: 99%

Determining the Role of Sost and Sostdc1 During Fracture Healing

Yee¹

2016

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Early neonatal death in mice homozygous for a null allele of the insulin receptor gene

Cited by 542 publications

References 26 publications

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

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

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

Determining the Role of Sost and Sostdc1 During Fracture Healing

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