The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting |
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Authors: | Shoshana Yakar Hyunsook Kim Hong Zhao Yuka Toyoshima Patricia Pennisi Oksana Gavrilova Derek LeRoith |
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Affiliation: | (1) Diabetes Branch, National Institutes of Health, MSC 1758, Bethesda, MD 20892–1758, USA;(2) Diabetes Branch, National Institutes of Health, Room 8D12, Building 10, MSC 1758, Bethesda, MD 20892–1758, USA |
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Abstract: | We have created a liver-specific igf1 gene-deletion mouse model (LID) with markedly reduced circulating IGF-I levels. They demonstrate that while they have normal growth and development they develop insulin resistance secondary to the elevation of circulating growth hormone. When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation. In a separate transgenic mouse we created a model of severe insulin resistance and type 2 diabetes by the overexpression of a dominant-negative IGF-I receptor in skeletal muscle. In this model we show that lipotoxicity plays a major role in the progression of the disease and is affected by treatment with a fibrate, which reverses the insulin resistance and diabetic state. These models are therefore very useful in studying human physiology and disease states.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany |
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Keywords: | Insulin-like growth factor-1 Insulin-like growth factor-1 receptor Liver-specific igf1 deletion Transgenic overexpression Type 2 diabetes Mouse model Lipotoxicity |
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