The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting.
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.
Yakar
Shoshana
S
Diabetes Branch, National Institutes of Health, MSC 1758, Bethesda, MD 20892-1758, USA.
Kim
Hyunsook
H
Zhao
Hong
H
Toyoshima
Yuka
Y
Pennisi
Patricia
P
Gavrilova
Oksana
O
Leroith
Derek
D
D000818:Animals; D018390:Gene Targeting; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*
D018970:Insulin-Like Growth Factor Binding Protein 1; D013006:Growth Hormone; D017526:Receptor, IGF Type 1