Growth promotion by insulin-like growth factor I in hypophysectomized and diabetic rats.
Two animal models, the hypophysectomized (hypox) and the streptozotocin-diabetic rat, both of which are GH-deficient, were used to study the effects of infused IGF I and its molecular size distribution in serum, and to investigate whether GH and IGF I act identically on growth plate chondrocyte maturation. In hypox rats. IGF I (300 microg/rat per day) stimulated body weight gain, total growth plate height and longitudinal growth rate, although less than GH (200 mU/rat per day), and mimicked the effect of GH at all stages of chondrocyte differentiation. including stem cells. Infused IGF I was nearly exclusively found in a < 100 kDa IGF binding protein (IGFBP) complex, whereas free IGF I was barely detectable. These findings argue against the 'dual effector theory' in vivo which postulates priming of the stem cells by GH before IGF I stimulates proliferation. They also suggest that IGF I bound to the < 100 kDa IGFBP complex is bioavailable for growth. In diabetic rats infused with 2.5 mg/rat per day of IGF I, body weight, tibial epiphyseal width and accumulated bone growth increased dramatically despite persisting hyperglycemia. Insulin infusion (2.5 U/rat per day), which nearly normalized elevated blood sugar values, raised endogenous IGF I serum levels and stimulated growth parameters to a similar extent as IGF I, in line with a similar distribution of the infused exogenous and the insulin-induced endogenous IGF I between the free and the < 100 kDa-bound form. Since GH secretion is inhibited in diabetic rats and the animals are resistant to GH action, these results, like those in hypox rats, demonstrate that IGF I can act on growth independently of GH. Because insulin restores GH secretion and the responsiveness of the liver to GH in diabetic rats, one may conclude that insulin acts on growth of diabetic rats mainly via restoration of the GH/IGF I axis.
Department of Internal Medicine, University Hospital, Zürich, Switzerland.
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D000818:Animals; D048429:Cell Size / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D006128:Growth / Q000187:drug effects*; D006132:Growth Plate / Q000166:cytology; D019382:Human Growth Hormone / Q000494:pharmacology; D007016:Hypophysectomy; D007328:Insulin / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I