Resistance to growth hormone and insulin-like growth factor-I in acidotic rats.
Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean+/-SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26+/-2 vs. 49+/-6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41+/-3 vs. 104+/-10 ADU) transcripts and low serum GHBP (25+/-1 vs. 32+/-1 ng/ml) and IGF-I (279+/-50 vs. 366+/-6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
Ordóñez
F A
FA
Hospital Central de Asturias and School of Medicine, University of Oviedo, Spain.
Santos
F
F
Martínez
V
V
García
E
E
Fernández
P
P
Rodríguez
J
J
Fernández
M
M
Alvarez
J
J
Ferrando
S
S
D000136:Acid-Base Equilibrium / Q000187:drug effects / Q000502:physiology*; D000138:Acidosis / Q000503:physiopathology*; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002352:Carrier Proteins / Q000097:blood; D005260:Female; D006128:Growth / Q000187:drug effects; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D002352:Carrier Proteins; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C051815:somatotropin-binding protein