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.