Disturbances of growth hormone-insulin-like growth factor axis and response to growth hormone in acidosis

Abstract

Severe chronic metabolic acidosis (CMA) in rats is associated with poor food intake and downregulation of growth hormone (GH), insulin-like growth factors (IGFs), and liver receptors; the administration of recombinant GH (rGH) fails to improve the growth failure. In mice with carbonic anhydrase II deficiency (CAD), a model of moderate CMA with food intake close to normal, we studied serum levels of GH, IGFs, and IGF-binding proteins, and the growth response to rGH. CAD was associated with low serum levels of GH in males. Randomized administration of rGH from ∼5 to ∼12 wk to CAD mice improved food efficiency and increased serum IGF-I levels, final length, and weight compared with placebo without affecting blood pH. Although administration of rGH also increased linear growth in healthy animals, the effect was less than that in CAD mice and was only observed when started before 6 wk of life. Thus growth failure in CAD mice is associated with a decrease in GH secretion in males but not in females. Long-term administration of rGH increases linear growth in CAD mice despite persistent CMA.

Mechanism of STAT3 Activation by Insulin-like Growth Factor I Receptor

“…In the current protocol, each mouse was injected with 200 l of saline or a 10ϫ physiological concentration of IGF-I (2 g/ml) through the tail vein, which presumably would be diluted to the approximately physiological concentration in vivo. The physiological concentration of IGF-I in the mouse is ϳ200 ng/ml (47). Under similar stimulation with insulin, no phosphorylation of STAT3 was detected in spleen or kidney; therefore, the observed STAT3 activation by IGF-I was unlikely due to cross-activation of the insulin receptor.…”

Time course of the response to recombinant growth hormone in acidotic mice

“…The effect of GH on growth in CAD mice was observed without correction of acidosis [3]. In comparison, GH increased length in healthy animals by 2.81 SD (CI 1.67-3.95), or half that in CAD animals.…”

“…In comparison, GH increased length in healthy animals by 2.81 SD (CI 1.67-3.95), or half that in CAD animals. Analysis of variance showed that serum IGF-1 levels at 12 weeks of life were lower in CAD mice than in healthy animals (F=17, P<0.001) and that GH administration increased serum IGF-I levels more in CAD mice than in healthy animals (significant interaction, F=7.8, P=0.007) [3].…”

“…In contrast, in adult mice with congenital carbonic anhydrase II deficiency (CAD) growth failure is associated with moderate chronic metabolic or mixed acidosis [2,3,4] and adequate food intake [83±6% (mean±SEM) that in age-matched adult controls] [3]. In adult mice, CAD is associated with low secretion of GH in males and with normal serum levels of insulin-like growth factors (IGF) and IGF-binding proteins in both sexes [3].…”

“…In CAD mice a 7-week (range 4-9 weeks) randomized course of GH increased by 5.61 standard deviations (SD) [95% confidence interval (CI) 2.98-8.24, P<0.001) the final length standardized using the growth curve in genetically normal, healthy mice [3]. The effect of GH on growth in CAD mice was observed without correction of acidosis [3].…”