Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia

Abstract

Exogenous growth hormone (GH) stimulates the endogenous production of IGF-I and improves growth in uremia. We investigated whether exogenous IGF-I is also able to improve uremic growth failure in rats and whether the growth promoting effects of GH and IGF-I are additive. In female 150 g uremic (subtotal nephrectomy, NX) Sprague-Dawley rats, both rhGH in doses from 2 X 1.25 to 2 X 10 IU/kg bid s.c. and rhIGF-I in doses from 2 X 0.5 to 2 X 4.0 mg/kg bid s.c. caused a dose-dependent increase in weight gain and length gain. However, endogenous production of GH was suppressed by both agents. Peptide hormone treatment did not affect cumulative food intake, but significantly increased food efficiency ratio (weight gain/food intake). Concomitant s.c. treatment with maximally effective doses of rhGH (12 X 5 IU/kg bid) and of rhIGF-I (2 X 2 mg/kg bid) resulted in additive growth promoting effects in NX and pair-fed control (CO) animals during the observation period of 12 days. Cumulative length gain was 3.2 +/- 0.5 cm in solvent-treated NX-animals, 4.1 +/- 0.5 cm with rhGH (+ 28% above solvent), 4.2 +/- 0.6 cm with rhIGF-I (+ 31%) and 4.9 +/- 0.5 cm with both peptides (+ 53%). The food efficiency ratio was 0.16 +/- 0.05 in solvent NX, 0.33 +/- 0.04 with rhGH (+ 106% above solvent), 0.23 +/- 0.02 with rhIGF-I (+ 44%), and 0.38 +/- 0.02 with both peptides (+ 138%). Histomorphometric analysis and measurements of length gain by fluorescence microscopy in the upper tibial metaphysis confirmed the growth promoting effects of both peptide hormones. The serum concentrations of IGF binding protein (BP)-4 (Western ligand blotting analysis) and of IGFBP-2 (immunoblot) were increased in uremic animals whereas IGFBP-3 was unchanged. Treatment with IGF-I and/or rhGH increased serum concentration of IGF-I but did not change the IGFBP pattern. rhIGF-I lowered blood glucose levels within one to two hours after injection. The effect was most pronounced during the first treatment day and declined thereafter. Concomitant treatment with rhGH attenuated the glucose lowering effect of rhIGF-I (glucose serum concentration at day one: 120 +/- 11 mg% in solvent NX, 50 +/- 21 mg% with rhIGF-I, 80 +/- 24 mg% with both peptides). It is concluded that: (i) IGF-I is able to stimulate growth in NX animals but suppresses endogenous GH production in the long run; (ii) the concomitant treatment with IGF-I and GH has additive effects on growth; and (iii) concomitant treatment with rhGH prevents hypoglycemia that is noted with rhIGF-I alone.