GROWTH-PROMOTING EFFECTS OF GROWTH-HORMONE AND IGF-I ARE ADDITIVE IN EXPERIMENTAL UREMIA

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 wheth er the growth promoting effects of GH and IGF-I are additive. In femal e 150 g uremic (subtotal nephrectomy, NX) Sprague-Dawley rats, both rh GH in doses from 2 x 1.25 to 2 x 10 IU/kg bid s.c. and rhIGF-I in dose s from 2 x 0.5 to 2 x 4.0 mg/kg bid s.c. caused a dose-dependent incre ase in weight gain and length gain. However, endogenous production of GH was suppressed by both agents. Peptide hormone treatment did not af fect cumulative food intake, but significantly increased food efficien cy ratio (weight gain/food intake). Concomitant s.c. treatment with ma ximally 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 (GO) animals during the observation period of 12 days . Cumulative length gain was 3.2 +/- 0.5 cm in solvent-treated NX-anim als, 4.1 +/- 0.5 cm with rhGH (+ 28% above solvent), 4.2 +/- 0.6 cm wi th 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 w ith rhGH (+ 106% above solvent), 0.23 +/- 0.02 with rhIGF-I (+ 44%), a nd 0.38 +/- 0.02 with both peptides (+ 138%). Histomorphometric analys is and measurements of length gain by fluorescence microscopy in the u pper 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 wit hin one to two hours after injection. The effect was most pronounced d uring the first treatment day and declined thereafter. Concomitant tre atment with rhGH attenuated the glucose lowering effect of rhIGF-I (gl ucose 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 con cluded that: (i) IGF-I is able to stimulate growth in NX animals but s uppresses endogenous GH production in the long run; (ii) the concomita nt treatment with IGF-I and GH has additive effects on growth; and (ii i) concomitant treatment with rhGH prevents hypoglycemia that is noted with rhIGP-I alone.