THE EFFECT OF INSULIN-LIKE GROWTH-FACTOR-I ON PROTEIN-METABOLISM AND HEPATIC RESPONSE TO ENDOTOXEMIA IN PARENTERALLY FED RATS

To determine the influence of insulin-like growth factor-1 (IGF-1) on nitrogen loss and hepatic response to critical illness, 34 male Spragu e-Dawley rats (190-230 g) were randomized to receive parenteral nutrit ion (PN) only (Ctrl), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), or PN plus LPS plus rh IGF-1 (IGF-1) at 3 mg/kg/day for 48 hr. Prior to randomization, all an imals underwent iv cannulation and 30 hr of adaptation to PN. All anim als received isocaloric and isonitrogenous PN (glucose 170 kcal/kg/day and nitrogen 1.1 g/kg/day) and were kept NPO except for water ad libi tum, [N-15]glycine was infused in all animals for determination of liv er fractional synthetic rate. Cumulative nitrogen balance during endot oxemia was significantly different from each other (+72 +/- 42, -217 /- 131, -114 +/- 137 mg/kg/48 hr for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001). Endotoxin significantly increased the urinary 3-methylhistidine/creatinine ratio (0.24 +/- 0.05, 0.55 +/- 0 .12, 0.48 +/- 0.17 for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001); however, IGF-1 did not significantly reduce the rat io. Endotoxin induced a significant increase in liver fractional synth etic rate (29 +/- 8, 56 +/- 18, 64 +/- 12%/day for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.01) and depressed hepatic cyt ochrome P450 concentration (0.54 +/- 0.19, 0.22 +/- 0.07, 0.19 +/- 0.0 7 nmol/mg protein, respectively; ANOVA, P < 0.05) and ethoxycoumarin O -deethylase (ECOD) activity (103 +/- 73, 29 +/- 13, 17 +/- 11, pmol/mg /min, respectively; ANOVA, P < 0.01); however, rhIGF-1 did not signifi cantly alter these hepatic variables during endotoxin infusion. Recomb inant human insulin-like growth factor-1 significantly improved nitrog en balance without compromising hepatic response as measured by liver fractional synthetic rate, cytochrome P450 concentration, and ECOD act ivity in endotoxemic parenterally fed rats. (C) 1995 Academic Press, I nc.