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Recombinant human insulin-like growth factor I has significant anabolic effects in adults with growth hormone receptor deficiency: Studies on protein, glucose, and lipid metabolism

Abstract:

The physiological effects of insulin-like growth factor I (IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron's syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean ± SEM age, 29.2 ± 2.0 yr; 4 males and 6 females). At baseline, patients had infusions of stable tracers, including L-[13C]leucine, [2H2] glucose, and d5-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60 μg/kg, sc) for the next 8 weeks when the studies were repeated identically. Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 ± 1.5 μg/L to 153 ± 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods (P < 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid and β-hydroxybutyrate concentrations, and a significant increase in fat oxidation, as measured by indirect calorimetry (P = 0.04). There were significant decreases in insulin concentrations (P = 0.01) and a reciprocal increase in glucose production rates (P = 0.04) during rhIGF-I, yet plasma glucose concentrations remained constant, suggestive of a significant insulin-like action of this peptide. RhIGF-I was well tolerated by all patients. In conclusion, 8 weeks of treatment with rhIGF-I had significant positive effects on body composition and measures of intermediate metabolism independent of GH. These results suggest that, similar to GH treatment of adults with GH deficiency, rhIGF-I may be beneficial as long term replacement therapy for the adult patient with Laron's syndrome.