Objective: To study the effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats, and compare the effect of treatment between recombinant human growth hormone (rhGH) and polyethylene glycol rhGH (PEG-rhGH). Methods: Hypophysectomy was performed in juvenile rats to build the animal model of GH deficiency. The hypophysectomized animals were randomly assigned into three groups and treated with saline (negative control, n = 20), rhGH (n = 20) and PEG-rhGH (n = 20). A sham operation was performed to set up the normal control (n =20). Body weight, body length and tail length were recorded every 2 days for a 14-day treatment and bone growth was measured at the end of therapy. Glucose infusion rate (GIR) determined by euglycemic hyperinsulinemic clamp was used to evaluate insulin sensitivity after GE treatment. We also examined plasma glucose and serum insulin levels Results: Compared with the negative control, the body weight, body length, tail length and bone growth increased significantly in hypophesectomized rats treated by GH (P<0.01). Although the weight gain in the first 10 days was higher in the PEG-rhGH group than in the rhGH group (P<0.05), the growth promoting effect was similar between rhGH and PEG-rhGH (P>0.05). Neither rhGH nor PEG-rhGH impaired glucose tolerance of rats after hypophesectomy. Compared with negative controls, according to decreased serum insulin, reduced insulin expression in pancreatic cells and increased GIR in the clamp, both rhGH and PEG-rhGH groups had improved insulin sensitivity within 14 days (P<0.01). However, with prolonged treatment, the GIR in the rhGH-treated rats decreased significantly (P<0.05); while PEG-rhGH did not interfere with GIR, even after a doubled dose (P>0.05). Conclusions: PEG-rhGH had the same linear growth promoting efficacy as unmodified rhGH. The short-term GH replacement could improve insulin sensitivity in hypophysectomized rats, especially after PEGylation. (C) 2011 Elsevier Ltd. All rights reserved