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The Impact of Pegvisomant Treatment on Substrate Metabolism and Insulin Sensitivity in Patients with Acromegaly

Medical Department M (Endocrinology and Diabetes) and Institute of Clinical Experimental Research (R.L.-L., N.M., S.N., H.Ø., J.O.L.J.) and Department of Clinical Pharmacology (O.S.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; and Department of Endocrinology (M.A.), Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Dr. J. O. L. Jørgensen, Medical Department M, Aarhus Sygehus, Norrebrogade 44, DK-8000 C, Aarhus, Denmark. E-mail: jolj{at}dadlnet.dk.

Context: Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described.

Patients and Methods: We assessed basal and insulin-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design.

Results: After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 ± 82 vs. 247 ± 33 µg/liter, P = 0.02; GH, 5.3 ± 1.5 vs. 10.8 ± 3.3 µg/liter, P = 0.02). Basal serum insulin and plasma glucose levels decreased after treatment (insulin, 54 ± 5.9 vs. 42 ± 5.3 pmol/liter, P = 0.001; glucose, 5.7 ± 0.1 vs. 5.3 ± 0.0 mmol/liter, not significant), whereas palmitate kinetics were unaltered. During the clamp, the glucose infusion rate increased after pegvisomant (3.1 ± 0.5 vs. 4.4 ± 0.6 mg/kg·min, P = 0.02), whereas the suppression of endogenous glucose production tended to increase (0.7 ± 0.0 vs. 0.5 ± 0.1 mg/kg·min, not significant). Total resting energy expenditure decreased after pegvisomant treatment (1703 ± 109 vs. 1563 ± 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly.

Conclusions: 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free fatty acid metabolism is unaltered. 3) The data support the important direct effects of GH on glucose metabolism and add additional benefits to pegvisomant treatment for acromegaly.

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