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The Effect of Long-Term Pharmacological Antilipolysis on Substrate Metabolism in Growth Hormone (GH)-Substituted GH-Deficient Adults

Medical Department M, Aarhus Kommunehospital (S.N., N.M., J.S.C., J.O.L.J.), and Medical Department C, Aarhus Amtssygehus (S.B.P.), Aarhus University Hospital, DK-8000 Aarhus C, Denmark

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

Abstract

The lipolytic properties of GH are essential for the acute effects on glucose metabolism and insulin sensitivity, whereas its more long-term impact on substrate metabolism is uncertain. The aim of the study was to evaluate the influence of pharmacological antilipolysis on substrate metabolism during constant and continued GH exposure. Seven adult GH-deficient (GHD) patients were studied twice in a double-blind randomized order: 1) after 4 wk of acipimox treatment (250 mg, orally, three times daily) and 2) after 4 wk of placebo treatment. Daily GH replacement was continued throughout both study periods. At the end of each period glucose and lipid oxidation rates were assessed by indirect calorimetry, and the protein oxidation rate was estimated by urinary excretion of urea. Endogenous glucose production and whole body protein metabolism were assessed by isotope dilution techniques using tritiated glucose and stable phenylalanine and tyrosine isotopes, respectively. GH and IGF-I levels were not different between periods, whereas FFA and glycerol levels were distinctly suppressed after 4 wk of pharmacological antilipolysis [FFA, 256 ± 63 (acipimox) vs. 596 ± 69 (placebo) µmol/liter; P = 0.001]. Likewise, plasma levels of total and low density lipoprotein cholesterol as well as triglycerides were significantly reduced after acipimox. Despite this, lipid oxidation rates were identical at the end of the two treatment periods [589 ± 106 (acipimox) vs. 626 ± 111 (placebo) kcal/24 h; P = 0.698]. The total and oxidative rates of glucose as well as protein oxidation and urea excretion were identical at the end of the two treatment periods (P > 0.05). Phenylalanine flux, a measure of protein turnover, was increased [34.62 ± 1.83 (acipimox) vs. 33.15 ± 1.61 (placebo) µmol/kg·h; P = 0.049] as was phenylalanine incorporation into protein, a measure of protein synthesis [30.79 ± 1.67 (acipimox) vs. 28.97 ± 1.51 (placebo) µmol/kg·h; P = 0.035].

The following conclusions were reached: 1) prolonged antilipolysis by means of acipimox stimulates protein turnover without affecting net protein balance; and 2) acipimox in combination with constant GH exposure results in sustained suppression of circulating levels of FFA, glycerol, and triglycerides without a reduction in the rate of lipid oxidation. The site and origin of lipid fuels for oxidation during suppression of lipolysis remain to be determined.

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