Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects

Abstract

Context: Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH.

Objective: The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasting.

Design: We conducted a randomized, placebo-controlled, crossover study in 10 healthy young men.

Intervention: After 36 h of fasting with saline or pegvisomant (GHR blockade), the subjects were studied during a 4-h basal period and 2.5-h hyperinsulinemic euglycemic clamp.

Main outcome: We measured whole-body and forearm glucose, lipid, and protein metabolism, peripheral insulin sensitivity, and acyl and desacyl ghrelin.

Results: GHR blockade significantly suppressed circulating free fatty acids (1226 +/- 83 vs. 1074 +/- 65 micromol/liter; P = 0.03) and ketone bodies (3080 +/- 271 vs. 2015 +/- 235 micromol/liter; P <or= 0.01), as well as forearm uptake of free fatty acids (0.341 +/- 0.150 vs. 0.004 +/- 0.119 micromol/100 ml x min; P < 0.01) and lipid oxidation (1.3 +/- 0.1 vs. 1.2 +/- 0.1 mg/kg x min; P = 0.03) in the basal period. By contrast, IGF-I levels in either serum or peripheral tissues were not impacted by GHR blockade, and protein metabolism was also unaffected. Basal glucose levels were elevated by GHR blockade, but insulin sensitivity was similar; this was associated with an increased acyl/desacyl ghrelin ratio.

Conclusion: GHR blockade, without changes in circulating or tissue IGF-I levels, selectively suppresses lipid mobilization and oxidation after short-term fasting. This supports the notion that stimulation of lipolysis is a primary and important effect of GH.

Trial registration: ClinicalTrials.gov NCT00476879.

Figures

Figure 1

Study protocol after 36 h of fasting with placebo or GHR blockade. The level of pegvisomant throughout the GHR study day (mean ± se). See Subjects and Methods for further details.

Figure 2

The levels of desacyl ghrelin, acyl ghrelin, the ratio (acyl/desacyl) and glucose during the study day, after 36 h of fasting with saline (black) and GHR blockade (white). Initiation of the hyperinsulinemic euglycemic clamp is marked by the gray line. Data are presented as mean ± se and are compared during the basal and clamp period.

Figure 3

Whole body circulating levels (A) and forearm uptake (B) of FFA and 3-OHB after 36 h of fasting with saline (black) and GHR blockade (white) in the basal period and at the end of a hyperinsulinemic euglycemic clamp. Data are presented as mean ± se.

Figure 4

Energy metabolism after 36 h of fasting with saline (black) and GHR blockade (white) in the basal period and at the end of a hyperinsulinemic euglycemic clamp, as assessed by lipid oxidation and REE (energy gain from lipid oxidation is illustrated with gray lines; basal P = 0.02, clamp P = 0.28). Data are presented as mean ± se.