The roles of GH and its receptor (GHR) in metabolic control are not yet fully understood. We studied the roles of GH and the GHR using the GHR antagonist
pegvisomant for metabolic control of healthy nonobese men in fasting and nonfasting conditions. Ten healthy subjects were enrolled in a double blind, placebo-controlled study on the effects of
pegvisomant on GHRH and
GH-releasing peptide-6 (GHRP-6)-induced GH secretion before and after 3 days of fasting and under nonfasting conditions (n = 5). Under the condition of GHR blockade by
pegvisomant in the nonfasting state,
GHRP-6 (1 microg/kg) caused a increase in serum
insulin (10.3 +/- 2.1 vs. 81.3 +/- 25.4 mU/L; P < 0.001) and
glucose (4.2 +/- 0.3 vs. 6.0 +/- 0.6 mmol/L; P < 0.05) concentrations. In this group, a rapid decrease in serum
free fatty acids levels was also observed. These changes were not observed under GHR blockade during fasting or in the absence of
pegvisomant. We conclude that although these results were obtained from an acute study, and long-term administration of
pegvisomant could render different results, blockade of the GHR in the nonfasting state induces tissue-specific changes in
insulin sensitivity, resulting in an increase in
glucose and
insulin levels (indicating
insulin resistance of liver/muscle), but probably also in an increase in lipogenesis (indicating normal
insulin sensitivity of adipose tissue). These GHRP-6-mediated changes indicate that low GH bioactivity on the tissue level can induce changes in metabolic control, which are characterized by an increase in fat mass and a decrease in lean body mass. As a mechanism of these GHRP-6-mediated metabolic changes in the nonfasting state, direct nonpituitary-mediated
GHRP-6 effects on the gastroentero-hepatic axis seem probable.