Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance

The roles of GH and its receptor (GHR) in metabolic control are not yet ful ly understood. We studied the roles of GH and the GHR using the GHR antagon ist pegvisomant for metabolic control of healthy nonobese men in fasting an d nonfasting conditions. Ten healthy subjects were enrolled in a double bli nd, placebo-controlled study on the effects of pegvisomant on GHRH and GH-r eleasing peptide-6 (GHRP-6)-induced GH secretion before and after 3 days of fasting and under nonfasting conditions (n = 5). Under the condition of GH R blockade by pegvisomant in the nonfasting state, GHRP-6 (1 mug/kg) caused a increase in serum insulin (10.3 +/- 2.1 vs. 81.3 +/- 25.4 mU/L; P < 0.00 1) and glucose (4.2 +/- 0.3 vs. 6.0 +/- 0.6 mmol/L; P < 0.05) concentration s. In this group, a rapid decrease in serum free fatty acids levels was als o observed. These changes were not observed under GHR blockade during fasti ng or in the absence of pegvisomant. We conclude that although these result s were obtained from an acute study, and long-term administration of pegvis omant 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 o f liver/muscle), but probably also in an increase in lipogenesis (indicatin g normal insulin sensitivity of adipose tissue). These GHRP-6-mediated chan ges indicate that low GH bioactivity on the tissue level can induce changes in metabolic control, which are characterized by an increase in fat mass a nd a decrease in lean body mass. As a mechanism of these GHRP-6-mediated me tabolic changes in the nonfasting state, direct nonpituitary-mediated GHRP- 6 effects on the gastroentero-hepatic axis seem probable.