Acute effects of ghrelin administration on glucose and lipid metabolism.

Abstract

Ghrelin infusion increases plasma glucose and nonesterified fatty acids, but it is uncertain whether this is secondary to the concomitant release of GH. Our objective was to study direct effects of ghrelin on substrate metabolism. This was a randomized, single-blind, placebo-controlled two-period crossover study. The study was performed in a university clinical research laboratory. Eight healthy men aged 27.2 +/- 0.9 yr with a body mass index of 23.4 +/- 0.5 kg/m(2) were included in the study. Subjects received infusion of ghrelin (5 pmol x kg(-1) x min(-1)) or placebo for 5 h together with a pancreatic clamp (somatostatin 330 microg x h(-1), insulin 0.1 mU x kg(-1) x min(-1), GH 2 ng x kg(-1) x min(-1), and glucagon 0.5 ng.kg(-1) x min(-1)). A hyperinsulinemic (0.6 mU x kg(-1) x min(-1)) euglycemic clamp was performed during the final 2 h of each infusion. Basal and insulin-stimulated glucose disposal decreased with ghrelin [basal: 1.9 +/- 0.1 (ghrelin) vs. 2.3 +/- 0.1 mg x kg(-1) x min(-1), P = 0.03; clamp: 3.9 +/- 0.6 (ghrelin) vs. 6.1 +/- 0.5 mg x kg(-1) x min(-1), P = 0.02], whereas endogenous glucose production was similar. Glucose infusion rate during the clamp was reduced by ghrelin [4.0 +/- 0.7 (ghrelin) vs. 6.9 +/- 0.9 mg.kg(-1) x min(-1); P = 0.007], whereas nonesterified fatty acid flux increased [131 +/- 26 (ghrelin) vs. 69 +/- 5 micromol/min; P = 0.048] in the basal period. Regional lipolysis (skeletal muscle, sc fat) increased insignificantly with ghrelin infusion. Energy expenditure during the clamp decreased after ghrelin infusion [1539 +/- 28 (ghrelin) vs. 1608 +/- 32 kcal/24 h; P = 0.048], but the respiratory quotient did not differ. Minor but significant elevations in serum levels of GH and cortisol were observed after ghrelin infusion. Administration of exogenous ghrelin causes insulin resistance in muscle and stimulates lipolysis; these effects are likely to be direct, although a small contribution of GH and cortisol cannot be excluded.