title: Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4.
abstract: OBJECTIVE
  Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.
  
  
  METHODS
  To study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic-euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique.
  
  
  RESULTS
  Ghrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.
  
  
  CONCLUSIONS
  i) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.
authors.affiliation: Medical Research Laboratories Institute of Clinical Medicine, Aarhus University Norrebrogade 44DK-8000, Aarhus C Denmark ; Department of Endocrinology and Diabetes Aarhus University Hospital Norrebrogade 44DK-8000, Aarhus C Denmark ; Department of Pediatrics Regional Hospital West Jutland Gl. Landevej 61DK-7400, Herning Denmark.
authors.forename: Esben Thyssen
authors.initials: ET
authors.lastname: Vestergaard
authors.forename: Morten B
authors.initials: MB
authors.lastname: Krag
authors.forename: Morten M
authors.initials: MM
authors.lastname: Poulsen
authors.forename: Steen B
authors.initials: SB
authors.lastname: Pedersen
authors.forename: Niels
authors.initials: N
authors.lastname: Moller
authors.forename: Jens Otto Lunde
authors.initials: JO
authors.lastname: Jorgensen
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
keywords: GH; acyl ghrelin; glucose metabolism; type 2 diabetes