title: Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects.
abstract: Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol.kg body wt(-1).min(-1) in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model. s-Ghrelin initial half-life was 24 +/- 2 min and terminal half-life 146 +/- 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 +/- 16 min. MRT correlated positively with both BMI (r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels (r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 +/- 0.1 mmol/l (P < 0.01) and free fatty acid levels more than doubled (to 1.03 +/- 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity (P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.
authors.affiliation: Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Dk-8000 Aarhus C, Denmark. e.t.vestergaard@ki.au.dk
authors.forename: Esben Thyssen
authors.initials: ET
authors.lastname: Vestergaard
authors.forename: Troels Krarup
authors.initials: TK
authors.lastname: Hansen
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Gormsen
authors.forename: Preben
authors.initials: P
authors.lastname: Jakobsen
authors.forename: Niels
authors.initials: N
authors.lastname: Moller
authors.forename: Jens Sandahl
authors.initials: JS
authors.lastname: Christiansen
authors.forename: Jens Otto Lunde
authors.initials: JO
authors.lastname: Jorgensen
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D054439:Ghrelin; D006207:Half-Life; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D007328:Insulin / Q000502:physiology; D008297:Male; D008954:Models, Biological; D036361:Peptide Hormones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D008076:Cholesterol, HDL; D005230:Fatty Acids, Nonesterified; D054439:Ghrelin; D007328:Insulin; D036361:Peptide Hormones