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Acute Effects of Ghrelin Administration on Glucose and Lipid Metabolism

Medical Department M (Endocrinology and Diabetes) (E.T.V., C.B.D., J.G., S.N., N.M., J.O.L.J.), Aarhus University Hospital, DK-8000 Aarhus C, Denmark; Department of Biomedical Sciences (J.J.H.), the Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (O.S.), University of Aarhus, DK-8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Esben Thyssen Vestergaard, M.D., Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, DK-8000 Aarhus C, Denmark. E-mail: e.t.vestergaard{at}ki.au.dk.

Context: Ghrelin infusion increases plasma glucose and nonesterified fatty acids, but it is uncertain whether this is secondary to the concomitant release of GH.

Objective: Our objective was to study direct effects of ghrelin on substrate metabolism.

Design: This was a randomized, single-blind, placebo-controlled two-period crossover study.

Setting: The study was performed in a university clinical research laboratory.

Participants: Eight healthy men aged 27.2 ± 0.9 yr with a body mass index of 23.4 ± 0.5 kg/m² were included in the study.

Intervention: Subjects received infusion of ghrelin (5 pmol·kg^–1·min^–1) or placebo for 5 h together with a pancreatic clamp (somatostatin 330 µg·h^–1, insulin 0.1 mU·kg^–1·min^–1, GH 2 ng·kg^–1·min^–1, and glucagon 0.5 ng·kg^–1·min^–1). A hyperinsulinemic (0.6 mU·kg^–1·min^–1) euglycemic clamp was performed during the final 2 h of each infusion.

Results: Basal and insulin-stimulated glucose disposal decreased with ghrelin [basal: 1.9 ± 0.1 (ghrelin) vs. 2.3 ± 0.1 mg·kg^–1·min^–1, P = 0.03; clamp: 3.9 ± 0.6 (ghrelin) vs. 6.1 ± 0.5 mg·kg^–1·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·min^–1; P = 0.007], whereas nonesterified fatty acid flux increased [131 ± 26 (ghrelin) vs. 69 ± 5 µmol/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.

Conclusions: 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.

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