Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling.
OBJECTIVE
Ghrelin is a gut-derived peptide and an endogenous ligand for the growth hormone (GH) secretagogue receptor. Exogenous ghrelin stimulates the release of GH (potently) and adrenocorticotropic hormone (ACTH) (moderately). Ghrelin is also orexigenic, but its impact on substrate metabolism is controversial. We aimed to study direct effects of ghrelin on substrate metabolism and insulin sensitivity in human subjects.


METHODS
Six healthy men underwent ghrelin (5 pmol . kg(-1) . min(-1)) and saline infusions in a double-blind, cross-over study to study GH signaling proteins in muscle. To circumvent effects of endogenous GH and ACTH, we performed a similar study in eight hypopituitary adults but replaced with GH and hydrocortisone. The methods included a hyperinsulinemic-euglycemic clamp, muscle biopsies, microdialysis, and indirect calorimetry.


RESULTS
In healthy subjects, ghrelin-induced GH secretion translated into acute GH receptor signaling in muscle. In the absence of GH and cortisol secretion, ghrelin acutely decreased peripheral, but not hepatic, insulin sensitivity together with stimulation of lipolysis. These effects occurred without detectable suppression of AMP-activated protein kinase phosphorylation (an alleged second messenger for ghrelin) in skeletal muscle.


CONCLUSIONS
Ghrelin infusion acutely induces lipolysis and insulin resistance independently of GH and cortisol. We hypothesize that the metabolic effects of ghrelin provide a means to partition glucose to glucose-dependent tissues during conditions of energy shortage.
Vestergaard
Esben Thyssen
ET
Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark. etv@dadlnet.dk
Gormsen
Lars Christian
LC
Jessen
Niels
N
Lund
Sten
S
Hansen
Troels Krarup
TK
Moller
Niels
N
Jorgensen
Jens Otto Lunde
JO
D000324:Adrenocorticotropic Hormone / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D054439:Ghrelin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013006:Growth Hormone / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007018:Hypopituitarism / Q000097:blood*; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D015398:Signal Transduction; D055815:Young Adult
D054439:Ghrelin; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D006854:Hydrocortisone
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