Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling

Abstract

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.

Research design and 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.

Trial registration: ClinicalTrials.gov NCT00116025 NCT00139945.

Figures

FIG. 1.

Study protocol. Please refer to research design and methods for further details.

FIG. 2.

Hormones and metabolites during saline and ghrelin administration in study 2. A: Serum levels of ghrelin increased in response to ghrelin infusion to a plateau of 5.33 ± 0.45 μg/l in the basal state and a higher plateau of 5.86 ± 0.50 μg/l during the clamp period (mean ghrelin levels basal period vs. clamp period P = 0.001). B: Serum levels of GH. C: Serum levels of FFA. D: Serum levels of insulin. Serum insulin was similar during both basal and clamp conditions. E: Plasma glucose levels. F: Interstitial skeletal muscle glucose levels. Printed P values refer to two-way ANOVA significance levels. ▪, saline infusion; □, ghrelin infusion. All data are presented as means ± SE.

FIG. 3.

A: Effects of ghrelin infusion on STAT5 phosphorylation and total STAT5 levels in skeletal muscle in healthy subjects (study 1). Values are means ± SE. B: Representative Western blots and quantitative bar-graphs regarding JAK/STAT, MAPK, AMPK, and insulin signaling pathways in skeletal muscle in hypopituitary patients (study 2) during ghrelin and saline infusion. PAS, pAkt substrate.

FIG. 4.

A: Glucose metabolism during saline and ghrelin administration in study 2. Hyperinsulinemic clamp. Glucose infusion rates and M value during saline and ghrelin administration. •, saline infusion; □, ghrelin infusion. B: Accumulative glucose infusion dosage during saline and ghrelin administration. The accumulative glucose dose was significantly decreased during the clamp period in the ghrelin study (P = 0.002). C: Glucose utilization during the terminal 30 min of basal and clamp periods in saline and ghrelin studies. Ghrelin did not significantly impact glucose metabolism in the basal period. During the clamp ghrelin infusion reduced the rates of oxidative, nonoxidative, and total glucose disposal (P = 0.009, P = 0.03, and P = 0.012, respectively). All data are presented as means ± SE.