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 ⅐ kgϪ1 ⅐ min Ϫ1 ) 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. Diabetes 57:3205-3210, 2008 G hrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R), stimulates GH and adrenocorticotropic hormone (ACTH) secretion (1) in addition to having orexigenic and gastrokinetic effects (2,3). The observation that GHS-R is located in peripheral tissues suggests that ghrelin may exert direct effects (4). The effects of ghrelin on substrate in humans are uncertain, but insulin resistance and stimulation of lipolysis have been reported (5-7). However, it remains difficult to segregate direct effects from effects related to GH and cortisol, and we have recently demonstrated that somatostatin infusion fails to sufficiently suppress ghrelin-induced GH and cortisol secretion (8). Hormonally replaced hypopituitary patients constitute a means for studying putative GH-and cortisol-independent effects of ghrelin in human subjects in vivo.We aimed to study potential direct effects of ghrelin on substrate metabolism and insulin sensitivity in the postabsorptive state. In one experiment in healthy adults, we assessed whether ghrelin-induced GH release translated into GH signaling in skeletal muscle, in the event of which the importance of abrogating indirect effects of ghrelin is obvious. Second, we studied the effects of ghrelin exposure on whole-body and regional substrate metabolism in the basal and insulin-stimulated state in hypopituitary patients on stable replacement with GH and hydrocortisone. RESEARCH DESIGN ...

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

“…Other groups have reported no change in the phosphorylation of insulin signaling markers, such as AKT, in acute response to ghrelin administration (Vestergaard et al. 2008a). However, the response to chronic ghrelin injections appears to be quite different.…”

“…2004; Vestergaard et al. 2008a). However, somatostatin is unable to fully blunt significant elevations in serum GH (Vestergaard et al.…”

“…However, somatostatin is unable to fully blunt significant elevations in serum GH (Vestergaard et al. 2008a), and GH‐deficient individuals often exhibit impaired insulin sensitivity (Hoffman et al. 1994).…”

“…2007; Vestergaard et al. 2008a, 2008b, 2011) suggest that AG infusion acutely impairs the clearance of glucose from the blood. Furthermore, ghrelin KO and ghrelin receptor KO mice are protected from the negative effects of a high fat diet on glucose tolerance and insulin sensitivity (Qi et al.…”

“…2007) in response to in vivo AG injections over a period of several days in rats, while others exhibit no alteration in AKT following injection or infusion, in both rats and humans (Vestergaard et al. 2008a; Barazzoni R et al. 2011).…”