Ghrelin Infusion in Humans Induces Acute Insulin Resistance and Lipolysis Independent of Growth Hormone Signaling

Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark.
Diabetes (Impact Factor: 8.1). 10/2008; 57(12):3205-10. DOI: 10.2337/db08-0025
Source: PubMed


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.
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.
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.
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.

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Available from: Lars Christian Gormsen
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    • "The observation that the GHS-R is also located in peripheral tissues indicates that ghrelin also exerts direct peripheral effects (5, 6). It has recently been reported that exogenous ghrelin causes insulin resistance (7, 8, 9, 10, 11) and induces lipolysis (7, 9, 10, 11, 12, 13). The diabetogenic effects of GH are well established (14, 15), although the exact mechanisms by which GH induces insulin resistance remain to be elucidated. "
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    ABSTRACT: Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects. To study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic-euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique. Ghrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance. i) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.
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    • "Promotes lipolysis in terms of increased palmitate flux, FFA levels, and regional glycerol release Humans [124] Directly induces lipolysis and resistance to insulin-stimulated glucose disposal Humans [125] Increases food intake and independently regulates adipocyte metabolism Rats [126] Positive effects on PON I, an esterase Humans [135] Together with atherogenic lipoproteins may play a role in predicting vascular dis- ease Humans [136], [138] Ghrelin may have antiinflammatory role in increased inflammation such as enhancing the binding and removal oxidized LDL Humans, mice [139] FFA = free fatty acids LDL = low density lipoprotein PON I = paraoxonase I ghrelin concentrations in poorly controlled diabetic patients [143]. Furthermore, rosiglitazone increased ghrelin level in patients with T2DM [143]. "
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    ABSTRACT: Ghrelin is a peptide hormone produced mainly in the stomach that has widespread tissue distribution and diverse hormonal, metabolic and cardiovascular activities. The circulating ghrelin concentration increases during fasting and decreases after food intake. Ghrelin secretion may thus be initiated by food intake and is possibly controlled by nutritional factors. Lean subjects have increased levels of circulating ghrelin compared with obese subjects. Recent reports show that low plasma ghrelin is associated with elevated fasting insulin levels, insulin resistance and type 2 diabetes mellitus. Factors involved in the regulation of ghrelin secretion have not yet been defined; however, it is assumed that blood glucose levels represent a significant regulator. Recent evidence indicates that ghrelin can increase myocardial contractility, enhance vasodilatation, and has protective effect from myocardial damage. It has been shown that ghrelin may improve cardiac function through growth hormone (GH)-dependent mechanisms but there is also evidence to suggest that ghrelin's cardioprotective activity is independent of GH. Recent data demonstrate that ghrelin can influence key events in atherogenesis. Thus, ghrelin may be a new target for the treatment of some cardiovascular diseases. In this review, we consider the current literature focusing on ghrelin as a potential antiatherogenic agent in the treatment of various pathophysiological conditions.
    Full-text · Article · Dec 2012 · Current pharmaceutical design
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    • "The best-established regulation of lipolysis is exerted on the one hand by insulin that inhibits it (Saltiel and Kahn, 2001) and on the other hand by glucocorticoids and the sympathetic nervous system that favor it (Vegiopoulos and Herzig, 2007; Zechner et al., 2012). In addition, FGF21, glucagon, and ghrelin have been identified as potential regulators of lipolysis (Inagaki et al., 2007; Perea et al., 1995; Vestergaard et al., 2008). However, both the physiological importance of lipolysis and the identification in recent years through mouse genetics of novel regulators of this process suggest that additional, yet to be identified hormones regulating positively or negatively this survival function may exist. "
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    ABSTRACT: Energy release from cellular storage is mandatory for survival during fasting. This is achieved through lipolysis and liver gluconeogenesis. We show here that in the mouse, gut-derived serotonin (GDS) is upregulated during fasting and that it favors both mechanisms. In adipocytes, GDS signals through the Htr2b receptor to favor lipolysis by increasing phosphorylation and activity of hormone-sensitive lipase. In hepatocytes, GDS signaling through Htr2b promotes gluconeogenesis by enhancing activity of two rate-limiting gluconeogenic enzymes, FBPase and G6Pase. In addition, GDS signaling in hepatocytes prevents glucose uptake in a Glut2-dependent manner, thereby further favoring maintenance of blood glucose levels. As a result, inhibition of GDS synthesis can improve glucose intolerance caused by high-fat diet. Hence, GDS opposes deleterious consequences of food deprivation by favoring lipolysis and liver gluconeogenesis while preventing glucose uptake by hepatocytes. As a result, pharmacological inhibition of its synthesis may contribute to improve type 2 diabetes.
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