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: 8.47). 10/2008; 57(12):3205-10. DOI: 10.2337/db08-0025
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Lars Christian Gormsen, Aug 27, 2015
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Current pharmaceutical design 12/2012; 19(27). DOI:10.2174/1381612811319270018 · 3.29 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Cell metabolism 10/2012; 16(5). DOI:10.1016/j.cmet.2012.09.014 · 16.75 Impact Factor
  • Source
    • "It suggests the incidence of insulin resistance at hatching time or in newly hatched chicks from in ovo ghrelin administered to eggs, for stability of the blood glucose level. This effect is similar to that of ghrelin in the occurrence of insulin resistance in humans (Vestergaard et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT: Ghrelin is a regulatory peptide in glucose homeostasis in animal species. Its effect in the avian embryo is unclear. The aim of this study was to investigate the effects of in ovo ghrelin administration on serum glucose and insulin levels of hatched chicks. A total of 250 fertilized eggs were divided into 5 groups; group T1 as control (without injection), group T2 (in ovo injected with 50 ng/egg ghrelin on day 5), group T3 (in ovo injected with 100 ng/egg ghrelin on day 5), group T4 (in ovo injected with 50 ng/egg ghrelin on day 10) and group T5 (in ovo injected with 100 ng/egg ghrelin on day 10). After hatching, serum insulin and glucose concentrations were determined. Group T4 and T5 showed significantly higher serum insulin levels (0.43 and 0.60 ng/ml, respectively) compared with T1, T2 and T3 (0.09, 0.10, and 0.23 ng/ml, respectively) in hatched chicks. Glucose concentrations have not been affected by in ovo administered ghrelin in all injected groups. It seems that embryonic β-cells were stimulated to secrete a considerable level of insulin in response to in ovo ghrelin in the late embryonic life. The observed stability of glucose rate suggests the incidence of insulin resistance at hatching time or in newly hatched chicks from in ovo ghrelin administered eggs on day 10.
    Czech Journal of Animal Science 08/2011; 8(56):377-380. · 0.87 Impact Factor
Show more