Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects

Takeno, Ryoko; Okimura, Yasuhiko; Iguchi, Genzo; Kishimoto, Megumi; Kudo, Takumi; Takahashi, Kentaro; Takahashi, Yutaka; Kaji, Hidesuke; Ohno, Masakazu; Ikuta, Hajime; Kuroda, Yoshikazu; Obara, Tetsuji; Hosoda, Hiroshi; Kangawa, Kenji; Chihara, Kazuo

doi:10.1530/eje.0.1510447

Cited by 26 publications

(20 citation statements)

References 23 publications

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“…11 Takeno et al have recently described a normal GH response to continuous intravenous ghrelin administration in vagotomised humans. 41 In support of this, in the current study, all subjects showed a significant GH secretory response to intravenous ghrelin with no correlation between CAN and GH levels.…”

Section: Discussionsupporting

confidence: 70%

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Murray

Martin²,

Patterson³

et al. 2005

Gut

286

175

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Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)-3). Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p,0.05) but did not correlate with GER. Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.

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Section: Discussionsupporting

confidence: 70%

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Murray

Martin²,

Patterson³

et al. 2005

Gut

286

175

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“…1, D-F). In the high-dose treatment, the rats treated with either of the ghrelin agonists BIM-28125 and BIM-28131, as well as the rats treated with ghrelin, gained lean mass compared with the controls (42,49,46, and 29%, respectively, P Ͻ 0.001). However, the major weight gain in the high-dose groups was due to an increase in fat mass (BIM-28125, 234%; BIM-28131, 298%; ghrelin, 248%; and vehicle, 52%).…”

Section: Resultsmentioning

confidence: 97%

“…Hypothalamic neurons producing these two neuropeptides also express the GHS-R (19,55). Despite controversial reports based on models (3,10), afferent signaling of the vagus nerve does not seem to play an important role for metabolic actions of ghrelin, as shown in humans (49). Although there are numerous peptides affecting appetite or eating behavior in rodents, ghrelin is the first and only gut peptide with orexigenic properties in humans (7,38).…”

mentioning

confidence: 99%

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Strassburg¹,

Anker²,

Castañeda³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

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“…Critically, it points to the fact that vagal signalling is not essential to relay ascending orexigenic messages, likely due to the fact that the area postrema can facilitate diffusive access of ghrelin from the bloodstream to the NTS, enabling ascending signalling even without vagal innervation of the NTS. This is supported by the fact that intravenous ghrelin administration stimulates growth hormone secretion in vagotomised patients [208]. Taken together, all of the above information strongly suggests an interlinked role between blood and neural pathways for conveying ghrelin’s signal from the periphery to the CNS.…”

Section: Ghrelin and Ghrelin Ligands: Pharmacokinetic Perspectivesmentioning

confidence: 90%

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

Howick

Griffin

Cryan

et al. 2017

IJMS

131

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Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.

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Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects

Cited by 26 publications

References 23 publications

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

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