Ilaria Olivetti

Other than Growth Hormone Neuroendocrine Actions of Ghrelin

Besides its growth hormone-releasing effect, ghrelin has been demonstrated to influence other hormonal systems, such as the hypothalamo-pituitary-adrenal axis, prolactin secretion, the thyroid axis as well as the gonadal axis. Ghrelin and its analogues stimulate the hypothalamo-pituitary-adrenal axis independent of the pituitary, via the hypothalamus, involving both corticotrophin-releasing hormone, arginine-vasopressin and neuropeptide Y stimulation. In adrenocortocotropic hormone (ACTH)-secreting tumors, the ghrelin receptor is pathologically expressed, thus accounting for especially high ACTH and cortisol responses to ghrelin and GH secretagogues in patients with Cushings disease. Ghrelin stimulates prolactin release most probably from the somatomammotroph cells of the pituitary gland. The effect of ghrelin on the pituitary regulation of the thyroid axis is controversial and its role in the physiological control of thyroid function is still matter of investigation. On the other hand, ghrelin has been reported to exert an inhibitory effect on follicle-stimulating hormone and, in particular, on luteinizing hormone, probably via an inhibitory effect exerted at the hypothalamic level on gonadotropin-releasing hormone secretion.

Circulating obestatin levels in normal and Type 2 diabetic subjects.

Background: Obestatin has been discovered as a new product of the ghrelin gene. Its physiological actions are still a matter of debate, but it seems that this peptide is likely to be involved in the control of insulin secretion and action as well as of adipocyte function. It has been already shown that obestatin secretion in humans is negatively modulated by food intake. Aim: To clarify obestatin secretion in normal subjects and in patients with Type 2 diabetes (T2D) in basal conditions and after a standardized meal. Subjects/methods: Five normal subjects and 5 T2D patients were studied during infusion of saline (iv for over 5 h from −120 to +180 min). A standardized lunch was served at 0 min. Obestatin, glucose, and insulin levels were assayed at −120, −90, −60, −45, −30, −15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. Results: From −120 to 0 min, obestatin levels in normal and T2D subjects were similar (area under the curve: 32.3±5.6 pg/ml/min vs 31.1 ±1.0 pg/ml/min). After the meal, circulating obestatin levels underwent a clear decrease in normal subjects (0 min: 300.6±34.7 pg/ml vs nadir at 60 min: 161.8±29.4 pg/ml; p=0.002) but not in diabetic patients (0 min: 267.2±16.5 pg/ml vs nadir at 180 min: 226.0±10.5 pg/ml). Conclusion: This study shows that normal and diabetic subjects display similar levels of circulating obestatin in fasting condition. However patients with T2D look refractory to the inhibitory effect of meal on obestatin secretion.

The metabolic response to the activation of the β- adrenergic receptor by salbutamol is amplified by acylated ghrelin

Background: It is well recognized that β-adrenergic receptors mediate important endocrine and metabolic actions. In fact, β-adrenergic receptor activation negatively influences GH secretion while exerting relevant metabolic actions such as the stimulation of insulin secretion, glycogenosis, and lipolysis. Aim: We have already shown that the activation of the GH secretagogue receptor (GHS-R)-1a by acylated ghrelin (AG) counteracts the inhibitory effect of salbutamol (SALB), a β2-adrenergic agonist, on GH release. The aim of the present study in humans was to clarify whether the metabolic response to SALB is affected by the infusion of AG, also known to exert significant metabolic actions. Methods: Six healthy young male volunteers underwent the following testing sessions in random order at least 5 days apart: a) SALB (0.06 μg/kg/min iv from 0 to 60 min) alone; b) SALB in combination with AG (1.0 μg/kg/min iv from −60 to 60 min); c) isotonic saline. Insulin, glucose, and free fatty acids (FFA) levels were evaluated every 15 min. Results: As expected, with respect to saline, SALB administration tended to increase both insulin secretion [Δ area under the curve (ΔAUC): 0.16±0.09 vs 0.003±0.077 × 103 μU/ml/min; p>0.05] and FFA levels (ΔAUC: 8.0±7.3 vs ∼-4.0±4.0 mEq/l/min; p>0.05), while glucose levels did not change. The metabolic response to SALB was significantly modified under the exposure of AG. In fact, under AG infusion, SALB elicited a more marked increase of FFA (ΔAUC: 22.3±3.2 vs 8.0±7.3 mEq/l/min; p<0.05) as well as a slight elevation in insulin (ΔAUC: 0.37±0.11 vs 0.16±0.09 × 103 μU/ml/min; p>0.05). Under AG, the baseline glucose levels were more elevated but, again, in combination with AG, SALB did not significantly modify glucose levels. Conclusions: β-adrenergic receptors and AG are likely to interact at the metabolic level. In humans, the lypolitic response to a β2-adrenergic agonist such as SALB is amplified by AG. Meanwhile, during the co-treatment, the marginal insulinotropic effect was not associated with an increase in glycemia.

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase.

OBJECTIVE GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. DESIGN AND METHODS In six healthy volunteers, we studied the GH response to acute AG administration (1.0 μg/kg i.v.) during saline or rhGH infusion (4.0 μg/kg per h i.v.) or after 4-day rhGH (10.0 μg/kg s.c.) administration. RESULTS Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. CONCLUSIONS The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Beta‐adrenergic agonism does not impair the GH response to acylated ghrelin in humans

Background  Acylated ghrelin (AG) is a physiological GH secretion amplifier, in part stimulating GHRH neurones and antagonizing somatostatin activity. In humans, AG is one of the most potent pharmacological stimuli of GH secretion and, unlike GHRH, is refractory to the inhibitory effect of glucose, free fatty acids (FFA) and somatostatin. Somatotroph secretion is also profoundly modulated by the adrenergic system. Indeed, beta‐adrenergic agonists abolish spontaneous and GHRH‐stimulated GH secretion. Based on these data, the aim of the present study was to investigate the effects of beta adrenergic agonism on the GH response to AG.

Disturbi del sonno e sindrome metabolica: quali relazioni eziopatogenetiche?

RiassuntoNelle ultime decadi si è assistito a un incremento dell’incidenza dei disturbi quali-quantitativi del sonno. Parallelamente è aumentata l’incidenza della sindrome metabolica. Quest’ultimo fenomeno è certamente imputabile in primo luogo a fattori ambientali (iper-alimentazione e sedentarietà) ma numerose evidenze epidemiologiche e sperimentali suggeriscono che i disturbi del sonno possano agire come concausa. Del resto un sonno quantitativamente e qualitativamente adeguato è fondamentale per il mantenimento di un ottimale metabolismo glicidico, dell’integrità dei meccanismi di regolazione dell’appetito e di un normale pattern pressorio. La consapevolezza di una possibile associazione tra i disturbi del sonno e le diverse componenti della sindrome metabolica offre importanti spunti nel campo della prevenzione e del trattamento di queste ultime.