Ghrelin circulates in two different forms. Acylated ghrelin (AG), a natural ligand of the GH Secretagogue receptor (GHS-R) type 1a, exerts several biologic central and peripheral actions including stimulation of GH secretion, but also modulation of insulin secretion, glucose and lipid metabolism. Unacylated ghrelin (UAG), despite unable to bind the GHS-R1a, is biologically active showing some influence in vitro and in vivo on glucose and lipid metabolism likely mediated by still unknown receptors. Based on these data, the aim of our study was to investigate the endocrine and metabolic effects of prolonged UAG administration in humans in physiological conditions. To this goal, the effects of UAG (1.0 mcg/kg/h infused iv over 16 hours from 21.00 to 13.00 h) or saline were studied in 8 normal subjects who had isocaloric balanced standardized meals at h21.20 and h09.00. Blood samples were collected every 20 min. Compared to saline, UAG infusion significantly modified the profile of all parameters, except glucagon. Compared to saline, UAG decreased glucose (P<0.01) and FFA AUCs (P<0.01). The glucose decrease during UAG was particularly relevant at fasting during nighttime (P<0.01) while FFA profile was reduced both post-prandially and at fasting(P<0.01). UAG did not modify total insulin AUC; however, the early insulin response to both dinner (P<0.01) and breakfast (P<0.05) was enhanced by UAG infusion that was associated to decrease in the nighttime HOMA index (P<0.01). During UAG, cortisol (P<0.01) and GH (P<0.05) AUCs were lower than those during saline, but cortisol levels remained within physiological values. Thus, the intravenous infusion of UAG in normal subjects enhances the early insulin response to meals, improves glucose metabolism and insulin sensitivity, and inhibits lipolysis. Thus, UAG displays a remarkable metabolic impact suggesting a promising anti-diabetogenic action through an original mechanism of action.