Ghrelin plasma concentrations increase during fasting and fall rapidly after nutrient ingestion. We hypothesized that insulin or glucose could regulate ghrelin secretion by a feedback mechanism. In this randomized, double-blind, placebo-controlled crossover study, three different study days were carried out in nine healthy volunteers (age 26 +/- 6 years). On each day, stepwise increasing systemic glucose concentrations of 5.0, 8.3, and 11.1 mmol/l were attained by intravenous infusion of glucose, representing fasting and postprandial conditions. Ghrelin plasma concentration was studied during concomitant exogenous hyperinsulinemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control, respectively. Elevated glucose concentrations increased circulating insulin to 612 +/- 85 pmol/l (P < 0.01), but they did not affect ghrelin concentrations. Prolonged hyperinsulinemia by exogenous infusion resulted in circulating insulin of 1,602 +/- 261 pmol/l (P < 0.01) and suppressed plasma ghrelin to 49.6% of baseline (P < 0.01). During administration of somatostatin, insulin concentration remained constant, but an even greater decrease in ghrelin to 39.5% of baseline was noted (P < 0.01). Hyperglycemia does not decrease ghrelin, and a reduction in ghrelin is only seen at supraphysiological insulin concentrations. In contrast, systemic ghrelin concentrations are decreased by somatostatin. The meal-related suppression of ghrelin appears not directly regulated by glucose or insulin.