Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans

Background: Infusion of ghrelin to supraphysiologic levels inhibits glucose-stimulated insulin secretion, reduces insulin sensitivity, and worsens glucose tolerance in humans. Objective: The purpose of this study was to determine the effects of lower doses of ghrelin on insulin secretion and insulin sensitivity in healthy men and women. Methods: Acyl ghrelin (0.2 and 0.6 nmol kg^-1 h^-1) or saline was infused for 225 minutes in 16 healthy subjects on 3 separate occasions in randomized order. An iv glucose tolerance test was performed, and the insulin sensitivity index (S_I) was derived from the minimal model. Insulin secretion was measured as the acute insulin response to glucose (AIRg) and the disposition index was computed as AIRg x S_I. Results: Ghrelin infusions at 0.2 and 0.6 nmol kg ^-1 h^-1 raised steady-state plasma total ghrelin levels 2.2- and 6.1-fold above fasting concentrations. Neither dose of ghrelin altered fasting plasma insulin, glucose, or S_I, but both doses reduced insulin secretion compared with the saline control, computed either as AIRg (384 ± 75 and 354 ± 65 vs 520 ± 110pM· min [mean ± SEM], respectively; P < .01 for both low- and high-dose vs saline) or disposition index (2238 ± 421 and 2067 ± 396 vs 3339 ± 705, respectively; P < .02 for both comparisons). The high-dose ghrelin infusion also decreased glucose tolerance. Conclusions: Ghrelin infused to levels occurring in physiologic states such as starvation decreases insulin secretion without affecting insulin sensitivity. These findings are consistent with a role for endogenous ghrelin in the regulation of insulin secretion and suggest that ghrelin antagonism could improve β-cell function.