Vestergaard Esben Thyssen, Hansen Troels Krarup, Gormsen Lars Christian, Jakobsen Preben, Moller Niels, Christiansen Jens Sandahl, Jorgensen Jens Otto Lunde
Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Dk-8000 Aarhus C, Denmark.
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1829-36. doi: 10.1152/ajpendo.00682.2006. Epub 2007 Feb 20.
Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol.kg body wt(-1).min(-1) in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model. s-Ghrelin initial half-life was 24 +/- 2 min and terminal half-life 146 +/- 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 +/- 16 min. MRT correlated positively with both BMI (r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels (r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 +/- 0.1 mmol/l (P < 0.01) and free fatty acid levels more than doubled (to 1.03 +/- 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity (P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.
胃饥饿素水平会迅速且动态地波动，在进餐前出现高峰，餐后则降至低谷，胃饥饿素会增加食欲和食物摄入量。循环中的胃饥饿素与体重指数（BMI）呈负相关，但肥胖个体餐后胃饥饿素水平的下降幅度较小。这是否反映了胃饥饿素分泌或清除的变化尚不确定。因此，我们研究了胃饥饿素的药代动力学与人体测量学和生化指标之间的关系。我们还研究了胃饥饿素对激素和代谢产物的影响。在禁食的人体中，我们在一项随机、双盲、安慰剂对照的交叉研究中，于下午5点以5 pmol·kg体重（-1）·min（-1）的恒定输注速率持续输注胃饥饿素180分钟。血清胃饥饿素（s-胃饥饿素；总水平）根据二室模型进行分布和消除。s-胃饥饿素的初始半衰期分别为24±2分钟和终末半衰期146±36分钟。胃饥饿素的平均驻留时间（MRT）为93±16分钟。MRT与BMI（r = 0.51，P < 0.001）和高密度胆固醇（HDL）水平（r = 0.75，P < 0.001）均呈正相关。在胃饥饿素输注期间，血清胰岛素水平保持恒定，而血浆葡萄糖升高了0.3±0.1 mmol/l（P < 0.01），游离脂肪酸水平增加了一倍多（至1.03±0.08 mmol/l，P < 0.001），这导致胰岛素敏感性显著降低（P < 0.001）。总之，1）我们描述了胃饥饿素的新药代动力学，这在临床实验中调整胃饥饿素输注速率时很有用，2）BMI和HDL与输注的胃饥饿素的MRT呈正相关，3）超生理水平的胃饥饿素会损害胰岛素敏感性。
