Regulation of Ghrelin

描述(由申请人提供)： Ghrelin是一种主要来自胃的多肽，以活性(酰化)和非活性(去酰化)形式存在于血浆中。Ghrelin的主要活性形式含有28个氨基酸，具有独特的翻译后修饰：Ser3的羟基被辛酸酯化。正辛酰基是生长激素(GH)释放活性所必需的。血浆Ghrelin在能量平衡、食物摄取、生长激素释放和肥胖方面起着重要作用。到目前为止，还不清楚循环中的Ghrelin水平是如何受到调节的。这一应用的总体假设是，葡萄糖、胰岛素以及胰岛素敏感性在Ghrelin的急性调节中发挥作用。还将研究年龄和体重指数对循环中生长激素对这些因素的反应的影响。 具体目的1.确定Ghrelin的短期调节在多大程度上是通过葡萄糖(外周或外周)和/或外周胰岛素介导的。在人类中，服用葡萄糖后循环中的生长激素释放素水平下降。目前尚不清楚葡萄糖给药途径在多大程度上影响其对血液中生长激素释放素的影响。在正常血糖条件下胰岛素对生长激素释放素水平的影响的研究得出了不一致的结果，即循环中的生长激素释放素减少或没有变化。目前还不清楚葡萄糖给药途径在多大程度上影响其对循环Ghrelin的影响，以及胰岛素抵抗的差异是否影响胰岛素和/或葡萄糖对循环Ghrelin的影响。在两组体重指数匹配、具有不同胰岛素抵抗的年轻人中，我们将检测正常血糖条件下胰岛素对外周Ghrelin的影响，并将其与口服和静脉注射葡萄糖的效果进行比较。我们还将比较口服和静脉注射葡萄糖对外周Ghrelin的影响。静脉注射后达到的血糖水平将与口服葡萄糖测试时达到的水平相匹配。胰岛素和葡萄糖对Ghrelin生物活性的影响尚未见报道。使用我们实验室开发的分析方法，可以测量生物活性和非活性生长激素释放蛋白。 具体目的2.确定胰岛素介导的血液中生长激素水平下降是否与年龄有关。胰岛素敏感性随年龄增长而降低。这在一定程度上是腹部内脏脂肪随年龄增加的结果。建议的研究将调查年轻人和老年人在胰岛素介导的急性循环Ghrelin(生物活性、非活性形式)水平下降方面是否存在差异。

DESCRIPTION (provided by applicant): Ghrelin a peptide which is mainly derived from the stomach, is present in plasma in an active (acylated) and inactive (des-acylated) form. The major active form of ghrelin contains 28 amino acids with a unique post-translational modification: the hydroxyl group of ser3 is esterified by octanoic acid. The n-octanoyl group is essential for the GH (growth hormone) releasing activity. Plasma ghrelin plays a role in energy homeostasis, food intake, and possibly in GH release and obesity. To date it is unclear how circulating ghrelin levels are regulated. The overall hypothesis of this application is that glucose, insulin as well as insulin sensitivity play a role in the acute regulation of ghrelin. The influence of age and BMI on the response of circulating ghrelin to these factors will also be examined. Specific Aim 1. To determine to what extent the short-term regulation of ghrelin is mediated through glucose (peripheral or luminal) and/or peripheral insulin. In man, circulating ghrelin levels decrease after glucose administration. It is unclear to what extent the route of glucose administration plays a role in its effects on circulating ghrelin. Studies of insulin effects on ghrelin levels under euglycemic conditions have yielded inconsistent results, i.e., a decrease in circulating ghrelin vs. no change. It is also unclear to what extent the route of glucose administration plays a role in its effects on circulating ghrelin and whether differences in insulin resistance have an impact on the effects of insulin and/or glucose on circulating ghrelin. In two groups of BMI matched young adults with different insulin resistance, we will examine the effects of insulin under euglycemic conditions on peripheral ghrelin and compare them with the effects of oral and IV glucose. We will also compare the effects of oral and IV glucose on peripheral ghrelin with each other. The glucose levels reached after IV administration will match those reached during the oral glucose test. The effects of insulin and glucose on bioactive ghrelin have not been reported. Using assays developed in our laboratory, both bioactive and inactive ghrelin will be measured. Specific Aim 2. To determine whether the insulin-mediated decrease in circulating ghrelin levels is age dependent. Insulin sensitivity decreases with age. This is partially a result of the age-dependent increase in abdominal visceral fat. The studies proposed will investigate whether there are differences between young and older adults regarding the acute insulin mediated decrease in circulating ghrelin (bioactive, inactive form) levels.