Regulation by endogenous ghrelin of insulin release, feeding and glucose metabolism

在本研究中，Ghrelin及其受体生长激素(GH)促分泌受体(GHS-R)在胰岛表达。腹腔注射GHS-R拮抗剂可显著降低空腹血糖浓度，抑制血糖升高，增强糖耐量试验(GTT)时的胰岛素反应。相反，在GTT期间，腹膜腔内外源性Ghrelin可升高空腹血糖浓度，增强血糖升高并减弱胰岛素反应。在保持完整循环的灌流大鼠胰腺中，GHS-R阻断剂和Ghrelin抗血清可促进葡萄糖诱导的胰岛素释放，而外源性Ghrelin则抑制其释放。在分离的胰岛上，GHS-R阻断剂和Ghrelin免疫中和显著增强葡萄糖诱导的胰岛素释放和胞内[Ca^&lt；2+&gt；]i浓度的增加，而较高浓度(10 Nm)的Ghrelin则抑制胰岛素释放。GHR…更多的Elin可减弱葡萄糖诱导的单个β细胞[Ca^&lt；2+&gt；]i升高和延迟外向钾电流的增加。这些结果表明，胰岛内源性Ghrelin通过减弱钙信号转导来限制葡萄糖诱导的胰岛素释放，这种胰岛素抑制作用与血糖的上调有关。我们研究了Ghrelin和厌食激素瘦素对下丘脑弓状核(ARC)神经肽Y(NPY)神经元的影响，该神经元在摄食过程中起着中心作用。Ghrelin通过磷脂酶C、腺苷环化酶和蛋白激酶A(PKA)介导的途径增加ARC NPY神经元的[Ca^&lt；2+&gt；]_i。Ghrelin诱导的[Ca^&lt；2+&gt；]_i升高可被随后给予的瘦素抑制。Ghrelin和Leptin的这种相互调节可能在控制ARC NPY神经元的活性从而调节摄食方面发挥重要作用。本研究揭示了Ghrelin在调节胰岛素释放和葡萄糖代谢中的新功能，以及Ghrelin促食欲素作用的神经信号。与GH释放功能一起，Ghrelin可能是能量稳态的综合调节基础。较少

In this study, ghrelin and its receptor, growth hormone (GH) secretagogue-receptor (GHS-R), were expressed in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GHS-R antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation and enhanced insulin responses during glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin elevated fasting glucose concentrations, enhanced plasma glucose elevation and attenuated insulin responses during GTT. In perfused rat pancreas that retains intact circulation, GHS-R blockade and antiserum against ghrelin enhanced glucose-induced insulin release, while exogenous ghrelin suppressed it. In isolated islets, GHS-R blockade and ghrelin immunoneutralization markedly enhanced glucose-induced increases in insulin release and cytosolic Ca^<2+> concentration ([Ca^<2+>]_i), while ghrelin at a relatively high concentration (10nM) suppressed insulin release. Ghr … More elin attenuated glucose-induced [Ca^<2+>]_i increases and increased delayed outward K^+ currents in single β-cells. These findings demonstrate that endogenous ghrelin in islets restricts glucose-induced insulin release via attenuating Ca^<2+> signaling and that this insulinostatic action is implicated in the upward control of blood glucose.We studied the effects of ghrelin and an anorectic hormone, leptin, on neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC), the neurons playing a central role in feeding. Ghrelin increased [Ca^<2+>]_i in ARC NPY neurons via phospholipase C-, adenylate cyclase- and protein kinase A (PKA)-mediated pathways. Ghrelin-induced [Ca^<2+>]_i increases were suppressed by subsequent administration of leptin. This reciprocal regulation by ghrelin and leptin may play an important role in the control of the ARC NPY neuron activity and, thereby, feeding.This study has revealed a novel function of ghrelin in regulation of insulin release and glucose metabolism and a neural signaling for orexigenic action of ghrelin. Together with the GH-releasing function, ghrelin may underlie the integrative regulation of energy homeostasis. Less