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

本研究中，胃饥饿素及其受体生长激素（GH）分泌激素受体（GHS-R）在胰岛中表达。在葡萄糖耐量试验（GTT）中，通过腹腔注射特异性GHS-R拮抗剂来对抗内源性ghrelin可显著降低空腹葡萄糖浓度，减轻血浆葡萄糖升高，增强胰岛素反应。相反，在GTT期间，腹腔内外源性胃饥饿素升高空腹葡萄糖浓度，增强血浆葡萄糖升高，减弱胰岛素反应。在保持完整循环的灌注大鼠胰腺中，GHS-R阻断和抗胃饥饿素血清增强了葡萄糖诱导的胰岛素释放，而外源性胃饥饿素抑制了胰岛素释放。在离体胰岛中，GHS-R阻断和ghrelin免疫中和显著增强了葡萄糖诱导的胰岛素释放和胞质Ca^<2+>浓度的增加（[Ca^<2+>]_i），而ghrelin在相对高浓度（10nM）时抑制胰岛素释放。在单个β-细胞中，更多的elin减薄葡萄糖诱导的[Ca^<2+>]_i增加和延迟的外向K^+电流增加。这些发现表明，胰岛内的内源性胃饥饿素通过减弱Ca^<2+>信号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升高有关。我们研究了胃饥饿素和一种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，这些神经元在进食中起着核心作用。Ghrelin通过磷脂酶C-、腺苷酸环化酶-和蛋白激酶A （PKA）介导的途径增加ARC NPY神经元[Ca^<2+>]_i。随后给予瘦素可抑制ghrelin诱导的[Ca^<2+>]_i升高。ghrelin和leptin的这种相互调节可能在ARC NPY神经元活动的控制中发挥重要作用，从而控制摄食。本研究揭示了胃饥饿素在调节胰岛素释放和葡萄糖代谢中的新功能，以及胃饥饿素在促氧作用中的神经信号。与gh释放功能一起，ghrelin可能是能量稳态综合调节的基础。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