Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in β-cells -: Implication in the glycemic control in rodents
Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in β-cells -: Implication in the glycemic control in rodents
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DOI：
10.2337/diabetes.53.12.3142
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Yada, T
中科院分区：
文献类型：
--
作者：
Dezaki, K;Hosoda, H;Yada, T
从人和大鼠胃中分离出的胃饥饿素（Ghrelln）是生长激素促分泌素受体的内源性配体，该受体在包括胰岛在内的多种组织中表达。研究表明，血浆胃饥饿素水平低与空腹胰岛素水平升高和2型糖尿病相关。在此我们展示了内源性胃饥饿素在调节啮齿动物胰岛素释放和血糖方面的生理作用。在胰岛中检测到了酰化胃饥饿素，即该肽的活性形式。通过腹腔注射特异性生长激素促分泌素受体拮抗剂来拮抗内源性胃饥饿素，可显著降低空腹血糖浓度，减弱葡萄糖耐量试验（GTT）期间的血糖升高，并增强胰岛素反应。相反，腹腔外源性胃饥饿素不依赖生长激素而升高空腹血糖浓度，增强GTT期间的血糖升高，并减弱胰岛素反应。生长激素促分泌素受体拮抗剂和胃饥饿素均不影响胰岛素耐量试验的曲线。在分离的胰岛中，生长激素促分泌素受体阻断和抗酰化胃饥饿素血清显著增强葡萄糖诱导的胰岛素释放和细胞内Ca2+浓度（[Ca2+](i)）的增加，而相对高浓度（10 nmol/L）的胃饥饿素则抑制胰岛素释放。在单个β细胞中，胃饥饿素通过生长激素促分泌素受体并以百日咳毒素敏感的方式减弱葡萄糖诱导的第一相和振荡性[Ca2+](i)增加。胃饥饿素还增加了单个β细胞中对四乙铵敏感的延迟外向K+电流。这些发现表明，胰岛中的内源性胃饥饿素作用于β细胞，至少部分通过减弱Ca2+信号传导来限制葡萄糖诱导的胰岛素释放，并且这种胰岛素抑制作用可能与血糖的升高调控有关。胃饥饿素的这一功能，连同其诱导生长激素释放和进食的作用，表明胃饥饿素是能量稳态综合调控的基础。
Ghrelln, isolated from the human and rat stomach, is the endogenous ligand for the growth hormone (GH) secretagogue receptor, which is expressed in a variety of tissues, including the pancreatic islets. It has been shown that low plasma ghrelin levels correlates with elevated fasting insulin levels and type 2 diabetes. Here we show a physiological role of endogenous ghrelin in the regulation of insulin release and blood glucose in rodents. Acylated ghrelin, the active form of the peptide, was detected in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GH secretagogue receptor antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation, and enhanced insulin responses during the glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin GH-independently elevated fasting glucose concentrations, enhanced plasma glucose elevation, and attenuated insulin responses during GTT. Neither GH secretagogue receptor antagonist nor ghrelin affected the profiles of the insulin tolerance test. In isolated islets, GH secretagogue receptor blockade and antiserum against acylated ghrelin markedly enhanced glucose-induced increases in insulin release and intracellular Ca2+ concentration ([Ca2+](i)), whereas ghrelin at a relatively high concentration (10 nmol/l) suppressed insulin release. In single beta-cells, ghrelin attenuated glucose-induced first-phase and oscillatory [Ca2+](i) increases via the GH secretagogue receptor and in a pertussis toxin-sensitive manner. Ghrelin also increased tetraethylanmonium-sensitive delayed outward K+ currents in single beta-cells. These findings reveal that endogeous ghrelin in islets acts on beta-cells to restrict glucoseinduced insulin release at least partly via attenuation of Ca2+ signaling, and that this insulinostatic action may be implicated in the upward control of blood glucose. This function of ghrelin, together with inducing GH release and feeding, suggests that ghrelin underlies the integrative regulation of energy homeostasis.