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

内源性生长素释放肽对胰岛素释放、摄食和葡萄糖代谢的调节

• 批准号: 16390053
• 负责人: YADA Toshihiko
• 金额: $ 8.96万
• 依托单位: JICHI MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390053/
• 关键词: ghrelin; insulin release; β-cells; cytosolic Ca^<2+>; plasma glucose; feeding center; NPY neuron; leptin; カルシウム; Kチャネル; 膵灌流; Ca; 膵島; NPY; 摂食; 弓状核

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

在这项研究中，生长素蛋白及其受体，生长本（GH）促促肌感受器（GHS-R）在胰岛中表达。通过腹膜内注射特定的GHS-R拮抗剂对内源性生长素的反射显着降低了空腹葡萄糖浓度，减弱血浆葡萄糖升高和葡萄糖耐受性测试期间胰岛素反应增强。相反，腹膜内外源性生长素素升高的空腹葡萄糖浓度，增强的血浆葡萄糖升高和GTT期间胰岛素反应减弱。在保留完整循环的灌注大鼠胰腺中，GHS-R阻滞和针对生长素蛋白的抗血清增强了葡萄糖诱导的胰岛素释放，而外源性生长素释放了它。在孤立的岛屿中，GHS-R阻滞和生长素蛋白免疫中性化显着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），而在相对较高的浓度（10nm）抑制胰岛素释放下，生长素蛋白。 GHR…更多的Elin减弱了葡萄糖诱导的[Ca^<2+>] _ I在单个β细胞中增加并增加了向外的K^+电流。 These findings demonstrate that endogenous ghrelin in islets restricts glucose-induced insulin release via attenuating Ca^<2+> signaling and that this insulinostatic action is implemented in the upward control of blood glucose.We studied the effects of ghrelin and an anorectic homone, leptin, on neuropeptide Y (NPY) neurons in the hypothalamic arcuate nuclearus （ARC），神经元在喂养中起着核心作用。在ARC NPY神经元中，炎性蛋白通过磷脂酶C-，腺苷酸环化酶和蛋白激酶A（PKA）介导的途径增加了[Ca^<2+>] _ I。加勒林诱导的[Ca^<2+>] _ I增加通过随后的瘦素抑制。生长素蛋白和瘦素的这种相互调节可能在控制弧Npy神经元活性中起重要作用，从而喂养喂养。这项研究揭示了生长素素在调节胰岛素释放和葡萄糖代谢和神经化作用中的新功能，以实现Ghrelelin orexenic ot of ghrelelin的神经剂。与释放GH的功能一起，生长素素可能是能量稳态综合调节的基础。较少的

项目成果

Idenitification of N-arachidonylglacine, U18666A, and 4-androstene-3, 17-dione as novel insulin Secretagogues.

鉴定 N-花生四烯基甘氨酸、U18666A 和 4-雄烯-3, 17-二酮作为新型胰岛素促分泌剂。

• 发表时间: 2005
• 期刊: Biochem Biophys Res Commun 333
• 作者: Hashimoto;M.;Maekawa F;Kuramochi M;Nakata M;Kuramochi M;Kuramochi M;Fujiwara K;Oneka T;Muroya S;Fujiwara K;Nakata M;Ikeda Y
• 通讯作者: Ikeda Y

Galanin-like peptide stimulates vasopressin, oxytocin and ACTH release in rats.

甘丙肽样肽刺激大鼠体内加压素、催产素和促肾上腺皮质激素的释放。

• 发表时间: 2005
• 期刊: Neuroreport 16
• 作者: Hashimoto;M.;Maekawa F;Kuramochi M;Nakata M;Kuramochi M;Kuramochi M;Fujiwara K;Oneka T
• 通讯作者: Oneka T

Orexins (Hypocretins) directly interacts with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca^<2+> signaling in a reciprocal manner to leptin : orexigenic neuronal pathways in the mediobasal hypothalamus.

食欲素(Hypocretins)直接与神经肽Y、POMC和葡萄糖反应性神经元相互作用，以与瘦素互惠的方式调节Ca^2信号传导：中基底下丘脑中的食欲产生神经元通路。

• 发表时间: 2004
• 期刊: Eur.J Neurosci. 19
• 作者: Hashimoto;M.;Maekawa F;Kuramochi M;Nakata M;Kuramochi M;Kuramochi M;Fujiwara K;Oneka T;Muroya S;Fujiwara K;Nakata M;Ikeda Y;Kuramochi M;Onaka T;Fujiwara K;Nakata M;Ikeda Y;Yada T;Fujiwara K;Ikeda Y;Muroya S;Yamada H;Nakata M;Dezaki K;Muroya S
• 通讯作者: Muroya S

Galanin-like peptide increases cytosolic Ca^2+ in neurons containing growth hormone-releasing hormone in the arcuate nucleus.

甘丙肽样肽可增加弓状核中含有生长激素释放激素的神经元中的胞质 Ca^2。

• 发表时间: 2005
• 期刊: Regulatory Peptides 126
• 作者: Hashimoto;M.;Maekawa F;Kuramochi M;Nakata M;Kuramochi M;Kuramochi M
• 通讯作者: Kuramochi M

グレリンと糖脂質代謝

生长素释放肽和糖脂代谢

• 发表时间: 2004
• 作者: Dezaki K;Yada T;Muroya S;Nakata M;Dezaki K;矢田俊彦;出崎克也
• 通讯作者: 出崎克也