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，生长激素释放肽及其受体，生长激素（GH）促分泌素受体（GHS-R），表达在胰岛。通过腹腔注射特异性GHS-R拮抗剂对抗内源性ghrelin，可显著降低空腹血糖浓度，减弱血糖升高，并增强葡萄糖耐量试验（GTT）期间的胰岛素反应。相反，腹膜内外源性ghrelin升高空腹血糖浓度，增强血糖升高和减弱胰岛素反应在GTT。在保持完整循环的灌流大鼠胰腺中，GHS-R阻断和ghrelin抗血清可增强葡萄糖诱导的胰岛素释放，而外源性ghrelin可抑制该作用;在离体胰岛中，GHS-R阻断和ghrelin免疫中和可显著增强葡萄糖诱导的胰岛素释放和胞浆Ca^2+浓度的增加（[Ca^<2+>]_i），而ghrelin在相对高的浓度（10 nM）抑制胰岛素释放。GHR ...更多信息 在单个β细胞中，elin可减弱葡萄糖诱导的[Ca^<2+>]_i增加和延迟外向K^+电流增加。这些发现表明，胰岛中内源性ghrelin通过减弱Ca^2+信号抑制葡萄糖诱导的胰岛素释放，并且这种胰岛素抑制作用与血糖的向上控制有关。我们研究了ghrelin和厌食激素leptin对下丘脑弓状核（ARC）中神经肽Y（NPY）神经元的影响，该神经元在摄食中起核心作用。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神经元内[Ca^<2+>] i。Ghrelin诱导的[Ca^<2+>]_i升高被随后给予瘦素抑制。Ghrelin和leptin的这种相互调节可能在控制ARC NPY神经元活动中发挥重要作用，从而，feeding.This研究揭示了一种新的功能，ghrelin在调节胰岛素释放和葡萄糖代谢和食欲的神经信号ghrelin的行动。生长激素释放肽与生长激素释放肽共同参与能量平衡的综合调节。少

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

GABA regulates glucosensitive NPY neurons in arcuate nucleus via A/B receptors.

GABA 通过 A/B 受体调节弓状核中的葡萄糖敏感性 NPY 神经元。

• 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;Muroya S
• 通讯作者: Muroya S

Oleic acid interacts with GPR40 to induce Ca^2+ signaling in rat islet β-cells : mediation by phospholipase C and L-type Ca^2+ channel and link to insulin release.

油酸与 GPR40 相互作用，诱导大鼠胰岛 β 细胞中的 Ca^2+ 信号传导：通过磷脂酶 C 和 L 型 Ca^2+ 通道介导，并与胰岛素释放相关。

• 发表时间: 2005
• 期刊: Am J Physiol (Endocrinol Metab) 289
• 作者: Hashimoto;M.;Maekawa F;Kuramochi M;Nakata M;Kuramochi M;Kuramochi M;Fujiwara K;Oneka T;Muroya S;Fujiwara K
• 通讯作者: Fujiwara K

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

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