Ghrelin : its status as a pancreatic hormone, mechanisms by which it regulates insulin release and glucose metabolism, and its application for treating diabetes.

• Project/Area Number: 20390061
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Jichi Medical University
• Principal Investigator: YADA Toshihiko Jichi Medical University, 医学部, 教授 (60166527)
• Co-Investigator(Kenkyū-buntansha): DEZAKI Katsuya 自治医科大学, 医学部, 准教授 (90337329) ; NAKATA Masanori 自治医科大学, 医学部, 准教授 (10305120) ; KAKEI Masafumi 自治医科大学, 医学部, 教授 (90214270)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2010: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2009: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2008: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: グレリン / cAMP / Kvチャネル / インスリン分泌 / 糖代謝 / 膵島G / HS-R / GKラット / 膵島 / Kチャネル / グルコース / グレリン受容体 / GHS-R / β細胞 / カルシウム

Research Abstract

The effect of ghrelin on islet β-cells was mediated by GHSR, similarly to other organs. Ghrelin, via interacting with GHSR, attenuated glucose-induced cAMP production, which in turn activated Kv channels and attenuated glucose-induced increases in cytosolic Ca^<2+> and insulin secretion. In type 2 diabetic GK rats, ghrelin mRNA expression was elevated and infusion of GHSR receptor antagonist enhanced insulin release and decreased blood glucose levels, indicating an anti-diabetic effect.

Research Products

• [Journal Article] Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca^<2+> influx through L-type channels in mouse isletdd β-cells (2011)
  • Author(s): Nakata M., Manaka K., Yamamoto S., Mori M., Yada T.
  • Journal Title: Endocr.J. 58 Pages: 305-313
  • Peer Reviewed
• [Journal Article] Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice (2011)
  • Author(s): Uchida K., Dezaki K., Damdindorj B., Inada H., Shiuchi T., Mori Y., Yada T., Minokoshi Y., Tominaga M.
  • Journal Title: Diabetes 60 Pages: 119-126
  • Peer Reviewed
• [Journal Article] Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. (2011)
  • Author(s): Uchida K
  • Journal Title: Diabetes Volume: 60 Pages: 119-126
  • Peer Reviewed
• [Journal Article] Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca^<2+> influx through L-type channels in mouse islet β-cells. (2011)
  • Author(s): Nakata M
  • Journal Title: Endocr.J.Epub ahead of print
  • NAID: 10029588379
  • Peer Reviewed
• [Journal Article] Intra-islet PACAP protects pancreatic β-cells against glucotoxicity and lipotoxicity (2010)
  • Author(s): Nakata M., Shintani N., Hashimoto H., Baba A., Yada T.
  • Journal Title: J.Mol.Neurosci 42 Pages: 404-410
  • Peer Reviewed
• [Journal Article] Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic β-cells (2010)
  • Author(s): Yoshida M., Nakata M., Yamato S., Dezaki K., Sugawara H., Ishikawa S., Kawakami M., Yada T., Kakei M.
  • Journal Title: Biochem.Biophys.Res.Commun 396 Pages: 304-309
  • Peer Reviewed
• [Journal Article] Reconstruction-dependent recovery from anorexia and time-related recovery of regulatory ghrelin system in gastrectomized rats (2010)
  • Author(s): Koizumi M., Dezaki K., Hosoda H., Damdindorj B., Sone H., Ming L., Hosoya Y., Sata N., Kobayashi E., Kangawa K., Nagai H., Yasuda Y., Yada T.
  • Journal Title: International J. Peptides 2010 Pages: 10-10
  • Peer Reviewed
• [Journal Article] Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic β-cells. (2010)
  • Author(s): Yoshida M
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 396 Pages: 304-309
  • Peer Reviewed
• [Journal Article] Intra-islet PACAP protects pancreatic β-cells against glucotoxicity and lipotoxicity. (2010)
  • Author(s): Nakata M
  • Journal Title: J.Mol.Neurosci. Volume: 42 Pages: 404-410
  • Peer Reviewed
• [Journal Article] Long-term infusion of brain-derived neurotrophic factor reduces food intake and body weight via a corticotropin-releasing hormone pathway in the paraventricular nucleus of the hypothalamus. (2010)
  • Author(s): Toriya M
  • Journal Title: J.Neuroendocrinology Volume: 22 Pages: 987-995
  • Peer Reviewed
• [Journal Article] Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenalaxis. (2010)
  • Author(s): Yoshida N
  • Journal Title: Aging(Albany NY) Volume: 2 Pages: 775-784
  • Peer Reviewed
• [Journal Article] PDK1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake (2010)
  • Author(s): Iskandar K
  • Journal Title: Am.J.Physiol.Endocrinol.Metab. 298
  • Peer Reviewed
• [Journal Article] Reconstruction-dependent recovery from anorexia and time-related recovery of regulatory ghrelin system in gastrectomized rats (2010)
  • Author(s): Koizumi M
  • Journal Title: International J.Peptides (in press)
  • Peer Reviewed
• [Journal Article] Regulation of voltage-gated K^+ channels by glucose metabolism in pancreatic β-cells (2009)
  • Author(s): Yoshida M., Dezaki K., Yamato S., Aoki A., Sugawara H., Toyoshima H., Ishikawa S., Kawakami M., Nakata M., Yada T., Kakei M.
  • Journal Title: FEBS Lett 583 Pages: 2225-2230
  • Peer Reviewed
• [Journal Article] Peripheral administration of nesfatin-1 reduces food intake in mice : the lentin-independent mechanism (2009)
  • Author(s): Shimizu H
  • Journal Title: Endocrinology 150 Pages: 662-671
  • Peer Reviewed
• [Journal Article] Body fat mass reduction and up-regulation of uncoupling protein by novel lipolysis-promoting plant extract (2009)
  • Author(s): Mori S
  • Journal Title: Int.J.Biol.Sci. 5 Pages: 311-318
  • Peer Reviewed
• [Journal Article] A selective small molecule GLP-1 secretagogue acting via depolarization and Ca^<2+> influx (2009)
  • Author(s): Eiki J
  • Journal Title: J.Endocrinology 201 Pages: 361-367
  • Peer Reviewed
• [Journal Article] Regulation of voltage-gated K^+ channels by glucose metabolism in pancreatic β-cells (2009)
  • Author(s): Yoshida M
  • Journal Title: FEBS Lett. 583 Pages: 2225-2230
  • Peer Reviewed
• [Journal Article] Nesfatin-1 evokes Ca^<2+> signaling in isolated vagal afferent neurons via Ca^<2+> influx through N-type channels (2009)
  • Author(s): Iwasaki Y
  • Journal Title: Biochem.Biophys.Res.Commun. 390 Pages: 958-962
  • Peer Reviewed
• [Journal Article] Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway (2009)
  • Author(s): Maejima Y
  • Journal Title: Cell Metabolism 10 Pages: 355-365
  • Peer Reviewed
• [Journal Article] Enhancement of lipolytic responsiveness of adipocytes by novel plant extract in rat (2009)
  • Author(s): Mori S
  • Journal Title: Exp.Biol.Med.(Maywood) 234 Pages: 1445-1449
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 矢田俊彦
  • Journal Title: 日本肥満学会誌:肥満研究 中枢グルコース感知と全身代謝・摂食調節:開拓的研究とその継承(日本肥満学会) Pages: 14-19
• [Journal Article] Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis (2008)
  • Author(s): Dezaki K., Sone H., Yada T.
  • Journal Title: Pharmacol.Ther 118 Pages: 239-249
  • Peer Reviewed
• [Journal Article] Leptin transiently antagonizes ghrelin and long-lastingly orexin in regulation of Ca^<2+> signaling in neuropeptide Y neurons of the arcuate nucleus. (2008)
  • Author(s): Kohno D
  • Journal Title: World J Gastroenterol. 14 Pages: 6347-6354
  • Peer Reviewed
• [Journal Article] Endogenous prolactin-releasing peptide regulates food intake in rodents. (2008)
  • Author(s): Takayanagi Y
  • Journal Title: J Clin. Invest. 118 Pages: 4014-4244
  • Peer Reviewed
• [Journal Article] Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. (2008)
  • Author(s): Dezaki K
  • Journal Title: Pharmacol. Therapeut. 118 Pages: 239-249
  • Peer Reviewed
• [Presentation] グレリンによる膵ランゲルハンス島β細胞の新しいインスリン分泌制御 (2011)
  • Author(s): 出崎克也, 矢田俊彦
  • Organizer: 第88回日本生理学会大会第116回日本解剖学会総会・全国学術集会合同大会28-29
  • Place of Presentation: 横浜
• [Presentation] グレリンによる膵ランゲルハンス島β細胞の新しいインスリン分泌制御 (2011)
  • Author(s): 出崎克也
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会合同大会
  • Place of Presentation: 横浜
• [Presentation] 視床下部室傍核の新規摂食調節因子 (2011)
  • Author(s): 前島裕子
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会合同大会
  • Place of Presentation: 横浜
• [Presentation] インスリンによるインスリン受容体カスケードを介した求心性迷走神経細胞Ca^<2+>シグナリング (2011)
  • Author(s): 岩崎有作
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会合同大会
  • Place of Presentation: 横浜
• [Presentation] TRPM2は細胞内Ca^<2+>濃度変化依存的及び非依存的にインスリン分泌を促進する (2011)
  • Author(s): 内田邦敏
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会合同大会
  • Place of Presentation: 横浜
• [Presentation] Kv2.1-channel currents are mediated by phosphorylation of the channels during glucose stimulation (2010)
  • Author(s): 吉田昌史, 出崎克也, 青木厚, 豊島秀男, 石川三衛, 川上正舒, 中田正範, 矢田俊彦., 加計正文
  • Organizer: The American Diabetes Association 70th scientific sessions Abstracts: Diabetes:59(suppl. 1)A454, 2010
  • Place of Presentation: Orlando, USA
• [Presentation] グレリンによるβ細胞Kv2.1チャネル活性化を介したグルコース誘発インスリン分泌抑制 (2010)
  • Author(s): 出崎克也, Damdindorj Boldbaatar, 加計正文, 矢田俊彦
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] 膵β細胞Kv2.1チャネルの代謝依存性調節機構 (2010)
  • Author(s): 加計正文, 吉田昌史, 出崎克也, 青木厚, 菅原斉, 豊島秀男, 石川三衛, 川上正舒, 中田正範, 矢田俊彦
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] グレリンによるインスリン分泌制 (2010)
  • Author(s): 出崎克也, Damdindorj Boldbaatar, 加計正文, 矢田俊彦
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] TRPM2とインスリン分泌 (2010)
  • Author(s): 内田邦敏, 出崎克也, Damdindorj Boldbaatar, 森泰生, 箕越靖彦, 矢田俊彦, 富永真琴
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] Ghrelin receptor antagonist improves glucose intolerance in type 2 diabetic GK rats. (2010)
  • Author(s): Damdindorj B., Dezaki K., Sone H., Yaguchi T., Kakei M., Yada T.
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: Kyoto, Japan
• [Presentation] Kv2.1-channel currents are mediated by phosphorylation of the channels during glucose stimulation. (2010)
  • Author(s): Yoshida M
  • Organizer: The American Diabetes Association 70^<th> scientific sessions(Diabetes : 59(suppl.1)A454)
  • Place of Presentation: Orlando, Florida
• [Presentation] Nesfatin-1-regulated oxytocinergic signalling in the paraventricular nucleus causes anorexia via melanocortin pathway. (2010)
  • Author(s): Maejima Y
  • Organizer: 46^<th> EASD Annual Meeting
  • Place of Presentation: Stockholm, Sweden
• [Presentation] 視床下部Nesfatin-1によるOxytocin・POMC依存性摂食抑制経路 (2010)
  • Author(s): 矢田俊彦
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] グレリンによるインスリン分泌制御 (2010)
  • Author(s): 出崎克也
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] Nesfatin-1は求心性迷走神経細胞の細胞内Ca^<2+>濃度を上昇させる:末梢Nesfatin-1の摂食抑制経路 (2010)
  • Author(s): 岩崎有作
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] 膵島内インスリン分泌促進因子としてのNesfatin-1 (2010)
  • Author(s): 中田正範
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] AAV1-mediated IL-10 gene-delivery improves glucose and energy metabolism in high-fat diet-induced obese mice. (2010)
  • Author(s): Nakata M
  • Organizer: 第16回日本遺伝子治療学会学術集会
  • Place of Presentation: 宇都宮
• [Presentation] 視床下部室傍核Nesfatin-1はレプチン非依存性にOxytocin-POMC摂食抑制経路を作動する (2010)
  • Author(s): 矢田俊彦
  • Organizer: 第28回内分泌代謝学サマーセミナー
  • Place of Presentation: 長崎
• [Presentation] Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes melanocortin-dependent anorexia. (2010)
  • Author(s): Udval Sedbazar
  • Organizer: 日本味と匂学会第44回大会
  • Place of Presentation: 北九州
• [Presentation] Nesfatin-1はオキシトシン-メラノコルチン系を介して摂食抑制する (2010)
  • Author(s): 前島裕子
  • Organizer: 第31回日本肥満学会
  • Place of Presentation: 前橋
• [Presentation] インスリンによる求心性迷走神経細胞活性化とシグナル伝達 (2010)
  • Author(s): 岩崎有作
  • Organizer: 第31回日本肥満学会
  • Place of Presentation: 前橋
• [Presentation] AgRPニューロンによる骨代謝 (2010)
  • Author(s): 笹沼秀幸
  • Organizer: 第25回日本整形外科学会基礎学術集会
  • Place of Presentation: 京都
• [Presentation] 中枢・交感神経の調節異常と食塩感受性 (2010)
  • Author(s): 矢田俊彦
  • Organizer: 第67回日本循環器心身医学会
  • Place of Presentation: 自治医科大学
• [Presentation] Ghrelin receptor antagonist improves glucose intolerance in type 2 diabetic GK rats (2010)
  • Author(s): Damdindorj B
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: Kyoto, Japan
• [Presentation] Ghrelin receptor antagonist enhances glucose-induced insulin release in type 2 diabetic GK rats (2009)
  • Author(s): Damdindorj B., Dezaki K.,Sone H., Yaguchi T., Kakei M., Yada T.
  • Organizer: The 2009 International Symposium on Ghrelin
  • Place of Presentation: Tokyo, Japan
• [Presentation] Ghrelin activates voltage-dependent K^+ channels by modulation of cAMP/PKA signaling in islet β-cells (2009)
  • Author(s): Dezaki K., Damdindorj B., Yoshida M., Kakei M., Yada T.
  • Organizer: The 2009 International Symposium on Ghrelin
  • Place of Presentation: Tokyo, Japan
• [Presentation] Excessive expression and activity of Kv2.1 channels in islet β-cells of type 2 diabetic GK rats (2009)
  • Author(s): Dezaki K., Damdindorj B., Ando A., Yoshida M., Kakei M., Yada T.
  • Organizer: 45^<th> EASD Annual Meeting
  • Place of Presentation: Vienna, Austria
• [Presentation] Kv2.1 channel blockers enhance glucose-induced cytosolic Ca^<2+> increases and insulin release in islet β-cells of type 2 diabetic rats (2009)
  • Author(s): Dezaki K., Damdindorj B., Kakei M., Yada T.
  • Organizer: The 36th International Congress of Physiological Sciences (IUPS)
  • Place of Presentation: Kyoto, Japan
• [Presentation] Ghrelin receptor antagonist potentiates glucose-induced insulin release in diabetic GK rats (2009)
  • Author(s): Damdindorj B., Dezaki K., Sone H., Kakei M., Yada T.
  • Organizer: The 36th International Congress of Physiological Sciences (IUPS)
  • Place of Presentation: Kyoto, Japan
• [Presentation] Ghrelin receptor antagonist potentiates glucose-induced insulin release in diabetic GK rats (2009)
  • Author(s): Damdindorj B
  • Organizer: The 36th International Congress of Physiological Sciences(IUPS)
  • Place of Presentation: Kyoto, Japan
• [Presentation] Kv2.1 channel blockers enhance glucose-induced cytosolic Ca^<2+> increases and insulin release in islet β-cells of type 2 diabetic rats (2009)
  • Author(s): Dezaki K
  • Organizer: The 36th International Congress of Physiological Sciences(IUPS)
  • Place of Presentation: Kyoto, Japan
• [Presentation] グレリンによるβ細胞Kvチャネル活性化を介したグルコース誘発インスリン分泌抑制 (2008)
  • Author(s): 出崎克也, Damdindorj Boldbaatar, 加計正文, 矢田俊彦
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Book] 膵臓の内分泌機能と炭水化物代謝の調節(翻訳).Inギャノング生理学.原書23版 (2011)
  • Author(s): 矢田俊彦
  • Publisher: 丸善出版株式会社
• [Book] 糖尿病ナビゲーター(インスリン分泌におけるカルシウムシグナリングの役割)(門脇孝(編))第2版 (2010)
  • Author(s): 出崎克也,中田正範,矢田俊彦
  • Publisher: メディカルビュー社
• [Book] その他のインクレチン.In DPP-4阻害薬のすべて (2010)
  • Author(s): 中田正範
  • Publisher: 先端医学社
• [Book] インスリン分泌におけるカルシウムシグナリングの役割.In 糖尿病ナビゲーター第2版 (2010)
  • Author(s): 出崎克也
  • Publisher: メディカルビュー社
• [Book] 糖尿病学グレリンによるインスリン分泌 (2008)
  • Author(s): 出崎克也、曽根英行、矢田俊彦
  • Publisher: 診断と治療社
• [Book] 糖尿病学「グレリンによるインスリン分泌」 (2008)
  • Author(s): 出崎克也
  • Publisher: 診断と治療社
• [Remarks] ホームページ等
  • URL: http://www.jichi.ac.jp/physio2/physiol_new_HP2008/index.htm
• [Remarks] 掲載ホームページ名?URL
• [Remarks] 産経新聞
  • URL: http://www.iza.ne.jp/news/newsarticle/natnews/science/320306/
• [Remarks] 山陽新聞
  • URL: http://svr.sanyo.oni.co.jp/news_k/news/d/2009110301000308/
• [Remarks] 読売新聞
  • URL: http://osaka.yomiuri.co.jp/university/research/20091119-OYO8T00659.htm
• [Remarks] 京都新聞
  • URL: http://kyoto-np.jp/article.php?mid=P2009110400017&genre=G1&area=Z10
• [Remarks]
  • URL: http://www.jichi.ac.jp/physio2/physiol_new_HP2008/index.htm
• [Remarks]
  • URL: http://www.jichi.ac.jp/physio2/physiol_new_HP2008/index.htm
• [Patent(Industrial Property Rights)] 組成物?保護/再生促進組成物?及びCamp産生促進組成物 (2009)
  • Inventor(s): 矢田俊彦(届出・代表)、出崎克也
  • Industrial Property Rights Holder: 自治医科大学
  • Filing Date: 2009-05-27
• [Patent(Industrial Property Rights)] 組成物、保護/再生促進組成物、及び Camp 産生促進組成物 (2009)
  • Inventor(s): 矢田俊彦(届出・代表)
  • Industrial Property Rights Holder: 自治医科大学
  • Industrial Property Number: 2009-127901
  • Filing Date: 2009-05-27