A study of neuronal and hormonal mediations of insulin secretion by inretins.

• Project/Area Number: 24591340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: KAKEI Masafumi 自治医科大学, 医学部, 教授 (90214270)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: insulin secretion / incretin / diabetes / membrane potential / インスリン分泌 / 糖尿病 / 膜電位機構 / TRPチャネル / グルコース刺激インスリン分泌 / インクレチン / イオンチャネル

Outline of Final Research Achievements

In this stduy, we clarified the mechanistic pathway for stimulation of insulin secretion by incretins that include GLP-1 and GIP. These hormones open TRPM2 channel (transient receptor potential channe) that is a class of background current channel and its openings evoke increase in membrane excitability of pancreatic beta cells and consequently potentiate insulin secretion induced by glucose. We are expecting a novel antidiabetic drugs development as a target site against this channel protein.

Research Products

• [Journal Article] Partial Blockade of Kv2.1 Channel Potentiates GLP-1's Insulinotropic Effects in Islets and Reduces Its Dose Required for Improving Glucose Tolerance in Type 2 Diabetic Male Mice. (2015)
  • Author(s): Sukma Rita, R., K. Dezaki, T. Kurashina, M. Kakei, and T. Yada,
  • Journal Title: Endocrinology. Volume: Endocrinology. 1(1): Issue: 1 Pages: 114-123
  • DOI: 10.1210/en.2014-1728
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity. (2015)
  • Author(s): Iwasaki, Y., Y. Maejima, S. Suyama, M. Yoshida, T. Arai, K. Katsurada, P. Kumari, H. Nakabayashi, M. Kakei, and T. Yada,
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. Volume: 308 Issue: 5 Pages: R360-R369
  • DOI: 10.1152/ajpregu.00344.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prediction of 90-day mortality in patients without diabetes by severe hypoglycemia: blood glucose level as a novel marker of severity of underlying disease. (2015)
  • Author(s): Tsujimoto, T., R. Yamamoto-Honda, H. Kajio, M. Kishimoto, H. Noto, R. Hachiya, A. Kimura, M. Kakei, and M. Noda,
  • Journal Title: Acta Diabetol. Volume: 52 Issue: 2 Pages: 307-314
  • DOI: 10.1007/s00592-014-0640-9
  • Peer Reviewed
• [Journal Article] Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion (2014)
  • Author(s): Yoshida M, Dezaki K, Uchida K, Kodera S, Lam NV, Ito K, Rita RS, Yamada H, Shimomura K, Ishikawa SE, Sugawara H, Kawakami M, Tominaga M, Yada T, Kakei M
  • Journal Title: Diabetes Volume: (Epub ahead of print) Issue: 10 Pages: 3394-3403
  • DOI: 10.2337/db13-1868
  • NAID: 40020531124
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion. (2014)
  • Author(s): Masashi Yoshida, Katsuya Dezaki, Kunitoshi Uchida, Shiho Kodera, Nien V. Lam, Kiyonori Ito, Rauza S. Rita, Hodaka Yamada, Kenju Shimomura, San-e Ishikawa, Hitoshi Sugawara, Masanobu Kawakami, Makoto Tominaga, Toshihiko Yada Masafumi Kakei1
  • Journal Title: Diabetes Volume: in press
  • Peer Reviewed
• [Journal Article] Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. (2014)
  • Author(s): Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, Kimura A, Kakei M, Noda M:
  • Journal Title: Diabetes Care Volume: 37 Pages: 217-225
  • Peer Reviewed
• [Journal Article] Serotonin regulates glucose-stimulated insulin secretion from pancreatic beta cells during pregnancy (2013)
  • Author(s): Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, Nakamichi Y, Nishiwaki C, Okamura T, Uchida T, Fujitani Y, Akagawa K, Kakei M, Watada H, German MS, Nagamatsu S:
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 19420-19425
  • Peer Reviewed
• [Journal Article] Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca2+ Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity. (2013)
  • Author(s): Iwasaki Y1, Shimomura K, Kohno D, Dezaki K, Ayush EA, Nakabayashi H, Kubota N, Kadowaki T, Kakei M, Nakata M, Yada T.
  • Journal Title: PLoS One. Volume: 8
  • Peer Reviewed
• [Journal Article] Inhibition of insulin secretion from rat pancreatic islets by dexmedetomidine and medetomidine, two sedatives frequently used in clinical settings (2013)
  • Author(s): Yamato Kodera, S., Yoshida, M., Dezaki, K., Yada, T., Murayama, T., Kawakami, M., and Kakei, M.
  • Journal Title: Endocr J Volume: 60 Pages: 337-346
  • NAID: 10031170619
• [Journal Article] alpha-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs (2013)
  • Author(s): Kumazaki, M., Ando, H., Kakei, M., Ushijima, K., Taniguchi, Y., Yoshida, M., Yamato, S., Washino, S., Koshimizu, T.A., and Fujimura, A
  • Journal Title: Eur J Pharmacol Volume: 705 Pages: 1-10
• [Journal Article] Pancreatic polypeptide and peptide YY3-36 induce Ca2+ signaling in nodose ganglion neurons (2013)
  • Author(s): Iwasaki, Y., Kakei, M., Nakabayashi, H., Ayush, E.A., Hirano-Kodaira, M., Maejima, Y., and Yada, T.
  • Journal Title: Neuropeptides Volume: 47 Pages: 19-23
• [Journal Article] Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet beta-cells (2012)
  • Author(s): Damdindorj, B., Dezaki, K., Kurashina, T., Sone, H., Rita, R., Kakei, M., and Yada, T.
  • Journal Title: FEBS Lett Volume: 586 Pages: 2555-2562
• [Presentation] 膵β細胞Trpm2チャネルはインクレチンホルモン・グルコース代謝依存性に開港し、インスリン分泌を刺激する (2014)
  • Author(s): 吉田昌史、出崎克也、中田正範、山田穂高、石川三衛、矢田俊彦、川上正舒、加計正文
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] GRP40/FFR1を介する新規インスリン分泌メカニズム (2014)
  • Author(s): 山田穂高、吉田昌史、伊藤聖学、川上正舒、矢田俊彦、石川三衛、加計正文
  • Organizer: 第57回日本糖尿病学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] 膵β細胞Trpm2チャネルは，インクレチンホルモン・グルコース代謝依存性に開口し，インスリン分泌を 促進する (2014)
  • Author(s): 吉田昌史
  • Organizer: 日本糖尿病学会
  • Place of Presentation: 大阪
• [Presentation] Serotonin Regulates Glucose Stimulated Insulin Secretion from Pancreatic β-Cells during Pregnancy (2013)
  • Author(s): MICA OHARA-IMAIZUMI, HAIL KIM, MASASHI YOSHIDA, YUKIKO TOYOFUKU, TADASHI OKAMURA, TOYOYOSHI UCHIDA, YOSHIO FUJITANI, MASAFUMI KAKEI, HIROTAKA WATADA, MICHAEL S. GERMAN, SHINYA NAGAMATSU,
  • Organizer: 73rd Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago
• [Presentation] Activation of Trpm2 Channel by Glucose Metabolism and GLP-1 in Pancreatic Beta-Cell (2013)
  • Author(s): MASASHI YOSHIDA, SHIHO YAMATO, KATSUYA DEZAKI, MASANOBU KAWAKAMI, TOSHIHIKO YADA, MASAFUMI KAKEI
  • Organizer: 73rd Scientific Session of American Diabetes Association
  • Place of Presentation: Chicago
• [Presentation] 膵β細胞グルコース刺激活動電位形成持のCa2+依存性Kv2.1チャネルの役割 (2012)
  • Author(s): 吉田昌史、中田正範、大和志保、出崎克也、石川三衛、川上正舒、矢田俊彦、加計正文
  • Organizer: 第55回日本糖尿病学会
  • Place of Presentation: 横浜
• [Presentation] 妊娠期膵β細胞でのセロトニンによるインスリン分泌亢進機構 (2012)
  • Author(s): 今泉美佳、吉田昌史、豊福優希子、青柳共太、中道洋子、西脇知世乃、加計正文、綿田裕孝、永松信哉
  • Organizer: 第55回日本糖尿病学会
  • Place of Presentation: 横浜