IKdelay is related to a novel GLP-1 pathway that is KATP-independent insulin secretion.

• Project/Area Number: 20591071
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: KAKEI Masafumi Jichi Medical University, 医学部, 教授 (90214270)
• Co-Investigator(Kenkyū-buntansha): YADA Toshihiko 自治医科大学, 医学部, 教授 (60166527)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エネルギー / 糖質代謝異常 / Kvチャネル / 膵β細胞 / 膜電位 / インスリン分泌 / 脱リン酸化 / カルシニューリン / 膜電位固定

Research Abstract

IKdelay in pancreatic β-cells plays important roles in glucose-stimulated insulin secretion. IKdelay current is active during action potentials produced by glucose stimulation. Amplitudes of IKdelay are increased by increasing glucose concentrations from 2.8mM to 16.7mM. These increases were observed only at positive potentials were accompanied by the current decreases in the ranges of negative potentials. Conversely glucose reduction or metabolic inhibition by using FCCP, AMPPNP or 0mM ATP exposure at cytoplasm produced IKdelay increases at negative potentials associated with current decreases at positive potentials. We further observed the similar results in the HEK293 cells expressed with Kv2.1 channels during metabolic inhibition. Exposure to alkaline phosphatase at the cytoplasm showed current increases at negative potentials in Kv2.1 channel-expressed HEK293 cells. Thus, IKdelay changes observed in pancreatic β-cells during metabolic inhibition were resulted from the dephosphorylation of Kv2.1 channels because the channel protein has amino acid residues that can be highly phosphorylated at basal state. We concluded that Kv2.1 channel current is regulated by phosphorylation/dephosphorylation of the channel. These results may suggest that Kv2.1 channel regulation is involved in GLP-1 effect that is revealed with increases insulin secretion in the presence of the hormone.

Research Products

• [Journal Article] Circulating osteocalcin is increased in early-stage diabetes. (2011)
  • Author(s): Aoki, A., Muneyuki, T., Yoshida, M., Munakata, H., Ishikawa, S. E., Sugawara, H., Kawakami, M., Kakei, M.
  • Journal Title: Journal
• [Journal Article] Low serum amylase in association with metabolic syndrome and diabetes : A community-based study. (2011)
  • Author(s): Nakajima, K., Nemoto, T., Muneyuki, T., Kakei, M., Fuchigami, H., Munakata, H.
  • Journal Title: Journal 10 Pages: 34-34
  • NAID: 120005518443
• [Journal Article] Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic beta-cells. (2010)
  • Author(s): Yoshida, M., Nakata, M., Yamato, S., Dezaki, K., Sugawara, H., Ishikawa, S. E., Kawakami, M., Yada, T., Kakei, M.
  • Journal Title: Journal 396 Pages: 304-309
• [Journal Article] Class IA phosphatidylinositol 3-kinase in pancreatic beta cells controls insulin secretion by multiple mechanisms. (2010)
  • Author(s): Kaneko, K., Ueki, K., Takahashi, N., Hashimoto, S., Okamoto, M., Awazawa, M., Okazaki, Y., Ohsugi, M., Inabe, K., Umehara, T., Yoshida, M., Kakei, M., Kitamura, T., Luo, J., Kulkarni, R. N., Kahn, C. R., Kasai, H., Cantley, L. C., Kadowaki, T.
  • Journal Title: Journal 12 Pages: 619-632
• [Journal Article] Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. (2010)
  • Author(s): Ohara-Imaizumi, M., Yoshida, M., Aoyagi, K., Saito, T., Okamura, T., Takenaka, H., Akimoto, Y., Nakamichi, Y., Takanashi-Yanobu, R., Nishiwaki, C., Kawakami, H., Kato, N., Hisanaga, S., Kakei, M., Nagamatsu, S.
  • Journal Title: Journal 5
• [Journal Article] Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic beta-cells. (2010)
  • Author(s): Yoshida M, Nakata M, Yamato S, Dezaki K, Sugawara H, Ishikawa SE, Kawakami M, Yada T, Kakei M
  • Journal Title: Biochem Biophys Res Commun Volume: 396 Pages: 304-309
  • Peer Reviewed
• [Journal Article] Class IA phosphatidylinositol 3-kinase inpancreatic β cells controls insulin secretion by multiple mechanisms. (2010)
  • Author(s): Kaneko K, Ueki K, Takahashi N, Hashimoto S, Okamoto M, Awazawa M, Okazaki Y, Ohsugi M, Inabe K, Umehara T, Yo shida M, Kakei M, Kitamura T, Luo J, Kulkarni RN, Kahn CR, Kasai H, Cantley LC, Kadowaki T
  • Journal Title: Cell Metab. Volume: 12 Pages: 619-632
  • Peer Reviewed
• [Journal Article] Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. (2010)
  • Author(s): Ohara-Imaizumi M, Yoshida M, Aoyagi K, Saito T, Okamura T, Takenaka H, Akimoto Y, Nakamichi Y, Takanashi-Yanobu R, Nishiwaki C, Kawakami H, Kato N, Hisanaga S, Kakei M, Nagamatsu S.
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] Regulation of voltage-gated K+ channels by glucose metabolism in pancreatic beta-cells. (2009)
  • Author(s): Yoshida, M., Dezaki, K., Yamato, S., Aoki, A., Sugawara, H., Toyoshima, H., Ishikawa, S. E., Kawakami, M., Nakata, M., Yada, T., Kakei, M.
  • Journal Title: Journal 583 Pages: 2225-2230
• [Journal Article] Regulation of voltage-gated K^+ channels by glucose metabolism in pancreatic beta-cells (2009)
  • Author(s): M.Yoshida, K.Dezaki, S.Yamato, A.Aoki, H.Sugawara, H.Toyoshima, S.E.Ishikawa, M.Kawakami, M.Nakata, T.Yada, M.Kakei
  • 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): Y.Iwasaki, H.Nakabayashi, M.Kakei, H.Shimizu, M.Mori, T.Yada
  • Journal Title: Biochem Biophys Res Commun 390 Pages: 958-962
  • NAID: 120001871396
  • Peer Reviewed
• [Journal Article] Ghrelin regulates insulin release and glycemia : physiological role and therapeutic potential. (2008)
  • Author(s): Yada T, Dezaki K, Sone H, Koizumi M, Damdindorj B, Nakata M, Kakei M
  • Journal Title: Curr Diabetes Rev. 4(1) Pages: 18-23
  • Peer Reviewed
• [Journal Article] Nesfatin-1 evokes Ca(2+) signaling in isolated vagal afferent neurons via Ca(2+) influx through N-type channels.
  • Author(s): Iwasaki, Y., Nakabayashi, H., Kakei, M., Shimizu, H., Mori, M., Yada, T.
  • Journal Title: Journal 2009
  • NAID: 120001871396
• [Presentation] Voltage-gated Potassium Channels in Pancreatic β-cells are Regulated via Phosphorylation/dephosphorylatio and Divalent Cations. (2011)
  • Author(s): Yoshida M, Yamato S, Nakata M, Ishikawa S, Kawakami M, Yada, T, Kakei M
  • Organizer: 71^<st> The Meeting of Amereican Diabetes Association
  • Place of Presentation: San-Diaego
• [Presentation] シンポジウム9:膵β細胞研究の最前線(1)「インスリン分泌」Cell metabolism-dependent regulation of Kv channels in pancreatic β-cells. (2010)
  • Author(s): 加計正文、吉田昌史、大和志保、石川三衛、川上正舒
  • Organizer: 第53回日本糖尿病学会総会
  • 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、豊島秀雄、石川三衛、川上正舒、中田正範、矢田俊彦
  • Organizer: 第53回日本糖尿病学会総会
  • Place of Presentation: 岡山
• [Presentation] Kv2.1-channel currents are mediated by phosphorylation of the channels during glucose stimulation (2010)
  • Author(s): Yoshida M, Kakei M, et al.
  • Organizer: 70^<th> Scientific Sessions for American Diabetes Association.
  • Place of Presentation: Orlando, USA
• [Presentation] 膵β細胞Kv2.1チャネルのブドウ糖代謝による新規調節機構 (2009)
  • Author(s): 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、加計正文
  • Organizer: 第52回日本糖尿病学会総会
  • Place of Presentation: 大阪
• [Presentation] ブドウ糖刺激インスリン分泌におけるKvチャネル活動の役割 (2008)
  • Author(s): 加計正文
  • Organizer: 第51回日本糖尿病学会学会学術集会
  • Place of Presentation: 東京
• [Remarks] ホームページ等