Regulation of KATP channel and insulin secretion by PIP2 and its application to diabetes treatment

• Project/Area Number: 20K08865
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Shimomura Kenju 福島県立医科大学, 医学部, 教授 (90636226)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: KATPチャネル / インスリン分泌 / 新生児糖尿病 / 電気生理 / PIP2

Outline of Research at the Start

膵β細胞に存在するKATPチャネルの閉鎖はインスリン分泌を促すことからその閉鎖薬であるSU剤は糖尿病治療薬として長年臨床で用いられてきたが近年は低血糖などの副作用の誘発から敬遠されている。しかし、日本人の糖尿病の発症機序はインスリン分泌不全型が大多数を占めていることが知られており、KATPチャネルは日本人糖尿病患者の治療標的として無視することはできない。本研究ではKATPチャネル開閉制御因子である PIP2に着目し、不明の点が多いインスリン分泌においてPIP2の果たす生理的役割を明らかにし、安全かつ有効な糖尿病の治療標的としての可能性についても検討を行う。

Outline of Final Research Achievements

Although the channel-opening effect of PIP2 was confirmed in wild-type channels, its effect on GPCR-mediated KATP channel activity was limited.On the other hand, the regulation of KATP channel activity by PIP2 was more prominent in the mutant KATP channels that induce neonatal diabetes than in the wild type, suggesting that PIP2 may be a potential therapeutic target in specific conditions such as neonatal diabetes associated with genetic mutations rather than type 2 diabetes mellitus.

Academic Significance and Societal Importance of the Research Achievements

内向き整流静カリウムチャネルはKATPチャネルのチャネルポアを構成するKir6.2に限らずほかのサブタイプにおいてもＰＩＰ２によって開口することは知られている。しかし、本研究成果は細胞内の生理的状態下においてはPIP2量の制御が困難であること、またSUR1を加えたKATPチャネル全体でみると活性に変化を与えにくいことが明らかとなった。しかし新生児糖尿病などKATPチャネルが変異によって活性が変わっている場合においてはPIP2のチャネル開閉制御は顕著となる可能性が示唆された。

Research Products

• [Journal Article] Efficacy of SGLT2 inhibitors as additional treatment in Japanese type 2 diabetic patients: second or third choice? (2022)
  • Author(s): Fujiwara Makoto、Shimizu Masaru、Maejima Yuko、Shimomura Kenju
  • Journal Title: BMC Research Notes Volume: 15 Issue: 1 Pages: 120-120
  • DOI: 10.1186/s13104-022-06010-6
  • Peer Reviewed
• [Journal Article] Surface translocation of Kir2.1 channel induces IL-1β secretion in microglia (2022)
  • Author(s): Maejima Yuko、Horita Shoichiro、Yokota Shoko、Yamachi Megumi、Shimizu Masaru、Ono Tomoyuki、Yu Zhiquian、Tomita Hiroaki、Shimomura Kenju
  • Journal Title: Molecular and Cellular Neuroscience Volume: 120 Pages: 103734-103734
  • DOI: 10.1016/j.mcn.2022.103734
  • Peer Reviewed
• [Journal Article] The effects of ninjin’yoeito on the electrophysiological properties of dopamine neurons in the ventral tegmental area/substantia nigra pars compacta and medium spiny neurons in the nucleus accumbens (2022)
  • Author(s): Imai Ryota、Mizuno Keita、Omiya Yuji、Mizoguchi Kazushige、Maejima Yuko、Shimomura Kenju
  • Journal Title: Aging Volume: 14 Issue: 11 Pages: 4634-4652
  • DOI: 10.18632/aging.204109
  • Peer Reviewed
• [Journal Article] Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers (2022)
  • Author(s): Misaka Shingen、Ono Yuko、Taudte R. Verena、Hoier Eva、Ogata Hiroshi、Ono Tomoyuki、Konig Jorg、Watanabe Hiroshi、Fromm Martin F.、Shimomura Kenju
  • Journal Title: Clinical Pharmacology & Therapeutics Volume: 112 Issue: 3 Pages: 627-634
  • DOI: 10.1002/cpt.2682
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Optimization of the use of Py?Tag for next generation derivatization reagents in imaging mass spectrometry (2022)
  • Author(s): Shikano Hitomi、Ikeda Akari、Maejima Yuko、Kobayashi Shoko、Terauchi Tsutomu、Yokoyama Jun、Shimomura Kenju、Taira Shu
  • Journal Title: Journal of Bioscience and Bioengineering Volume: 134 Issue: 3 Pages: 264-268
  • DOI: 10.1016/j.jbiosc.2022.06.007
  • Peer Reviewed / Open Access
• [Journal Article] C188-9, a specific inhibitor of STAT3 signaling, prevents thermal burn-induced skeletal muscle wasting in mice (2022)
  • Author(s): Ono Yuko、Saito Masafumi、Sakamoto Kazuho、Maejima Yuko、Misaka Shingen、Shimomura Kenju、Nakanishi Nobuto、Inoue Shigeaki、Kotani Joji
  • Journal Title: Frontiers in Pharmacology Volume: 13 Pages: 1031906-1031906
  • DOI: 10.3389/fphar.2022.1031906
  • Peer Reviewed / Open Access
• [Journal Article] Identification of oxytocin expression in human and murine microglia (2022)
  • Author(s): Maejima Yuko、Yokota Shoko、Ono Tomoyuki、Yu Zhiqian、Yamachi Megumi、Hidema Shizu、Nollet Kenneth E.、Nishimori Katsuhiko、Tomita Hiroaki、Yaginuma Hiroyuki、Shimomura Kenju
  • Journal Title: Progress in Neuro-Psychopharmacology and Biological Psychiatry Volume: 119 Pages: 110600-110600
  • DOI: 10.1016/j.pnpbp.2022.110600
  • Peer Reviewed
• [Journal Article] Surface translocation of Kir2.1 channel induces IL-1β secretion in microglia (2022)
  • Author(s): Yuko Maejima, Shoichiro Horita, Shoko Yokota, Megumi Yamachi, Masaru Shimizu, Tomoyuki Ono, Zhiquian Yu, Hiroaki Tomita, Kenju Shimomura
  • Journal Title: Molecular Cell Neuroscence Volume: 120 Pages: 103734-103734
  • Peer Reviewed
• [Journal Article] The deletion of glucagon-like peptide-1 receptors expressing neurons in the dorsomedial hypothalamic nucleus disrupts the diurnal feeding pattern and induces hyperphagia and obesity (2021)
  • Author(s): Maejima Yuko、Yokota Shoko、Shimizu Masaru、Horita Shoichiro、Kobayashi Daisuke、Hazama Akihiro、Shimomura Kenju
  • Journal Title: Nutrition & Metabolism Volume: 18 Issue: 1 Pages: 58-58
  • DOI: 10.1186/s12986-021-00582-z
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of organ glucose metabolism by 18F-FDG accumulation with insulin loading in aged mice compared with young normal mice (2021)
  • Author(s): Zhao Jingmin、Tan Chengbo、Imai Ryota、Ukon Naoyuki、Shimoyama Saki、Maejima Yuko、Omiya Yuji、Takahashi Kazuhiro、Ito Hiroshi、Nan Guangxian、Zhao Songji、Shimomura Kenju
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 7421-7421
  • DOI: 10.1038/s41598-021-86825-8
  • Peer Reviewed / Open Access
• [Journal Article] Structure based analysis of KATP channel with a DEND syndrome mutation in murine skeletal muscle (2021)
  • Author(s): Horita Shoichiro、Ono Tomoyuki、Gonzalez-Resines Saul、Ono Yuko、Yamachi Megumi、Zhao Songji、Domene Carmen、Maejima Yuko、Shimomura Kenju
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 6668-6668
  • DOI: 10.1038/s41598-021-86121-5
  • Peer Reviewed / Open Access
• [Journal Article] Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P‐Glycoprotein (2021)
  • Author(s): Shimazaki Sho、Kuroda Junko、Shimomura Kenju、Misaka Shingen
  • Journal Title: The Journal of Clinical Pharmacology Volume: 61 Issue: 6 Pages: 799-805
  • DOI: 10.1002/jcph.1812
  • Peer Reviewed
• [Journal Article] Opening of Intermediate Conductance Ca2+-Activated K+ Channels in C2C12 Skeletal Muscle Cells Increases the Myotube Diameter via the Akt/Mammalian Target of Rapamycin Pathway (2020)
  • Author(s): Iseki Yuzo、Ono Yuko、Hibi Chihiro、Tanaka Shoko、Takeshita Shunya、Maejima Yuko、Kurokawa Junko、Murakawa Masahiro、Shimomura Kenju、Sakamoto Kazuho
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 376 Issue: 3 Pages: 454-462
  • DOI: 10.1124/jpet.120.000290
  • Peer Reviewed / Open Access
• [Journal Article] Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models (2020)
  • Author(s): Horiai Machi、Otsuka Ayano、Hidema Shizu、Hiraoka Yuichi、Hayashi Ryotaro、Miyazaki Shinji、Furuse Tamio、Mizukami Hiroaki、Teruyama Ryoichi、Tamura Masaru、Bito Haruhiko、Maejima Yuko、Shimomura Kenju、Nishimori Katsuhiko
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 22173-22173
  • DOI: 10.1038/s41598-020-79109-0
  • Peer Reviewed / Open Access
• [Journal Article] Detection of NUCB2/nesfatin-1 in cerebrospinal fluid of multiple sclerosis patients (2020)
  • Author(s): Shimizu Masaru、Manome Taizo、Kumami Masumi、Matsumura Kouzou、Kanai Kazuaki、Shimomura Kenju、Maejima Yuko
  • Journal Title: Aging Volume: 12 Issue: 23 Pages: 24134-24140
  • DOI: 10.18632/aging.202287
  • Peer Reviewed / Open Access
• [Journal Article] Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes (2020)
  • Author(s): Oduori Okechi S.、Murao Naoya、Shimomura Kenju、Takahashi Harumi、Zhang Quan、Dou Haiqiang、Sakai Shihomi、Minami Kohtaro、Chanclon Belen、Guida Claudia、Kothegala Lakshmi、Tol? Johan、Maejima Yuko、Yokoi Norihide、Minami Yasuhiro、Miki Takashi、Rorsman Patrik、Seino Susumu
  • Journal Title: Journal of Clinical Investigation Volume: 130 Issue: 12 Pages: 6639-6655
  • DOI: 10.1172/jci140046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Green Tea Catechin Ingestion on the Pharmacokinetics of Lisinopril in Healthy Volunteers (2020)
  • Author(s): Misaka Shingen、Ono Yuko、Uchida Atsushi、Ono Tomoyuki、Abe Osamu、Ogata Hiroshi、Sato Hideyuki、Suzuki Masahiko、Onoue Satomi、Shikama Yayoi、Shimomura Kenju
  • Journal Title: Clinical and Translational Science Volume: 14 Issue: 2 Pages: 476-480
  • DOI: 10.1111/cts.12905
  • Peer Reviewed / Open Access
• [Journal Article] Single administration of resveratrol improves social behavior in adult mouse models of autism spectrum disorder (2020)
  • Author(s): Hidema Shizu、Kikuchi Shohei、Takata Ryoji、Yanai Takaaki、Shimomura Kenju、Horie Kengo、Nishimori Katsuhiko
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84 Issue: 11 Pages: 2207-2214
  • DOI: 10.1080/09168451.2020.1794783
  • Peer Reviewed
• [Journal Article] Early life high-fat diet exposure evokes normal weight obesity (2020)
  • Author(s): Maejima Yuko、Yokota Shoko、Horita Shoichiro、Shimomura Kenju
  • Journal Title: Nutrition & Metabolism Volume: 17 Issue: 1 Pages: 2020-2020
  • DOI: 10.1186/s12986-020-00464-w
  • Peer Reviewed
• [Journal Article] Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers (2020)
  • Author(s): Misaka Shingen、Abe Osamu、Ono Tomoyuki、Ono Yuko、Ogata Hiroshi、Miura Itaru、Shikama Yayoi、Fromm Martin F.、Yabe Hirooki、Shimomura Kenju
  • Journal Title: British Journal of Clinical Pharmacology Volume: - Issue: 11 Pages: 2314-2318
  • DOI: 10.1111/bcp.14315
  • Peer Reviewed / Open Access / Int'l Joint Research