Development of anti-diabetic zinc medicine protecting the pancreatic B cells through the GPR39-stimulating Pdx-1 expression

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590653
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: YASUI Hiroyuki 京都薬科大学, 薬学部, 教授 (20278443)
• Co-Investigator(Kenkyū-buntansha): YOSHIKAWA Yutaka 神戸女子大学, 健康福祉学部, 教授 (20388028)
• Project Period (FY): 2011 – 2013
• Keywords: 膵β細胞保護作用 / GPR39 / Pdx-1 / 亜鉛医薬品 / インスリン

Research Abstract

Zinc is one of the essential trace elements playing an important role in our life. From the recent studies of molecular biology, the zinc-homeostasis in the animal body has been found to be properly controlled by 22 kinds of zinc transporters. Concerning the Japanese aging of the population, lifestyle-related diseases as metabolic-syndromes mainly derived from obesity and type-2 diabetes are more urgent issues.
From these backgrounds, we have investigated the anti-diabetic action and effects of zinc closely related with insulin homeostasis and activity, and succeeded the development of several orally-active zinc complexes. In this study, first we focused to cure both the type 1 and type 2 diabetes on the basis of activatiing transpciption factor, Pdx-1, expressed in the pancreas. Secondly, we indicated the new positive results for both the biochemical and morphological analyses of dramatically improved pancreas and liver in zinc complex-treated type-2 diabetic KK-Ay mice.

Research Products

• [Journal Article] Morphological characterization of systemic changes in KK-Ay mice as an animal model of type 2 diabetes (2013)
  • Author(s): Takayasu Moroki, Yutaka Yoshikawa, Katsuhiko Yoshizawa, Airo Tsubura, and Hiroyuki Yasui
  • Journal Title: In Vivo Volume: 27 Pages: 465-472
• [Journal Article] Development of a novel antidiabetic zinc complex with an organoselenium ligand at the lowest dosage in KK-Ay mice (2013)
  • Author(s): Shigeyuki Fujimoto, Hiroyuki Yasui, and Yutaka Yoshikawa
  • Journal Title: J. Inorg. Biochem Volume: 121 Pages: 10-15
• [Journal Article] Zinc complexes developed as metallopharmaceutics for treating diabetes mellitus based on the biomedicinal inorganic chemistry (2012)
  • Author(s): Yutaka Yoshikawa and Hiroyuki Yasui
  • Journal Title: Curr. Topics Med. Chem Volume: 12 Pages: 210-218
• [Journal Article] Pharmacological and pharmacokinetic studies of anti-diabetic tropolonate-Zn(II) complexes with Zn(S_2O_2) coordination mode (2012)
  • Author(s): Hiroki Murakami, Hiroyuki Yasui, and Yutaka Yoshikawa
  • Journal Title: Chem. Pharm. Bull Volume: 60 Pages: 1096-1104
• [Journal Article] Challenge of studies on the development of new Zn complexes (Zn(opt)_2) to treat diabetes mellitus (2011)
  • Author(s): Yutaka Yoshikawa, Akito Murayama, Yusuke Adachi, Hiromu Sakurai, and Hiroyuki Yasui
  • Journal Title: Metallomics Volume: 3 Pages: 686-692
• [Journal Article] Effects of Zn(II) complex with vitamins C and U, and carnitine on metabolic syndrome model rats (2011)
  • Author(s): Kinuyo Matsumoto, Nao Motoyasu, Kyoko Sera, Takako Fujii, Yutaka Yoshikawa, Hiroyuki Yasui, Hiroshi Taniguchi, and Naemi Kajiwara
  • Journal Title: Metallomics Volume: 3 Pages: 683-685
• [Journal Article] Synthesis and in vitro insulin-mimetic activities of zinc(II) complexes of ethyl 2, 5-dihydro-4- hydroxy-5-oxo- 1H-pyrrole-3-carboxylates (2011)
  • Author(s): Hikaru Kawarada, Yutaka Yoshikawa, Hiroyuki Yasui, Shunsuke Kuwahara, Yoichi Habata, and Ryota Saito
  • Journal Title: Metallomics Volume: 3 Pages: 675-679
• [Journal Article] Cellular mechanism of zinc-hinokitiol complexes in diabetes mellitus (2011)
  • Author(s): Yuki Naito, Yutaka Yoshikawa, and Hiroyuki Yasui
  • Journal Title: Bull. Chem. Soc. Jpn Volume: 84 Pages: 298-305
• [Journal Article] Morphological analysis of the pancreas and liver in diabetic KK-Ay mice treated with zinc and oxovanadium complexes
  • Author(s): Takayasu Moroki, Yutaka Yoshikawa, Katsuhiko Yoshizawa, Airo Tsubura, and Hiroyuki Yasui
  • Journal Title: Metallomics Volume: 6(in press)
• [Journal Article] New insulin-mimetic and hypoglycemic hetero-binuclear zinc(II)/ oxovanadium(IV) complex
  • Author(s): Takayasu Moroki, Hiroyuki Yasui, Yusuke Adachi, Katsuhiko Yoshizawa, Airo Tsubura, Kazuhiko Ozutsumi, Misaki Katayama, and Yutaka Yoshikawa
  • Journal Title: Curr. Inorg. Chem Volume: 4(in press)
• [Presentation] Gamma-Ray Emission Imaging (GREI)による亜鉛錯体の体内動態解析 (2013)
  • Author(s): 宗兼将之, 本村信治, 神野伸一郎, 羽場宏光, 吉川豊, 安井裕之, 廣村信, 榎本秀一
  • Organizer: メタルバイオサイエンス研究会2013
  • Place of Presentation: 静岡
  • Year and Date: 20130900
• [Presentation] 2型糖尿病における生体金属恒常性の破綻と亜鉛製剤による糖尿病治療戦略 (2013)
  • Author(s): 安井裕之
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 神奈川(シンポジウム講演)
  • Year and Date: 20130900
• [Presentation] Anti-diabetic action of Zn complex Zn(OPT)_2 on the expression and activation of PDX-1 in pancreas of mice (2013)
  • Author(s): Hiroyuki Yasui, Yutaro Natsume, Miki Kobayashi, Yuki Naito, Yutaka Yoshikawa
  • Organizer: 4th International Symposium on Metallomics
  • Place of Presentation: Oviedo, Spain
  • Year and Date: 20130700
• [Presentation] Imbalance of metal homeostasis in diabetic state and treatment of diabetes by zinc-based therapy (2013)
  • Author(s): Hiroyuki Yasui, and Yutaka Yoshikawa
  • Organizer: International Franco-Japanese Workshop on Metallomics
  • Place of Presentation: Pau, France
  • Year and Date: 20130700
  • Invited
• [Presentation] 疾患メタロミクスと亜鉛製剤による糖尿病治療研究 (2013)
  • Author(s): 安井裕之
  • Organizer: 滋賀医科大学‐京都薬科大学第1回ジョイント・シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 20130500
  • Invited
• [Presentation] 抗酸化活性を有するアスコルビン酸亜鉛錯体(ZnC)の開発 (2012)
  • Author(s): 安井裕之, 柴谷衣里, 吉川豊
  • Organizer: 第3回メタロミクス研究フォーラム
  • Place of Presentation: 東京
  • Year and Date: 20120800
• [Presentation] シンポジウム「亜鉛錯体の経口投与は2型糖尿病動物を何故に治療できるのか―亜鉛の体内分布変動からの考察―」 (2012)
  • Author(s): 安井裕之, 吉川豊
  • Organizer: 第23回日本微量元素学会学術集会
  • Place of Presentation: 東京(シンポジウム講演)
  • Year and Date: 20120700
• [Presentation] 疾患メタロミクスと酸化ストレス (2012)
  • Author(s): 安井裕之, 伊賀瑞紗, 松尾岳志, 吉川豊, 中村任, 久米学, 江原正明, 福田浩之, 平岡勇二
  • Organizer: 第65回日本酸化ストレス学会学術集会
  • Place of Presentation: 徳島(シンポジウム講演)
  • Year and Date: 20120600
• [Presentation] Effect of anti-diabetic Zn complex (Zn(opt)_2) on protein expression of Pdx-1 in pancreas of mice (2012)
  • Author(s): Miki Kobayashi, Yutaro Natsume, Yuki Naito, Yutaka Yoshikawa, and Hiroyuki Yasui
  • Organizer: 第22回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 石川
  • Year and Date: 20120500
• [Presentation] Anti-diabetic action of zinc complex Zn(opt)_2 on the expression of Pdx-1 in both the cultured RIN-5F insulinoma cell and pancreas of STZ-mice
  • Author(s): Hiroyuki Yasui, Yutaro Natsume, and Yutaka Yoshikawa
  • Organizer: 5th International Conference on
  • Invited
• [Book] 第1, 2, 3, 6, 11, 13, 14章.コンパス分析化学 (2013)
  • Author(s): 安井裕之(編集)
  • Total Pages: 320
  • Publisher: 株式会社南江堂
• [Book] 序章,第1, 2, 3, 5, 6, 7, 8, 9, 10章.医薬品分析化学 (2013)
  • Author(s): 安井裕之(黒田幸弘, 安井裕之, 吉川豊共著)
  • Total Pages: 427
  • Publisher: 京都廣川書店