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Development of anti-diabetic agents based on investigating the mechanism of the onset of type 2 diabetes due to protein glycosilation

Research Project

Project/Area Number 18590517
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied pharmacology
Research InstitutionKyoto Pharmaceutical University

Principal Investigator

YASUI Hiroyuki  Kyoto Pharmaceutical University, Department of Analytical and Bioinorganic Chemistry, Professor (20278443)

Co-Investigator(Kenkyū-buntansha) YOSHIKAWA Yutaka  Kyoto Pharmaceutical University, Department of Analytical and Bioinorganic Chemistry, Research Associate (20388028)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsO-glycosilation / type 2 diabetes / insulin resistance / OGT / O-G1cNAcase / metal complexes / zinc complexes / manganese complexes / バナジル錯体
Research Abstract

There are many nonle.ar and cytoplasmic proteins that are modified by a single O-linked N-acetylglucosamine (O-GlcNAc) moiety at serine or threonine residues. We proposed that this O-GlcNAc modification (tanned O-GlcNAcylation) is a regulatory modification, analogous to phosphorylation, that is, capping of the potential phosphorylation sites. O-GlcNAc transferase (OGT) is an enzyme responsible for O-GlcNAcylation of proteins. The hexosmine biosynthesis pathway plays an important part in the induction of insulin resistance. In this pathway, glutamine: fructose-6-phosphate amidotransferase (GFAT) has an integral role in the development of insulin resistance. The OGT enzyme uses cytoplasmic uridine diphospho-N-acetylglucosamine (UDP-GlcNAc), which is synthesized in the hexosamine biosynthetic pathway. Animals with diabetes and hyperglycaemia show greatly increased concentrations of hexosamine metabolites including UDP-GlcNAc. This increase in hexosamine biosynthesis could stimulate OGT activity, including O-GlcNAc modification of proteins that are involved in the glucose transport system or in granule secretion. Therefore, it is likely that the effects of hyperglycaemia result from abnormal O-GlcNAcylation. In this study, the effects of metal complexes such as vanadium, zinc, and manganese on the inhibition of OGT activity and on O-GlcNAcylation were investigated in the streptozotocin (STZ)-induced diabetic mice and 3T3-L1 cell lines. As a result, vanadyl-maltolate related complexes were exhibited to suppress the O-GlcNAcylation of proteins in organs of STZ-mice. In addition, zinc compounds were hind to stimulate the de-GlcNAcylation of proteins in the cultured 3T3-L1 cells, without inhibiting the OGT activity, indicating that zinc compounds may enhance the activity of O-GlcNAcase, an degradating enzyme of O-GlcNAcylated proteins.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (33 results)

All 2007 2006

All Journal Article (17 results) (of which Peer Reviewed: 7 results) Presentation (14 results) Book (2 results)

  • [Journal Article] Metallokinetic characterization of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat2007

    • Author(s)
      Hiroyuki Yasui, Yusuke Adachi, Akira Katoh, and Hiromu Sakurai
    • Journal Title

      J.Biol.Inorg.Chem. 12

      Pages: 843-853

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Metallokinetic characterization of antidiabetic bis(allixinato) oxovanadium(IV)-related complexes in the blood of rat.2007

    • Author(s)
      Hiroyuki Yasui, Yusuke Adachi, Akira Katoh, Hiromu Sakurai
    • Journal Title

      J. Biol. Inorg. Chem. 12

      Pages: 843-853

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Chemical structure-dependent differential effects of flavonoids on flavonoids on the catalase activity as evaluated by a chmiluminescent method2007

    • Author(s)
      Nataliya Doronicheva, Hiroyuki Yasui, and Hiromu Sakurai
    • Journal Title

      Biol.Pharm.Bull 30(2)

      Pages: 213-217

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metallokinetic characterization of antidiabetic bis(allixinato)oxovanadium (IV)-related complexes in the blood of rat2007

    • Author(s)
      Hiroyuki Yasui, Yusuke Adachi, Akira Katoh, and Hiromu Sakurai
    • Journal Title

      J.Biol.Inorg.Chem. 12

      Pages: 843-853

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Suppressive effect of orally administerd copper(II)-asphinate (Cu_2(asp)_4) complex on the generation of reactive oxygen species in the skin of animals subjected to UVA exposure2007

    • Author(s)
      Takako Fujimori, Hiroyuki Yasui, and Hiromu Sakurai
    • Journal Title

      Exper.Dermatol. 16

      Pages: 746-752

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The universal concentrations and cancer signs of trace elements in hair observed by X-ray fluorescence analysis2007

    • Author(s)
      Jun-ichi Chikawa, Kousaku Sakurai, Hiroyuki Yasui, Hitoshi Yamamoto, Shinichiro Okabe, Masaaki Ebara
    • Journal Title

      J.X-ray Sci.Tech. 15

      Pages: 109-129

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metallokinetic characteristics of anti-diabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat.2007

    • Author(s)
      Hiroyuki Yasui, Yusuke Adachi, AkiraKatoh, Hiromu Sakurai
    • Journal Title

      J. Biol. Inorg. Chem. 12(In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Chemical structure-dependent differential effects of flavonoids on the catalase activity as evaluated by a chemiluminescent method.2007

    • Author(s)
      Doronicheva Nataliya, Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      Biol. Pharm. Bull. 30

      Pages: 213-217

    • NAID

      110006162831

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A novel drug delivery system for type 1 diabetes:Insulin-mimetic vanadyl-poly(γ-glutamic acid)complex2006

    • Author(s)
      Subarna Karmaker Tapan Kumar Saha, Yutaka Yoshikawa Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      J.Inorg.Biochem. 100

      Pages: 1535-1546

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Oxovanadium(IV)-porphyrin complex as a potent insulin-mimetic.Treatment of experimental type 1 diabetic mice by the complex [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4-)2006

    • Author(s)
      Tapan Kumar Saha, Yutaka Yoshikawa, Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      Bull.Chem.Soc.Jpn. 79

      Pages: 1191-1200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A novel drug delivery system for type 1 diabetes : Insulin-mimetic vanadyl-poly(γ-glutamic acid) complex.2006

    • Author(s)
      Subarna Karmaker, Tapan Kumar Saha, Yutaka Yoshikawa, Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      J. lnorg. Biochem. 100

      Pages: 1535-1546

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Oxovanadium(IV)-porphyrin complex as a potent insulin-mimetic. Treatment of experimental type 1diabetic mice by the complex[meso-tetrakis(4-sulfonatophenyl) porphyrinato] oxovanadate(IV)(4-).2006

    • Author(s)
      Tapan Kumar Saha, Yutaka Yoshikawa, Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      Bull. Chem. Soc. Jpn. 79

      Pages: 1191-1200

    • NAID

      10018210747

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Frontier of development of vanadyl and zinc complexes with insulinomimetic activity in Pathophysiological and Biochemical Analyses of Life-Style Related or Intractable Diseases.2006

    • Author(s)
      Hiromu Sakurai, Yusuke Adachi, Kojiro Tayama, Yutaka Yoshikawa, Hiroyuki Yasui, Asuka Tamura, Toshikazu Takino, Akira Katoh
    • Journal Title

      Research Signpost, Trivandrum, India 262

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Suppressive effect of caffeic acid and its derivatives on the generation of UVA-induced reactive oxygen species in the skin of hairless mice and pharmacokinetic analysis on organ distribution of caffeic acid in ddY mice.2006

    • Author(s)
      Yumiko Yamada, Hiroyuki Yasui, HiromuSakurai
    • Journal Title

      Photochem. Photobiol. 82

      Pages: 1668-1676

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A new physiologically based pharmacokinetic analysis for in vivo organ disposition of nitroxyl spin probes in mice as measured by multisite detection L-band ESR(MSD-ESR)2006

    • Author(s)
      Masayuki Kamatari, Hiroyuki Yasui, Masahiro Nakamura, Tateaki Ogata, Hiromu Sakurai
    • Journal Title

      Chem. Lett. 35

      Pages: 1170-1171

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Oxovanadium(IV)-porphyrin complex as a potent insulin-mimetic. Treatment of experimental type 1 diabetic mice by the complex [meso-tetrakis(4-sulfonatophenyl) porphyrinato]oxovanadate(IV)(4-).2006

    • Author(s)
      Tapan Kumar Saha, Yutaka Yoshikawa, Hiroyuki Yasui, Hiromu Sakurai
    • Journal Title

      Bull. Chem. Soc. Jpn. 79

      Pages: 1191-1200

    • NAID

      10018210747

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A novel drug delivery system for type 1 diabetes : Insulin-mimetic vanadyl-poly (γ-glutamic acid) complex.2006

    • Author(s)
      Subarna Karmaker Tapan Kumar Saha, Yutaka Yoshikawa Hiroyuki Yasui, HiromuSakura
    • Journal Title

      J. Inorg. Biochem. 100

      Pages: 1535-1546

    • Related Report
      2006 Annual Research Report
  • [Presentation] 抗糖尿病作用を有する経口投与可能な高活性亜鉛錯体(1)-bis(1-oxy-2-pyridinethiolato)zinc(II)complex-2007

    • Author(s)
      村山 彰人, 吉川 豊, 安達 祐介, 安井 裕之, 桜井 弘
    • Organizer
      第57回錯体化学討論会
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] 抗糖尿病作用を有する経口投与可能な高活性亜鉛錯体(2)-bis(dithiocarbamato)zinc(II)complex-2007

    • Author(s)
      吉川 豊, 安達 祐介, 安井 裕之, 桜井 弘
    • Organizer
      第57回錯体化学討論会
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 第一遷移系列金属-2-メルカプトピリジン-N-オキシド錯体の抗糖尿病作用2007

    • Author(s)
      吉川 豊, 村山 彰人, 安達 祐介, 安井 裕之, 桜井 弘
    • Organizer
      第26回メディシナルケミストリーシンポジウム
    • Place of Presentation
      横浜
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Improvement of diabetes mellitus and metabolic syndromes in KK-A^y mice by Zn(II) complexes with Zn(SxOy)coordination modes2007

    • Author(s)
      Yutaka Yoshikawa. Akito Murayama, Yusuke Adachi, Hiroyuki Yasui, and Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Metallokinetic and metallodynamic analyses of antidiabetic oxovanadium(IV)complexes in STZ mice2007

    • Author(s)
      Hiroyuki Yasui, Tapan Kumar Saha, Yusuke Adachi, Yutaka Yoshikawa, and Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Improvement of diabetes mellitus and metabolic syndromes in KK-A^Y mice by Zn(II) complexes with Zn(SxOy) coordination modes2007

    • Author(s)
      Yutaka Yoshikawa. Akito Murayama, Yusuke Adachi, Hiroyuki Yasui, Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      Nagoya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Metallokinetic and metallodynamic analyses of antidiabetic oxovanadium(IV) complexes in STZ mice.2007

    • Author(s)
      Hiroyuki Yasui, Tapan Kumar Saha, Yusuke Adachi, Yutaka Yoshikawa, Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      Nagoya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Antidiabetic activities of first transition metals-2-mercaptopyridine-N-oxide complexes.2007

    • Author(s)
      Yutaka Yoshikawa. Akito Murayama, Yusuke Adachi, Hiroyuki Yasui, Hiromu Sakurai
    • Organizer
      The 26th Medicinal Chemistry Symposium
    • Place of Presentation
      Yokohama
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Orally-active Zn(II) complex with potent anti-diabetic action(1) : -bis(1-oxy-2-pyridinethiolato) zinc(11) complex-2007

    • Author(s)
      Akito Murayama, Yutaka Yoshikawa. Yusuke Adachi, Hiroyuki Yasui, Hiromu Sakurai
    • Organizer
      The 57th Annual Conference of Japanese Coordination Chemical Society
    • Place of Presentation
      Nagoya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Orally-active Zn(II) complex with potent anti-diabetic action(2) : -bis(dithiocarbamato) zinc(ll) complex-2007

    • Author(s)
      Yutaka Yoshikawa. Yusuke Adachi, Hiroyuki Yasui, Hiromu Sakurai
    • Organizer
      The 57th Annual Conference of Japanese Coordination Chemical Society
    • Place of Presentation
      Nagoya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 抗糖尿病作用を有する経口投与可能な高活性亜鉛錯体(2)-bis(dithiocarbamato)zinc(II)comnlex-2007

    • Author(s)
      吉川 豊, 安達 祐介, 安井 裕之, 桜井 弘
    • Organizer
      第57回錯体化学討論会
    • Place of Presentation
      名古屋
    • Related Report
      2007 Annual Research Report
  • [Presentation] 第一遷移系列金属-2-メルカプトピリジン・貼オキシド錯体の抗糖尿病作用2007

    • Author(s)
      吉川 豊, 村山 彰人, 安達 祐介, 安井 裕之, 桜井 弘
    • Organizer
      第26回メディシナルケミストリーシンポジウム
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Improvement of diabetes mellitus and metabolic syndromes in KK-A^y mice by Zn(II) complexeswith Zn(SxOy)coordination modes2007

    • Author(s)
      Yutaka Yoshikawa, AkitoMurayama, Yusuke Adachi, Hiroyuki Yasui, and Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      名古屋
    • Related Report
      2007 Annual Research Report
  • [Presentation] Metallokinetic and metallodynamic analyses of antidiabetic oxovanadium(IV) complexes in STZ mice2007

    • Author(s)
      Hiroyuki Yasui, Tapan Kumaz Saha, Yusuke Adachi, Yutaka Yoshikawa, and Hiromu Sakurai
    • Organizer
      International Symposium on Metallomics 2007
    • Place of Presentation
      名古屋
    • Related Report
      2007 Annual Research Report
  • [Book] Frontier of development of vanadyl and zinc complexes with insulinomimetic activity in Pat hophysiological and Biochemical Analyses of Life-Style Related or Intractable Diseases.2006

    • Author(s)
      Hiromu Sakurai, Yusuke Adachi, Kojiro Tayama, Yutaka Yoshikawa, Hiroyuki Yasui, Asuka Tamura, Toshikazu Takino, Akira Katoh
    • Total Pages
      262
    • Publisher
      Research Signpost,Trivandrum,India
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Frontier of development of vanadyl and zinc complexes with insulinomimetic activity in Pathophysiological and Biochemical Analyses of Life-Style Related or Intractable Diseases.2006

    • Author(s)
      Hiromu Sakurai, Yusuke Adachi, KojiroTayama, Yutaka Yoshikawa, HiroyukiYasui, Asuka Tamura, Toshikazu Takino, Akira Katoh
    • Total Pages
      262
    • Publisher
      Research Signpost, Trivandrum, India
    • Related Report
      2006 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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