Reduceds β-cell proliferation and impaired glucose tolerance in pancreatics β-cell specific Extl3 knockout mice.

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590312
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Iwate Medical University
• Principal Investigator: NATA Koji Iwate Medical University, 薬学部, 教授 (90202233)
• Co-Investigator(Kenkyū-buntansha): SUGAWARA Akira 東北大学, 大学院・医学系研究科, 教授 (90270834)
• Project Period (FY): 2008 – 2010
• Keywords: 膵β細胞 / 糖尿病 / 糖鎖 / ヘパラン硫酸 / 糖転移酵素 / EXTL3 / ノックアウトマウス

Research Abstract

EXTL3 functions as a glycosyltransferase involved in heparan sulfate proteoglycans biosynthesis. We generated pancreatic β-cell specific Extl3 knockout (βExtl3KO) mice. In βExtl3KO mice at 2-8 weeks old, the β-cell proliferation activity was decreased and histological examination of pancreatic islets revealed an atypical organization. βExtl3KO mice at 8 weeks old showed glucose intolerance coupled to impaired insulin secretion upon glucose challenge. These data indicate that heparan sulfate plays important role(s) in β-cell proliferation and the mechanism of insulin secretion.

Research Products

• [Journal Article] All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells : possible involvement of protein kinase C-δ. (2011)
  • Author(s): Uruno A, Noguchi N, Matsuda K, Nata K, Yoshikawa T, Chikamatsu Y, Kagechika H, Harigae H, Ito S, Okamoto H, Sugawara A.
  • Journal Title: J Leukoc Biol. in press
  • Peer Reviewed
• [Journal Article] Expression profile of the REG gene family in colorectal carcinoma. (2011)
  • Author(s): Zheng HC, Sugawara A, Okamoto H, Takasawa S, Takahashi H, Masuda S, Takano Y.
  • Journal Title: J Histochem Cytochem. vol.59 Pages: 106-115
  • Peer Reviewed
• [Journal Article] A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene. (2010)
  • Author(s): Takasawa S, Kuroki M, Nata K, Noguchi N, Ikeda T, Yamauchi A, Ota H, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Takahashi I, Yoshikawa T, Shimosegawa T, Okamoto H.
  • Journal Title: Biochem Biophys Res Commun. Vol.397 Pages: 140-145
  • Peer Reviewed
• [Journal Article] Up-regulation of REG Iα accelerates tumor progression in pancreatic cancer with diabetes. (2010)
  • Author(s): Zhou L, Zhang R, Wang L, Shen S, Okamoto H, Sugawara A, Xia L, Wang X, Noguchi N, Yoshikawa T, Uruno A, Yao W, Yuan Y.
  • Journal Title: Int J Cancer. vol.127 Pages: 1795-1803
  • Peer Reviewed
• [Journal Article] Important role of heparan sulfate in the morphogenesis, s-cell proliferation, and insulin secretion of mouse pancreatic islets. (2009)
  • Author(s): Takahashi I, Noguchi N, Nata K, Yamada S, Kaneiwa T, Mizumoto S, Ikeda T, Sugihara K, Asano M, Yoshikawa T, Yamauchi A, Shervani NJ, Uruno A, Kato I, Unno M, Sugahara K, Takasawa S, Okamoto H, Sugawara A.
  • Journal Title: Biochem Biophys Res Commun. vol.383 Pages: 113-118
  • Peer Reviewed
• [Journal Article] Thiazolidinediones inhibit REG Iα gene transcription in gastrointestinal cancer cells. (2009)
  • Author(s): Yamauchi A, Takahashi I, Takasawa S, Nata K, Noguchi N, Ikeda T, Yoshikawa T, Shervani NJ, Suzuki I, Uruno A, Unno M, Okamoto H, Sugawara A.
  • Journal Title: Biochem Biophys Res Commun. vol.379 Pages: 743-748
  • Peer Reviewed
• [Journal Article] FKBP12.6 disruption impairs glucose-induced insulin secretion. (2008)
  • Author(s): Noguchi N, Yoshikawa T, Ikeda T, Takahashi I, Shervani NJ, Uruno A, Yamauchi A, Nata K, Takasawa S, Okamoto H, Sugawara A.
  • Journal Title: Biochem Biophys Res Commun. vol.371 Pages: 735-740
  • Peer Reviewed
• [Presentation] Contribution of heparan sulfate fine structure to Insulin secretion. (2010)
  • Author(s): Takahashi I, Ohashi K, Shervani NJ, Nata K.
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] Structural characterization of heparan sulfate in the Extl3 knockout mice and the pancreatic β-cell specific Extl3 knockout mice. (2010)
  • Author(s): Kaneiwa T, Yamada S, Sugahara K, Takahashi I, Noguchi N, Nata K, Okamoto H, Sugawara A
  • Organizer: 25th International Carbohydrate Symposium.
  • Place of Presentation: Tokyo
  • Year and Date: 2010-08-02
• [Presentation] Role of heparan sulfate in glucose-induced insulin secretion in mouse pancreatic β-cell line MIN6 cells. (2010)
  • Author(s): Yoshikawa T, Takayanagi S, Noguchi N, Zhang D, Ariyama Y, Uruno A, Okamoto H, Sugawara A, Yanai K.
  • Organizer: 16th World Congress of Basic and Clinical Pharmacology.
  • Place of Presentation: Copenhagen
  • Year and Date: 2010-07-20
• [Presentation] Role of heparan sulfate in glucose-induced insulin secretion in MIN6 cells. (2010)
  • Author(s): Yoshikawa T, Takayanagi S, Noguchi N, Uruno A, Okamoto H, Sugawara A, Yanai K.
  • Organizer: American Diabetes Association 70th Scientific Sessions.
  • Place of Presentation: Orlando
  • Year and Date: 2010-06-02
• [Presentation] (2010)
  • Author(s): Shervani NJ, Takahashi I, Ohashi K, Noguchi N, Okamoto H, Takasawa S, Sugawara A, Nata K.
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2010-05-29
• [Presentation] Autoimmunity against REG family antigens in Japanese diabetes patients. (2009)
  • Author(s): Shervani NJ, Nata K, Noguchi N, Takahashi I, Ikeda T, Yamauchi A, Yoshikawa T, Uruno A, Takasawa S, Okamoto H, Sugawara A
  • Organizer: The 20th World Diabetes Congress.
  • Place of Presentation: Montreal
  • Year and Date: 20091018-20091022
• [Presentation] Autoantibodies to REG family proteins in Japanese diabetes patients. (2009)
  • Author(s): Shervani NJ, Noguchi N, Ikeda T, Takahashi I, Yoshikawa T, Uruno A, Nata K, Takasawa S, Okamoto H, Sugawara A
  • Organizer: 45th Annual Meeting of the European Association for the Study of Diabetes.
  • Place of Presentation: Vienna
  • Year and Date: 20090929-20091002
• [Presentation] All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells : possible involvement of protein kinase C-δ. (2009)
  • Author(s): Uruno A, Noguchi N, Nata K, Yoshikawa T, Takahashi I, Shervani NJ, Chikamatsu Y, Kagechika H, Harigae H, Ito S, Okamoto H, Sugawara A
  • Organizer: The Endocrine Society 91st Annual Meeting.
  • Place of Presentation: Washington, DC
  • Year and Date: 20090610-20090613
• [Presentation] Sera from Japanese diabetes patients show autoimmunity to REG family antigens. (2009)
  • Author(s): Shervani NJ, Nata K, Noguchi N, Takahashi I, Ikeda T, Ohashi K, Yoshikawa T, Uruno A, Takasawa S, Okamoto H, Sugawara A
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] 2型リアノジン受容体遺伝子にはGG-AG配列で切断されるイントロンが存在する (2009)
  • Author(s): 池田崇之, 野口直哉, 吉川雄朗, 宇留野晃, 那谷耕司, 高澤伸, 岡本宏, 米倉秀人, 菅原明
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] Structural characterization of heparan sulfate in conventional and conditional Extl3-deficient mice. (2009)
  • Author(s): Kaneiwa T, Yamada S, Sugahara K, Takahashi I, Noguchi N, Nata K, Okamoto H, Sugawara A
  • Organizer: Hokkaido University-Mahidol University Joint Symposium.
  • Place of Presentation: Sapporo
  • Year and Date: 2009-05-12
• [Presentation] Predominant role of REG Iα among the REG gene family in the proliferation of human colorectal adenocarcinoma. (2009)
  • Author(s): Yoshikawa T, Ikeda T, Sakai K, Noguchi N, Takahashi I, Shervani NJ, Uruno A, Yamauchi A, Sakai E, Onogawa T, Okabe M, Ando T, Kinouchi M, Miura K, Unno M, Emura T, Fujiwara M, Takasawa S, Okamoto H, Sugawara A
  • Organizer: American Association for Cancer Research 100th Annual Meeting 2009.
  • Place of Presentation: Denver
  • Year and Date: 2009-04-22
• [Presentation] Extl3ノックアウトマウスにおけるヘパラン硫酸の分析 (2009)
  • Author(s): 金岩知之, 山田修平, 菅原一幸, 高橋巌, 野口直哉, 那谷耕司, 岡本宏, 菅原明
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-26
• [Presentation] Reduced β-cell proliferation and impaired glucose tolerance in β-cell specific Extl3 knockout mice. (2008)
  • Author(s): Takahashi I, Nata K, Noguchi N, Ikeda T, Sugihara K, Asano M, Yoshikawa T, Yamauchi A, Shervani NJ, Uruno A, Unno M, Takasawa S, Okamoto H, Sugawara A
  • Organizer: 44th Annual Meeting of the European Association for the Study of Diabetes.
  • Place of Presentation: Rome
  • Year and Date: 20080907-20080911
• [Presentation] マウス膵ランゲルハンス島の形態形成やβ細胞増殖,インスリン分泌機能におけるヘパラン硫酸の重要性 (2008)
  • Author(s): 高橋巌, 野口直哉, 那谷耕司, 山田修平, 金岩知之, 水本秀二, 池田崇之, 杉原一司, 浅野雅秀, 吉川雄朗, Nausheen J. Shervani, 宇留野晃, 海野倫明, 菅原一幸, 高澤伸, 岡本宏, 菅原明
  • Organizer: 第20回分子糖尿病学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-12-13
• [Presentation] ヘパラン硫酸はマウス膵ランゲルハンス島の形態形成やβ細胞増殖,インスリン分泌機能に重要な役割を果たしている (2008)
  • Author(s): 高橋巌, 野口直哉, 那谷耕司, 山田修平, 金岩知之, 水本秀二, 池田崇之, 杉原一司, 浅野雅秀, 吉川雄朗, Nausheen J. Shervani, 宇留野晃, 海野倫明, 菅原一幸, 高澤伸, 岡本宏, 菅原明
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Impaired glucose-induced insulin secretion in FK506-binding protein 12.6-deficient mice. (2008)
  • Author(s): Yoshikawa T, Noguchi N, Ikeda T, Takahashi I, Shervani NJ, Uruno A, Yamauchi A, Nata K, Takasawa S, Okamoto H, Sugawara A
  • Organizer: The American Diabetes Association 68th Scientific Sessions.
  • Place of Presentation: San Francisco
  • Year and Date: 2008-06-08
• [Presentation] 膵β細胞特異的糖転移酵素Extl3欠損マウスはβ細胞増殖能低下と耐糖能異常を生じる (2008)
  • Author(s): 高橋巌, 那谷耕司, 野口直哉, 池田崇之, 吉川雄朗, 山内晶世, Nausheen J. Shervani, 宇留野晃, 杉原一司, 浅野雅秀, 海野倫明, 高澤伸, 岡本宏, 菅原明
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-24
• [Presentation] FK506結合蛋白質12.6ノックアウトマウスにおけるグルコース刺激インスリン分泌の低下 (2008)
  • Author(s): 吉川雄朗, 野口直哉, 池田崇之, 高橋巌, Nausheen J. Shervani, 宇留野晃, 山内晶世, 那谷耕司, 高澤伸, 岡本宏, 菅原明
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-23