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Studies on the beta cell differentiation signal in AR42J cells and in vivo effect on islet neogenesis in diabetic mice by betacellulin

Research Project

Project/Area Number 09671056
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionOsaka University

Principal Investigator

MIYAGAWA Jun-ichiro  Osaka University Medical School, Assistant Professor, 医学部, 助手 (00127721)

Co-Investigator(Kenkyū-buntansha) HAMAGUCHI Tomoya  Osaka University Medical School, Medical Staff, 医学部・附属病院, 医員
HIGASHIYAMA Shigeki  Osaka University Medical School, Assistant Professor, 医学部, 助手 (60202272)
NAMBA Mitsuyoshi  Osaka University Medical School, Lecturer, 医学部, 講師 (00183533)
HANAFUSA Toshiaki  Osaka University Medical School, Lecturer, 医学部, 講師 (60164886)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordsbeta cell / Betacellulin / Differentiation / Regeneration / Diabetes mellitus / Growth factor / Alloxan / EGF / EGFレセプター
Research Abstract

We tried to clarify the mechanism of differentiation of AR42J cells into insulin-secreting cells induced by betacellulin, and in vivo effects of betacellulin on the islet neogenesis and glucose intolerance in diabetic mice induced by selective perfusion of alloxan.In AR42J cells, stimulation with recombinant human betacellulin induced insulin immunoreactivlty and beta granule-like secretory vesicles in the cytoplasm.Phosphorylation of erbB receptor tyrosine was mainly occurred in erbB2 which could not bind directly to betacellulin, suggesting that crossactivation of erbB2 in the form of heterodimer is important for the intracellular differentiation signaling in AR42J cells into insulin-producing cells.However, it was difficult to clone the cells dominant negative for erbB2 by transfecting mutant form to confirm this result.We could not detect the betacellulin-specific receptor or binding protein on the cell surface of AR42J cells.
Betacellulin was expressed predominantly in the fetal and adult pancreas, and we found this factor was produced in duct cells and alpha cells of islets.In the pancreas of diabetic mice induced by selective perfusion of alloxan, islet neogenesis was observed mainly in the alloxan-perfused beta cell-depleted segment.Expression of insulin transscription factor, IPF1/PDX-1 was detected in the duct cells directly associated with newly formed islet-like cell clusters (ICCs).In ICCs, endocrine cells with double positive immunoreactivities to pancreatic hormones including insulin were observed, suggesting duct cells are important for the islet neogenesis in diabetic pancreas.Based on these findings, we examined in vivo effect of betacellulin by injecting recombinant human betacellulin in these diabetic mice.In the mice treated with betacellulin, the number of ICCs was increased, and the glucose intolerance was ameliorated.These results suggested betacellulin, as observed in AR42J cells, may act as beta cell differentiation factor in the pancreas.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (54 results)

All Other

All Publications (54 results)

  • [Publications] M.Waguri: "Demonstration of two different processes of β-cell regeneration in a new diabetic model induced by selective perfusion of alloxan" Diabetes. 46(8). 1281-1290 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yamamoto: "Differentiation of B-cells from ductal cells and acceleration of this process by nicotinamide : ultrastructural study on the non-obese diabetic (NOD) mice" Biomedical Res.18(2). 171-178 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yamamoto: "Proliferation and differentiation of pancreatic β-cells : ultrastructural analysis of the pancreas in diabetic mice induced by selective alloxan perfusion" Med.Electron Microsc.30. 170-175 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Kaneto: "Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development" J.Biol.Chem.30(4). 29137-29143 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] S.Higashiyama: "A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4" J.Biolchem.123. 675-680 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Waguri: "Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM" Endocrine J.44(1). 23-33 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Itoh: "Requirement of Fas for the development of autoimmune diabetes in non-obese diabetic mice" J.Exp.Med.186(4). 613-618 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Iwahashi: "Mollecular mechanism of beta cell destruction in autoimmune diabetes : potential target for preventive therapy" Cytokines Cell.Mol.Ther.4. 45-51 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 綿田裕孝: "PDX-1(IPF1)の膵β細胞特異的遺伝子発現における重要性" 分子糖尿病学. 8. 163-169 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 金藤秀明: "転写因子IPF1(PDX-1)を介した膵島細胞の発生、分化機構の検討-IPF1によるHB-EGF遺伝子の活性化-" 分子糖尿病学. 8. 171-177 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 宮川潤一郎: "Betacellulinによる膵外分泌細胞からインスリン分泌細胞へのtransdifferentiation" 分子糖尿病学. 8. 189-192 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 宮川潤一郎: "膵β細胞の分化・増殖・再生の立場から" 内分泌・糖尿病科. 6(1). 64-73 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本浩司: "ベータセルリンによるβ細胞分化促進と耐糖能改善促進効果-アロキサン膵部分灌流糖尿病マウスにおける検討-" Diabetes Frontier. 8(4). 498 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 和栗雅子: "Diphenylthiocarbazone (dithizone)を用いたマウス膵島の絶対数、総体積の評価-アロキサン膵部分灌流糖尿病マウスにおける検討-" Diabetes Frontier. 8(4). 509 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本浩司: "ベータセルリン" 内分泌・糖尿病科. 6(6). 505-509 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本浩司: "ベータセルリンノックアウトマウスにおける耐糖能の変化および膵内分泌細胞の形態学的分析" Diabetes Frontier. 9(3). 362 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 岩橋博見: "膵島細胞のアポトーシス-生理的側面および病理的側面とその関連分子-" 医学のあゆみ. 187(5). 510-514 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 宮川潤一郎: "膵β細胞再生促進療法の可能性" 医学のあゆみ. 187(5). 121-125 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 宮川 潤一郎: "膵β細胞の発生・分化・増殖・再生・アポトーシスと糖尿病. 分子糖尿病学の進歩-基礎から臨床まで-" 金原出版(門脇 孝、春日雅人、清野 進、渥美義仁 編), 11-23 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 宮川 潤一郎: "膵β細胞の発生・分化機構 専門医のための糖尿病レビュー-最新主要文献と解説-" 総合医学社(河盛隆造、春日雅人 監修), 28-40 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Waguri.: "Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan" Diabetes. 46(8). 1281-1290 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yamamoto.: "Differentiation of beta-cells from ductal cells and acceleration of this process by nicotinamide : ultrastructural study on the non-obese diabetic(NOD)mice with overt diabetes" Biomedical Res.18(2). 171-178 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Waguri.: "Histopathologic study shows a characteristic lymphocyticinfiltration in Japanesepatients with IDDM" Endocrine J.44(1). 23-33 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yamamoto.: "Proliferation and differentiation of pancreatic beta-cells : ultrastructural analysis of the pancreas in diabetic mice induced by selective alloxan perfusion" Med.Electron Microsc.30. 170-175 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Kaneto.: "Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development" J.Biol.Chem.46(4). 29137-29143 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] S.Higashiyama.: "A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4" J.Biochem.123. 675-680 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Itoh.: "Requirement of Fas for the development of autoimmune diabetes in non-obese diabetic mice" J.Exp.Med. 186(4). 613-618 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Iwahashi.: "Molecular mechanism of pancreatic beta-cell destruction in autoimmune diabetes : potential targets for preventive therapy" Cytokines Cell.Mol.Ther.4. 45-51 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Waguri: "Demonstration of two different processes of β-cell regeneration in a new diabetic model induced by selective perfusion of alloxan" Diabetes. 46(8). 1281-1290 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Yamamoto: "Differentiation of β-cells from ductal cells and acceleration of the process by nicotinamide: ultrastructural study on the non-obese diabetic(NOD)mice" Biomedical Res.18(2). 171-178 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Yamamoto: "Proliferation and differentiation of pancreatic β-cells: ultrastructural analysis of the pancreas in diabetic mice induced by selective alloxan perfusion" Med.Electron Microsc.30. 170-175 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Kaneto: "Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development" J.Biol.Chem.30(4). 29137-29143 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] S.Higashiyama: "A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4" J.Biochem.123. 675-680 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Waguri: "Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM" Endocrine J.44(1). 23-33 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] N.Itoh: "Requirement of Pas for the development of autoimmune diabetes in non-obese diabetic mice" J.Exp.Med.186(4). 613-618 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Iwahashi: "Mollecular mechanism of beta cell destruction in autoimmune diabetes: potential target for preventive therapy" Cytokines Cell.Mol.Ther.4. 45-51 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 綿田裕孝: "PDX-1(IPF1)膵β細胞特異的遺伝子発現における重要性" 分子糖尿病学. 8. 163-169 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 金藤秀明: "転写因子IPF1(PDX-1)を介した膵島細胞の発生、分化機構の検討-IPF1によるHB-" 分子糖尿病学. 8. 171-177 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 宮川潤一郎: "Betacellollnによる膵外分泌細胞からインスリン分泌細胞へのtransdifferentiation" 分子糖尿病学. 8. 189-192 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 宮川潤一郎: "膵β細胞の分化・増殖・再生の立場から" 内分泌・糖尿病科. 6(1). 64-73 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本浩司: "ベータセルリンによるβ細胞分化促進と耐糖能改善促進効果-アロキサン膵部分灌流糖尿病マウスにおける検討-" Diabetes Prontler. 8(4). 498 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 和栗雅子: "Diphenytihiocarbazone(dithizone)を用いたマウス膵島の絶対数、総体積の評価-アロキサン膵部分灌流糖尿病マウスにおける検討-" Diabetes Prontier. 8(4). 509 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本浩司: "ベータセルリン" 内分泌・糖尿病科. 6(6). 505-509 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本浩司: "ベータセルリンノックアウトマウスにおける耐糖能の変化および膵内分泌細胞の形態学的分析" Diabetes Prontier. 9(3). 362 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 岩橋博見: "膵島細胞のアポトーシス-生理的側面および病理的側面とその関連分子-" 医学のあゆみ. 187(5). 510-514 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 宮川潤一郎: "膵β細胞再生促進療法の可能性" 医学のあゆみ. 187(5). 121-125 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 宮川 潤一郎: "膵β細胞の発生・分化・増殖・再生・アポトーシスと糖尿病.分子糖尿病学の進歩-基礎から臨床まで-" 金原出版(門脇 孝、春日雅人、清野 進、渥美義仁 編), 11-23 (1988)

    • Related Report
      1998 Annual Research Report
  • [Publications] 宮川 潤一郎: "膵β細胞の発生・分化●専門医のための糖尿病●--最新主要文献と解説-" 総合医学社(河盛隆造、春日雅人 監修), 28-40 (199●

    • Related Report
      1998 Annual Research Report
  • [Publications] Waguri M., Yamamoto K., Miyagawa J.et al.: "Demonstration of two different processes in β-cell regeneration : differentiation and proliferation - From the studies on a new diabetic mouse model induced by selective perfusion of alloxan -" Diabetes. 46・8. 1281-1290 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamamoto K., Miyagawa J., Itoh N.et al.: "Differentiation of B-cells from ductal cells and acceleration of this process by nicotinamide : Ultrastructural study on the non-obese diabetic (NOD) mice with overt diabetes" Biomed.Res.18・2. 171-178 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamamoto K., Miyagawa J., Waguri M., et al.: "Proliferation and differentiation of pancreatic β-cells : Ultrastructural analysis of the pancreas in diabetic mice induced by selective alloxan perfusion" Med.Electron Microsc.30・3. 1281-1290 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kaneto H., Miyagawa J, Kajimoto Y.et al.: "Expression of HB-EGF during pancreas development : a potential role of PDX-1 in the transcriptional activation" J.Biol.Chem.272・4. 29137-29143 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Higashiyama S., Horikawa M., Miyagawa J.et al.: "A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4" J.Biochem.122・9. 675-680 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Miyagawa J., Yamamoto K, Waguri M.et al.: "Betacellulin potentiates the differentiation of islet cells - in vivo effect on the diabetic pancreas -" Exp.Clin.Endocrinol.Diabetes. 150・4. A29-A30 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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