Development of novel therapeutic strategies that targets intestinal epithelial endocrine cells

• Project/Area Number: 21659232
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: Nagoya University
• Principal Investigator: HAYASHI Yoshitaka 名古屋大学, 環境医学研究所, 准教授 (80420363)
• Co-Investigator(Kenkyū-buntansha): SAWADA Makoto 名古屋大学, 環境医学研究所, 教授 (10187297)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,140,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2009: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: 内分泌学 / 糖尿病 / 発生 / 分化 / インクレチン / GLP-1 / バイオイメージング / L-細胞 / 創薬

Research Abstract

Glucagon-like peptide-1(GLP-1), which stimulates insulin secretion from islet.-cells, is produced in enteroendocrine L cells. As L cells are distributed in a scattered manner in intestinal epithelium, selective isolation of L cells has been difficult. Elucidation of mechanisms regulating differentiation and proliferation of L cells, and regulatory mechanism of GLP-1 secretion, should contribute to development of novel drugs to treat diabetes, which regulate production of endogenous GLP-1. In the present study, we developed a novel gene-modified animal model, in which green fluorescent protein is expressed in an L cell specific manner. We succeeded in selective isolation of L cells and identification of genes expressed in an L cell specific manner. Functional analyses of such genes should lead to development of novel drugs to treat diabetes mellitus.

Research Products

• [Journal Article] Remodeling of hepatic metabolism and hyper aminoacidemia in mice deficient in proglucagon-derived peptides (2012)
  • Author(s): Watanabe, C., Seino, Y., Miyahira, H., Yamamoto, M., Fukami, A., Ozaki, N., Takagishi, Y., Sato, J., Fukuwatari, T., Shibata, K., Oiso, Y., Murata, Y., and Hayashi, Y.
  • Journal Title: Diabetes Volume: 61 Pages: 74-84
  • Peer Reviewed
• [Journal Article] Remodeling of hepatic metabolism and hyperaminoacidemia in mice deficient in proglucagon-derived peptides (2012)
  • Author(s): C.Watanabe, et al
  • Journal Title: Diabetes Volume: 61(1) Issue: 1 Pages: 74-84
  • DOI: 10.2337/db11-0739
  • Peer Reviewed
• [Journal Article] Metabolic impact of glucagon deficiency (2011)
  • Author(s): Hayashi, Y.
  • Journal Title: Diabetes Obes. Metab Volume: 13 Pages: 151-157
  • Peer Reviewed
• [Journal Article] Metabolic impact of glucagon deficiency (2011)
  • Author(s): Y.Hayashi
  • Journal Title: Diabetes Obes.Metab. Volume: 13(Suppl1) Issue: s1 Pages: 151-157
  • DOI: 10.1111/j.1463-1326.2011.01456.x
  • Peer Reviewed
• [Journal Article] Inactivation of the rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake. (2010)
  • Author(s): X.Y.Sun, Y.Hayashi, et al
  • Journal Title: PLoS One Volume: 6
  • Peer Reviewed
• [Journal Article] Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet a-cells but not of intestinal L-cells (2009)
  • Author(s): Hayashi, Y., Yamamoto, M., Mizoguchi, H., Watanabe, C., Ito, R., Yamamoto, S., Sun, X. Y., and Murata, Y.
  • Journal Title: Mol. Endocrinol Volume: 23 Pages: 1990-1999
  • Peer Reviewed
• [Journal Article] Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of lslet α-Cells But Not of lntestinal L-Cells (2009)
  • Author(s): Y.Hayashi, et al
  • Journal Title: Molecular Endocrinology 23 Pages: 1990-1999
  • Peer Reviewed
• [Journal Article] Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes. (2009)
  • Author(s): Y.Sugimura, Y.Hayashi, et al
  • Journal Title: Diabetologia 52 Pages: 962-971
  • Peer Reviewed
• [Journal Article] Possible involvement of BRAFV600E in altered gene expression in papillary thyroid cancer. (2009)
  • Author(s): R.Watanabe, Y.Hayashi, et al
  • Journal Title: Endocrine Journal 56 Pages: 407-414
  • NAID: 10026913638
  • Peer Reviewed
• [Journal Article] A novel Caspr mutation causes the shambling mouse phenotype by disrupting axo-glial interactions of myelinated nerves. (2009)
  • Author(s): X.Y.Sun, Y.Hayashi, et al
  • Journal Title: Journal of Neuropathology and Experimental Neurology 68 Pages: 1207-1218
  • Peer Reviewed
• [Presentation] 大磯ユタカプログルカゴン遺伝子欠損マウスは膵島由来のGIPを介してグルコース応答性インスリン分泌を増強する (2012)
  • Author(s): 深見亜也子,清野祐介,尾崎信暁,三浦英里子,恒川新,林良敬
  • Organizer: 第3回東海インクレチン研究会
  • Place of Presentation: 名古屋(愛知県)
  • Year and Date: 2012-02-24
• [Presentation] プログルカゴン遺伝子欠損マウスは膵島由来のGIPを介してグルコース応答性インスリン分泌を増強する (2012)
  • Author(s): 深見亜也子, ほか
  • Organizer: 第3回東海インクレチン研究会
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2012-02-24
• [Presentation] Evaluation of b-cell function in proglucagon-EGFP knock-in mice (2011)
  • Author(s): Fukami, A., Seino, Y., Ozaki, N., akamoto, E., Kato, J., Tsunekawa, S., Hayashi, Y., Murata, Y., Oiso, Y.
  • Organizer: 47^<th> EASD annual meeting
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2011-09-14
• [Presentation] Evaluation of β-cell function in proglucagon-EGFP knock-in mice (2011)
  • Author(s): A.Fukami, et al
  • Organizer: 47^<th> EASD annual Meeting
  • Place of Presentation: リスボン(ポルトガル)
  • Year and Date: 2011-09-14
• [Presentation] 大磯ユタカプログルカゴン遺伝子GFPノックインマウスにおけるインスリン分泌更新の機序の解明 (2011)
  • Author(s): 深見亜也子,尾崎信暁,坂本英里子,清野祐介,恒川新,林良敬
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌(北海道)
  • Year and Date: 2011-05-19
• [Presentation] プログルカゴン遺伝子GFPノックインマウスにおけるインスリン分泌更新の機序の解明 (2011)
  • Author(s): 深見亜也子, ほか
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2011-05-19
• [Presentation] Hepatic gene expression profile in mice deficient for glucagon gene-derived peptides (2011)
  • Author(s): Watanabe, C., Hayashi, Y., Oiso, Y., Murata, Y.
  • Organizer: SERVIER International Group of Insulin Secretion Symposia XII
  • Place of Presentation: Saint-Jean-Cap-Ferrat, France
  • Year and Date: 2011-04-03
• [Presentation] Hepatic gene expression profile in mice deficient for glucagon gene-derived peptides (2011)
  • Author(s): C.Watanabe, et al
  • Organizer: SERVIER International Group of Insulin Secretion Symposia
  • Place of Presentation: サンジャンキャプフェラ(フランス)(招待講演)
  • Year and Date: 2011-04-03
• [Presentation] Metabolic impact of glu-cagon deficiency (2011)
  • Author(s): Hayashi, Y.
  • Organizer: SERVIER International Group of Insulin Secretion Symposia XII
  • Place of Presentation: Saint-Jean-Cap-Ferrat, France
  • Year and Date: 2011-04-02
• [Presentation] Metabolic impact of glucagon deficiency (2011)
  • Author(s): Y.Hayashi
  • Organizer: SERVIER International Group of Insulin Secretion Symposia XII
  • Place of Presentation: サンジャンキャプフェラ(フランス)
  • Year and Date: 2011-04-02
• [Presentation] グルカゴン遺伝子ノックアウトマウスとプログルカゴン由来ペプチドによる代謝制御 (2011)
  • Author(s): 林良敬
  • Organizer: 第16回OSAKA BAY DIABETES FORUM
  • Place of Presentation: 大阪(大阪府)
  • Year and Date: 2011-03-06
• [Presentation] グルカゴン遺伝子ノックアウトマウスとプログルカゴン由来ペプチドによる代謝制御 (2011)
  • Author(s): 林良敬
  • Organizer: 第16回 OSAKA BAY DIABETES FORUM
  • Place of Presentation: 大阪 招待講演
  • Year and Date: 2011-03-06
• [Presentation] グルカゴン遺伝子ノックアウトマウスとプログルカゴン由来ペプチドによる代謝制御 (2010)
  • Author(s): 林良敬
  • Organizer: 第7回群馬大学生体調節研究所名古屋大学環境医学研究所合同シンポジウム
  • Place of Presentation: 名古屋(愛知県)
  • Year and Date: 2010-11-19
• [Presentation] グルカゴン遺伝子ノックアウトマウスとプログルカゴン由来ペプチドによる代謝制御 (2010)
  • Author(s): 林良敬
  • Organizer: 群馬大学生体調節研究所 名古屋大学環境医学研究所 第7回 合同シンポジウム
  • Place of Presentation: 名古屋 招待講演
  • Year and Date: 2010-11-19
• [Presentation] 大磯ユタカプログルカゴン遺伝子GFPノックインマウスにおける膵SS細胞機能と形態学的評価 (2010)
  • Author(s): 深見亜也子,尾崎信暁,坂本英里子,福山貴広,水谷直広,清野祐介,林良敬
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山(岡山県)
  • Year and Date: 2010-05-28
• [Presentation] プログルカゴン遺伝子GFPノックインマウスにおける膵β細胞機能と形態学的評価 (2010)
  • Author(s): 深見亜也子、林良敬, ほか
  • 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: 2010-05-28
• [Presentation] Hepatic gene expression profile in mice deficient for glucagon gene-derived peptides (2010)
  • Author(s): Watanabe C.
  • Organizer: 14^<th> Inter national Congress of Endocrinology
  • Place of Presentation: 京都(京都府)
  • Year and Date: 2010-03-27
• [Presentation] Hepatic gene expression profile in mice deficient for glucagon gene-derived peptides. (2010)
  • Author(s): C.Watanabe, Y.Hayashi, ほか
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: 京都
  • Year and Date: 2010-03-27
• [Presentation] グルカゴンーGFPノックインマウスの作成と解析 (2009)
  • Author(s): 林良敬,伊藤諒一,山本美智代,渡邊千香,孫暁陽,村田善晴
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 前橋(群馬県)
  • Year and Date: 2009-04-25
• [Presentation] グルカゴン-GFPノックインマウスの作成と解析 (2009)
  • Author(s): 林良敬, ほか
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 前橋
  • Year and Date: 2009-04-25