Study on the differentiation and proliferation of GLP-1-producing L cells and the development of new incretin-based therapy for diabetes mellitus

• Project/Area Number: 20591075
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Hyogo College of Medicine
• Principal Investigator: MIYAGAWA Jun-Ichiro Hyogo College of Medicine, 医学部, 教授 (00127721)
• Co-Investigator(Kenkyū-buntansha): NAMBA Mitsuyoshi 兵庫医科大学, 医学部, 教授 (00183533) ; HAMAGUCHI Tomoya 兵庫医科大学, 医学部, 講師 (60330461) ; KATSUNO Tomoyuki 兵庫医科大学, 医学部, 助教 (30441257) ; MIUCHI Masayuki 兵庫医科大学, 医学部, 助教 (90434951) ; MURAI Kazuki 兵庫医科大学, 医学部, 助教 (40588373) ; KONYA Hiroyuki 市立芦屋病院, 糖尿病内科, 部長 (50340956)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: インクレチン / 膵β細胞 / GLP-1(glucagon-like peptide-1) / 糖尿病 / L細胞 / 分化 / GLP-1 / 再生 / 消化管ホルモン

Research Abstract

Incretin hormone GLP-1(glucagon-like peptide-1) secreted from gastrointestinal tract has multi-potent physiological actions including increase or maintenance of beta cell mass (promotion of proliferation and neogenesis, and inhibition of apoptosis in beta cells). In addition to the incretin action, these effects that have not been demonstrated in human, are also important in view of regenerative medicine in diabetes mellitus.
We studied on the development and differentiation of GLP-1 secreting L cells in mice, and the change in the number of L cells in model mice of type 2 diabetes mellitus. In the intestinal tract, GLP-1-positive cells are difficult to detect in fetal period, and most of them appear in post-natal period, suggesting complicated mechanism for differentiation of L cells requiring endogenous and exogenous factors. Both in vivo and in vitro (GLP-1 secreting L cell line NCI-H716) studies, it was difficult and failed in detecting GLP-1-secretory factors (GLPSF) and L-cell proliferation factors (LCPF) suitable for the development of anti-diabetic drugs. In diabetic mice (db/db mice), relative L cell number appeared to be increased compared to that of control mice which showed the trend to decrease with aging.
In human study on the secretory response of incretin hormones (GIP and GLP-1) to oral glucose intake (75g OGTT) in Japanese subjects with normal glucose tolerance, both incretin hormones showed different actions to the change of plasma concentrations of glucose and insulin. The secretory response of GIP correlated positively to insulin secretion, while that of GLP-1 did not, and appeared to be involved at least in part in inhibition glucagon secretion.

Research Products

• [Journal Article] Comparison of efficacy of concomitant administration of mitiglinide with voglibose and double dose of mitiglinide in patients with type 2 diabetes mellitus. (2011)
  • Author(s): Katsuno T, Wtanabe N, Nagai E, Hamaguchi T, Miyagawa J-I, Namba M.
  • Journal Title: J.Diab. Invest. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Incretin responses to oral glucose load in Japanese non-obese healthy subjects. (2011)
  • Author(s): Nagai E, Katsuno T, Miyagawa J, Konishi K, Miuchi M, Ochi F, Kusunoki Y, Tokuda M, Murai K, Hamaguchi T, Namba M.
  • Journal Title: Diabetes Ther. Volume: 2(2)(in press)
  • Peer Reviewed
• [Journal Article] Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus. (2010)
  • Author(s): Konya H, Hasegawa Y, Hamaguchi T, Satani K, Umehara A, Katsuno T, Ishikawa T, Miuchi M, Kohri K, Suehiro A, Kakishita E, Miyagawa J-I, Namba M.
  • Journal Title: Metabolism 59 Pages: 1294-1299
  • Peer Reviewed
• [Journal Article] 糖尿病治療の新たな展開-インクレチン治療薬を中心に-,インクレチン治療薬と他剤の併用:423-433,2010 (2010)
  • Author(s): 宮川潤一郎, 難波光義
  • Journal Title: 診断と治療 Volume: 98(3) Pages: 423-433
• [Journal Article] 新しい糖尿病治療薬2-GLP-1製剤 (2010)
  • Author(s): 宮川潤一郎
  • Journal Title: プラクィス Volume: 27(2) Pages: 161-170
• [Journal Article] 糖尿病治療の新たな展開-インクレチンの登場,インクレチンの基礎-GLP-1の膵作用と膵外作用 (2010)
  • Author(s): 宮川潤一郎, 難波光義
  • Journal Title: Prog Med Volume: 30(2) Pages: 320-327
• [Journal Article] GLP-1誘導体による2型糖尿病の治療戦略 (2010)
  • Author(s): 美内雅之, 宮川潤一郎, 難波光義
  • Journal Title: 月刊糖尿病 Volume: 2 Pages: 98-105
• [Journal Article] Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus. (2010)
  • Author(s): Konya H, Hasegawa Y, Hamaguchi T, Satani K, Umehara A, Katsuno T, Ishikawa T, Miuchi M, Kohri K, Suehiro A, Kakishita E, Miyagawa J-I, Namba M.
  • Journal Title: Metabolism Volume: 59 Pages: 1294-1299
  • Peer Reviewed
• [Journal Article] Pleiotropic effects of mitiglinide in type 2 diabetic patients. (2009)
  • Author(s): Konya M, Miuchi M, Konishi K, Nagai E, Ueyama T, Kusunoki Y, Kimura Y, Nakamura Y, Ishikawa T, Inokuchi C, Katsuno T, Hamaguchi T, Miyagawa J, Namba M
  • Journal Title: J.Int.Med.Res. 37 Pages: 1904-1912
  • Peer Reviewed
• [Journal Article] Role of macrophages in the development of pancreatic islet injury in spontaneously diabetic Torii rats. (2009)
  • Author(s): Inoguchi C., Ueda H., Hamaguchi T., Miyagawa J., Shinohara M., Okamura H, Namba M.
  • Journal Title: J.Exp.Anim. 58(4) Pages: 383-394
  • NAID: 130000122245
  • Peer Reviewed
• [Journal Article] 診断と治療の進歩IV.最近の話題 2.インクレチン関連治療 (2009)
  • Author(s): 宮川潤一郎、美内雅之、難波光義、糖尿病
  • Journal Title: 日本内科学会雑誌 98(4) Pages: 809-816
• [Journal Article] Role of macrophages in the development of pancreatic islet injury in spontaneously diabetic Torii rats. (2009)
  • Author(s): Inoguchi C., Ueda H., Hamaguchi T., Miyagawa J., Shinohara M., Okamura H, Namba M.
  • Journal Title: J.Exp.Anim 58(4) Pages: 383-394
  • NAID: 130000122245
  • Peer Reviewed
• [Journal Article] Pleiotropic effects of mitiglinide in type 2 diabetic patients. (2009)
  • Author(s): Konya M, Miuchi M, Konishi K, Nagai E, Ueyama T, Kusunoki Y, Kimura Y, Nakamura Y, Ishikawa T, Inokuchi C, Katsuno T, Hamaguchi T, Mivaeawa J, Namba M.
  • Journal Title: J.Int.Med.Res. 37 Pages: 1904-1912
  • Peer Reviewed
• [Journal Article] 糖尿病 : 診断と治療の進歩IV. 最近の話題2. インクレチン関連治療 (2009)
  • Author(s): 宮川潤一郎, 美内雅之, 難波光義
  • Journal Title: 日本内科学会雑誌 98(4) Pages: 809-816
• [Journal Article] 医学と医療の最前線、インクレチンの糖尿病治療への応用 (2008)
  • Author(s): 宮川潤一郎、難波光義
  • Journal Title: 日本内科学会雑誌 97(4) Pages: 827-835
• [Journal Article] 医学と医療の最前線. インクレチンの糖尿病治療への応用 (2008)
  • Author(s): 宮川潤一郎, 難波光義
  • Journal Title: 日本内科学会雑誌 97(4) Pages: 827-835
• [Journal Article] Comparison of efficacy of concomitant administration of mitiglinide with voglibose and double dose of mitiglinide in patients with type 2 diabetes mellitus.
  • Author(s): Katsuno T, Wtanabe N, Nagai E, Hamaguchi T, Miyagawa J-I, Namba M.
  • Journal Title: J.Diab.Invest. (in press)
  • Peer Reviewed
• [Journal Article] Incretin responses to oral glucose load in Japanese healthy subjects.
  • Author(s): Nagai E., Katsuno T., Miyagawa J., Konishi K., Miuchi M., Ochi F., Kusunoki Y., Tokuda M., Murai K., Hamaguchi T., Namba M.
  • Journal Title: Diabetes Ther. (in press)
  • Peer Reviewed
• [Journal Article] Effect of gliclazide on platelet aggregation and the plasminogen activator inhibitor typel level in type 2 diabetic patients.
  • Author(s): Konya H., Hasegawa Y., Hamaguchi T., Satani K., Umehara A., Katsuno T., Ishikawa T., Miuchi M., Kohri K., Suehiro A., Kakishita E., Miyaeawa J., Namba M.
  • Journal Title: Metabolism (In press)
  • Peer Reviewed
• [Presentation] インクレチン系の機序とその糖尿病治療への応用.GLP-1の分泌調節と膵内および膵外作用 (2011)
  • Author(s): 宮川潤一郎
  • Organizer: 第45回糖尿病学の進歩
  • Place of Presentation: 福岡市(シンポジウム)
  • Year and Date: 2011-02-19
• [Presentation] インクレチン系の機序とその糖尿病治療への応用.GLP-1の分泌調節と膵内および膵外作用 (2011)
  • Author(s): 宮川潤一郎(特別講演)
  • Organizer: 第45回糖尿病学の進歩
  • Place of Presentation: 福岡(シンポジウム)
  • Year and Date: 2011-02-19
• [Presentation] Incretin responses to oral glucose load in Japanese non-obese healthy subjects. (2010)
  • Author(s): Nagai E, Miyagawa J, Konishi K, Miuchi M, Katsuno T, Kusunoki Y, Tokuda M, Murai K, Hamaguchi T, Namba M
  • Organizer: The 8^<th> IDF WPR Conference
  • Place of Presentation: Busan, Korea
  • Year and Date: 2010-10-20
• [Presentation] GLP-1シグナルに基づく最新の糖尿病治療-基礎と臨床 (2010)
  • Author(s): 宮川潤一郎
  • Organizer: 第55回日本臨床検査医学会近畿支部例会
  • Place of Presentation: 神戸市(特別講演)
  • Year and Date: 2010-06-05
• [Presentation] GLP-1シグナルに基づく最新の糖尿病治療-基礎と臨床- (2010)
  • Author(s): 宮川潤一郎
  • Organizer: 第55回日本臨床検査医学会近畿支部例会
  • Place of Presentation: 神戸
  • Year and Date: 2010-06-05
• [Presentation] 2型糖尿病における結腸L細胞の変化～2型糖尿病モデルマウスを用いた分析～ (2010)
  • Author(s): 小西康輔、宮川潤一郎、永井悦子、美内雅之、勝野朋幸、神谷麻衣、楠宜樹,徳田八大,村井一樹,浜口朋也,難波光義
  • Organizer: 第53回日本糖尿病学会年次総会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-27
• [Presentation] 日本人2型糖尿病膵島におけるα、β両細胞の組織形態学的変化 (2010)
  • Author(s): 美内雅之,宮川潤一郎,永井悦子,小西康輔,勝野朋幸,神谷麻衣,楠宜樹,徳田八大,村井一樹,浜口朋也,難波光義
  • Organizer: 第53回日本糖尿病学会年次総会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-27
• [Presentation] Morphologic changes of theendocrine pancreas in Japanese non-obese type 2 diabetes with special reference to the relative β-cell area, so-called "β-cell mass" (2010)
  • Author(s): Miuchi M., Miyagawa J., Konishi K.,Nagai E., Katsuno T., Hamaguchi T. Namba M.
  • Organizer: 14^<th> International Congress of Endocrinology.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-03-30
• [Presentation] Morphologic changes of the endocrine pancreas in Japanese non-obese type 2 diabetes with special reference to the relative β-cell area, so-called "β-cell mass" (2010)
  • Author(s): Miuchi M, Miyagawaw J, Konishi K, Nagai E, Katsuno T, Hamaguchi T, Namba M
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-03-30
• [Presentation] GLP-1シグナルに基づく新しい糖尿病治療と心血管系 (2010)
  • Author(s): 宮川潤一郎
  • Organizer: 第74回日本循環器学会・学術集会
  • Place of Presentation: 京都市(ランチタイムセミナー)
  • Year and Date: 2010-03-07
• [Presentation] GLP-1シグナルを利用した新しい糖尿病治療-基礎と臨床- (2010)
  • Author(s): 宮川潤一郎
  • Organizer: 第8回日本フットケア学会年次学術集会
  • Place of Presentation: 東京都(ランチタイムセミナー)
  • Year and Date: 2010-02-28
• [Presentation] 日本人2型糖尿病膵島におけるα、β両細胞の組織形態学的変化 (2010)
  • Author(s): 美内雅之, 宮川潤一郎, 永井悦子, 小西康輔, 勝野朋幸, 神谷麻衣, 楠宜樹, 徳田八大, 村井一樹, 浜口朋也, 難波光義
  • Organizer: 第53回日本糖尿病学会年次総会
  • Place of Presentation: 岡山
• [Presentation] (教育講演)インクレチン関連薬と1型糖尿病-臨床応用の可能性- (2009)
  • Author(s): 宮川潤一郎
  • Organizer: 第7回1型糖尿病研究会
  • Place of Presentation: 日光市
  • Year and Date: 2009-11-08
• [Presentation] インクレチン関連薬と1型糖尿病-臨床応用の可能性- (2009)
  • Author(s): 宮川潤一郎
  • Organizer: 第7回1型糖尿病研究会
  • Place of Presentation: 日光市(教育講演)
  • Year and Date: 2009-11-06
• [Presentation] 糖尿病治療での規律と寛容 (2009)
  • Author(s): 宮川潤一郎
  • Organizer: 第46回日本糖尿病学会近畿地方会
  • Place of Presentation: 京都市(シンポジウム)
  • Year and Date: 2009-11-03
• [Presentation] (シンポジウム)糖尿病治療での規律と寛容 (2009)
  • Author(s): 宮川潤一郎
  • Organizer: 第46回日本糖尿病学会近畿地方会
  • Place of Presentation: 京都市
  • Year and Date: 2009-11-03
• [Presentation] Is asymmetric dimetylarginine (ADMA) a predictor of the diabetic cardiovascular diseases? (2009)
  • Author(s): Miuchi M., Konya H., Kataoka S., Konishi K., Nagai E., Nakamura Y., Katsuno T., Hamaguchi T.,Miyagawa J., Namba M.
  • Organizer: 20^<th> International Diabetes Federation Congress
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2009-10-20
• [Presentation] Is asymmetric dimetylarginine(ADMA)a predictor of the diabetic cardiovascular diseases? (2009)
  • Author(s): Miuchi M., Konya H., Kataoka S., Konishi K., Nagai E., Nakamura Y., Katsuno T., Hamaguchi T., Miyaeawa J., Namba M.
  • Organizer: 20^<th> International Diabetes Federation Congress
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2009-10-20
• [Presentation] Morphologic changes of the endocrine pancreas in Japanese non-obese type 2 diabetes. (2009)
  • Author(s): Miuchi M., Miyagawa J., Konishi K., Nagai E., Katsuno T., Kataoka S., KonyaH., Hamaguchi T., Namba M.
  • Organizer: 45^<th> EASD Annual Meeting
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2009-10-02
• [Presentation] Morphologic changes of the endocrine pancreas in Japanese non-obesetype 2 diabetes (2009)
  • Author(s): Miuchi M., Miyagawa J., Konishi K., Nagai E., Katsuno T., Kataoka S., Konya H., Hamaeuchi T., Namba M.
  • Organizer: 45^<th> EASD Annual Meeting
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2009-10-02
• [Presentation] 高齢者糖尿病患者における慢性腎臓(CKD)-進行例の特徴と対策- (2009)
  • Author(s): 浜口朋也、宮川潤一郎、難波光義
  • Organizer: 第51回日本老年医学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-06-10
• [Book] 糖尿病研修ノート(永井良三総監集)(第3章 検査.Cペプチド(血清、尿)) (2010)
  • Author(s): 宮川潤一郎
  • Publisher: 診断と治療社
• [Book] インクレチンとDPP-4阻害薬のすべて(清野裕編)(Part 6糖尿病治療の問題点とインクレチン・DPP-4への期待をさぐる.2.2型糖尿病とインクレチン作用) (2010)
  • Author(s): 宮川潤一郎、難波光義
  • Publisher: 先端医学社
• [Book] インクレチンとDPP-4阻害薬のすべて(清野裕編):Part 6糖尿病治療の問題点とインクレチン・DPP-4への期待をさぐる.2.2型糖尿病とインクレチン作用 (2010)
  • Author(s): 宮川潤一郎、難波光義
  • Publisher: 先端医学社
• [Book] 糖尿病研修ノート(永井良三 総監集):第3章 検査.Cペプチド(血清、尿) (2010)
  • Author(s): 宮川潤一郎
  • Publisher: 診断と治療社
• [Book] 治療薬 UP-TO-DATE2010(糖尿病治療薬) (2010)
  • Author(s): 美内雅之、宮川潤一郎、難波光義
  • Total Pages: 987
  • Publisher: メディカルレビュー社
• [Book] 糖尿病最新の治療(2010～2012、II.糖尿病治療の基本.2.1型糖尿病) (2009)
  • Author(s): 宮川潤一郎
  • Publisher: 南江堂
• [Book] インクレチン治療GLP-1受容体作動薬とDPP-4阻害薬による新たな糖尿病治療(6.インクレチン治療の展開1)GLP-1誘導体,エキセンジン-4のポジショニング) (2009)
  • Author(s): 難波光義、宮川潤一郎
  • Publisher: フジメディカル出版
• [Book] GLP-1受容体作動薬とDPP-4阻害薬による新たな糖尿病治療(2.GIP,GLP-1の多彩な作用 2)GLP-1) (2009)
  • Author(s): 宮川潤一郎、美内雅之、難波光義
  • Publisher: フジメディカル出版
• [Book] インクレチン治療 GLP-1受容体作動薬とDPP-4阻害薬による新たな糖尿病治療(2.GIP,GLP-1の多彩な作用2)GLP-1) (2009)
  • Author(s): 宮川潤一郎、美内雅之、難波光義
  • Total Pages: 87
  • Publisher: フジメディカル出版
• [Book] インクレチン治療 GLP-1受容体作動薬とDPP-4阻害薬による新たな糖尿病治療(6.インクレチン治療の展開1)GLP-1誘導体,エキセンジン-4のポジショニング) (2009)
  • Author(s): 難波光義、宮川潤一郎
  • Total Pages: 87
  • Publisher: フジメディカル出版
• [Book] 糖尿病最新の治療 2010～2012(II.糖尿病治療の基本.2.1型糖尿病) (2009)
  • Author(s): 宮川潤一郎
  • Total Pages: 239
  • Publisher: 南江堂
• [Book] 膵島の構造と機能(新時代の糖尿病学(1)-病因・診断・治療研究の進歩-、B.糖尿病基礎研究の進歩、I.糖代謝とその調節機序、膵の発生とβ細胞の機能) (2008)
  • Author(s): 宮川潤一郎
  • Publisher: 日本臨床社
• [Book] 新時代の糖尿病学(1)-病因・診断・治療研究の進歩-(日本臨床66(増3))、B. 糖尿病基礎研究の進歩、I. 糖代謝とその調節機序、膵の発生とβ細胞の機能、膵島の構造と機能 : 111-114 (2008)
  • Author(s): 宮川潤一郎
  • Total Pages: 652
  • Publisher: 日本臨床社