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Regulation of adipocyte function by inhibitin of dipeptidyl peptidase-4

Research Project

Project/Area Number 23591316
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionYokohama City University

Principal Investigator

KIMURA Mari  横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (40363840)

Co-Investigator(Kenkyū-buntansha) TERAUCHI Yasuo  横浜市立大学, 医学系研究科, 教授 (40359609)
NAKAMURA Akinobu  横浜市立大学, 医学研究科, 客員研究員 (70552420)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsジペプチジルペプチダーゼ-4 / 膵島 / マクロファージ / 遊離脂肪酸 / 内臓脂肪 / インクレチン / インスリン / ジペプチジルペプチダーゼ / ンスリン
Research Abstract

We investigated the extra-pancreatic effects of DPP-4 inhibition on visceral fat and the liver. The epididymal fat weight was significantly higher in beta-cell-specific glucokinase haploinsufficient (Gck+/-) mice fed a diet containing a combination of sucrose and linoleic acid (SL) than in mice fed a diet containing a combination of sucrose and oleic acid (SO). Compared with SO, SL increased the numbers of CD11c+ M1 macrophages and CD8+ T cells in visceral adipose tissue. DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8+ T cells and M1 macrophages and decreased the expression of PAI-1. DPP-4 inhibition also prevented fatty liver in both wild-type mice and Gck+/- mice. DPP-4 inhibition also decreased the expressions of SREBP-1c, SCD-1 and FAS and increased the expression of PPARalpha in the liver. Thus, DPP-4 inhibition has extra-pancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (55 results)

All 2014 2013 2012 2011 Other

All Journal Article (23 results) (of which Peer Reviewed: 23 results) Presentation (22 results) (of which Invited: 2 results) Book (7 results) Remarks (3 results)

  • [Journal Article] Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control,βcell functions, andβcell proliferation in male mice2014

    • Author(s)
      Shirakawa J, Okuyama T, Yoshida E, Shimizu M, Horigome Y, Tuno T, Hayasaka M, Abe S, Fuse M, Togashi Y, Terauchi Y
    • Journal Title

      Endocrinology

      Volume: (Epub ahead of print)

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] βcell proliferation after a partial pancreatectomy is independent of IRS-2 in mice2014

    • Author(s)
      Togashi Y, Shirakawa J, Orime K, Kaji M, Sakamoto E, Tajima K, Inoue H, Nakamura A, Tochino Y, Goshima Y, Shimomura I, Terauchi Y
    • Journal Title

      Endocrinology

      Volume: (Epub ahead of print)

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] β cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice.2014

    • Author(s)
      Togashi Y, Shirakawa J, Orime K, Kaji M, Sakamoto E, Tajima K, Inoue H, Nakamura A, Tochino Y, Goshima Y, Shimomura I, Terauchi Y.
    • Journal Title

      Endocrinology

      Volume: 155 Issue: 5 Pages: 1643-52

    • DOI

      10.1210/en.2013-1796

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β cell functions, and β cell proliferation in male mice.2014

    • Author(s)
      Shirakawa J, Okuyama T, Yoshida E, Shimizu M, Horigome Y, Tuno T, Hayasaka M, Abe S, Fuse M, Togashi Y, Terauchi Y.
    • Journal Title

      Endocrinology

      Volume: 155

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 Mice2013

    • Author(s)
      Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y
    • Journal Title

      Am. J. Physiol. Endocrinol. Metab.

      Volume: 305(8)

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreaticβcells2013

    • Author(s)
      Shirakawa J, Togashi Y, Sakamoto E, Kaji M, Tajima K, Orime K, Inoue H, Kubota N, Kadowaki T, Terauchi Y
    • Journal Title

      Diabetes

      Volume: 62(10) Pages: 3448-58

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β cells.2013

    • Author(s)
      Shirakawa J, Togashi Y, Sakamoto E, Kaji M, Tajima K, Orime K, Inoue H, Kubota N, Kadowaki T, Terauchi Y.
    • Journal Title

      Diabetes

      Volume: 62 Issue: 10 Pages: 3448-58

    • DOI

      10.2337/db13-0052

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 Mice.2013

    • Author(s)
      Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y.
    • Journal Title

      Am. J. Physiol. Endocrinol. Metab.

      Volume: 305 Issue: 8 Pages: 987-998

    • DOI

      10.1152/ajpendo.00133.2013

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients2012

    • Author(s)
      Kubota A, Maeda H, Kanamori A, Matoba K, Jin Y, Minagawa F, Obana M, Iemitsu K, Ito S, Amemiya H, Kaneshiro M, Takai M, Kaneshige H, Hoshino K, Ishikawa M, Minami N, Takuma T, Sasai N, Aoyagi S, Kawata T, Mokubo A, Takeda H, Honda S, Machimura H, Motomiya T, Waseda M, Naka Y, Tanaka Y, Terauchi Y, Matsuba I
    • Journal Title

      J Clin Med Res

      Volume: 4(5) Pages: 309-13

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Control of beta cell function and proliferation in mice stimulated by small molecule glucokinase activator under various conditions2012

    • Author(s)
      Nakamura A , Togashi Y, Orime K, Sato K, Shirakawa J, Ohsugi M, Kubota N, Kadowaki T, Terauchi Y
    • Journal Title

      Diabetologia

      Volume: 55(6) Pages: 1745-54

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effects of liraglutide onβcell-specific glucokinase-deficient neonatal mice2012

    • Author(s)
      Shirakawa J, Tanami R, Togashi Y, Tajima K, Orime K, Kubota N, Kadowaki T, Goshima Y, Terauchi T
    • Journal Title

      Endocrinology

      Volume: 153(7) Pages: 3066-75

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Plasminogen activator inhibitor-1 is associated with renal dysfunction independent of BMI and serum lipid levels in patients with type 2 diabetes2012

    • Author(s)
      Shirakawa J, Togashi Y, Tajima K, Orime K, Kikuchi K, Miyazaki T, Sato K, Kimura M, Goshima Y, Terauchi Y
    • Journal Title

      Diabetes Res. Clin. Pract.

      Volume: 97(1)

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, beta cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet2012

    • Author(s)
      Sato K, Nakamura A, Shirakawa J, Muraoka T, Togashi Y, Shinoda K, Orime K, Kubota N, Kadowaki T, Terauchi Y
    • Journal Title

      Endocrinology

      Volume: 153(3) Pages: 1093-102

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, beta cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet.2012

    • Author(s)
      Sato K
    • Journal Title

      Endocrinology

      Volume: 153 Pages: 1093-1102

    • Related Report
      2012 Research-status Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of liraglutide on β cell-specific glucokinase-deficient neonatal mice.2012

    • Author(s)
      Shirakawa J
    • Journal Title

      Endocrinology

      Volume: 153 Pages: 3066-3075

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Control of beta cell function and proliferation in mice stimulated by small molecule glucokinase activator under various conditions.2012

    • Author(s)
      Nakamura A
    • Journal Title

      Diabetologia

      Volume: 55 Pages: 1745-1754

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients.2012

    • Author(s)
      Kubota A
    • Journal Title

      J Clin Med Res

      Volume: 4 Pages: 309-313

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Plasminogen activator inhibitor-1 is associated with renal dysfunction independent of BMI and serum lipid levels in patients with type 2 diabetes..2012

    • Author(s)
      Shirakawa J
    • Journal Title

      Diabetes Res. Clin. Pract.

      Volume: 97

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Shirakawa J, et al.Effects of liraglutide on β cell-specific glucokinase-deficient neonatal mice2012

    • Author(s)
      Shirakawa J, et al.
    • Journal Title

      Endocrinology

      Volume: 153

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Protective effect of a dipeptidyl peptidase-4 (DPP-4) inhibitor against increasedβcell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes2011

    • Author(s)
      Shirakawa J, Amo K, Ohminami H, Orime K, Togashi Y, Ito Y, Tajima K, Koganei M, Sasaki H, Takeda E, Terauchi Y
    • Journal Title

      J Biol Chem

      Volume: 286(29) Pages: 25467-76

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice2011

    • Author(s)
      Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, Sakamoto E, Koganei M, Sasaki H, Nagashima Y, Amo K, Aoki K, Morimoto C, Takeda E and Terauchi Y
    • Journal Title

      Diabetes

      Volume: 60 Pages: 1246-1257

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Protective effect of a dipeptidyl peptidase-4 (DPP-4) inhibitor against increased β cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes2011

    • Author(s)
      Shirakawa J, et al.
    • Journal Title

      J Biol Chem

      Volume: 286 Pages: 25467-25476

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.2011

    • Author(s)
      Shirakawa J, et al.
    • Journal Title

      Diabetes

      Volume: 60 Pages: 1246-1257

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] メトホルミンは高脂肪食下での肝腫瘍形成を抑制する2013

    • Author(s)
      田島一樹、中村昭伸、白川純、折目和基、富樫優、井上英昭、長嶋洋治、寺内康夫
    • Organizer
      第86回日本内分泌学会学術総会
    • Place of Presentation
      仙台
    • Year and Date
      2013-04-25
    • Related Report
      2013 Final Research Report
  • [Presentation] 2型糖尿病に対するインクレチン療法:基礎と臨床2013

    • Author(s)
      寺内康夫
    • Organizer
      第90回日本生理学会大会
    • Place of Presentation
      東京
    • Year and Date
      2013-03-29
    • Related Report
      2013 Final Research Report
  • [Presentation] メタボリックシンドロームと炎症2013

    • Author(s)
      寺内康夫
    • Organizer
      第47回糖尿病学の進歩
    • Place of Presentation
      津
    • Year and Date
      2013-02-15
    • Related Report
      2013 Final Research Report
  • [Presentation] Coordinated effects of macrophages and free fatty acids on the inflammatory gene expression in pancreatic islets2013

    • Author(s)
      Inoue H, Shirakawa J, Orime K, Togashi Y, Terauchi Y
    • Organizer
      49^<th> Annual Meeting of the European Association for the Study of Diabetes
    • Place of Presentation
      Barcelona, Spain
    • Related Report
      2013 Final Research Report
  • [Presentation] Characterization of target genes of glucokinase activator (GKA) in pancreatic islets2013

    • Author(s)
      Shirakawa J, Terauchi Y
    • Organizer
      73rd American Diabetes Association (ADA) meeting
    • Place of Presentation
      Chicago, USA
    • Related Report
      2013 Final Research Report
  • [Presentation] Postprandial Hyperglycemia and Vascular Disorder2012

    • Author(s)
      Terauchi Y
    • Organizer
      The 10^<th> Korea-Japan Joint Symposium on Vascular Biology
    • Place of Presentation
      Tokushima, Japan
    • Year and Date
      2012-12-05
    • Related Report
      2013 Final Research Report
  • [Presentation] Signaling pathway ofβCell proliferation in pancreatectomy is distinct from that in high-fat diet-loading in Mice2012

    • Author(s)
      Togashi Y, Shirakawa J, Nakamura A, Terauchi Y
    • Organizer
      American Diabetes Association 72^st Scientific Sessions
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2012-06-08
    • Related Report
      2013 Final Research Report
  • [Presentation] Glucokinase Activator Amelioratesβcell ER Stress and Apoptosis by both IRS-2-dependent and -Independent Pathways2012

    • Author(s)
      Shirakawa J, Terauchi Y
    • Organizer
      72th American Diabetes Association (ADA) meeting
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2012-06-08
    • Related Report
      2013 Final Research Report
  • [Presentation] Regulation of expression of incretin receptors in islet by dephosphorylation of AMPK2012

    • Author(s)
      Tajima K, Shirakawa J, Orime K, Togashi Y, Terauchi Y
    • Organizer
      72th American Diabetes Association (ADA) meeting
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2012-06-08
    • Related Report
      2013 Final Research Report
  • [Presentation] シンポジウム2型糖尿病インスリン分泌Insulin Secretion in Type 2 Diabetes Effects of glucokinase activator (GKA) on the regulation ofβcell ER stress and incretin receptor expressions2012

    • Author(s)
      白川純、田島一樹、富樫優、折目和基、寺内康夫
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2012-05-17
    • Related Report
      2013 Final Research Report
  • [Presentation] 膵β細胞特異的グルコキナーゼ欠損マウスにおけるリラグルチドの効果2012

    • Author(s)
      白川純、寺内康夫
    • Organizer
      第26回日本糖尿病・肥満動物学会年次学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2012-02-17
    • Related Report
      2013 Final Research Report
  • [Presentation] Effects of glucokinase activator (GKA) on the regulation of β cell ER stress and incretin receptor expressions.2012

    • Author(s)
      Shirakawa J
    • Organizer
      第55回日本糖尿病学会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Recent progress in blood glucose control.2012

    • Author(s)
      Terauchi Y
    • Organizer
      The 30th Annual Meeting of the International Society of Blood Purification.
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Glucokinase activator ameliorates β cell ER stress and apoptosis by both IRS-2-dependent and -independent pathways.2012

    • Author(s)
      Shirakawa J
    • Organizer
      第72回米国糖尿病学会
    • Place of Presentation
      フィラデルフィア(米国)
    • Related Report
      2012 Research-status Report
  • [Presentation] Trefoil factor 2 promotes cell proliferation in pancreatic β cells through A CXCR4-mediated ERK1/2 pathway.2012

    • Author(s)
      Orime K
    • Organizer
      第72回米国糖尿病学会
    • Place of Presentation
      フィラデルフィア(米国)
    • Related Report
      2012 Research-status Report
  • [Presentation] Signaling pathway of β cell proliferation after partial pancreatectomy is distinct from that on a high-fat diet in mice.2012

    • Author(s)
      Togashi Y
    • Organizer
      第72回米国糖尿病学会
    • Place of Presentation
      フィラデルフィア(米国)
    • Related Report
      2012 Research-status Report
  • [Presentation] The regulatory mechanism of incretin receptor expressions by dephosphorylation of AMPK in islet.2012

    • Author(s)
      Tajima K
    • Organizer
      第72回米国糖尿病学会
    • Place of Presentation
      フィラデルフィア(米国)
    • Related Report
      2012 Research-status Report
  • [Presentation] 膵β細胞特異的グルコキナーゼ欠損マウスにおけるリラグルチドの効果2012

    • Author(s)
      白川 純 他
    • Organizer
      第26回日本糖尿病肥満動物学会
    • Place of Presentation
      愛知県産業労働センター(名古屋)
    • Related Report
      2011 Research-status Report
  • [Presentation] Trefoil factor 2 (TFF2) induces proliferation of pancreaticβcells2011

    • Author(s)
      Orime K, Shirakawa J, Nakamura A, Togashi Y, Tajima K, Sato K, Terauchi Y
    • Organizer
      71st Scientific Sessions for American Diabetes Association (ADA)
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2011-06-24
    • Related Report
      2013 Final Research Report
  • [Presentation] Impact of vildagliptin on glucose tolerance, and beta cell mass in insulin receptor substrate-2-knockout mice2011

    • Author(s)
      Sato K, Shirakawa J, Muraoka T, Togashi, Orime K, Nakamura A, Terauchi Y
    • Organizer
      71st Scientific Sessions for American Diabetes Association (ADA)
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2011-06-24
    • Related Report
      2013 Final Research Report
  • [Presentation] Impact of vildagliptin on glucose tolerance, and beta cell mass in insulin receptor substrate-2-knockout mice2011

    • Author(s)
      Sato K, et al.
    • Organizer
      第71回米国糖尿病学会
    • Place of Presentation
      サンディエゴ(米国)
    • Related Report
      2011 Research-status Report
  • [Presentation] Trefoil factor 2 (TFF2) induces proliferation of pancreatic β cells2011

    • Author(s)
      Orime K, et al.
    • Organizer
      第71回米国糖尿病学会
    • Place of Presentation
      サンディエゴ(米国)
    • Related Report
      2011 Research-status Report
  • [Book] Annual Review糖尿病・代謝・内分泌20142014

    • Author(s)
      寺内康夫、伊藤裕、石橋俊編
    • Total Pages
      213
    • Publisher
      中外医学社
    • Related Report
      2013 Final Research Report
  • [Book] Annual Review糖尿病・代謝・内分泌20132013

    • Author(s)
      寺内康夫、伊藤裕、石橋俊編
    • Total Pages
      229
    • Publisher
      中外医学社
    • Related Report
      2013 Final Research Report
  • [Book] ここが知りたいインクレチン関連薬2013

    • Author(s)
      寺内康夫編
    • Total Pages
      195
    • Publisher
      中外医学社
    • Related Report
      2013 Final Research Report
  • [Book] ここが知りたい インクレチン関連薬2013

    • Author(s)
      寺内康夫
    • Total Pages
      170
    • Publisher
      中外医学社
    • Related Report
      2012 Research-status Report
  • [Book] Annual Review糖尿病・代謝・内分泌20122012

    • Author(s)
      寺内康夫、伊藤裕、石橋俊編
    • Total Pages
      245
    • Publisher
      中外医学社
    • Related Report
      2013 Final Research Report
  • [Book] 2型糖尿病の薬物療法ハンドブック2011

    • Author(s)
      寺内康夫編
    • Total Pages
      170
    • Publisher
      南江堂
    • Related Report
      2013 Final Research Report
  • [Book] 2型糖尿病の薬物療法ハンドブック2011

    • Author(s)
      寺内康夫
    • Total Pages
      170
    • Publisher
      南江堂
    • Related Report
      2011 Research-status Report
  • [Remarks]

    • URL

      http://www-user.yokohama-cu.ac.jp/~nai3naib/

    • Related Report
      2013 Final Research Report
  • [Remarks] 横浜市立大学分子内分泌・糖尿病内科学教室

    • URL

      http://www-user.yokohama-cu.ac.jp/~nai3naib/

    • Related Report
      2013 Annual Research Report
  • [Remarks] 横浜市立大学 分子内分泌・糖尿病内科学

    • URL

      http://www-user.yokohama-cu.ac.jp/~nai3naib/

    • Related Report
      2012 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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