Regulation of adipocyte function by inhibitin of dipeptidyl peptidase-4

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591316
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Yokohama 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
• 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

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.

Research Products

• [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 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: (Epub ahead of print) Pages: en20132032
  • Peer Reviewed
• [Journal Article] βcell 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: (Epub ahead of print) Pages: en20131796
  • 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(8) Pages: E987-98
  • Peer Reviewed
• [Journal Article] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreaticβcells (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(10) Pages: 3448-58
  • Peer Reviewed
• [Journal Article] Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients (2012)
  • 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
  • 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 , 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
  • Peer Reviewed
• [Journal Article] Effects of liraglutide onβcell-specific glucokinase-deficient neonatal mice (2012)
  • 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
  • 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, 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) Pages: e7-e10
  • 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, 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
  • 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 diabetes (2011)
  • 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
  • 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, 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
  • Peer Reviewed
• [Presentation] Coordinated effects of macrophages and free fatty acids on the inflammatory gene expression in pancreatic islets (2013)
  • 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
  • Year and Date: 20130923-27
• [Presentation] Characterization of target genes of glucokinase activator (GKA) in pancreatic islets (2013)
  • Author(s): Shirakawa J, Terauchi Y
  • Organizer: 73rd American Diabetes Association (ADA) meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 20130621-25
• [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
• [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
• [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
• [Presentation] Postprandial Hyperglycemia and Vascular Disorder (2012)
  • 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
• [Presentation] Signaling pathway ofβCell proliferation in pancreatectomy is distinct from that in high-fat diet-loading in Mice (2012)
  • 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
• [Presentation] Glucokinase Activator Amelioratesβcell ER Stress and Apoptosis by both IRS-2-dependent and -Independent Pathways (2012)
  • Author(s): Shirakawa J, Terauchi Y
  • Organizer: 72th American Diabetes Association (ADA) meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2012-06-08
• [Presentation] Regulation of expression of incretin receptors in islet by dephosphorylation of AMPK (2012)
  • 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
• [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 expressions (2012)
  • 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
• [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
• [Presentation] Trefoil factor 2 (TFF2) induces proliferation of pancreaticβcells (2011)
  • 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
• [Presentation] Impact of vildagliptin on glucose tolerance, and beta cell mass in insulin receptor substrate-2-knockout mice (2011)
  • 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
• [Book] Annual Review糖尿病・代謝・内分泌2014 (2014)
  • Author(s): 寺内康夫、伊藤裕、石橋俊編
  • Total Pages: 213
  • Publisher: 中外医学社
• [Book] Annual Review糖尿病・代謝・内分泌2013 (2013)
  • Author(s): 寺内康夫、伊藤裕、石橋俊編
  • Total Pages: 229
  • Publisher: 中外医学社
• [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
• [Book] Annual Review糖尿病・代謝・内分泌2012 (2012)
  • Author(s): 寺内康夫、伊藤裕、石橋俊編
  • Total Pages: 245
  • Publisher: 中外医学社
• [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
• [Remarks]
  • URL: http://www-user.yokohama-cu.ac.jp/~nai3naib/