To unveil mechanisms triggering pancreatic beta cell dysfunction in type 2 diabetes possibly via RAGE, glucolipotoxicity and insufficient leptin signaling.

• Project/Area Number: 25461335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: Yamamoto Hiroshi 金沢大学, その他部局等, 理事 (00115198)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Yasuhiko 金沢大学, 医薬保健研究域医学系, 教授 (20313637) ; Munesue Seiichi 金沢大学, 医薬保健研究域医学系, 助教 (10399040)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 2型糖尿病 / 膵β細胞 / インスリン / RAGE / 糖脂肪毒性 / 膵β細胞障害 / ２型糖尿病

Outline of Final Research Achievements

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. We examined whether advanced glycation end-products (AGE) and RAGE contribute to β-cell failure in a type 2 diabetes mouse model. Pretreatment of FFA combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by AGE in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.

Research Products

• [Journal Article] Epidermal expression of receptor for advanced glycation end-products (RAGE) is related to inflammation and apoptosis in human skin (2016)
  • Author(s): Iwamura M, Yamamoto Y, Kitayama Y, Higuchi K, Fujimura T, Hase T, Yamamoto H.
  • Journal Title: Exp Dermatology 25(3): 235-237, 2016 Volume: 25(3) Issue: 3 Pages: 235-237
  • DOI: 10.1111/exd.12899
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The receptor for advanced glycation end-products is associated with apoptosis of alveolar epithelial cells in hyperoxia exposure in vitro and in vivo (2016)
  • Author(s): Ota C, Ishizawa K, Yamada M, Tando Y, Mei H, Takahashi T, Yamamoto Y, Yamamoto H, Kubo H.
  • Journal Title: Respiratory Invest Volume: 54(2) Issue: 2 Pages: 98-108
  • DOI: 10.1016/j.resinv.2015.08.009
  • Peer Reviewed
• [Journal Article] Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination (2016)
  • Author(s): Yamaguchi T, Fushida S, Yamamoto Y, Tsukada T, Kinoshita J, Oyama K, Miyashita T, Tajima H, Ninomiya I, Munesue S, Harashima A, Harada S, Yamamoto H, Ohta T.
  • Journal Title: Gastric Cancer
  • NAID: 40020959187
  • Peer Reviewed
• [Journal Article] Enzymatic and non-enzymatic post-translational modifications linking diabetes and heart disease. (2015)
  • Author(s): Yamamoto Y, Yamamoto H
  • Journal Title: J Diabetes Invest Volume: 6(1) Issue: 1 Pages: 16-17
  • DOI: 10.1111/jdi.12248
  • NAID: 120005821074
  • Peer Reviewed / Open Access
• [Journal Article] Gadd34 regulates liver regeneration in hepatic steatosis. (2015)
  • Author(s): Inaba Y, Furutani T, Kimura K, Watanabe H, Haga S, Kido Y, Yamamoto Y, Harada K, Kaneko S, Oyadomari S, Ozaki M, Kasuga M, Inoue H.
  • Journal Title: Hepatology Volume: 61(4) Issue: 4 Pages: 1343-1356
  • DOI: 10.1002/hep.27619
  • Peer Reviewed / Open Access
• [Journal Article] Emphysema requires the receptor for advanced glycation end products triggering on structural cells. (2015)
  • Author(s): Waseda K, Miyahara N, Taniguchi A, Kurimoto E, Ikeda G, Koga H, Fujii U, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A.
  • Journal Title: Am J Respir Cell Mol Biol Volume: 52(4) Issue: 4 Pages: 482-491
  • DOI: 10.1165/rcmb.2014-0027oc
  • Peer Reviewed
• [Journal Article] RAGE mediates the interactivation of nAChRs in sympathetic neurons during high glucose conditions. (2015)
  • Author(s): Chandna AR, Baskaran MN, Chang C, Pennington PR, Mousseau DD, Yamamoto Y, Campanucci VA.
  • Journal Title: Eur J Neurosci Volume: 41(3) Issue: 3 Pages: 341-351
  • DOI: 10.1111/ejn.12795
  • Peer Reviewed
• [Journal Article] Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness. (2015)
  • Author(s): Taniguchi A, Miyahara N, Waseda K, Kurimoto E, Fujii U, Tanimoto Y, Kataoka M, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 309 Issue: 8 Pages: L789-L800
  • DOI: 10.1152/ajplung.00087.2015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Longistatin in tick saliva blocks advanced glycation end-product receptor activation (2014)
  • Author(s): Anisuzzaman, Hatta T, Miyoshi T, Matsubayashi M, Islam MK, Alim MA, Anas MA, Hasan MM, Matsumoto Y, Yamamoto Y, Yamamoto H, Fujisaki K, Tsuji N
  • Journal Title: Journal of Clinical Investigation Volume: 124 Issue: 10 Pages: 4429-4444
  • DOI: 10.1172/jci74917
  • Peer Reviewed
• [Journal Article] RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. (2014)
  • Author(s): Chen X, Zhang L, Zhang IY, Liang J, Wang H, Ouyang M, Wu S, da Fonseca AC, Weng L, Yamamoto Y, Yamamoto H, Natarajan R, Badie B.
  • Journal Title: Cancer Res Volume: 74(24) Pages: 7285-7297
  • Peer Reviewed
• [Journal Article] cAMP ameliorates inflammation in macrophages by modulation of receptor for advanced glycation end-products. (2014)
  • Author(s): Motoyoshi S, Yamamoto Y, Munesue S, Igawa H, Harashima A, Saito H, Han H, Watanabe T, Sato H, Yamamoto H.
  • Journal Title: Biochem J Volume: 463(1) Issue: 1 Pages: 75-82
  • DOI: 10.1042/bj20140084
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Glycyrrhizin inhibits traumatic brain injury by reducing HMGB1-RAGE interaction. (2014)
  • Author(s): OkumaY, Liu K, Wake H, Liu R, Nishimura Y, Zhong H, Teshigawara K, Haruma J, Yamamoto Y, Yamamoto H, Date I, Takahashi HK, Mori S, Nishibori M.
  • Journal Title: Neuropharmacology Volume: 85 Pages: 18-26
  • DOI: 10.1016/j.neuropharm.2014.05.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thrombomodulin Modulates Dendritic Cells via Both Antagonism of High Mobility Group Protein B1 and an Independent Mechanism (2014)
  • Author(s): Toda M, D'Alessandro-Gabazza CN, Takagi T, Chelakkot-Govindalayathila AL, Taguchi O, Roeen Z, Munesue S, Yamamoto Y, Yamamoto H, Gabazza EC, Morser J.
  • Journal Title: Allergology International Volume: 63 Issue: 1 Pages: 57-66
  • DOI: 10.2332/allergolint.13-OA-0595
  • NAID: 130004873109
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Maltitol endows foods with lower 3-deoxyglucosone content and less RAGE agonism as a sweetener against sucrose. (2014)
  • Author(s): Kuretani A, Kawamura R, Munesue S, Yamamoto Y, Honda J, Yamamoto H
  • Journal Title: Glycative Stress Res Volume: 1(2) Pages: 25-31
  • NAID: 40021134946
  • Peer Reviewed
• [Journal Article] Low molecular weight heparin suppresses receptor for advanced glycation end products-mediated expression of malignant phenotype in human fibrosarcoma cells. (2013)
  • Author(s): Takeuchi A, Yamamoto Y, Munesue S, Harashima A, Watanabe T, Yonekura H, Yamamoto H, Tsuchiya H.
  • Journal Title: Cancer Sci. Volume: 104(6) Issue: 6 Pages: 740-749
  • DOI: 10.1111/cas.12133
  • NAID: 120005830605
  • Peer Reviewed
• [Journal Article] Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreaticβ-cell failure in type 2 diabetes. (2013)
  • Author(s): Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MT, Watanabe T, Tsuneyama K, Yamamoto H.
  • Journal Title: Genes Cells. Volume: 18(4) Issue: 4 Pages: 302-14
  • DOI: 10.1111/gtc.12036
  • Peer Reviewed
• [Journal Article] Role of cell-cell interactions in high mobility group box 1 cytokine activity in human peripheral blood mononuclear cells and mouse splenocytes. (2013)
  • Author(s): Kohka Takahashi H, Sadamori H, Liu K, Wake H, Mori S, Yoshino T, Yamamoto Y, Yamamoto H, Nishibori M.
  • Journal Title: Eur J Pharmacol Volume: 701(1-3) Pages: 194-202
  • Peer Reviewed
• [Journal Article] Receptor for advanced glycation end-products (RAGE) regulates adipocyte hypertrophy and insulin sensitivity in mice: involvement of Toll-like receptor 2 (2013)
  • Author(s): Monden M, Koyama H, Otsuka Y, Morioka T, Mori K, Shoji T, Mima Y, Motoyama K, Fukumoto S, Shioi A, Emoto M, Yamamoto H, Nishizawa Y, Kurajoh M, Tetsuya Yamamoto T, Inaba M
  • Journal Title: Ｄｉａｂｅｔｅｓ Volume: 62 Issue: 2 Pages: 478-489
  • DOI: 10.2337/db11-1116
  • Peer Reviewed
• [Journal Article] Validated Liquid Culture Monitoring System for Lifespan Extension of Caenorhabditis elegans through Genetic and Dietary Manipulations. (2013)
  • Author(s): Win MT, Yamamoto Y, Munesue S, Han D, Harada S, Yamamoto H.
  • Journal Title: Aging Dis Volume: 4(4) Pages: 178-185
  • Peer Reviewed
• [Journal Article] RAGE-Mediated Inflammation, Type 2 Diabetes, and Diabetic Vascular Complication. (2013)
  • Author(s): Yamamoto Y, Yamamoto H
  • Journal Title: Front Endocrinol Volume: 4 Pages: 105-105
  • DOI: 10.3389/fendo.2013.00105
  • Peer Reviewed
• [Journal Article] Low-molecular weight fractions of Japanese soy sauce act as a RAGE antagonist via inhibition of RAGE trafficking to lipid rafts. (2013)
  • Author(s): Munesue S, Yamamoto Y, Urushihara R, Inomata K, Saito H, Motoyoshi S, Watanabe T, Yonekura H, Yamamoto H.
  • Journal Title: Food Funct. Volume: 4(12) Issue: 12 Pages: 1835-1842
  • DOI: 10.1039/c2fo30359k
  • NAID: 120005373515
  • Peer Reviewed
• [Presentation] 糖尿病合併症発症におけるグリケーション (2016)
  • Author(s): 山本靖彦
  • Organizer: 第50回糖尿病学の進歩
  • Place of Presentation: 東京
  • Year and Date: 2016-02-19
  • Invited
• [Presentation] 内在性分泌型RAGEは脳虚血から神経細胞を保護する (2015)
  • Author(s): 清水 有、山本靖彦、原島愛、棟居聖一、大石正博、林 康彦、中田光俊、北尾康子、堀 修、山本 博
  • Organizer: 第30回日本糖尿病合併症学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-27
• [Presentation] 粘液型脂肪肉腫におけるPPARγの発現と予後因子解析 (2015)
  • Author(s): 武内章彦、山本憲男、林 克洋、三輪真嗣、稲谷弘幸、青木 裕、樋口貴史、阿部健作、棟居聖一、山本靖彦、土屋弘行
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-29
• [Presentation] Neuroprotective effects of endogenous secretory rage in ischemic cerebrovasculr diseases (2015)
  • Author(s): Shimizu Y, Munesue S, Yamamoto Y, Harashima A, Oishi M, Hayashi Y, Nakada M, Kitao Y, Hori O, Yamamoto H
  • Organizer: 12th International Symposium on the Maillard Reaction 2015
  • Place of Presentation: 東京
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] RAGE of donor iselts is a novel target to improve the efficiency of islet transplantation (2015)
  • Author(s): Yasunami Y, Yamamoto Y, Munesue S, Yamamoto H
  • Organizer: 12th International Symposium on the Maillard Reaction 2015
  • Place of Presentation: 東京
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] Insufficient leptin action induces RAGE expression and triggers pancreatic beta-cell failure in type 2 diabetes (2015)
  • Author(s): Han D, Yamamoto Y, Munesue S, Harashima A, Yamamoto H
  • Organizer: 12th International Symposium on the Maillard Reaction 2015
  • Place of Presentation: 東京
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] 脳血管保護因子としての内在性分泌型RAGEの機能解析 (2014)
  • Author(s): 清水有、山本靖彦、原島愛、棟居聖一、林康彦、北尾康子、堀修、山本博
  • Organizer: 第24回日本メイラード学会学術集会
  • Place of Presentation: 熊本市国際交流会館
  • Year and Date: 2014-11-07 – 2014-11-08
• [Presentation] 内在性分泌型RAGEの血液脳関門を越えてデコイ受容体としての神経細胞保護作用を発揮する (2014)
  • Author(s): 清水有、山本靖彦、原島愛、棟居聖一、大石正博、林康彦、北尾康子、堀修、山本博
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会議
  • Year and Date: 2014-10-18
• [Presentation] 「膵β細胞のレプチンシグナル不全はRAGEの発現誘導を介して膵β細胞疲弊に関わる (2014)
  • Author(s): 山本靖彦、韓冬、棟居聖一、山本博
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-06-06
• [Presentation] Absence of mature adipocytes and adipocyte precursor cells in mesentery of Suncus murinus (2013)
  • Author(s): Yasuhiko Yamamoto, Yi Shuang-Qin, Hidehito Saito, Munesue Seiichi, Ozaki Noriyuki, Hiroshi Yamamoto
  • Organizer: 73th Scientific sessions of American Diabetes Association
  • Place of Presentation: Chicago, IL, U.S.A. (Convention Ctr)
• [Presentation] Suncus murinus is a unique animal model lacking mesenteric fat and adipocyte progenitor cells (2013)
  • Author(s): Yasuhiko Yamamoto, Yi Shuang-Qin, Hidehito Saito, Munesue Seiichi, Ozaki Noriyuki, Hiroshi Yamamoto
  • Organizer: 第56回日本糖尿病学会年次学術総会
  • Place of Presentation: 熊本（ホテル日航熊本）
• [Presentation] レプチンシグナル不全はRAGEの発現誘導を介して膵β細胞の糖脂肪毒性を増強する (2013)
  • Author(s): 韓冬、山本靖彦、棟居聖一、常山幸一、山本博
  • Organizer: 第56回日本糖尿病学会年次学術総会
  • Place of Presentation: 熊本（ホテル日航熊本）
• [Presentation] A feasible liquid culture assay for monitoring C. elegans lifespan by genetic, dietary and pharmacological interventions (2013)
  • Author(s): Thu Thu Win Myat, Yasuhiko Yamamoto, Shinichi Harada, Hiroshi Yamamoto
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜（国際会議場）
• [Presentation] 食品由来AGEによるAGE-RAGEシグナル阻害機構の解析 (2013)
  • Author(s): 棟居聖一、山本靖彦、漆原涼太、齋藤英仁、本吉創、渡邉琢夫、山本博
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜（国際会議場）
• [Presentation] 在性分泌型RAGEの脳血管保護因子としての機能の解明 (2013)
  • Author(s): 清水有、山本靖彦、棟居聖一、原島愛、林康彦、濱田潤一郎、山本博
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜（国際会議場）
• [Presentation] Low-molecular weight heparin inhibits human fibrosarcoma cell proliferation, migration and invasion by blocking RAGE signaling (2013)
  • Author(s): 原島愛、武内章彦、山本靖彦、棟居聖一、山本博
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜（国際会議場）
• [Presentation] 低分子ヘパリンは線維肉腫細胞における後期糖化産物受容体（RAGE）を介する悪性度を抑制する (2013)
  • Author(s): 武内章彦、山本靖彦、原島愛、棟居聖一、山本博、土屋弘行
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: 横浜（国際会議場）
• [Presentation] 脳血管保護因子としての内在性分泌型RAGEの機能解析 (2013)
  • Author(s): 清水有、山本靖彦、棟居聖一、原島愛、林康彦、濱田潤一郎、山本博
  • Organizer: 第23回日本メイラード学会学術集会
  • Place of Presentation: 大阪（ナレッジキャピタルコングレコンベンションセンター）
• [Book] 日本臨床 AGE-RAGE系 (2016)
  • Author(s): 原島愛, 棟居聖一, 山本靖彦
  • Total Pages: 4
  • Publisher: 日本臨床社
• [Book] BIO Clinica 糖尿病合併症の分子機構：避けられない糖化反応とその終末糖化産物受容体RAGE (2016)
  • Author(s): 山本靖彦
  • Total Pages: 4
  • Publisher: 北隆社
• [Book] BIO Clinica パターン認識受容体RAGEの切断により糖尿病合併症を制御する (2016)
  • Author(s): 山本靖彦
  • Total Pages: 7
  • Publisher: 北隆社
• [Book] 日本食生活学会誌 糖化制御と生活習慣病の予防 (2015)
  • Author(s): 山本靖彦, 棟居聖一
  • Total Pages: 4
  • Publisher: 日本食生活学会
• [Book] 最新医学 メイラード反応と終末糖化産物AGEs (2015)
  • Author(s): 山本靖彦
  • Total Pages: 5
  • Publisher: 最新医学社
• [Book] メイラード反応の機構・制御・利用 (監修 宮澤陽夫) 第6章AGE受容体RAGE (2015)
  • Author(s): 棟居聖一, 原島愛, 山本靖彦
  • Total Pages: 5
  • Publisher: シーエムシー出版
• [Book] 日本薬理学会雑誌 (2014)
  • Author(s): 山本靖彦，山本博
  • Publisher: 日本薬理学会
• [Book] アンチ・エイジング医学 特集今後期待される新規バイオマーカー (2014)
  • Author(s): 山本靖彦, 後藤久典, 山本博
  • Publisher: 日本抗加齢医学会
• [Book] 日本加齢医学会雑誌 (2014)
  • Author(s): 山本靖彦，後藤久典，山本博
  • Publisher: メジカルレビュー社
• [Book] 日本薬理学会雑誌 (2014)
  • Author(s): 山本靖彦，山本博
  • Publisher: 日本薬理学会雑誌
• [Remarks] 金沢大学医薬保健研究域医学系血管分子生物学ホームページ
  • URL: http://biochem2.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学医薬保健研究域医学系血管分子生物学ホームページ
  • URL: http://biochem2.w3.kanazawa-u.ac.jp/
• [Patent(Industrial Property Rights)] オキシトシントランスポーター (2014)
  • Inventor(s): 山本博（他5名）
  • Industrial Property Rights Holder: 山本博（他5名）
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-255721
  • Filing Date: 2014-12-18