Molecular mechanisms of anti-inflammatory and anti- diabetic effects in the activation of heat shock response

• Project/Area Number: 15K09394
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Kondo Tatsuya 熊本大学, 医学部附属病院, 講師 (70398204)
• Co-Investigator(Kenkyū-buntansha): 荒木 栄一 熊本大学, 大学院生命科学研究部(医), 教授 (10253733)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 糖尿病 / 抗炎症 / ミトコンドリア / 慢性炎症 / 熱ショック応答経路 / インスリン抵抗性 / 内臓脂肪

Outline of Final Research Achievements

Activation of heat shock response exerts anti-inflammatory and anti-diabetic effects in mouse models of type 2 diabetes as well as in human type 2 diabetes.
In this study, we have investigated the mechanisms of heat shock response activation in vitro, in vivo and in vivo human. As a result, we have identified the mRNA reductions of inflammatory cytokines in liver, muscle and fat. We also observed the induction of mitochondria associated genes, that may explain the increase in energy expenditure. In human monocytes, pro-inflammatory prone phenotype was attenuated by the activation of heat shock response.

Research Products

• [Journal Article] Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial (2018)
  • Author(s): Shun Ishibashi, Hidenori Arai, Koutaro Yokote, Eiichi Araki, Hideki Suganami, Shizuya Yamashita
  • Journal Title: J Clin Lipidol. Volume: 12 Issue: 1 Pages: 173-184
  • DOI: 10.1016/j.jacl.2017.10.006
  • Peer Reviewed / Open Access
• [Journal Article] The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report (2018)
  • Author(s): Kondo Tatsuya、Nakamura Miwa、Kitano Sayaka、Kawashima Junji、Matsumura Takeshi、Ohba Takashi、Yamaguchi Munekage、Katabuchi Hidetaka、Araki Eiichi
  • Journal Title: BMC Endocrine Disorders Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12902-018-0234-6
  • Peer Reviewed / Open Access
• [Journal Article] Identification of microRNA that represses IRS-1 expression in liver. (2018)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Y, Hanatani S, Sakaguchi M, Goto R, Senokuchi T, Kawashima J, Furukawa N, Motoshima H, Araki E
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: 0191553-0191553
  • DOI: 10.1371/journal.pone.0191553
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis. (2018)
  • Author(s): Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 印刷中 Issue: 5 Pages: 994-1006
  • DOI: 10.1161/atvbaha.117.310320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy and safety of dapagliflozin over 1?year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial (2017)
  • Author(s): Araki Eiichi、Onishi Yukiko、Asano Michiko、Kim Hyosung、Yajima Toshitaka
  • Journal Title: Diabetes Obes Metab. Volume: 19 Issue: 4 Pages: 562-570
  • DOI: 10.1111/dom.12853
  • Peer Reviewed / Open Access
• [Journal Article] New glysemic targets for patients with diabetes from the Japan Diabetes Society (2017)
  • Author(s): Araki E, Haneda M, Kasuga M, Nishikawa T, Kondo T, Ueki K, Kadowaki T
  • Journal Title: J Diabetes Investig Volume: 8 Issue: 1 Pages: 123-125
  • DOI: 10.1111/jdi.12600
  • Peer Reviewed / Open Access
• [Journal Article] Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: Report of the Committee on Causes of Death in Diabetes Mellitus (2017)
  • Author(s): Nakamura Jiro、Kamiya Hideki、Haneda Masakazu、Inagaki Nobuya、Tanizawa Yukio、Araki Eiichi、Ueki Kohjiro、Nakayama Takeo
  • Journal Title: Journal of Diabetes Investigation Volume: 8 Issue: 3 Pages: 397-410
  • DOI: 10.1111/jdi.12645
  • NAID: 40021217934
  • Peer Reviewed / Open Access
• [Journal Article] Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells. (2017)
  • Author(s): Kajihara N, Kukidome D, Sada K, Motoshima H, Furukawa N, Matsumura T, Nishikawa T, Araki E.
  • Journal Title: J Diabetes Investig. Volume: 印刷中 Issue: 6 Pages: 750-761
  • DOI: 10.1111/jdi.12678
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia (2017)
  • Author(s): Hidenori Arai, Shizuya Yamashita, Koutaro Yokote, Eiichi Araki, Hideki Suganami, Shun Ishibashi
  • Journal Title: Atherosclerosis. Volume: 261 Pages: 144-152
  • DOI: 10.1016/j.atherosclerosis.2017.03.032
  • Peer Reviewed / Open Access
• [Journal Article] Potential of Monocyte Count for the Assessment of Cardiovascular Disease (2017)
  • Author(s): Matsumura T, Yamamoto E, Tsujita K, Araki E
  • Journal Title: Cardiovasc Pharmacol Volume: 6 Pages: 217-217
  • Peer Reviewed / Open Access
• [Journal Article] Impaired balance is related to the progression of diabetic complications in both young and older adults (2017)
  • Author(s): Kukidome D, Nishikawa T, Sato M, Nishi Y, Shimamura R, Kawashima J, Shimoda S, Mizuta H, Araki E
  • Journal Title: J Diabetes Complications. Volume: 8 Issue: 8 Pages: 1275-1282
  • DOI: 10.1016/j.jdiacomp.2017.05.014
  • Peer Reviewed / Open Access
• [Journal Article] Intraoperative Scoring System to Predict Postoperative Remission in Endoscopic Endonasal Transsphenoidal Surgery for Growth Hormone-Secreting Pituitary Adenomas. (2017)
  • Author(s): Yano S, Shinojima N, Kawashima J, Kondo T, Hide T.
  • Journal Title: World Neurosurg. Volume: Sep;105 Pages: 375-385
  • DOI: 10.1016/j.wneu.2017.05.162
  • Peer Reviewed / Open Access
• [Journal Article] Activation of heat shock response to treat obese subjects with type 2 diabetes: a prospective, frequency-escalating, randomized, open-label, triple-arm trial. (2016)
  • Author(s): Kondo T, Goto R, Ono K, Kitano S, Suico MA, Sato M, Igata M, Kawashima J, Motoshima H, Matsumura T, Kai H, Araki E.
  • Journal Title: Sci Rep. Volume: 19 Issue: 1 Pages: 35690-35690
  • DOI: 10.1038/srep35690
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cellular Stress Response Pathways and Diabetes Mellitus (2015)
  • Author(s): Eiichi Araki , Tatsuya Kondo, Hirofumi Kai
  • Journal Title: Diabetology International Volume: 6 Issue: 4 Pages: 239-242
  • DOI: 10.1007/s13340-015-0229-8
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 2型糖尿病の成因と病態Update. (2018)
  • Author(s): 荒木栄一
  • Organizer: 第52回糖尿病学の進歩. 専門医更新のための指定講演
• [Presentation] The Metabolic Roles of Heat Shock Protein 72 in Mice Model of Type 2 Diabetes. (2017)
  • Author(s): Kondo T, Kitano S, Goto R, Ono K, Igata M, Kawashima J, Motoshima H, Matsumura T, Kai H, Araki E
  • Organizer: The 77th ADA scientific meeting
• [Presentation] Semaglutide reduces HA1c and body weight across baseline HbA1c subgroups in the SUSTAIN 1-5 clinical trials. (2017)
  • Author(s): Bain S, Araki E, Desouza C, Garg S, Rose L, Tsoukas G, Bergan E, Karsb JD, DeVries J.
  • Organizer: 53th EASD Annual Meeting
• [Presentation] The anti diabetic role of heat shock protein 72 in mice model of type 2 diabetes. (2017)
  • Author(s): Kondo T, Kitano S, Goto R, Ono K, Igata M, Kawashima J, Motoshima H, Matsumura T, Kai H, Araki E
  • Organizer: 53th EASD Annual Meeting
• [Presentation] Renal protective effect of sodium dependent glucose transporter 2 inhibitor in combination with the renin angiotensin system blockers in early stage of diabetic nephropathy. (2017)
  • Author(s): Kukidome D, Kajihara N, Hanatani S, Kawashima J, Matsumura T, Araki E
  • Organizer: 53th EASD Annual Meeting
• [Presentation] Obesity-induced microRNA-222 impairs insulin signaling through the repression of IRS-1 expression in hepatocytes. (2017)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Yuki, Hanatani S, Goto R, Senokuchi T, Kawashima J, Furukawa N, Motoshima H, Araki E
  • Organizer: 53th EASD Annual Meeting
• [Presentation] The therapeutic potential of heat shock protein 72 in mice model of type 2 diabetes. (2017)
  • Author(s): Kondo T, Kitano S, MIyakawa N, Goto R, Ono K, Igata M, Kawashima J, Motoshima H, Matsumura T, Kai H, Araki E
  • Organizer: IDF congress 2017
• [Presentation] Impaired balance strongly correlated with advanced microvascular complications in younger participants with diabetes (2017)
  • Author(s): Kukidome D, Kajihara N, Hanatani S, Kawashima J, Matsumura T, Araki E
  • Organizer: IDF congress 2017
• [Presentation] 慢性炎症とインスリン抵抗性：熱ストレス応答経路の関与. (2017)
  • Author(s): 近藤龍也, 北野さやか, 後藤理英子, 小野 薫, 松村 剛, 井形元維, 河島淳司, 本島寛之, Mariam Piruzyan, 甲斐広文, 荒木栄一
  • Organizer: 第60回日本糖尿病学会総会 シンポジウム
• [Presentation] 「1型糖尿病の成因と治療：最近の新展開」 (2017)
  • Author(s): 近藤龍也、荒木栄一
  • Organizer: 第17回 内分泌学会九州地方会九州支部 教育講演
• [Presentation] 動脈硬化と体質. (2017)
  • Author(s): 松村 剛, 瀬ノ口隆文, 荒木栄一
  • Organizer: 第67回日本体質医学会年次学術集会 シンポジウム
• [Presentation] 分子糖尿病学から新規糖尿病治療法開発を目指して. (2017)
  • Author(s): 荒木栄一
  • Organizer: 第55回日本糖尿病学会九州地方会. 宮崎
• [Presentation] SGLT-2阻害薬によるマクロファージ活性抑制を介した糖尿病大血管症進展抑制効果の解析. (2017)
  • Author(s): 松村剛, 村上彩子, 瀬ノ口隆文, 石井規夫, 山田沙理恵, 守田雄太郎, 西田周平, 久木留大介, 本島寛之, 近藤龍也, 沼田朋大, 荒木栄一
  • Organizer: 第32回日本糖尿病合併症学会, ワークショップ
• [Presentation] 糖尿病病態の分子生物学的解析と新規糖尿病治療法開発への応用. (2017)
  • Author(s): 荒木栄一
  • Organizer: 日本医師会設立70周年記念式典並びに医学大会. 医学賞受賞講演
• [Presentation] 分子糖尿病学から新規糖尿病治療法開発を目指して. (2017)
  • Author(s): 荒木栄一
  • Organizer: 日本糖尿病学会中国四国地方会第55回総会. 特別講演
• [Presentation] 肥満2型糖尿病に対する熱ショック応答経路活性化の臨床的有効性. (2017)
  • Author(s): 近藤龍也, 北野さやか, 後藤理英子, 小野 薫, 松村 剛, 井形元維, 河島淳司, 本島寛之, 甲斐広文, 荒木栄一
  • Organizer: 第114回日本内科学会講演会.
• [Presentation] Heat Shock Protein 72ノックアウトマウスにおける糖代謝異常発生機構の解明. (2017)
  • Author(s): 北野さやか, 近藤龍也, 荒木栄一
  • Organizer: 第60回日本糖尿病学会総会.
• [Presentation] 平成28年熊本地震」における糖尿病患者の血糖コントロールに関わる因子の検討. (2017)
  • Author(s): 近藤龍也, 宮川展和, 石井則夫, 井形元維, 吉永佳代, 久木留大介, 河島淳司, 瀬ノ口隆文, 松村剛, 本島寛之, 荒木栄一
  • Organizer: 第55回日本糖尿病学会九州地方会.
• [Presentation] Heat Shock Protein 72ノックアウトマウスにおける糖代謝異常発生機構の解明. (2017)
  • Author(s): 北野さやか, 近藤龍也, 小野 薫, 後藤理英子, 高木優樹, 花谷聡子, 井形元維, 河島淳司, 本島寛之, 荒木栄一
  • Organizer: 第55回日本糖尿病学会九州地方会.
• [Presentation] Activation of Heat Shock Response Improves Glucose Metabolism and Inflammation in Obese Subjects with Type 2 Diabetes. (2016)
  • Author(s): Tatsuya Kondo1, Rieko Goto1, Kaoru Ono1, Sayaka Kitano1, Motoyuki Igata1, Junji Kawashima1, Hiroyuki Motoshima1, Takeshi Matsumura1, Hirofumi Kai2, Eiichi Araki1.
  • Organizer: AASD 2016
  • Place of Presentation: Taipei
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Activation of Heat Shock Response Provided by Mild Electrical Stimulation with Heat Shock Improves Metabolic Abnormalities in Obese Subjects with Type 2 Diabetes. (2016)
  • Author(s): Tatsuya Kondo1, Rieko Goto1, Kaoru Ono1, Sayaka Kitano1, Motoyuki Igata1, Junji Kawashima1, Hiroyuki Motoshima1, Takeshi Matsumura1, Hirofumi Kai2, Eiichi Araki1.
  • Organizer: EASD 2016
  • Place of Presentation: Munchen
  • Year and Date: 2016-09-12
  • Int'l Joint Research
• [Presentation] 至適条件における熱ショック応答経路活性化は肥満2型糖尿病治療に有効である (2016)
  • Author(s): 近藤 龍也、北野さやか、後藤理英子、小野 薫、松村 剛、井形 元維、河島 淳司、本島 寛之、甲斐広文、荒木 栄一
  • Organizer: 第59回日本糖尿病学会年次学術総会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] Mild Electrical Stimulation with Heat Treatment Improves Metabolic Profiles and Attenuates Systemic Inflammation in Type 2 Diabetes. (2015)
  • Author(s): Tatsuya Kondo, Rina Matsuyama, Sayaka Kitano, Rieko Goto, Kaoru Ono, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: Keystone meeting 2015
  • Place of Presentation: Westin Miyako Kyoto, Kyoto, Japan
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] The Roles of Heat Shock Protein 72 in Hepatic Glucose Metabolism in Mice Model of Type 2 Diabetes. (2015)
  • Author(s): Tatsuya Kondo, Rina Matsuyama, Sayaka Kitano, Rieko Goto, Kaoru Ono, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: European Association of Study group of Diabetes 2015
  • Place of Presentation: Stockholmsmassan, Sweden
  • Year and Date: 2015-09-14
  • Int'l Joint Research
• [Presentation] Impacts of Heat Shock Protein 72 in Hepatic Glucose Metabolism in Model Mice of Type 2 Diabetes. (2015)
  • Author(s): Tatsuya Kondo, Rina Matsuyama, Sayaka Kitano, Rieko Goto, Kaoru Ono, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: ADA scientific meeting 2015
  • Place of Presentation: World Trade Center, Boston, MA
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] Heat Shock Protein 72欠損マウスの耐糖能異常における肝臓の役割 (2015)
  • Author(s): 近藤 龍也、松山 利奈、北野さやか、後藤理英子、小野 薫、松村 剛、井形 元維、河島 淳司、本島 寛之、岸川秀樹、甲斐広文、荒木 栄一
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 海峡メッセ下関
  • Year and Date: 2015-05-21
• [Book] 特集／激増する糖尿病の診療最前線 糖尿病診断の進め方. (2018)
  • Author(s): 阪口雅司, 荒木栄一
  • Total Pages: 198
  • Publisher: 臨床と研究 96(1):7-14, 2018
• [Book] 2型糖尿病におけるHDL亜分画とインスリン抵抗性との関連. (2017)
  • Author(s): 松村 剛, 松嶋和美, 杉内博幸, 荒木栄一
  • Total Pages: 155
  • Publisher: The Lipid 28(1):92-97, 2017
• [Book] 微弱電流と温熱刺激による新規糖尿病治療. (2017)
  • Author(s): 近藤龍也、荒木栄一
  • Total Pages: 218
  • Publisher: 実験医学増刊 35(2):163-165, 2017
• [Book] 座談会「Islet Equality」創刊5年を振り返る-膵島研究の変遷- (2017)
  • Author(s): 門脇 孝, 荒木栄一, 石原寿光, 稲垣暢也, 寺内康夫
  • Total Pages: 119
  • Publisher: Islet Equality 6(1):5-18, 2017
• [Book] 熊本宣言2013とその後について. 糖尿病診療に役立つ情報誌 (2017)
  • Author(s): 荒木栄一
  • Total Pages: 98
  • Publisher: つなぐ 04 Spring: 2-3, 2017
• [Book] 成因と治療 3）マクロファージ. (2017)
  • Author(s): 松村剛, 荒木栄一
  • Total Pages: 524
  • Publisher: 糖尿病 60(7):481-484, 2017
• [Book] ペマフィブラートに適した病態：どのような患者が適しているのか. (2017)
  • Author(s): 松村剛, 荒木栄一
  • Total Pages: 231
  • Publisher: Progress in Medicine 37(9):1047-1050, 2017
• [Book] 糖尿病病態の分子生物学的解析と新規糖尿病治療法開発への応用. (2017)
  • Author(s): 荒木栄一:
  • Total Pages: 432
  • Publisher: 日本医師会雑誌 146(9):1845-1849, 2017
• [Book] 微弱電流と温熱刺激による新規糖尿病治療. 糖尿病 研究の“いま”と治療の“これから” (2017)
  • Author(s): 近藤龍也, 荒木栄一
  • Total Pages: 188
  • Publisher: 実験医学増刊. Vol. 35, No. 2(増刊), pp163-168, 羊土社, 東京, 2017
• [Book] 微弱電流と温熱刺激による新規糖尿病治療. (2017)
  • Author(s): 近藤龍也、荒木栄一
  • Total Pages: 143
  • Publisher: 実験医学増刊号. Vol. 35, No. 2（増刊）2017
• [Book] 実験医学増刊号 (2016)
  • Author(s): 近藤龍也、荒木栄一
  • Total Pages: 235
  • Publisher: 羊土社
• [Book] 「内分泌・糖尿病・代謝内科」 (2015)
  • Author(s): 近藤龍也、本島寛之、松村剛、甲斐広文、荒木栄一
  • Total Pages: 254
  • Publisher: 科学評論社
• [Book] 「Angiology Frontier」 (2015)
  • Author(s): 近藤龍也、甲斐広文、荒木栄一
  • Total Pages: 76
  • Publisher: メディカルレビュー社
• [Book] 「Diabetes Journal」 (2015)
  • Author(s): 近藤龍也、甲斐広文、荒木栄一
  • Total Pages: 165
  • Publisher: （株）協和企画
• [Book] ファルマシア (2015)
  • Author(s): 甲斐広文、近藤龍也、荒木栄一
  • Total Pages: 1065
  • Publisher: 日本薬学会
• [Remarks] 熊本大学大学院生命科学研究部 総合医薬科学部門生体機能病態学講座 代謝内科学分野
  • URL: http://www2.kuh.kumamoto-u.ac.jp/met/research/index.html
• [Remarks] 熱ショック応答経路活性化によるインスリン抵抗性改善効果
  • URL: http://www2.kuh.kumamoto-u.ac.jp/met/research/research/index.html
• [Remarks] 熊本大学大学院生命科学研究部代謝内科学
  • URL: http://www2.kuh.kumamoto-u.ac.jp/met/