熱ショック応答経路活性化による抗炎症効果の分子メカニズム解析

2013 Fiscal Year Research-status Report

• Project/Area Number: 24591336
• Research Institution: Kumamoto University
• Principal Investigator: 近藤 龍也 熊本大学, 生命科学研究部, 助教 (70398204)
• Co-Investigator(Kenkyū-buntansha): 荒木 栄一 熊本大学, 生命科学研究部, 教授 (10253733)
• Keywords: 糖尿病 / インスリン抵抗性 / 慢性炎症 / 小胞体ストレス

Research Abstract

研究１（in vitro）
肝臓、筋肉、脂肪、膵β細胞株さらに末梢血単球においてMETの抗炎症作用の検証を行った。小胞体ストレス誘導作用を持つthapsigarginやtunicamycinを作用させると小胞体ストレスが誘導されるがMET施行により、その程度が軽減された。HSP72 siRNAを作用させた場合、インスリン作用の回復はある程度消失したが、単球における炎症性サイトカインの発現抑制は不変であった。すなわち、微弱電流のみでも抗炎症効果が発揮されることが明らかとなった。この現象には、AMPKの活性化が関与していると想定され、現在AMPK siRNAにより効果が消失するかを検討している。
研究２（in vivo）
肥満糖尿病モデルマウス(HFD、db/dbマウス)の各臓器においてMET作用により炎症性シグナルがどのように変化するかを検討した。AMPK, p53は活性化され、JNK, NF-κB, TNF-α, CRP, IL-6, IL-8, MCP-1は減少もしくは減少傾向を認めた。in vivoでもAMPK siRNAの効果を検証中である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

およそ計画通りに研究が進行している。

Strategy for Future Research Activity

MET治療の主たるターゲットとしてはHSP72が想定されていたが、短期的な血糖改善効果などのHSP72蛋白発現のみでは説明できない現象を得ている。微弱電流の主たるターゲットをAMPKと考えているため、AMPK制御によりMET治療効果の有無を確認する。

Expenditure Plans for the Next FY Research Funding

当該年度ではマウス実験に想定を越える研究費がかかったため、次年度使用額を使うこととなった。
平成26年度は最終年度であるため、研究費枠内で研究を完遂する。

Research Products

• [Journal Article] The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling. (2014)
  • Author(s): Uchimura K, Hayata M, Mizumoto T, Miyasato Y, Kakizoe Y, Morinaga J, Onoue T, Yamazoe R, Ueda M, Adachi M, Miyoshi T, Shiraishi N, Ogawa W, Fukuda K, Kondo T, Matsumura T, Araki E, Tomita K, Kitamura K
  • Journal Title: Nat Commun Volume: 5 Pages: 3428
  • DOI: doi: 10.1038/ncomms4428.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] For the Tofogliflozin 004 and 005 Study group. Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials (2014)
  • Author(s): Tanizawa Y, Kaku K, Araki E, Tobe K, Terauchi Y, Utsunomiya K, Iwamoto Y, Watada H, Ohtsuka W, Watanabe D, Suganami H
  • Journal Title: Expert Opin Pharmacother Volume: 15(6) Pages: 749-766
  • DOI: 10.1517/14656566.2014.887680.
  • Peer Reviewed
• [Journal Article] Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes. (2014)
  • Author(s): 10. Matsumura T, Taketa K, Motoshima H, Senokuchi T, Ishii N, Kinoshita H, Fukuda K, Yamada S, Kukidome D, Kondo T, Hisada A, Katoh T, Shimoda S, Nishikawa T, Araki E.
  • Journal Title: Cardiovascular Doabetology Volume: 12 Pages: 177
  • DOI: 10.1186/1475-2840-12-177.
  • Peer Reviewed
• [Journal Article] Insulin receptor activation through its accumulation in lipid rafts by mild electrical stress. (2013)
  • Author(s): Morino-Koga S, Yano S, Kondo T, Shimauchi Y, Matsuyama S, Okamoto Y, Suico MA, Koga T, Sato T, Shuto T, Arima H, Wada I, Araki E, Kai H
  • Journal Title: J Cell Physio Volume: 228(2) Pages: 439-446
  • DOI: 10.1002/jcp.24149.
  • Peer Reviewed
• [Journal Article] Evaluation of a new device for measurement of hemoglobin A1c for Japanese subjects. (2013)
  • Author(s): Shimoda S, Maeda T, Furukawa N, Ichinose K, Taketa K, Igata M, Senokuchi T, Matsumura T, Araki E
  • Journal Title: Diabetol Int Volume: 4 Pages: 112-116
  • Peer Reviewed
• [Journal Article] Relationship between lifestyle and lifestyle-related factors in a rural-urban population of Japan. (2013)
  • Author(s): Zhang SC, Wei CN, Harada K, Ueda K, Fukumoto K, Matsuo H, Minamoto K, Nishikawa T, Araki E, Ueda A, Fang J
  • Journal Title: Environ Health Prev Med. Volume: 18 Pages: 267-274
  • DOI: 10.1007/s12199-012-0315-5.
  • Peer Reviewed
• [Journal Article] Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes. (2013)
  • Author(s): Araki E, Kawamori R, Inagaki N, Watada H, Hayashi N, Horie Y, Sarashina A, Thiemann S, von Eynatten M, Dugi K, Woerle HJ
  • Journal Title: Diabetes Obes Metab Volume: 15 Pages: 364-371
  • DOI: 10.1111/dom.12039.
  • Peer Reviewed
• [Journal Article] The phosphatase Dullard negatively regulates BMP signalling and is essential for nephron maintenance after birth (2013)
  • Author(s): Sakaguchi M, Sharmin S, Taguchi A, Ohmori T, Fujimura S, Abe T, Kiyonari H, Komatsu Y, Mishina Y, Asashima M, Araki E, Nishinakamura R
  • Journal Title: Nature Communications Volume: 4 Pages: 1398
  • DOI: 10.1038/ncomms2408.
  • Peer Reviewed
• [Journal Article] Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy. (2013)
  • Author(s): Shimoda S, Iwashita S, Ichimori S, Matsuo Y, Goto R, Maeda T, Matsuo T, Sekigami T, Kawashima J, Kondo T, Matsumura T, Motoshima H, Furukawa N, Nishida K, Araki E
  • Journal Title: Endocrine Journal Volume: 60 Pages: 1207-1214
  • DOI: 10.1507/endocrj.EJ13-0198
  • Peer Reviewed
• [Journal Article] Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes. (2013)
  • Author(s): Miyagawa K, Kondo T, Goto R, Matsuyama R, Ono K, Kitano S, Kawasaki S, Igata M, Kawashima J, Matsumura T, Motoshima H, Araki E
  • Journal Title: Cardiovascular Doabetology Volume: 12 Pages: 160
  • DOI: 10.1186/1475-2840-12-160.
  • Peer Reviewed
• [Journal Article] Mechanism-based antioxidant therapies promise to prevent diabetic complications? (2013)
  • Author(s): Nishikawa T, Araki E
  • Journal Title: Diabetes Invest Volume: 4 Pages: 105-107
  • Peer Reviewed
• [Journal Article] Prevalence of metabolic syndrome in stroke patients: a prospective multicenter study in Japan. (2013)
  • Author(s): Takahashi T, Harada M, Kikuno T, Ujihara M, Sadamitsu D, Manabe Y, Yasaka M, Takayama H, Kobori S, Araki E
  • Journal Title: Acute Med Surg Volume: 1 Pages: 17-22
  • Peer Reviewed
• [Presentation] Heat Treatment with Mild Electrical Stimulation Attenuates Systemic Inflammation and Reduces Cytokine Expression in Monocytes from subjects with Metabolic Syndrome (2014)
  • Author(s): Tatsuya Kondo, Rina Matsuyama, Rieko Goto, Kaoru Ono, Sayaka Kitano, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: The 74h Annual Meeting of American Diabetes Association
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20140613-20140617
• [Presentation] Activation of Heat Shock Response Improves Metabolic Profiles in Type 2 Diabetes. (2013)
  • Author(s): atsuya Kondo, Rina Matsuyama, Rieko Goto, Kaoru Ono, Sayaka Kitano, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: 2013 International Conference on Diabetes and Metabolism & 5th AASD
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20131106-20131109
  • Invited
• [Presentation] 熱ショック応答経路活性化による糖代謝改善効果と分子機構の解明. (2013)
  • Author(s): 近藤龍也, 荒木栄一
  • Organizer: 第63回日本体質医学会
  • Place of Presentation: 久留米、久留米大学筑水会館
  • Year and Date: 20131005-20131006
• [Presentation] Pain threshold values of small fibers are associated with the severity of diabetic complications. (2013)
  • Author(s): Kukidome D, Sato M, Shimoda S, Nishikawa T, Araki E
  • Organizer: 49th EASD Annual Meeting
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20130923-20130927
• [Presentation] Heat Shock Response Activation using Heat Treatment with Mild Electrical Stimulation Reduces Visceral Adiposity and Improves Insulin Resistance and Inflammation in Male Subjects with Type 2 Diabetes (2013)
  • Author(s): atsuya Kondo, Rina Matsuyama, Rieko Goto, Kaoru Ono, Sayaka Kitano, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, Eiichi Araki.
  • Organizer: CSSI scientific meeting 2014.
  • Place of Presentation: Sheffield, United Kingdom
  • Year and Date: 20130818-20130822
• [Presentation] The Role of Aldosterone in the Pathogenesis of Diabetes in Human and Rats. (2013)
  • Author(s): Goto R, Kondo T, Ono K, Matsuyama R, Miyagawa K, Igata M, Kawashima J, Matsumura T, Motoshima H, Shimoda S, Araki E
  • Organizer: The 73th Annual Meeting of American Diabetes Association
  • Place of Presentation: Chicago, USA
  • Year and Date: 20130621-20130625
• [Presentation] The Critical Role of Heat Shock Protein 72 in Diabetic Pathophysiology. (2013)
  • Author(s): Matsuyama R, Kondo T, Miyagawa K, Goto R, Ono K, Igata M, Kawashima J, Matsumura T, Motoshima H, Araki E
  • Organizer: The 73th Annual Meeting of American Diabetes Association
  • Place of Presentation: Chicago, USA
  • Year and Date: 20130621-20130625
• [Presentation] Activation of Heat Shock Response ameliorates Metabolic Abnormalities in Diabetes with Attenuation of Cell Stress. (2013)
  • Author(s): 近藤龍也、荒木栄一
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本、ホテル日航熊本
  • Year and Date: 20130516-20130518
• [Book] 2型糖尿病. 糖尿病最新の治療2013-2015(岩本安彦, 羽田勝計編) (2013)
  • Author(s): 荒木栄一
  • Total Pages: 366
  • Publisher: 南江堂
• [Book] 特集：肥満症 2型糖尿病と耐糖能異常. (2013)
  • Author(s): 古川昇, 荒木栄一
  • Total Pages: 169
  • Publisher: 日本臨床
• [Book] PPARγの最新動向 PPAR標的薬の開発動向. 期待されるチアゾリジン薬 (2013)
  • Author(s): 松村剛, 荒木栄一
  • Total Pages: 308
  • Publisher: フジメディカル出版
• [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/