The role of endothelial IRS in the regulation of glucose uptake by muscle during exercise and arteriosclerosis

• Project/Area Number: 24390232
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: KUBOTA Naoto 東京大学, 医学部附属病院, 准教授 (50396719)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: インスリン受容体基質 / 血管内皮細胞 / インスリン作用 / インスリン抵抗性 / 運動 / 動脈硬化症

Outline of Final Research Achievements

Insulin-stimulated phosphorylation of Akt and eNOS were significantly impaired in the endothelium from endothelial cell specific IRS-1/IRS2 double deficient mice. In these mice, glucose uptake by skeletal muscle during exercise was significantly decreased, suggesting that endothelial IRSs were crucial roles in the regulation of glucose metabolism during exercise. Moreover, neointima formation and arteriosclerosis were significantly exacerbated in endothelial cell specific IRS-2 knockout mice, suggesting that IRS-2 was important for protection of atherosclerosis in the endothelium.

Research Products

• [Journal Article] Insulin receptor substrate-2 (irs2) in endothelial cells plays a crucial role in insulin secretion (2015)
  • Author(s): Hashimoto, S. Kubota, N. Sato, H. Sasaki, M. Takamoto, I. Kubota, T. Nakaya, K. Noda, M. Ueki, K. Kadowaki, T.
  • Journal Title: Diabetes Volume: 64 Issue: 3 Pages: 876-886
  • DOI: 10.2337/db14-0432
  • Peer Reviewed
• [Journal Article] Effects of beraprost sodium, an oral prostacyclin analog, on insulin resistance in patients with type 2 diabetes. (2015)
  • Author(s): Katsuyama H, Kubota N, Kubota T, Haraguchi M, Obata A, Takamoto I, Shigematsu K, Miyata T, Ueki K, Kadowaki T
  • Journal Title: Diabetology International Volume: 6 Pages: 39-45
  • NAID: 40020406077
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass. (2014)
  • Author(s): Takamoto I, Kubota N, Nakaya K, Kumagai K, Hashimoto S, Kubota T, Inoue M, Kajiwara E, Katsuyama H, Obata A, Sakurai Y, Iwamoto M, Kitamura T, Ueki K, Kadowaki T
  • Journal Title: Diabetologia Volume: 57 Issue: 3 Pages: 542-553
  • DOI: 10.1007/s00125-013-3131-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vagal hyperactivity due to ventromedial hypothalamic lesions increases adiponectin production and release. (2014)
  • Author(s): Suzuki Y, Shimizu H, Ishizuka N, Kubota N, Kubota T, Senoo A, Kageyama H, Osaka T, Hirako S, Kim HJ, Matsumoto A, Shioda S, Mori M, Kadowaki T, Inoue S.
  • Journal Title: Diabetes. Volume: 63(5) Issue: 5 Pages: 1637-1648
  • DOI: 10.2337/db13-0636
  • Peer Reviewed
• [Journal Article] Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. (2014)
  • Author(s): Sato T, Goyama S, Kataoka K, Nasu R, Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai K, Kubota N, Nakagawa M, Arai S, Yoshimi A, Honda H, Kadowaki T, Kurokawa M.
  • Journal Title: Oncogene Volume: 33 Issue: 42 Pages: 5028-5038
  • DOI: 10.1038/onc.2014.108
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vagal hyperactivity due to ventromedial hypothalamic (VMH) lesions increases adiponectin production and release. (2014)
  • Author(s): Suzuki Y.et al.
  • Journal Title: Diabetes in press Volume: ０ Pages: 0-0
  • Peer Reviewed
• [Journal Article] Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β cells. (2013)
  • Author(s): Shirakawa J.et al.
  • Journal Title: Diabetes Volume: 62 Pages: 3448-3458
  • Peer Reviewed
• [Journal Article] Insulin Activates Vagal Afferent Neurons Including those Innervating (2013)
  • Author(s): Iwasaki Y.et al.
  • Journal Title: PLoS One Volume: 8 Pages: 3448-3458
  • Peer Reviewed
• [Journal Article] Automatic distance measurement of abdominal aorta for ultrasonography-based visceral fat estimation. (2013)
  • Author(s): Wang J.et al.
  • Journal Title: Conf. Proc. IEEE Eng. Med. Biol. Soc. Volume: 2013 Pages: 6486-6489
  • Peer Reviewed
• [Journal Article] TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass. (2013)
  • Author(s): Takamoto I.et al.
  • Journal Title: Diabetologia Volume: 57 Pages: 542-553
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiericy of glucokinase on a high-fat diet. (2013)
  • Author(s): Nakaya K., et al.
  • Journal Title: Metabolism
  • Peer Reviewed
• [Journal Article] Combined treatment with low-dose pioglitazone and beraprost so dium improves glucose intolerance without causing body weight gain. (2013)
  • Author(s): Kumagai H., et al.
  • Journal Title: Diabetology International
  • 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: (In press) Issue: 6 Pages: 1745-1754
  • DOI: 10.1007/s00125-012-2521-5
  • Peer Reviewed
• [Journal Article] Effects of liraglutide on β cell-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 Y
  • Journal Title: Endocrinology Volume: (In press) Issue: 7 Pages: 3066-75
  • DOI: 10.1210/en.2012-1165
  • Peer Reviewed
• [Journal Article] Adiponectin Regulates Cutaneous Wound Healing by Promoting Keratinocyte Proliferation and Migration via the ERK Signaling Pathway. (2012)
  • Author(s): Shibata S., et al.
  • Journal Title: J. Immunol. Volume: 189 Issue: 6 Pages: 3231-3241
  • DOI: 10.4049/jimmunol.1101739
  • Peer Reviewed
• [Journal Article] Protection from nonalcoholic steatohepatitis and liver tumorigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. (2012)
  • Author(s): Nakamura A, Tajima K, Zolzaya K, Sato K, Inoue R, Yoneda M, Fujita K, Nozaki Y, Kubota KC, Haga H, Kubota N, Nagashima Y, Nakajima A, Maeda S, Kadowaki T, Terauchi Y
  • Journal Title: Diabetologia Volume: 55(12) Issue: 12 Pages: 3382-3391
  • DOI: 10.1007/s00125-012-2703-1
  • Peer Reviewed
• [Journal Article] Depletion of homeodomain-interacting protein kinase 3 impairs in sulin secretion and glucose tolerance in mice. (2012)
  • Author(s): Shojima N., et al.
  • Journal Title: Diabetologia Volume: 55 Pages: 3318-3330
  • Peer Reviewed
• [Presentation] Pioglitazone Ameliorates Cuff Induced Neointimal Formation by both Adiponectin Dependent and Independent Pathways (2014)
  • Author(s): Tetsuya Kubota, Naoto Kubota, Mariko Inoue, Iseki Takamoto, Toshimasa Yamauchi, Kohjiro Ueki, Takashi Kadowaki
  • Organizer: 9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-09-12 – 2014-09-14
• [Presentation] The Effect of Dietary Glutamine Supplementation on Chemotherapy-Induced Oral Mucositis in Patients with Esophagogastric Cancer (2014)
  • Author(s): Yoko Uehata, Kumi Takagi, Kaori Kitakubo, Rie Sekine, Katsuhiko Nara, Harumi Watanabe, Kazuyo Saino, Nobuko Motojima, Hiroharu Yamashita, Yasuyuki Seto, Kazuhiko Fukatsu, Naoto Kubota:
  • Organizer: 96th ESPEN Congress
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2014-09-06 – 2014-09-09
• [Presentation] 肥満・2型糖尿病における肝臓の糖・脂質代謝調節の分子機構 (2014)
  • Author(s): 窪田直人
  • Organizer: 第19回アディポサイエンス・シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2014-08-23
  • Invited
• [Presentation] DPP-4 Inhibitor Anagliptin Increases Capillary Recruitment and Glucose Uptake in Skeletal Muscle via Endothelial NO-dependent Pathway (2014)
  • Author(s): Hiroyuki Sato, Naoto Kubota, Tesyuya Kubota, Iseki Takamoto, Kumpei Tokuyama, Keizo Nakaya, Shinji Hashimoto, Moritaka Goto, Takahito Jomori, Kohjiro Ueki, Takashi Kadowaki
  • Organizer: ADA 74th Scientific Sessions
  • Place of Presentation: San Francisco, California, USA
  • Year and Date: 2014-06-13 – 2014-06-17
• [Presentation] インスリン作用機構 (2014)
  • Author(s): 窪田直人、門脇孝
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
  • Invited
• [Presentation] 血管の機能生体イメージングそして血管内皮 : 血管障害からみたインスリン抵抗性 (2013)
  • Author(s): 窪田直人
  • Organizer: 第77回日本循環器学会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2013-03-16
• [Presentation] 脳内調節機構からみた肥満のメカニズムとその臨床応用: 中枢におけるインスリン作用の生理的・病態生理的役割 (2013)
  • Author(s): 窪田直人, 他
  • Organizer: 第27回日本糖尿病・肥満動物学会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2013-02-23
• [Presentation] 2型糖尿病の病態と薬物治療 : 今後の展望も含めて (2013)
  • Author(s): 窪田直人
  • Organizer: 第50回日本糖尿病学会関東甲信越地方会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2013-01-26
• [Presentation] Diabetic Vascular Complications; The role of endothelial insulin signaling in the regulation of glucose metabolism (2012)
  • Author(s): 窪田直人
  • Organizer: 第20回日本血管生物医学会学術集会
  • Place of Presentation: 徳島(招待講演)
  • Year and Date: 2012-12-06
• [Presentation] 2型糖尿病の病態と治療戦略 (2012)
  • Author(s): 窪田直人
  • Organizer: 日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会2012
  • Place of Presentation: 岐阜(招待講演)
  • Year and Date: 2012-11-18
• [Presentation] インスリン受容体基質(IRS)に着目した肥満・2型糖尿病における肝臓の糖・脂質代謝調節機構 (2012)
  • Author(s): 窪田直人, 他
  • Organizer: 第62回日本体質医学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-04
• [Presentation] The pathophysiological roles of hepatic IRS-1 and IRS-2 in the regulation of glucose and lipid metabolism (2012)
  • Author(s): Naoto Kubota, et al.
  • Organizer: 2012 Keystone Symposia on Molecular and Cellular Biology: Aging and Diseases of Aging
  • Place of Presentation: Tokyo Japan
  • Year and Date: 2012-10-23
• [Presentation] 中枢神経系と肥満研究のフロンティア;中枢におけるインスリン作用の生理的・病態生理的役割 (2012)
  • Author(s): 窪田直人, 他
  • Organizer: 第33回日本肥満学会
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2012-10-12
• [Presentation] インスリン受容体基質(IRS)に着目した肥満・2型糖尿病における肝臓の糖・脂質代謝調節機構 (2012)
  • Author(s): 窪田直人, 他
  • Organizer: 第33回日本肥満学会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-11
• [Presentation] 2型糖尿病の病態と薬物治療 (2012)
  • Author(s): 窪田直人
  • Organizer: 第一回日本くすりと糖尿病学会学術集会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2012-09-23
• [Presentation] Pioglitazone Ameliorates Cuff Induced Neointimal Formation by both Adiponectin Dependent and Independent Pathways. (2012)
  • Author(s): Naoto Kubota, et al.
  • Organizer: The 64^<th> Fujihara Seminar, International Symposium on Adiponectin Biology and Medicine
  • Place of Presentation: Hokkaido, Japan
  • Year and Date: 2012-08-05
• [Presentation] インスリン受容体基質(IRS)に着目した肥満・2型糖尿病における肝臓の糖・脂質代謝調節機構 (2012)
  • Author(s): 窪田直人, 他
  • 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] (インスリン抵抗性からみた全身血管の包括的治療 ～大血管から末梢動脈疾患まで～)血管から診た糖尿病～新たな臨床的意義～ (2012)
  • Author(s): 窪田直人
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2012-05-17
• [Presentation] 遺伝子改変マウスを用いた2型糖尿病の分子メカニズムの解明 (2012)
  • Author(s): 窪田直人
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2012-04-21
• [Presentation] 肝臓の糖・脂質代謝におけるIRS-1、IRS-2の役割の解明 (2012)
  • Author(s): 窪田直人, 他
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-21
• [Presentation] 遺伝子改変マウスを用いた2型糖尿病の分子メカニズムの解明 (2012)
  • Author(s): 窪田直人
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2012-04-14
• [Presentation] Molecular mechanisms of type 2 diabetes and insulin resistance
  • Author(s): Naoto Kubota et al.
  • Organizer: THE 36th NAITO CONFERENCE ON Molecular Aspects of Energy Balance and Feeding Behavior Lecturers
  • Place of Presentation: Sapporo,Japan
• [Presentation] Tofogliflozin improves insulin resistance as well as glucose tolerance by ameliorating fatty liver and obesity
  • Author(s): Obata A et al.
  • Organizer: 73th American Diabetes Association's Scientific Sessions
  • Place of Presentation: Chicago, USA
• [Presentation] AdipoR1 in Hematopoietic Cells via Anti-Inflammation and AdipoR2 in Endothelial Cells via PPARgamma/SOD Play the Protective Roles against Cardiovascular Diseases in vivo
  • Author(s): Iwabu M et al.
  • Organizer: 73th American Diabetes Association's Scientific Sessions
  • Place of Presentation: Chicago, USA
• [Presentation] インスリン作用研究の進化と展望「インスリン受容体基質(IRS)-1、IRS-2の生理的・病態生理的役割の解明」
  • Author(s): 窪田 直人
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] チアゾリジン誘導体はアディポネクチン依存性・非依存性にカフ誘導性の内膜肥厚を抑制する
  • Author(s): 窪田 直人
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] インスリン受容体基質(IRS)に着目した肥満・2型糖尿病における肝臓の糖・脂質代謝調節機構
  • Author(s): 窪田 直人
  • Organizer: 第110回日本内科学会総会
  • Place of Presentation: 東京
• [Presentation] インスリン受容体基質(IRS)に着目した肥満・2型糖尿病における肝臓の糖・脂質代謝調節機構
  • Author(s): 窪田 直人
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] チアゾリジン誘導体はアディポネクチン依存性・非依存性に動脈硬化を抑制する
  • Author(s): 窪田 直人
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] PGI2誘導体ベラプロストのヒトインスリン抵抗性改善効果に関する検討
  • Author(s): 窪田 直人
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 糖尿病合併歌舞伎症候群にDPP4阻害薬が奏功した1症例
  • Author(s): 窪田 直人
  • Organizer: 第597回日本内科学会関東地方会
  • Place of Presentation: 東京
• [Book] 血管内皮細胞インスリンシグナル障害と骨格筋インスリン抵抗性 (2012)
  • Author(s): 窪田直人, 窪田哲也, 門脇孝
  • Total Pages: 133
  • Publisher: 糖尿病学2012