Crosstalk between fat metabolism and insulin signaling in glucose homeostasis: Analysis in fat-sensitive diabetes mice

• Project/Area Number: 25293051
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Chiba University
• Principal Investigator: Miki Takashi 千葉大学, 医学(系)研究科(研究院), 教授 (50302568)
• Co-Investigator(Kenkyū-buntansha): MUKAI Eri 千葉大学, 大学院医学研究院, 講師 (60362539) ; LEE Eun Young 千葉大学, 大学院医学研究院, 助教 (60583424)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 糖尿病 / 栄養学 / 胆汁酸 / 脂質 / 糖 / インスリン

Outline of Final Research Achievements

The rapid increase in the number of patients with type 2 diabetes mellitus is considered to be due, at least in part, to excessive fat intake. However, the lack of animal model of high fat diet (HFD)-induced diabetes has hampered the elucidation of its underlying mechanism. We found that the insulin receptor mutant mice (mIR mice) develop overt hyperglycemia only under HFD feeding. Our pathophysiological analyses of mIR mice under HFD (mIR/HFD mice) revealed that unsuppressed lipolysis plus increased gluconeogenesis from glycerol evokes hyperglycemia and that bile acid physiology is markedly altered in mIR/HFD mice.

Research Products

• [Int'l Joint Research] University of Cambridge(英国)
• [Journal Article] Importance of adult Dmbx1 in long-lasting orexigenic effect of agouti-related peptide. (2016)
  • Author(s): Hirono S, Lee EY, Kuribayashi S, Takahiro Fukuda T, Saeki N, Minokoshi Y, Iwanaga T, Miki T.
  • Journal Title: Endocrinology Volume: 157 Issue: 1 Pages: 245-257
  • DOI: 10.1210/en.2015-1560
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function. (2016)
  • Author(s): Morita A, Mukai E, Hiratsuka A, Takatani T, Iwanaga T, Lee EY, Miki T.
  • Journal Title: Endocrine Volume: 51 Issue: 3 Pages: 429-439
  • DOI: 10.1007/s12020-015-0733-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Refeeding with glucose rather than fructose elicits greater hepatic inflammatory gene expression in mice (2015)
  • Author(s): Oarada M, et al.
  • Journal Title: Nutrition Volume: 31 Issue: 5 Pages: 757-65
  • DOI: 10.1016/j.nut.2014.11.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fructose induces glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and insulin secretion: Role of adenosine triphosphate-sensitive K+ channels (2015)
  • Author(s): Seino Y, Ogata H, Maekawa R, Izumoto T, Iida A, Harada N, Miki T, Seino S, Inagaki N, Tsunekawa S, Oiso Y, Hamada Y
  • Journal Title: J Diabetes Investig Volume: 6 Issue: 5 Pages: 522-526
  • DOI: 10.1111/jdi.12356
  • NAID: 120005770745
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation. (2015)
  • Author(s): Nakagomi, A., Okada, S., Yokoyama, M., Yoshida, Y., Shimizu, I., Miki, T., Kobayashi, Y., Minamino, T.
  • Journal Title: Aging and Mechanisms of Disease Volume: 1 Issue: 1 Pages: 15009-15009
  • DOI: 10.1038/npjamd.2015.9
  • Peer Reviewed
• [Journal Article] Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet. (2015)
  • Author(s): Lee EY, Sakurai K, Zhang X, Toda C, Tanaka T, Jiang M, Shirasawa T, Tachibana K, Yokote K, Vidal-Puig A, Minokoshi Y, Miki T.
  • Journal Title: Sci Rep Volume: 30 Issue: 1 Pages: 17565-17565
  • DOI: 10.1038/srep17565
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distinct action of the alpha-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion (2015)
  • Author(s): Lee EY, Kaneko S, Jutabha P, Zhang X, Seino S, Jomori T, Anzai N, Miki T
  • Journal Title: J Endocrinol Volume: 224 Issue: 3 Pages: 205-214
  • DOI: 10.1530/joe-14-0555
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1 (2015)
  • Author(s): Matsushita K, Kitamura K, Rahmutulla B, Tanaka N, Ishige T, Satoh M, Hoshino T, Miyagi S, Mori T, Itoga S, Shimada H, Tomonaga T, Kito M, Nakajima-Takagi Y, Kubo S, Nakaseko C, Hatano M, Miki T, Matsuo M, Fukuyo M, Kaneda A, Iwama A, Nomura F.
  • Journal Title: Oncotarget Volume: 6
  • Peer Reviewed
• [Journal Article] グルカゴン抑制作用を有する抗糖尿病薬 (2015)
  • Author(s): 三木隆司
  • Journal Title: 実験医学 Volume: 33 Pages: 908-913
• [Journal Article] KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state (2014)
  • Author(s): Ogata H, Seino Y, Harada N, Iida A, Suzuki K, Izumoto T, Ishikawa K, Uenishi E, Ozaki N, Hayashi Y, Miki T, Inagaki N, Tsunekawa S, Hamada Y, Seino S, Oiso Y
  • Journal Title: J Endocrinol Volume: 222 Issue: 2 Pages: 191-200
  • DOI: 10.1530/joe-14-0161
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Murine insulinoma cell-conditioned medium with ΒETA2/Neurod1 transduction efficiently induces the differentiation of adipose-derived mesenchymal stem cells into β-like cells both in vitro and in vivo. (2014)
  • Author(s): Kawamoto, K., Yabe, S., Konno, M., Ishii, H., Nishida. N., Jun Koseki, J., Fukuda, S., Tomimaru, Y., Hama, N., Wada, H., Kobayashi, S., Eguchi, H., Tanemura, M., Ito, T., Lee, E-Y., Mukai, E., Miki, T., Doki, Y., Mori, M., Hamazaki, T., Nagano, H., Okochi, H.
  • Journal Title: J Stem Cell Res Ther Volume: 4
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in Spontaneously Diabetic Torii rats. (2014)
  • Author(s): Mukai E, Ohta T, Kawamura H, Lee EY, Morita A, Sasase T, Miyajima K, Inagaki N, Iwanaga T, Miki T.
  • Journal Title: Diabetes Res Clin Pract Volume: 106 Issue: 2 Pages: 303-311
  • DOI: 10.1016/j.diabres.2014.08.023
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GLP-1の膵α細胞における作用とその機序 (2014)
  • Author(s): 三木隆司
  • Journal Title: 内分泌糖尿病代謝内科 Volume: 38 Pages: 424-430
• [Journal Article] Refeeding with a standard diet after a 48-h fast elicits an inflammatory response in the mouse liver (2013)
  • Author(s): Oarada M, Miki T, Kohno S, Sakai K, Nikawa T, Yoneyama M, Gonoi T.
  • Journal Title: J Nutr Biochem Volume: (in press) Issue: 7 Pages: 1314-1323
  • DOI: 10.1016/j.jnutbio.2012.10.006
  • Peer Reviewed
• [Journal Article] Cephalic phase insulin secretion is KATP channel-independent. (2013)
  • Author(s): Seino, Y., Miki, M., Fujimoto, W., Lee, EY., Takahashi, Y., Minami, K., Oiso, Y., Seino, S.
  • Journal Title: J Endocrinol Volume: 218 Issue: 1 Pages: 25-33
  • DOI: 10.1530/joe-12-0579
  • Peer Reviewed
• [Journal Article] A case of Type 1 diabetes with nocturnal hypoglycemia after desensitization therapy for insulin allergy. (2013)
  • Author(s): Kitamoto, T., Sakurai, K., Tachibana K., Yokoh H., Ishikawa, K., Miki, T., Yokote K.
  • Journal Title: Diabetes Care Volume: 36 Issue: 7 Pages: 89-89
  • DOI: 10.2337/dc12-2591
  • Peer Reviewed
• [Presentation] Approaches to diabetes therapy via modulation of bile acid metabolism. (2016)
  • Author(s): Takashi Miki, Eun Young Lee, Yasuhiko Minokoshi
  • Organizer: 第93回日本生理学会
  • Place of Presentation: 札幌コンベンションセンター（北海道、札幌）
  • Year and Date: 2016-04-22
  • Invited
• [Presentation] Fat transplantation ameliorates high-fat diet induced hyperglycemia in InsrP1195L/+ mice. (2015)
  • Author(s): Lee, EY., Sakurai K, Zhang, X., Minokoshi Y, Miki, T.
  • Organizer: 5th Annual Meeting of the American Diabetes Association.
  • Place of Presentation: Boston Convention & Exhibition Center (Ｂｏｓｔｏｎ, ＵＳＡ）
  • Year and Date: 2015-07-05
  • Int'l Joint Research
• [Presentation] 皮下脂肪移植による高脂肪食感受性糖尿病マウスの高血糖改善メカニズム (2015)
  • Author(s): 李恩瑛、櫻井健一、張錫麟、戸田知得、箕越靖彦、三木隆司
  • 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（山口県、下関市）
  • Year and Date: 2015-05-21
• [Presentation] 高脂肪食感受性糖尿病マウスにおけるＥＰＡの高血糖改善メカニズム (2015)
  • Author(s): 森本真有、李恩瑛、張錫麟、櫻井健一、三木隆司
  • 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（山口県、下関市）
  • Year and Date: 2015-05-21
• [Presentation] 癌抑制遺伝子p53によるグルタミン代謝調節作用の生活習慣病と癌における役割 (2015)
  • Author(s): 鈴木佐和子、中山哲俊、李恩瑛、 三木隆司、田中知明、横手幸太郎
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京（東京都、千代田区））
  • Year and Date: 2015-04-23
• [Presentation] Metabolite sensing and regulation of glucose metabolism in liver. Symposium in A better understanding of liver metabolism by multifaceted approaches (2015)
  • Author(s): Takashi Miki, Eun Young Lee, Yasuhiko Minokoshi
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] Dual roles of a DPP-4 inhibitor on cytoprotection and proliferation of pancreatic β-cells in a mouse model of β-cell injury/regeneration. (2014)
  • Author(s): Mukai, E., Morita, A., Hiratsuka, A., Takatani, T., Lee, EY., Miki, T.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2014-09-19
• [Presentation] Mechanism and physiological roles of glucose sensing in enteroendocrine cells. (2014)
  • Author(s): Lee, EY., Zhang, X., Miki, T.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2014-09-16
• [Presentation] 単糖類はKATPチャネル依存性の経路と非依存性の経路によりGIP分泌を惹起する (2014)
  • Author(s): 尾方秀忠、清野祐介、原田範雄、飯田淳史、鈴木和代、泉本貴子、石川孝太、上西栄太、尾崎信暁、林良敬、三木隆司、稲垣暢也、清野進、濱田洋司、恒川新、大磯ユタカ
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-05-24
• [Presentation] 腸内分泌L細胞のグルコース感知と脳への情報伝達 (2014)
  • Author(s): 李恩瑛 、張錫麟、 三木隆司
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-05-24
• [Presentation] DPP-Ⅳ阻害薬による膵β細胞死抑制と増殖促進-膵β細胞傷害/再生マウスを用いた検討- (2014)
  • Author(s): 森田亜州華、向英里、平塚文乃、高谷具純、李恩瑛、三木隆司
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-05-22
• [Presentation] VEGFシグナル阻害はSDTラットにおけるβ細胞傷害と糖尿病発症を抑制する
  • Author(s): 向英里、太田毅、河村治清、李恩瑛、森田亜州華、笹瀬智彦、稲垣暢也、岩永敏彦、三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] インスリン受容体変異マウスの高脂肪食感受性糖尿病発症のメカニズム
  • Author(s): 李恩瑛 櫻井健一 戸田知得 箕越靖彦 三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 高脂肪餌により糖尿病を発症する変異インスリン受容体ノックインマウスの肝臓における遺伝子発現
  • Author(s): 櫻井健一、李恩瑛、橘香穂里、石川耕、三木隆司
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] Unsuppressed Lipolysis in Adipose Tissue by Insulin Is Critical for Glucose Homeostasis under High Fat Diet
  • Author(s): Lee, E-Y., Sakurai, K., Toda,C., Minokoshi, Y., Miki, T
  • Organizer: 49th EASD Annual Meeting
  • Place of Presentation: Barcelona, Spain
• [Presentation] Dynamic regulation of metabolite flow between adipose tissues and liver by insulin
  • Author(s): Miki, T.
  • Organizer: 第91回日本生理学会
  • Place of Presentation: 鹿児島
• [Book] 新時代の臨床糖尿病学 (2015)
  • Author(s): 三木隆司
  • Total Pages: 671
  • Publisher: 日本臨床社
• [Book] グルカゴン革命 糖尿病の真の分子病態を追え！ (2015)
  • Author(s): 三木隆司
  • Total Pages: 243
  • Publisher: 羊土社
• [Book] 中枢神経系によるエネルギー代謝調節機構 (2015)
  • Author(s): 三木隆司
  • Total Pages: 88
  • Publisher: 科学評論社
• [Book] ギャノング生理学 原書24版、「肝臓の輸送機能と代謝機能」 (2014)
  • Author(s): 三木隆司
  • Total Pages: 860
  • Publisher: 丸善出版株式会社
• [Book] イオンチャネル病の全て「ATP感受性K+チャネルと疾患」 (2013)
  • Author(s): 三木隆司
  • Total Pages: 100
  • Publisher: 医歯薬出版株式会社
• [Remarks] 代謝生理学ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/physiol/index.html
• [Remarks] 千葉大学大学院医学研究院代謝生理学研究室ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/physiol/index.html
• [Remarks] 代謝生理学ホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/physiol/index.html