Development of novel therapies for diabetes by manipulating zinc transporters

• Project/Area Number: 25461364
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Juntendo University
• Principal Investigator: Fujitani Yoshio 順天堂大学, 医学(系)研究科(研究院), 准教授 (30433783)
• Co-Investigator(Kenkyū-buntansha): FUKUNAKA Ayako 順天堂大学, 大学院医学研究科, 研究員 (60586402)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 糖尿病 / 膵β細胞 / 亜鉛 / 亜鉛トランスポーター / 糖尿病の病態 / 糖尿病治療

Outline of Final Research Achievements

We showed that zinc ion secreted in concert with insulin from pancreatic beta cell suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis.
In addition, we demonstrated that inactivation of Zip13 preferentially promotes beige adipocyte biogenesis, energy expenditure and ameliorates diet-induced obesity in mice. Our data reveal unexpected association between zinc homeostasis and beige adipocyte biogenesis, which may contribute significantly to novel therapies for diabetes.

Research Products

• [Int'l Joint Research] USCF(米国)
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2016)
  • Author(s): Klionsky DJ., Abdelmohsen K., Abe A., Abedin MJ.,Inomata M., et al.
  • Journal Title: Autophagy Volume: 12(1) Issue: 1 Pages: 1-222
  • DOI: 10.1080/15548627.2015.1100356
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet. (2016)
  • Author(s): Kakehi S, Tamura Y, Takeno K, Sakurai Y, Kawaguchi M, Watanabe T, Funayama T, Sato F, Ikeda S, Kanazawa A, Fujitani Y, Kawamori R, Watada H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 310 Issue: 1 Pages: 32-40
  • DOI: 10.1152/ajpendo.00220.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 5. Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice. (2015)
  • Author(s): Sasaki S, Miyatsuka T, Matsuoka TA, Takahara M, Yamamoto Y, Yasuda T, Kaneto H, Fujitani Y, German MS, Akiyama H, Watada H, Shimomura I.
  • Journal Title: Diabetologia Volume: 58 Issue: 11 Pages: 2582-2591
  • DOI: 10.1007/s00125-015-3728-z
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Expression mechanism of tryptophan hydroxylase 1 in mouse islets during pregnancy. (2015)
  • Author(s): Iida H, Ogihara T, Min MK, Hara A, Kim YG, Fujimaki K, Tamaki M, Fujitani Y, Kim H, Watada H.
  • Journal Title: J Mol Endocrinol Volume: 55 (1) Issue: 1 Pages: 41-53
  • DOI: 10.1530/jme-14-0299
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell. (2015)
  • Author(s): Fujimaki K, Ogihara T, Morris DL, Oda H, Iida H, Fujitani Y, Mirmira RG, Evans-Molina C, Watada H
  • Journal Title: J Biol Chem Volume: 290 Issue: 27 Pages: 16607-18
  • DOI: 10.1074/jbc.m115.661777
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Minireview: Autophagy in pancreatic beta cells and its implication in diabetes. (2015)
  • Author(s): Watada H, Fujitani Y
  • Journal Title: Molecular Endocrinology Volume: 29 Issue: 3 Pages: 338-348
  • DOI: 10.1210/me.2014-1367
  • Peer Reviewed
• [Journal Article] Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy. (2014)
  • Author(s): Shigihara N, Fukunaka A, Hara A, Komiya K, Honda A, Uchida T, Abe H, Toyofuku Y, Tamaki M, Ogihara T, Miyatsuka T, Hiddinga HJ, Sakagashira S, Koike M, Uchiyama Y, Yoshimori T, Eberhardt NL, Fujitani Y, Watada H.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 8 Pages: 3634-44
  • DOI: 10.1172/jci69866
  • Peer Reviewed / Open Access
• [Journal Article] Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins. (2014)
  • Author(s): Bin et al.
  • Journal Title: EMBO Molecular Medicine Volume: 6 Issue: 8 Pages: 1028-1042
  • DOI: 10.15252/emmm.201303809
  • Peer Reviewed
• [Journal Article] Role of Zinc in Type 2 Diabetes (2014)
  • Author(s): Motoyuki Tamaki
  • Journal Title: Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) Volume: 69 Issue: 1 Pages: 15-23
  • DOI: 10.1265/jjh.69.15
  • NAID: 130003394510
  • ISSN: 0021-5082, 1882-6482
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance (2013)
  • Author(s): Tamaki, M., Fujitani, Y, Uchida, T., Tamura, Y., Takeno, K., Kawaguchi, M., Watanabe, T., Hara, A., Ogihara, T., Shimizu, T., Mita, T., Hirose, T., Ohara-Imaizumi, M., Abe, T., Kiyonari, H., Hojyo, S., Fukada, T., Nagamatsu, S., Hirano, T., Kawamori, R., Watada, H.
  • Journal Title: J Clin Invest Volume: 123 Issue: 10 Pages: 4513-4524
  • DOI: 10.1172/jci68807
  • Peer Reviewed
• [Presentation] Zinc transporter ZIP13 regulates adipocyte browning (2016)
  • Author(s): Fukunaka A
  • Organizer: The 93rd annual meeting of the physiology society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] エーラス・ダンロス症候群原因遺伝子Zip13による脂肪細胞褐色化制御 (2015)
  • Author(s): 藤谷与士夫
  • Organizer: 免疫病の発症機構研究会
  • Place of Presentation: 大阪大学中之島センター
  • Year and Date: 2015-10-18
  • Invited
• [Presentation] Zip13による脂肪細胞褐色化制御機構の解明 (2015)
  • Author(s): 福中彩子
  • Organizer: 第16回日本内分泌学会関東甲信越支部学術集会
  • Place of Presentation: 幕張
  • Year and Date: 2015-09-25
  • Invited
• [Presentation] Human IAPP impairs the success of islet transplantation. (2015)
  • Author(s): Hara A
  • Organizer: 51st EASD Annual Meeting
  • Place of Presentation: Stockholm（Sweden）
  • Year and Date: 2015-09-14
  • Int'l Joint Research
• [Presentation] 2型糖尿病における新たな治療標的：IAPPと亜鉛シグナル (2015)
  • Author(s): 福中彩子
  • Organizer: 第15回islet biology研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-18
  • Invited
• [Presentation] 亜鉛トランスポーターZIP13による脂肪細胞褐色化制御機構の解明 (2015)
  • Author(s): 福中彩子
  • Organizer: 第10回トランスポーター研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] Beta-to-PP cell de-differentiation and deficiency in zinc/insulin co-secretion as novel mechanisms of beta-cell failure in diabetes. (2015)
  • Author(s): Fujitani Y
  • Organizer: 熊本大学発生医学研究所リエゾンラボ研究会HIGOプログラム最先端研究セミナー
  • Place of Presentation: 熊本
  • Year and Date: 2015-06-17
  • Invited
• [Presentation] Fate conversion of beta cells induced by persistent hyperglycemia. (2015)
  • Author(s): Fujitani Y
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] Role of autophagy in pancreatic βcells. (2014)
  • Author(s): Fujitani Y, Watada H
  • Organizer: 2014 Northeastern Asian Symposium on Autophagy
  • Place of Presentation: Busan (South Korea)
  • Year and Date: 2014-12-19 – 2014-12-21
  • Invited
• [Presentation] 転写因子と亜鉛トランスポーターによる細胞分化と糖代謝の制御 (2014)
  • Author(s): 藤谷与士夫
  • Organizer: 群馬大学生体調節研究所 内分泌・代謝学共同利用共同研究拠点セミナー
  • Place of Presentation: 群馬
  • Year and Date: 2014-10-30
  • Invited
• [Presentation] Zinc transporter-8 regulates hepatic insulin clearance. (2014)
  • Author(s): Fujitani Y
  • Organizer: 第87回日本生化学会大会, シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Zn, diabetes and ZnT8 (2014)
  • Author(s): Fujitani Y
  • Organizer: ISZB (International Society for Zinc Biology) 2014 meeting
  • Place of Presentation: Asilomar, CA, USA
  • Year and Date: 2014-09-15 – 2014-09-18
  • Invited
• [Presentation] Roles of autophagy in pancreatic b cell function and type 2 diabetes (2014)
  • Author(s): Fujitani Y
  • Organizer: 第57回日本糖尿病学会年次学術集会, シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
  • Invited
• [Presentation] 2型糖尿病感受性遺伝子SLC30A8/ZnT8は肝インスリンクリアランスを制御する (2013)
  • Author(s): 藤谷与士夫
  • Organizer: 第５６回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] New players regulating pancreatic beta-cell function and their roles in diabetes
  • Author(s): Yoshio Fujitani
  • Organizer: 第１3回国際形態学会シンポジウム
  • Place of Presentation: Niigata
  • Invited
• [Book] 亜鉛によるインスリン分解の制御 Annual Review 糖尿病・代謝・内分泌 2015 (2015)
  • Author(s): 藤谷与士夫
  • Total Pages: 9
  • Publisher: 中外医学社
• [Book] IAPPによる膵β細胞障害. 糖尿病学2015. (2015)
  • Author(s): 藤谷与士夫, 綿田裕孝
  • Total Pages: 7
  • Publisher: 診断と治療社
• [Book] Zinc and its role in the pathogenesis of type 2 diabetes. Zinc Signals in Cellular Functions and Disorders, eds by Fukada T, Kambe T, , (2014)
  • Author(s): Fujitani Y, Tamaki M, Fukunaka A, Watada H.
  • Publisher: Springer, Tokyo (Japan),
• [Remarks] 亜鉛のながれによる糖代謝制御の研究
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/taisya_naibunpitsu/k4.html
• [Remarks] 順天堂大学代謝内分泌内科学 基礎研究
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/taisya_naibunpitsu/k4.html
• [Remarks] 糖尿病発症における亜鉛の役割を解明
  • URL: http://www.juntendo.ac.jp/albums/abm.php?f=abm00001125.pdf&n=news03.pdf
• [Remarks] 藤谷与士夫准教授らの研究がJＣＩに掲載され、同雑誌の表紙を飾りました。
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/taisya_naibunpitsu/news28.html