Understanding molecular mechanisms controlling incretin-induced beta cell proliferation

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09825
• Research Institution: Gifu University
• Principal Investigator: 矢部 大介 岐阜大学, 大学院医学系研究科, 教授 (60378643)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 膵β細胞 / インクレチン / 増殖 / シングルセル解析

Outline of Annual Research Achievements

膵β細胞量減少の重要性は、糖尿病の発症・重症化の観点で喫緊の課題であるが、生体における膵β細胞増殖能低下の分子基盤の全容は依然として不明であり、膵β細胞量を標的にした糖尿病の発症予防および治療法は確立されていない。本研究では、インクレチンを用いて、膵β細胞増殖制御の分子機構の研究を試みたが、既報と異なりインクレチンでは膵β細胞増殖を認めなかった。そこで、インクレチンに変えて、膵β細胞増殖を強力に誘導可能な膵部分切除術を行い、若齢・高齢マウス由来の膵β細胞に対して一細胞単位で網羅的遺伝子発現を解析可能なscRNA-seqを用いることで、若齢膵β細胞が5つの亜集団に分類され、膵部分切除に応答して細胞周期関連分子を発現する細胞群（増殖β細胞と定義）が増加することを見出した。一方、高齢膵β細胞では同様の細胞群がきわめて少ないことも確認した。また、増殖β細胞を含め５つの亜集団に対するTrajectory解析により、膵β細胞が膵部分切除応答性に分化マーカーの発現を減じ、小胞体ストレス関連遺伝子を一過性に活性化することで、最終的に増殖β細胞になる可能性が示唆された。また増殖β細胞にはE2Fファミリーが発現されることも見出し、現在、これら転写因子を膵β細胞特異的に欠損するマウスを作成中である。また、候補転写因子が膵β細胞増殖のどのタイミングを制御するか検討すべく、細胞増殖をライブイメージング可能な膵β細胞特異的Fucci2aマウスを樹立し、透明化技術と組み合わせることで、まるままの膵臓における膵β細胞増殖を評価することに世界で初めて成功した。さらに、２光子顕微鏡を用いて生体内において膵β細胞増殖を観察することにも成功しており、国際的にも高い評価をうけている。本研究を更に発展させることで、将来、膵β細胞量を標的にした糖尿病の発症や重症化を阻止する全く新たな治療法の開発に発展しうると確信する。

Research Products

• [Int'l Joint Research] University of Geneva Medical School(スイス)
  • Country Name: SWITZERLAND
  • Counterpart Institution: University of Geneva Medical School
• [Journal Article] Distinctive roles of Rb and p53 in the development of pancreatic neuroendocrine tumors. (2020)
  • Author(s): Yamauchi Y, Kodama Y, Shiokawa M, Kakiuchi N, Marui S, Kuwada T, Sogabe Y, Tomono T, Mima A, Morita T, Matsumori T, Ueda T, Tsuda M, Nishikawa Y, Kuriyama K, Sakuma Y, Ota Y, Maruno T, Uza N, Masuda A, Tatsuoka H, Yabe D, Minamiguchi S, Masui T, Inagaki N, Uemoto S, Chiba T, Seno H
  • Journal Title: Cancer Research Volume: . Pages: .
  • Peer Reviewed
• [Journal Article] Cardioprotective effects of GLP‐1(28‐36a): A degraded metabolite or GLP‐1’s better half? (2020)
  • Author(s): Liu Y, Kubota S, Iizuka K, Yabe D
  • Journal Title: Journal of Diabetes Investigation Volume: . Pages: .
  • DOI: 10.1111/jdi.13302
  • Peer Reviewed / Open Access
• [Journal Article] Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in?vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects (2020)
  • Author(s): Murakami T, Fujimoto H, Fujita N, Hamamatsu K, Yabe D, Inagaki N
  • Journal Title: Journal of Diabetes Investigation Volume: . Pages: .
  • DOI: 10.1111/jdi.13281
  • Peer Reviewed / Open Access
• [Journal Article] Tumor‐like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin‐induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat (2020)
  • Author(s): Hayami T, Yokoi N, Yamaguchi T, Honda K, Murao N, Takahashi H, Wang S, Seino Y, Kamiya H, Yabe D, Sweet IR, Mizoguchi A, Nakamura J, Seino S
  • Journal Title: Journal of Diabetes Investigation Volume: . Pages: .
  • DOI: 10.1111/jdi.13272
  • Peer Reviewed / Open Access
• [Journal Article] GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells (2019)
  • Author(s): Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manabe T, Baba Y, Kurosaki Tomohiro、, Herrera PL, Ogura M, Nagashima K, Inagaki N
  • Journal Title: Scientific Reports Volume: 9 Pages: .
  • DOI: 10.1038/s41598-019-52048-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dietary instructions focusing on meal-sequence and nutritional balance for prediabetes subjects: An exploratory, cluster-randomized, prospective, open-label, clinical trial (2019)
  • Author(s): Yabe D, Kuwata H, Fujiwara Y, Sakaguchi M, Moyama S, Makabe N, Murotani K, Asano H, Ito S, Mishima H, Takase H, Ota N, Seino Y, Hamamoto Y, Kurose T, Seino Y
  • Journal Title: Journal of Diabetes and its Complications Volume: 33 Pages: 107450～107450
  • DOI: 10.1016/j.jdiacomp.2019.107450
  • Peer Reviewed / Open Access
• [Journal Article] The journey to understanding incretin systems: Theory, practice and more theory (2019)
  • Author(s): Yabe D, Kuwata H, Seino Y
  • Journal Title: Journal of Diabetes Investigation Volume: 10 Pages: 1171～1173
  • DOI: 10.1111/jdi.13123
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine kinase 1?interacting protein is a dual regulator of insulin and incretin secretion (2019)
  • Author(s): Liu Y、Harashima SH, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Yo, Inagaki N
  • Journal Title: The FASEB Journal Volume: 33 Pages: 6239～6253
  • DOI: 10.1096/fj.201801783RR
  • Peer Reviewed
• [Journal Article] Twincretin as a potential therapeutic for the management of type?2 diabetes with obesity (2019)
  • Author(s): Usui R, Yabe Da, Seino Y
  • Journal Title: Journal of Diabetes Investigation Volume: 10 Pages: 902～905
  • DOI: 10.1111/jdi.13005
  • Peer Reviewed / Open Access
• [Journal Article] Three-dimensional analysis of β-cell proliferation by a novel mouse model (2019)
  • Author(s): Tokumoto S, Yabe D, Tatsuoka H, Usui R, Fauzi M, Botagarova A, Goto H, Herrera PL, Ogura M, Inagaki N
  • Journal Title: bioRxiv Volume: . Pages: .
  • DOI: 10.1101/659904
  • Open Access
• [Presentation] Sphingosine kinase 1-interacting protein (SKIP) is a dual regulator of insulin and incretin. (2019)
  • Author(s): Liu Y, Harashima SI, Wang Y, Suzuki K, Tokumoto S, Tanaka D, Yabe D, Harada N, Hayshi Y, Inagaki N
  • Organizer: 11th Asian Association for the Study of Diabetes Scientific Meeting
  • Int'l Joint Research
• [Presentation] Generation of a Novel Mouse Model to study beta cell proliferation (2019)
  • Author(s): Tokumoto S, Yabe D, Tatsuoka H, Usui R, Fauzi M, Goto H, Ogura M, Inagaki N
  • Organizer: 11th Asian Association for the Study of Diabetes Scientific Meeting
  • Int'l Joint Research
• [Presentation] Differnce in epigenetic regulations between young and old mice explored the mechanisms of beta cell proliferation (2019)
  • Author(s): Tatsuoka H, Yabe D, Sakamoto S, Watanabe A, Usui R, Tokumoto S, Usui R, Ainura B, Otani D, Goto H, Fauzi M, Ogura M, Inagaki N
  • Organizer: 11th Asian Association for the Study of Diabetes Scientific Meeting
  • Int'l Joint Research
• [Presentation] Possible Availability of Glucagon-like peptide-1 receptor (GLP-1R)-targeting imaging to predict GLP1R agonist’s efficacy (2019)
  • Author(s): Murakami T, Fujimoto H, Fujita N, Hamamatsu K, Yabe D, Inagaki N
  • Organizer: 11th Asian Association for the Study of Diabetes Scientific Meeting
  • Int'l Joint Research
• [Presentation] Single Cell RNA-Sequencing Dissects Proliferation of Pancreatic Beta Cells (2019)
  • Author(s): Tatsuoka H, Yabe D, Sakamoto S, Watanabe A, Usui R, Tokumoto S, Usui R, Ainura B, Otani D, Goto H, Fauzi M, Ogura M, Inagaki N
  • Organizer: 78th scientific sessions of the American diabetes association
  • Int'l Joint Research
• [Presentation] Store-Operated Ca2 + Entry Activated by STIM1 Plays an Essential Role in GPR40-Mediated GIIS Potentiation. (2019)
  • Author(s): Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manabe T, Baba Y, Kurosaki T, Herrera PL, Ogura M, Nagashima K, Inagaki N
  • Organizer: 78th scientific sessions of the American diabetes association
  • Int'l Joint Research
• [Presentation] Generation of a Novel Mouse Model to Study beta-Cell Proliferation. (2019)
  • Author(s): Tokumoto S, Yabe D, Tatsuoka H, Usui R, Fauzi M, Goto H, Ogura M, Inagaki N
  • Organizer: 78th scientific sessions of the American diabetes association
  • Int'l Joint Research
• [Presentation] Sphingosine kinase 1-interacting protein (SKIP) is a dual regulator of insulin and incretin. (2019)
  • Author(s): Liu Y, Harashima SI, Wang Y, Suzuki K, Tokumoto S, Tanaka D, Yabe D, Harada N, Hayshi Y, Inagaki N
  • Organizer: AIBIS2019
  • Int'l Joint Research
• [Presentation] Single Cell RNA-Sequencing Dissects Proliferation of Pancreatic Beta Cells. (2019)
  • Author(s): Tatsuoka H, Yabe D, Sakamoto S, Watanabe A, Usui R, Tokumoto S, Usui R, Ainura B, Otani D, Goto H, Fauzi M, Ogura M, Inagaki N
  • Organizer: AIBIS2019
  • Int'l Joint Research
• [Presentation] Generation of a Novel Mouse Model to Study beta-Cell Proliferation. (2019)
  • Author(s): Tokumoto S, Yabe D, Tatsuoka H, Usui R, Fauzi M, Goto H, Ogura M, Inagaki N
  • Organizer: AIBIS2019（YIA）
  • Int'l Joint Research
• [Presentation] Generation of a Novel Mouse Model to Study beta-Cell Proliferation. (2019)
  • Author(s): Tokumoto S, Yabe D, Tatsuoka H, Usui R, Fauzi M, Goto H, Ogura M, Inagaki N
  • Organizer: 55th Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] The importance of islet, hepatic, and intestinal ChREBP in metabolic disease (2019)
  • Author(s): Kiizuka K, Yabe D
  • Organizer: AIBIS2019
  • Int'l Joint Research
• [Presentation] RNAシークエンスとATACシークエンスを用いた加齢による膵β細胞増殖低下のメカニズムの解析 (2019)
  • Author(s): 龍岡久登、矢部大介、坂本智子、渡辺亮、徳本信介、バタガロワ・アイヌラ、臼井亮太、後藤久典、ファウジ・ムハンマド、小倉雅仁、稲垣暢也
  • Organizer: 第62回日本糖尿病学会年次学術集会
  • Int'l Joint Research
• [Presentation] 細胞周期可視化蛍光プローブFucci2aRを用いた膵β細胞増殖の新規定量法の開発 (2019)
  • Author(s): 徳本信介、矢部大介、龍岡久登、臼井亮太、後藤久典、ファウジ・ムハンマド、バタガロワ・アイヌラ、小倉雅仁、稲垣暢也
  • Organizer: 第62回日本糖尿病学会年次学術集会（YIA）
• [Presentation] 膵β細胞におけるGPR40シグナルに注目したストア依存性カルシウム流入の意義の解明 (2019)
  • Author(s): 井亮太、矢部大介、ファウジ・ムハンマド、バタガロワ・アイヌラ、後藤久典、龍岡久登、田原裕美子、小林静香、真鍋俊也、黒崎知博、ペドロ・ルイス・ヘレラ、小倉雅仁、長嶋一昭、稲垣暢也
  • Organizer: 第62回日本糖尿病学会年次学術集会（YIA）
• [Presentation] Sphingosine kinase 1-interacting proteinはインスリン及びインクレチン分泌の双方の制御因子である (2019)
  • Author(s): 27.劉彦言、原島伸一、王宇、鈴木和代、徳本信介、臼井亮太、龍岡久登、田中大祐、矢部大介、原田範雄、林良敬、稲垣暢也
  • Organizer: 第56回日本臨床分子医学会学術集会