Understanding molecular mechanisms controlling incretin-induced beta cell proliferation

2018 Fiscal Year Research-status 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 / インスリン / 増殖

Outline of Annual Research Achievements

若齢（8週齢）、高齢（52週齢）の野生型マウスC57BL/6Jに対して、膵β細胞の強力な増殖刺激である膵部分切除を実施し、切除術前後の膵島細胞に対して、シングルセルレベルでのRNA-seq（scRNA-seq）を行うことで増殖能をもつ膵β細胞について解析を行った。その結果、１）遺伝子発現の違いにより膵β細胞は４つの亜集団に分類されること、２）亜集団のひとつは細胞増殖に関連した遺伝子群を発現する増殖β細胞からなることを見出した。さらに若齢マウスにおいて、増殖β細胞からなる亜集団は、膵部分切除術により増加するが、高齢マウスでは増殖β細胞は刺激前後でほとんど認められなかった。興味深いことに、昨年度実施したATAC-Seqによる網羅的オープンクロマチン解析との統合解析から、膵β細胞増殖制御に関与していると考えらえる新規転写因子を同定することに成功した。今後、遺伝子改変マウスを作成、解析することで、同定した転写因子について膵β細胞の増殖における役割を検討する予定である。

生体内における膵β細胞増殖をリアルタイムに可視化する目的で膵β特異的に細胞周期プローブを発現する遺伝子改変マウス（βFucci2aRマウス）を作成、解析を行った。膵β細胞増殖を刺激するインスリン受容体拮抗薬S961を投与下にBrdUラベルしたβFucci2aRマウスの膵島切片を解析したところ、BrdUによる従来の評価系と矛盾することなく膵β細胞増殖を評価できること、透明化技術を組み合わせることで個体における膵β細胞増殖をより簡便に定量化することに成功した（投稿中）。一方、生体内における膵β細胞増殖のリアルタイム・モニタリングを試みたが、増殖するβ細胞が少ないことに加え、マウスを生かしたまま、G0からM期までの一連の細胞周期を観察することは難しく、現在、条件検討を行っている。

Current Status of Research Progress

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

Reason

インクレチンによる膵β細胞増殖についても並行して検討を行っているが増殖する膵β細胞が少なく探索的検討に苦慮しているが、膵部分切除刺激、S961刺激をツールとして順調に解析は進んでいる。

Strategy for Future Research Activity

インクレチンによる膵β細胞増殖についても並行して検討を行っているが増殖する膵β細胞が少なく、膵部分切除刺激、S961刺激をツールとして解析を進めていく。

Research Products

• [Int'l Joint Research] Universit de Geneve(スイス)
  • Country Name: SWITZERLAND
  • Counterpart Institution: Universit de Geneve
• [Int'l Joint Research] University of British Columbia(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: University of British Columbia
• [Journal Article] Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials. (2019)
  • Author(s): Yabe D, Yasui A, Ji L, Lee MK, Ma RCW, Chang TJ, Okamura T, Zeller C, Kaspers S, Lee J, Kohler S, Seino Y.
  • Journal Title: J Diabetes Investig. Volume: 10 Pages: 418-428
  • DOI: 10.1111/jdi.12910
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoglycemia Unawareness in Insulinoma Revealed with Flash Glucose Monitoring Systems. (2019)
  • Author(s): Sugawa T, Murakami T, Yabe D, Kashima R, Tatsumi M, Ooshima S, Joo E, Wada K, Yoshizawa A, Masui T, Nakamoto Y, Yamauchi Y, Kodama Y, Iemura Y, Ogura M, Yasoda A, Inagaki N.
  • Journal Title: Intern Med. Volume: 57 Pages: 3407-3412
  • DOI: 10.2169/internalmedicine.1173-18
  • Peer Reviewed / Open Access
• [Journal Article] Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity. (2019)
  • Author(s): Usui R, Yabe D, Seino Y.
  • Journal Title: J Diabetes Investig. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/jdi.13005
  • 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 SI, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Y, Inagaki N.
  • Journal Title: FASEB J. Volume: 33 Pages: 6239-6253
  • DOI: 10.1096/fj.201801783RR
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β-cell function and the achievement of the glycated hemoglobin target 1 year after initiation. (2018)
  • Author(s): Usui R, Sakuramachi Y, Seino Y, Murotani K, Kuwata H, Tatsuoka H, Hamamoto Y, Kurose T, Seino Y, Yabe D.
  • Journal Title: J Diabetes Investig. Volume: 9 Pages: 822-830
  • DOI: 10.1111/jdi.12773
  • Peer Reviewed / Open Access
• [Journal Article] Kuwata H, Okamoto S, Seino Y, Murotani K, Tatsuoka H, Usui R, Hamamoto Y, Kurose T, Seino Y, Yabe D. (2018)
  • Author(s): Relationship between deterioration of glycated hemoglobin-lowering effects in dipeptidyl peptidase-4 inhibitor monotherapy and dietary habits: Retrospective analysis of Japanese individuals with type 2 diabetes.
  • Journal Title: J Diabetes Investig. Volume: 9 Pages: 1153-1158
  • DOI: 10.1111/jdi.12779
  • Peer Reviewed / Open Access
• [Journal Article] Mental distress and health-related quality of life among type 1 and type 2 diabetes patients using self-monitoring of blood glucose: A cross-sectional questionnaire study in Japan. (2018)
  • Author(s): Tanaka N, Yabe D, Murotani K, Ueno S, Kuwata H, Hamamoto Y, Kurose T, Takahashi N, Akashi T, Matsuoka T, Osonoi T, Minami M, Shimono D, Seino Y; Positive SMBG Study Group Investigators.
  • Journal Title: J Diabetes Investig. Volume: 9 Pages: 1203-1211
  • DOI: 10.1111/jdi.12827
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Clinical Practice Guideline for Diabetes 2016. (2018)
  • Author(s): Haneda M, Noda M, Origasa H, Noto H, Yabe D, Fujita Y, Goto A, Kondo T, Araki E
  • Journal Title: J Diabetes Investig. Volume: 9 Pages: 657-697
  • DOI: 10.1111/jdi.12810
  • Peer Reviewed / Open Access
• [Journal Article] Case 23-2018: A Man with Episodes of Confusion and Hypoglycemia. (2018)
  • Author(s): Murakami T, Yabe D, Inagaki N.
  • Journal Title: N Engl J Med. Volume: 379 Pages: 1881-1882
  • DOI: 10.1056/NEJMc1811310
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Clinical Practice Guideline for Diabetes 2016. (2018)
  • Author(s): Haneda M, Noda M, Origasa H, Noto H, Yabe D, Fujita Y, Goto A, Kondo T, Araki E.
  • Journal Title: Diabetol Int. Volume: 9 Pages: 1-45
  • DOI: 10.1007/s13340-018-0345-3
  • Peer Reviewed / Open Access
• [Presentation] Macro Nutrients and Long-term Glucose-lowering Effects of DPP-4 Inhibitors in Individuals With Type 2 Diabetes (2018)
  • Author(s): Yabe D, Kuwata H, Seino Y.
  • Organizer: Asia Islet Biology & Incretin Symposium
  • Int'l Joint Research / Invited
• [Presentation] Diabetes patients with coronary heart disease: Target and Drug? Diabetes specialist’s perspectives (2018)
  • Author(s): Yabe D
  • Organizer: Asia Pacific Society of Cardiology Congress 2018 Symposium
  • Int'l Joint Research / Invited
• [Presentation] Keynote: Cardiovascular Effects of Anti-diabetes Drugs: Focusing upon East Asians (2018)
  • Author(s): Yabe D
  • Organizer: Asia Pacific Society of Cardiology Congress 2018 Symposium
  • Int'l Joint Research / Invited
• [Presentation] Current status of type 2 diabetes in Japan (2018)
  • Author(s): Yabe D
  • Organizer: Asia Pacific Society of Cardiology Congress 2018 Symposium
  • Int'l Joint Research / Invited
• [Presentation] Meal sequence, incretin secretion and glycemic control (2018)
  • Author(s): Yabe D
  • Organizer: Diabetes Preventing the Preventables 2018
  • Int'l Joint Research / Invited
• [Presentation] Effects of Dietary Instructions Including Meal-Sequence for Prediabetes Subjects: Comparison with Conventional Approach. (2018)
  • Author(s): Yabe D, Kuwata H, Fujiwara Y, Murotani K, Asano H, Mishima H, Hideto T, Noriyasu O, Seino Y, Hamamoto Y, Kurose T, Seino Y.
  • Organizer: 78th scientific sessions of the American diabetes association, Late breaking abstract
  • Int'l Joint Research
• [Presentation] Factors responsible for progression of microalbuminuria in Japanese patients with type 2 diabetes: Retrospective analysis. (2018)
  • Author(s): Kubota S, Kuwata H, Yabe D, Murotani K, Hamamoto Y, Kurose T, Seino Y.
  • Organizer: 78th scientific sessions of the American diabetes association, Late breaking abstract
  • Int'l Joint Research
• [Presentation] Safety and Tolerability of Empagliflozin in East Asian Patients with Type 2 Diabetes;Pooled Analysis of Phase I-III Clinical Trials (2018)
  • Author(s): Yasui A, Yabe D, Ji L, Lee MK, Ma RC, Chang TJ, Okamura T, Zeller C, Kaspers S, Lee J, Kohler S, Seino Y.
  • Organizer: 78th scientific sessions of the American diabetes association, Late breaking abstract
  • Int'l Joint Research
• [Presentation] Deterioration of HbA1c-Lowering Effects in Dipeptidyl-Peptidase Inhibitor and Dietary Habits in Japanese Type 2 Diabetes-Comparison with That of Metformin. (2018)
  • Author(s): Okamoto S, Kuwata H, Yabe D, Hamamoto Y, Kurose T, Seino Y.
  • Organizer: 78th scientific sessions of the American diabetes association, Late breaking abstract
  • Int'l Joint Research
• [Presentation] ER Ca2+ sensor, stromal interaction molecule 1 (STIM1) plays an important role in GPR40-mediated potentiation of glucose-induced insulin secretion. (2018)
  • Author(s): Usui R, Yabe D, Goto H, Fauzi M, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Ogura M, Nagashima K, Inagaki N.
  • Organizer: Asia Islet Biology & Incretin Symposium
  • Int'l Joint Research
• [Presentation] Effects of Dietary Instructions Including Meal-Sequence in Prediabetes Subjects. (2018)
  • Author(s): Fujita Y, Yabe D, Kuwata H, Fujiwara Y, Murotani K, Asano H, Mishima H, Hideto T, Noriyasu O, Seino Y, Hamamoto Y, Kurose T, Seino Y.
  • Organizer: Asia Islet Biology & Incretin Symposium
  • Int'l Joint Research
• [Presentation] The correlation between anti-GAD antibody titer evaluated by RIA and ELISA kit and pancreatic b-cell function (2018)
  • Author(s): Haraguchi T, Okamoto S, Kuwata H, Hamamoto Y, Yabe D, Seino Y.
  • Organizer: Asia Islet Biology & Incretin Symposium
  • Int'l Joint Research
• [Presentation] The role of ER Ca2+sensor, stromal interaction molecule 1 (STIM1) in GPR40-mediated potentiation of glucose-induced insulin secretion. (2018)
  • Author(s): Usui R, Yabe D, Goto H, Fauzi M, Tokumoto S, Tatsuoka H, Tahara Y, Ogura M, Nagashima K, Inagaki N.
  • Organizer: 54th Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] Safety and Tolerability of Empagliflozin in East Asian Patients with Type 2 Diabetes;Pooled Analysis of Phase I-III Clinical Trials (2018)
  • Author(s): Yabe D, Yasui A, Ji Linong, Lee MK, Ma RC, Chang TJ, Okamura T, Zeller C, Kaspers S, Lee J, Kohler S, Seino Y
  • Organizer: 54th Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] Sarcopenia is associated with decreased insulin secretion and increased arterial stiffness in Japanese elderly patients with type 2 diabetes. (2018)
  • Author(s): Moyama Y, Hamamoto Y, Kuwata H, Kurose T, Yabe D, Seino Y.
  • Organizer: 54th Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] Management of DKD with or without cardiovascular disease (2018)
  • Author(s): Yabe D
  • Organizer: Taipei Diabetes Society Congress
  • Int'l Joint Research / Invited
• [Presentation] 慣習的に摂取する食事内容と糖尿病治療薬の効果 (2018)
  • Author(s): 矢部大介、桑田仁司、清野裕
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 内因性GLP-1による迷走神経シグナリングと糖尿病・肥満・摂食リズム障害の改善 (2018)
  • Author(s): 矢田俊彦、岩崎有作、徳田雅明、矢部大介、清野裕
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 膵臓の再生を明らかにするシングルセル遺伝子発現及びマルチオミックス解析 (2018)
  • Author(s): 渡辺亮、中村正裕、龍岡久登、矢部大介、稲垣暢也
  • Organizer: 第61回日本糖尿病学会年次学術集会