Regulatory mechanism of mTORC1 activity in pancreatic beta cells in the development of type 2 diabetes

• Project/Area Number: 20K08860
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kobe University
• Principal Investigator: Asahara Shun-ichiro 神戸大学, 医学部附属病院, 助教 (00570342)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵β細胞 / 可塑性 / mTORC1 / 糖尿病 / 膵島 / 脱分化 / 2型糖尿病

Outline of Research at the Start

本研究では、高脂肪食負荷GCN2欠損マウスを用いて以下の解明を目指す。
・膵β細胞におけるmTORC1活性亢進経路の解明
・膵β細胞のmTORC1活性調節に及ぼす新規機序の解明
また、ヒトiPS細胞由来の膵β細胞やヒト膵島を用いることによって、EIF2AK4遺伝子のSNP の存在がモデルマウスの結果と合致することを確認する。

Outline of Final Research Achievements

Although the mechanism of pancreatic β-cell volume reduction has not yet been elucidated, mTORC1 activation in islets of type 2 diabetes patients is thought to be involved. In this study, we analyzed pancreatic β-cell-specific TSC2 knockout (βTSC2KO). βTSC2KO showed an increase in chromogranin A-positive and islet hormone-negative cells, suggesting a differentiation effect. βTSC2KO islets showed amylase-positive cells, which were associated with the exocrine cells, and co-positivity of Ptf1a and chromogranin A, a transcription factor of exocrine cells, was also observed. These results suggest that homeostatic activation of mTORC1 may cause a decrease in β-cells by converting them into exocrine cells in old age.

Academic Significance and Societal Importance of the Research Achievements

糖尿病は1型、2型いずれにおいても、膵β細胞量が発症において重要な因子となる。膵β細胞量減少機序については、これまでに多くの報告があるが、いまだに臨床応用されるようなものはない。代表者は糖尿病膵島でmTORC1が活性化されていることに注目し、mTORC1活性調節を制御することが出来れば、1型糖尿病の根治や2型糖尿病の発症予測ができるのではないかと考えた。本研究を進展させることによって、将来的な膵β細胞不全の治療・予防につながるものと期待している。

Research Products

• [Int'l Joint Research] Columbia University(米国)
• [Journal Article] Chlorogenic Acid and Caffeine in Coffee Restore Insulin Signaling in Pancreatic Beta Cells (2023)
  • Author(s): Ihara Y, Asahara SI, Inoue H, Seike M, Ando M, Kabutoya H, Kimura-Koyanagi M, Kido Y.
  • Journal Title: Kobe J Med Sci. Volume: 69
  • Peer Reviewed / Open Access
• [Journal Article] A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia (2023)
  • Author(s): Amano S, Suenaga S, Hamamoto K, Yada S, Tsuyama T, Shinoda S, Tanaka Y, Takemoto Y, Harada E, Tanabe K, Asahara S, Hoshii K, Takami T.
  • Journal Title: DEN Open Volume: 3 Issue: 1
  • DOI: 10.1002/deo2.230
  • Peer Reviewed / Open Access
• [Journal Article] l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells (2023)
  • Author(s): Seike M, Asahara SI, Inoue H, Kudo M, Kanno A, Yokoi A, Suzuki H, Kimura-Koyanagi M, Kido Y, Ogawa W.
  • Journal Title: Biochem Biophys Res Commun. Volume: 652 Pages: 121-130
  • DOI: 10.1016/j.bbrc.2023.02.035
  • Peer Reviewed / Open Access
• [Journal Article] Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes (2023)
  • Author(s): Watanabe H, Du W, Son J, Sui L, Asahara SI, Kurland IJ, Kuo T, Kitamoto T, Miyachi Y, de Cabo R, Accili D.
  • Journal Title: Sci Transl Med. Volume: 15 Issue: 681
  • DOI: 10.1126/scitranslmed.abq4126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice (2023)
  • Author(s): Inaba Yuka、Hashiuchi Emi、Watanabe Hitoshi、Kimura Kumi、Oshima Yu、Tsuchiya Kohsuke et al.
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 167-167
  • DOI: 10.1038/s41467-023-35804-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction (2022)
  • Author(s): Asahara SI, Inoue H, Kido Y.
  • Journal Title: Diabetes Metab J Volume: 46 Issue: 1 Pages: 38-48
  • DOI: 10.4093/dmj.2021.0045
  • Peer Reviewed / Open Access
• [Journal Article] Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion (2022)
  • Author(s): Asahara S, Inoue H, Watanabe H, Kido Y.
  • Journal Title: Biomolecules Volume: 12 Issue: 5 Pages: 618-618
  • DOI: 10.3390/biom12050614
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutamate is an essential mediator in glutamine‐amplified insulin secretion (2021)
  • Author(s): Han Guirong、Takahashi Harumi、Murao Naoya、Gheni Ghupurjan、Yokoi Norihide、Hamamoto Yoshiyuki、Asahara Shun‐ichiro、Seino Yutaka、Kido Yoshiaki、Seino Susumu
  • Journal Title: Journal of Diabetes Investigation Volume: - Issue: 6 Pages: 920-930
  • DOI: 10.1111/jdi.13497
  • NAID: 120007097043
  • Peer Reviewed / Open Access
• [Journal Article] Patch-seq shows the heterogeneity of pancreatic islet cells. (2021)
  • Author(s): Asahara S
  • Journal Title: J Diabetes Investig. Volume: - Issue: 5 Pages: 691-693
  • DOI: 10.1111/jdi.13514
  • NAID: 120007032320
  • Peer Reviewed / Open Access
• [Journal Article] Oral administration of D-serine prevents the onset and progression of colitis in mice. (2021)
  • Author(s): Takehito Asakawa, Michio Onizawa, Chikako Saito, Rie Hikichi, Daiki Yamada, Ai Minamidate, Tomoaki Mochimaru, Shun-ichiro Asahara, Yoshiaki Kido, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Hiromasa Ohira, Ryuichi Okamoto, Mamoru Watanabe.
  • Journal Title: Journal of Gastroenterolog. Volume: 56 Issue: 8 Pages: 732-745
  • DOI: 10.1007/s00535-021-01792-1
  • Peer Reviewed / Open Access
• [Journal Article] Histone deacetylase 6 regulates insulin signaling in pancreatic β cells (2021)
  • Author(s): Inoue H, Asahara SI, Sugiura Y, Kawada Y, Imai A, Hara C, Kanno A, Kimura-Koyanagi M, Kido Y.
  • Journal Title: Biochem Biophys Res Commun . Volume: 534 Pages: 896-901
  • DOI: 10.1016/j.bbrc.2020.10.078
  • NAID: 120007033584
  • Peer Reviewed / Open Access
• [Journal Article] Sex difference in the association of obesity with personal or social background among urban residents in Japan (2020)
  • Author(s): Asahara SI, Miura H, Ogawa W, Tamori Y.
  • Journal Title: PLoS One. Volume: 15 Issue: 11 Pages: e0242105-e0242105
  • DOI: 10.1371/journal.pone.0242105
  • NAID: 120006938919
  • Peer Reviewed / Open Access
• [Journal Article] GCN2 regulates pancreatic β-cell mass by sensing intracellular amino acid levels. (2020)
  • Author(s): Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y.
  • Journal Title: JCI Insight. Volume: 5 Issue: 9 Pages: 128820-128820
  • DOI: 10.1172/jci.insight.128820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between mean platelet volume in the pathogenesis of type 2 diabetes mellitus and diabetic macrovascular complications in Japanese patients. (2019)
  • Author(s): Inoue H, Saito M, Kouchi K, Asahara SI, Nakamura F, Kido Y.
  • Journal Title: J. Diab. Invest. Volume: - Issue: 4 Pages: 938-945
  • DOI: 10.1111/jdi.13198
  • NAID: 120006876706
  • Peer Reviewed / Open Access
• [Presentation] 2型糖尿病感受性遺伝子Kcnq1遺伝子領域による膵β細胞量調節機構の解明 (2020)
  • Author(s): 原千佐子、淺原俊一郎、木戸良明
  • Organizer: 第63回日本糖尿病学会年次学術集会