Analysis of pathogenic mechanism by susceptibility genes of T2DM using human iPS cells.

• Project/Area Number: 17K09882
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• 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): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヒトiPS細胞 / 糖尿病 / 膵β細胞 / 2型糖尿病感受性遺伝子 / 2型糖尿病 / iPS細胞

Outline of Final Research Achievements

It has been previously reported that KCNQ1 and EIF2AK4 were identified as T2DM susceptibility genes. We have clarified that the reduction of non-coding RNA Kcnq1ot1 expression induced pancratic beta cell failure in Kcnq1 mutant mice. Now, we analyzed the mechanism how T2DM susceptibility gene induces diabetes using human iPS cells derived pancreatic endocrine cell. As a result, we clarified that two iPS cells were differentiated into pancreatic endocrine cells. One cell has a risk allele of T2DM susceptibility gene, and the other without risl allele. The hiPS cell with a risk allele showed a reduced expression of Kcnq1ot1 compared to pancreatic endocrine cell without a risk allele.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、KCNQ1遺伝子において2型糖尿病発症のリスク因子となるSNPはKcnq1ot1発現低下に影響している可能性が考えられた。我々のこれまでの研究成果より、膵β細胞におけるp57発現増加が膵β細胞不全を介して2型糖尿病発症に繋がっていることがヒト細胞においても証明された。この結果、KCNQ1遺伝子のリスクアリルとなるSNPは2型糖尿病発症の予測因子として重要であり、将来的に検査項目の一つとなることが期待される。

Research Products

• [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] En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina (2020)
  • Author(s): Katsuyama Atsuko、Kusuhara Sentaro、Asahara Shun-Ichiro、Nakai Shun-Ichiro、Mori Sotaro、Matsumiya Wataru、Miki Akiko、Kurimoto Takuji、Imai Hisanori、Kido Yoshiaki、Ogawa Wataru、Nakamura Makoto
  • Journal Title: BMJ Open Diabetes Research & Care Volume: 8 Issue: 1 Pages: e001120-e001120
  • DOI: 10.1136/bmjdrc-2019-001120
  • NAID: 120006863549
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Early administration of dapagliflozin preserves pancreatic β-cell mass through a legacy effect in a mouse model of type 2 diabetes (2019)
  • Author(s): Kanno A, Asahara SI, Kawamura M, Furubayashi A, Tsuchiya S, Suzuki E, Takai T, Koyanagi-Kimura M, Matsuda T, Okada Y, Ogawa W, Kido Y.
  • Journal Title: J Diabetes Invest. Volume: 10 Issue: 3 Pages: 577-590
  • DOI: 10.1111/jdi.12945
  • NAID: 120006645694
  • Peer Reviewed / Open Access
• [Journal Article] Neuronatin and glucose-induced stress in pancreatic β-cells. (2019)
  • Author(s): Asahara SI
  • Journal Title: J Diabetes Invest. Volume: 10 Issue: 3 Pages: 574-576
  • DOI: 10.1111/jdi.12993
  • NAID: 120006645695
  • Open Access
• [Journal Article] PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. (2018)
  • Author(s): Yano H, Sakai M, Matsukawa T, Yagi T, Naganuma T, Mitsushima M, Iida S, Inaba Y, Inoue H, Unoki-Kubota H, Kaburagi Y, Asahara S, Kido Y, Minami S, Kasuga M, Matsumoto M.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 14290-14290
  • DOI: 10.1038/s41598-018-32575-z
  • NAID: 120006529679
  • Peer Reviewed / Open Access
• [Journal Article] Docosahexaenoic Acid Reduces Palmitic Acid-Induced Endoplasmic Reticulum Stress in Pancreatic Β Cells. (2018)
  • Author(s): Suzuki E, Matsuda T, Kawamoto T, Takahashi H, Mieda Y, Matsuura Y, Takai T, Kanno A, Koyanagi-Kimura M, Asahara SI, Inoue H, Ogawa W, Kido Y.
  • Journal Title: Kobe J Med Sci. Volume: 64
  • NAID: 120006523798
  • Peer Reviewed
• [Journal Article] SGLT2 inhibitors and protection against pancreatic beta cell failure. (2018)
  • Author(s): Asahara SI, Ogawa W.
  • Journal Title: Diabetol Int. Volume: 10 Issue: 1 Pages: 1-2
  • DOI: 10.1007/s13340-018-0374-y
• [Journal Article] Casein kinase 2 phosphorylates and stabilizes C/EBPβ in pancreatic β cells. (2018)
  • Author(s): Takai T, Matsuda T, Matsuura Y, Inoue K, Suzuki E, Kanno A, Kimura-Koyanagi M, Asahara SI, Hatano N, Ogawa W, Kido Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 497 Issue: 1 Pages: 451-456
  • DOI: 10.1016/j.bbrc.2018.02.108
  • Peer Reviewed / Open Access
• [Journal Article] MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling. (2018)
  • Author(s): 2.Bartolomé A, García-Aguilar A, Asahara S, Kido Y, Guillén C, Pajvani UB, Benito M.
  • Journal Title: Mol Cell Biol. Volume: 印刷中 Issue: 23
  • DOI: 10.1128/mcb.00441-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells. (2017)
  • Author(s): Kawada Y, Asahara SI, Sugiura Y, Sato A, Furubayashi A, Kawamura M, Bartolome A, Terashi-Suzuki E, Takai T, Kanno A, Koyanagi-Kimura M, Matsuda T, Hashimoto N, Kido Y.
  • Journal Title: PLoS ONE Volume: 12 Issue: 9 Pages: e0184435-e0184435
  • DOI: 10.1371/journal.pone.0184435
  • NAID: 120006353753
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effect of removal of glucotoxicity by SGLT2 inhibitor dapagliflozin on the gene expression in pancreatic beta cells (2017)
  • Author(s): Asahara S, Ohashi Y, Kido Y
  • Organizer: IDF2017
  • Int'l Joint Research
• [Presentation] Analysis of Pathogenic Mechanism by Susceptibility Genes of T2DM Using Human iPS Cells (2017)
  • Author(s): Shimono N, Asahara S, Kido Y
  • Organizer: 77th Scientific Sessions of American Diabetes Association
  • Int'l Joint Research
• [Presentation] 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割 (2017)
  • Author(s): 高井智子、松田友和、井上佳歩、松浦有希、鈴木江美、神野歩、木村真希、淺原俊一郎、小川渉、木戸良明
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 脂肪酸が膵β細胞の小胞体に及ぼす影響 (2017)
  • Author(s): 鈴木江美、松田友和、川本剛士、松浦有希、高井智子、神野歩、木村真希、淺原俊一郎、小川渉、木戸良明
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] ヒトiPS細胞を用いた2型糖尿病発症機序の解明 (2017)
  • Author(s): 下野名奈子、淺原俊一郎、原瑞季、田中孝一、松田友和、木村真希、神野歩、高井智子、鈴木江美、青井貴之、木戸良明
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割 (2017)
  • Author(s): 井上佳歩、高井智子、松田友和、鈴木江美、神野歩、木村真希、淺原俊一郎、木戸良明
  • Organizer: 第40回分子生物学会年会
• [Presentation] 高脂肪食負荷GCN2欠損マウスの膵島におけるmTORC1シグナル調節機構の解明 (2017)
  • Author(s): 古林鮎子、神野歩、増田勝久、吉富理紗、木村真希、松田友和、淺原俊一郎、木戸良明
  • Organizer: 第40回分子生物学会年会
• [Presentation] ヒトiPS細胞を用いた膵内分泌細胞への分化誘導法の確立 (2017)
  • Author(s): 山田瑞姫、淺原俊一郎、下野名奈子、田中孝一、松田友和、木村真希、神野歩、高井智子、鈴木江美、青井貴之、木戸良明
  • Organizer: 第40回分子生物学会年会