Functional analysis of type 2 diabetes susceptibility genes in human pancreatic beta cells

• Project/Area Number: 18KK0438
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Kobe University
• Principal Investigator: Asahara Shunichiro 神戸大学, 医学部附属病院, 助教 (00570342)
• Project Period (FY): 2019 – 2021
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 膵β細胞 / 2型糖尿病 / エピジェネティクス / ヒト膵島 / 2型糖尿病感受性遺伝子 / ２型糖尿病感受性遺伝子 / 可塑性 / ヒトiPS細胞

Outline of Final Research Achievements

In a previous study, the applicant showed in mice that mutations in the type 2 diabetes susceptibility gene Kcnq1 act to decrease pancreatic β-cell volume via down-regulation of a non-coding RNA called 'Kcnq1ot1'. In this study, we examined whether similar results were observed using human iPS cells and human pancreatic islets. When human iPS cells were induced to differentiate into pancreatic endocrine cells, Kcnq1ot1 expression was upregulated, but KCNQ1OT1 expression was downregulated in minor alleles of the KCNQ1 SNP. KCNQ1OT1 is also expressed in human islets, but the frequency of minor alleles of the KCNQ1 SNP is significantly lower in Westerners than in Japanese, so a comparative study was not possible.

Academic Significance and Societal Importance of the Research Achievements

日本人は肥満が少ないにもかかわらず糖尿病患者が欧米並みに多い。これは膵β細胞が脆弱であることが原因と言われている。その原因遺伝子として重要と考えられるのがKCNQ1遺伝子である。KCNQ1遺伝子に特有の変異があるとインスリン分泌低下が見られるが、その機序は明らかではなかった。今回の代表者の研究成果により、KCNQ1遺伝子変異はKCNQ1OT1発現低下を介して糖尿病を発症させる可能性が示唆された。今後、KCNQ1OT1発現が2型糖尿病の治療や早期診断などの実臨床に応用されることが期待できる。

Research Products

• [Int'l Joint Research] Columbia University in the City of New York(米国) (2020)
• [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] 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] 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] 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] 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] 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
• [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64回日本糖尿病学会年次学術集会
• [Presentation] GCN2欠損マウスの膵β細胞におけるmTORC1活性調節機構の解明 (2019)
  • Author(s): 工藤 倫代、神野 歩、淺原 俊一郎、木戸 良明
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] 膵β細胞特異的TSC2ノックアウトマウスにおける膵β細胞不全発症機序の解明 (2019)
  • Author(s): 伊東 春香、淺原 俊一郎、原 千佐子、木村 真希、神野 歩、高井 智子、木戸 良明
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] 2型糖尿病の病態把握におけるMPVの有用性に関する検討 (2019)
  • Author(s): 井上 裕行、斉藤 真裕美、胡内 久美子、淺原 俊一郎、木戸 良明、中村 文彦
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] SGLT2阻害薬早期導入における有用性ー臓器保護の観点を含めてー (2019)
  • Author(s): 淺原 俊一郎
  • Organizer: 第56回日本臨床分子医学会学術集会
  • Invited
• [Presentation] 2 型糖尿病モデルマウスを用いた早期診断のための新規バイオマーカーの探索 (2019)
  • Author(s): 土屋 匠子、淺原 俊一郎、河村 真緒、林田 彩花、木戸 良明
  • Organizer: 第56回日本臨床分子医学会学術集会
• [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 (2019)
  • Author(s): 高井 智子、松田 友和、井上 佳歩、淺原 俊一郎、神野 歩、木村 真希、小川 渉、木戸 良明
  • Organizer: 第56回日本臨床分子医学会学術集会
• [Presentation] 2 型糖尿病モデルマウスを用いた早期診断のための新規バイオマーカーの探索 (2019)
  • Author(s): 土屋 匠子、淺原 俊一郎、林田 彩花、武内 友香、河村 真緒、木戸 良明
  • Organizer: 第42日本分子生物学会年会
• [Presentation] ヒトips細胞を用いた膵内分泌細胞への分化誘導 (2019)
  • Author(s): 林田 彩花、淺原 俊一郎、土屋 匠子、武内 友香、遠山 春希、山田 瑞姫、木戸 良明
  • Organizer: 第42日本分子生物学会年会
• [Presentation] 膵β細胞特異的TSC2ノックアウトマウスにおける膵β細胞不全発症機序の解明 (2019)
  • Author(s): 伊東 春香、淺原 俊一郎、原 千佐子、伊藤 菜々子、鵜塚 仁菜、木村 真希、神野 歩、高井 智子、木戸 良明
  • Organizer: 第42日本分子生物学会年会
• [Presentation] Early administration od dapagliflozin preserves pancreatic beta cell mass through an epigenetic modification in a mouse model of type2 diabetes (2019)
  • Author(s): Asahara S
  • Organizer: International Congress of Diabetes and Metabolism
  • Int'l Joint Research / Invited
• [Presentation] Identification of the regulatory mechanism of mTORC1 signaling activity in pancreatic β-cells in GCN2 knockout mice (2019)
  • Author(s): KudoM, Kanno A, Asahara S, Kido Y
  • Organizer: 79th American Diabetes Association
  • Int'l Joint Research
• [Presentation] Early administration od dapagliflozin preserves pancreatic beta cell mass through an epigenetic modification in a mouse model of type2 diabetes (2019)
  • Author(s): Asahara S, Kannno A, Kido Y.
  • Organizer: 79th American Diabetes Association
  • Int'l Joint Research