Effect of type 2 diabetes susceptibility gene Kcnq1 gene region on pancreatic beta cells

• Project/Area Number: 26461382
• 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, 医学研究科, 特命助教 (00570342)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 膵β細胞 / 2型糖尿病感受性遺伝子 / エピジェネティクス / 膵β細胞不全 / Kcnq1ot1 / 2型糖尿病 / インプリンティング

Outline of Final Research Achievements

Numerous susceptibility genes for type 2 diabetes, including KCNQ1, have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, possible parent-of-origin effects for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic β cell mass in mice via epigenetic modulation only when it is paternally inherited. The noncoding RNA Kcnq1ot1 is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression and increased Cdkn1c expression, an imprinted gene encoding a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification of the Cdkn1c promoter in pancreatic islets was found to contribute to this phenomenon.

Research Products

• [Journal Article] Dietary Mung Bean Protein Reduces Hepatic Steatosis, Fibrosis, and Inflammation in Male Mice with Diet-Induced, Nonalcoholic Fatty Liver Disease. (2017)
  • Author(s): Watanabe H, Inaba Y, Kimura K, Asahara SI, Kido Y, Matsumoto M, Motoyama T, Tachibana N, Kaneko S, Kohno M, Inoue H*.
  • Journal Title: J Nutr. Volume: 147 Issue: 1 Pages: 52-60
  • DOI: 10.3945/jn.116.231662
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Centra insulin-action activates Kupffer cells by suppressing hepatic vagal activation through nicotinic alpha 7 acetylcholine receptor. (2016)
  • Author(s): Kimura K, Tanida M, Nagata N, Inaba Y, Watanabe H, Nagashimada M, Ota T, Asahara S, Kido Y, Matsumoto M, Toshinai K, Nakazato M, Shibamoto T, Kaneko S, Kasuga M, Inoue H
  • Journal Title: Cell reports Volume: 14 Issue: 10 Pages: 2362-2374
  • DOI: 10.1016/j.celrep.2016.02.032
  • Peer Reviewed / Open Access
• [Journal Article] Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β cell mass via epigenetic modification of Cdkn1c. (2015)
  • Author(s): Asahara S, Etoh H, Inoue H, Teruyama K, Shibutani Y, Ihara Y, Kawada Y, Bartolome A, Hashimoto N, Matsuda T, Koyanagi-Kimura M, Kanno A, Hirota Y, Hosooka T, Nagashima K, Nishimura W, Inoue H, Matsumoto M, Higgins MJ, Yasuda K, Inagaki N, Seino S, Kasuga M, Kido Y.
  • Journal Title: Proceedings of the National Acaddemy of Scienceof the United States of America Volume: 112(27) Issue: 27 Pages: 8332-8337
  • DOI: 10.1073/pnas.1422104112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of pancreatic β cell mass by cross-interaction between CCAAT enhancer binding protein β induced by endoplasmic reticulum stress and AMP-activated protein kinase activity. (2015)
  • Author(s): Matsuda T, Takahashi H, Mieda Y, Shimizu S, Kawamoto T, Matsuura Y, Takai T, Suzuki E, Koyanagi-Kimura M, Asahara S, Bartolome A, Yokoi N, Inoue H, Ogawa W, Seino S, Kido Y
  • Journal Title: PLoS ONE Volume: 10 Issue: 6 Pages: e0130757-e0130757
  • DOI: 10.1371/journal.pone.0130757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets (2015)
  • Author(s): Kanno A, Asahara SI, Masuda K, Matsuda T, Kimura-Koyanagi M, Seino S, Ogawa W, Kido Y
  • Journal Title: Biochem Biophys Res Commun Volume: 458 Issue: 3 Pages: 681-686
  • DOI: 10.1016/j.bbrc.2015.02.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreatic β cell failure mediated by mTORC1 hyperactivity and autophagic impairment. (2014)
  • Author(s): Bartolome A, Kimura-Koyanagi M, Asahara SI, Guillen C, Inoue H, Teruyama K, Shimizu S, Kanno A, Garcia-Aguilar A, Koike M, Uchiyama Y, Benito M, Noda T, Kido Y
  • Journal Title: Diabetes Volume: 未定 Issue: 9 Pages: 2996-3008
  • DOI: 10.2337/db13-0970
  • NAID: 40020504710
  • Peer Reviewed / Open Access
• [Presentation] Regulation of pancreatic beta cell mass through type 2 diabetes susceptibility genes (2017)
  • Author(s): Shun-ichiro Asahara
  • Organizer: Asia Islet Biology & Incretin Symposium2017
  • Place of Presentation: カトリック大学校
  • Year and Date: 2017-03-02
  • Int'l Joint Research / Invited
• [Presentation] Pancreatic β-cell failure in Asian patients with type2 diabetes (2016)
  • Author(s): Shun-ichiro Asahara
  • Organizer: 3rd Annual meeting of DDES
  • Place of Presentation: EXCO convention center
  • Year and Date: 2016-11-19
  • Int'l Joint Research / Invited
• [Presentation] Regulation of pancreatic beta cell mass through type 2 diabetes susceptibility genes (2016)
  • Author(s): 淺原俊一郎
  • Organizer: 第59回日本糖尿病学会シンポジウム
  • Place of Presentation: 京都国際会館
  • Year and Date: 2016-05-19
  • Invited
• [Presentation] Regulation of pancreatic beta cell mass through type 2 diabetes susceptibility genes (2016)
  • Author(s): 淺原俊一郎
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
  • Invited
• [Presentation] Reduction in pancreatic β-cell mass caused by enhanced expression of Cdkn1c via interaction between C/EBPβ and epigenetic control (2015)
  • Author(s): 淺原俊一郎
  • Organizer: 第75回アメリカ糖尿病学会
  • Place of Presentation: ボストンコンベンションセンター
  • Year and Date: 2015-06-05 – 2015-06-09
• [Presentation] Reduction in Pancreatic β-Cell Mass Caused by Enhanced Expression of Cdkn1c via Interaction between C/EBPβ and Epigenetic Control. (2015)
  • Author(s): Asahara S
  • Organizer: 75th Scientific Session of American Diabetes Association
  • Place of Presentation: ボストン
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] 2型糖尿病疾患感受性遺伝子による膵β細胞量調節機構 (2015)
  • Author(s): 木戸良明、淺原俊一郎
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 山口
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] 膵β細胞における細胞周期調節因子p57の機能解析 (2015)
  • Author(s): 原 瑞季、淺原俊一郎
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 山口
  • Year and Date: 2015-05-21
• [Presentation] 膵β細胞におけるヒストン脱アセチル化酵素HDACの機能解析 (2015)
  • Author(s): 淺原 俊一郎
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] 膵β細胞量の維持に向けた糖尿病治療 (2014)
  • Author(s): 木戸 良明
  • Organizer: 第15回日本内分泌学会近畿支部学術集会
  • Place of Presentation: 兵庫医科大学
  • Year and Date: 2014-11-02
  • Invited
• [Presentation] 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析 (2014)
  • Author(s): 伊原佑香
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪リーガロイヤルホテル
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析 (2014)
  • Author(s): 淺原俊一郎
  • Organizer: 第87回日本内分泌学会総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 膵β細胞のKcnq1遺伝子領域におけるエピジェネティクス制御機構の解析 (2014)
  • Author(s): 淺原俊一郎
  • Organizer: 第51回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-11 – 2014-04-12
• [Presentation] 膵β細胞とepigenetics (2014)
  • Author(s): 木戸 良明
  • Organizer: 第51回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-11 – 2014-04-12
  • Invited
• [Book] 糖尿病学2016 (2016)
  • Author(s): 淺原俊一郎、木戸良明
  • Total Pages: 9
  • Publisher: 診断と治療社